PART THREE

BIOPHARMACEUTICAL
PRINCIPLES OF DRUG
DELIVERY

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15
Introduction to biopharmaceutics

Marianne Ashford

CHAPTER CONTENTS WHAT IS BIOPHARMACEUTICS?

What is biopharmaceutics? 213 Biopharmaceutics can be defined as the study of
Background 213
how the physicochemical properties of drugs, dosage
The concept of bioavailabifity 214 forms and routes of administration affect the rate
and extent of drug absorption.
The concept of biopharmaceutics 215 The relationship between the drug, its dosage
Concluding comments 216 form and the route by which it is administered
governs how much of the drug and how fast it enters
Bibliography 216 the systemic circulation. For a drug to be effective,
enough of it needs to reach its site(s) of action and
stay there long enough to be able to exert its phar-
macological effect. This depends upon the route of
administration, the form in which it is administered
and the rate at which it is delivered.

Background
Apart from the intravenous route, where a drug is
introduced directly into the bloodstream, all other
routes of administration where a systemic action is
required, involve the absorption of the drug into the
blood from the route of administration. Once the
drug reaches the bloodstream it partitions between
the plasma and the red blood cells, the erythrocytes.
Drug in the plasma partitions between the plasma
proteins (mainly albumin) and the plasma water. It
is this free or unbound drug in plasma water, and not
the drug bound to the proteins, that can pass out of
the plasma through the capillary endothelium and
reach other body fluids and tissues and hence the
site(s) of action.
A dynamic equilibrium exists between the concen-
tration of the drug in the blood plasma and the drug
at its site(s) of action. This is termed distribution,
the degree of which will depend largely on the physic-
ochemical properties of the drug, in particular its
lipophilicity. As it is often difficult to access the drug
at its site(s) of action, its concentration in the plasma
is often taken as a surrogate for its concentration at its

213
 BIOPHARMACEUTICAL PRINCIPLES OF DRUG DELIVERY

site(s) of action. Even though the unbound drug in plasma and also at its site(s) of action.
the plasma would give a better estimate of the con- Biopharmaceutics is concerned with the first stage,
centration of the drug at its site(s) of action, this getting the drug from its route of administration to
requires a much more complex and sensitive assay the blood.
than a measurement of the total concentration of the
drug (i.e. the sum of the bound and unbound drug)
within the blood plasma. Thus it is this total drug con-
centration within the plasma that is usually measured THE CONCEPT OF BIOAVAILABILITY
for clinical purposes. Therefore, plasma protein
binding is a critical parameter to consider when inves- If a drug is given intravenously it is administered
tigating the therapeutic effect of a drug molecule. directly into the blood, and therefore we can be sure
The concentration of the drug in blood plasma that all the drug reaches the systemic circulation.
depends on numerous factors. These include the The drug is therefore said to be 100% bioavailable.
amount of an administered dose that is absorbed However, if a drug is given by another route there is
and reaches the systemic circulation; the extent of no guarantee that the whole dose will reach the sys-
distribution of the drug between the systemic cir- temic circulation intact. The fraction of an adminis-
culation and other tissues and fluids (which is tered dose of the drug that reaches the systemic
usually a rapid and reversible process); and the rate circulation in the unchanged form is known as the
of elimination of the drug from the body. The drug bioavailable dose. The relative amount of an
can either be eliminated unchanged or be enzymati- administered dose of a particular drug that reaches
cally cleaved or biochemically transformed, in which the systemic circulation intact and the rate at which
case it is said to have been metabolized. The study this occurs is known as the bioavailability.
and characterization of the time course of drug Unavailability is therefore defined as the rate and
absorption, distribution, metabolism and elimina- extent of drug absorption. The bioavailability exhib-
tion (ADME) is termed pharmacokinetics. ited by a drug is thus very important in determining
Pharmacokinetics is used in the clinical setting to whether a therapeutically effective concentration will
enhance the safe and effective therapeutic manage- be achieved at the site(s) of action.
ment of individual patients. In defining bioavailability in these terms it is
Figure 15.1 illustrates some of the factors that can assumed that the intact drug is the therapeutically
influence the concentration of the drug in the blood active form. This definition would not be valid in the

Fig. 15.1 Schematic representation of drug absorption, distribution and elimination.

214
 INTRODUCTION TO BIOPHARMACEUTICS

case of prodrugs, whose therapeutic action normally • by the same routes of administration but
depends on their being converted into a therapeuti- different types of dosage form, e.g. a tablet, a
cally active form prior to or on reaching the systemic hard gelatin capsule and an aqueous suspension
circulation. It should also be noted that, in the administered by the peroral route;
context of bioavailability, the term systemic circula- • in the same type of dosage form by the same
tion refers primarily to venous blood (excluding the route of administration but with different
hepatic portal vein, which carries blood from the formulations of the dosage form, e.g. different
gastrointestinal tract to the liver in the absorption formulations of an oral aqueous suspensions.
phase) and the arterial blood, which carries the
Variability in the bioavailability exhibited by a given
intact blood to the tissues.
drug from different formulations of the same type of
Therefore, for a drug which is administered orally
dosage form, or from different types of dosage
to be 100% bioavailable, the entire dose must move
forms, or by different routes of administration, can
from the dosage form to the systemic circulation.
cause the plasma concentration of the drug to be too
The drug must therefore be:
high and therefore cause side effects, or too low and
• completely released from the dosage form therefore the drug will be ineffective. Figure 15.2
• fully dissolved in the gastrointestinal fluids. shows the plasma concentration-time curve follow-
• stable in solution in the gastrointestinal fluids ing a single oral dose of a drug, indicating the para-
• pass through the gastrointestinal barrier into the meters associated with a therapeutic effect.
mesenteric circulation without being metabolized Poor biopharmaceutical properties often result in:
• pass through the liver into the systemic
• poor and variable bioavailability
circulation unchanged.
• difficulties in toxicological evaluation
Anything which adversely affects either the release of • difficulties with bioequivalence of formulations
the drug from the dosage form, its dissolution into • multi-daily dosing
the gastrointestinal fluids, its permeation through • the requirement for a non-conventional delivery
and stability in the gastrointestinal barrier or its sta- system
bility in the hepatic portal circulation will influence • long and costly development times.
the bioavailability exhibited by that drug from the
dosage form in which it was administered.

THE CONCEPT OF
BIOPHARMACEUTICS
Many factors have been found to influence the rate
and extent of absorption, and hence the time course
of a drug in the plasma and therefore at its site(s) of
action. These include the foods eaten by the patient,
the effect of the disease state on drug absorption,
the age of the patient, the site(s) of absorption of the
administered drug, the coadministration of other
drugs, the physical and chemical properties of the
administered drug, the type of dosage form, the com-
position and method of manufacture of the dosage
form, the size of the dose and the frequency of
administration.
Thus, a given drug may exhibit differences in its
bioavailability if it is administered:
• in the same type of dosage form by different
routes of administration, e.g. an aqueous solution Fig. 15.2 A typical blood plasma concentration-time curve
of a given drug administered by the oral and obtained following the peroral administration of a single dose of
intramuscular routes; a drug in a tablet.

215
 BIOPHARMACEUTICAL PRINCIPLES OF DRUG DELIVERY

CONCLUDING COMMENTS BIBLIOGRAPHY

The following chapters (Chapters 16 and 17) deal in Dressman J.B., Lennernas, H. (2000), Oral Drug Absorption,
Prediction & Assessment, Marcel Dekker, New York.
more detail with the physiological factors, dosage Gibaldi, M. (1991). Biopharmaceutics and Clinical
form factors and intrinsic properties of drugs that Pharmacokinetics, 4th edn, Lea & Febiger, Philadelphia.
influence the rate and extent of absorption. Chapter Johnson, L.R. (1994). Physiology of the Gastro-intestinal Tract,
18 looks at means of assessing the biopharmaceuti- Volume 2, 3rd edn. Raven Press, New York.
cal properties of compounds. Macheras, P., Reppas, C. & Dressman, J.B. (1995)
Biopharmaceutics of Orally Administered Drugs, Ellis
A thorough understanding of the biopharmaceuti- Horwood, London.
cal properties of a candidate drug are important Washington, N. and Wilson, C. (2000) Physiological
both in the discovery setting, where potential drug Pharmaceutics 2nd edn. Taylor and Francis, London.
candidates are being considered, and in the develop-
ment setting, where it is important to anticipate for-
mulation problems and assess whether the drug is a
candidate for a controlled-release formulation.

216
16
The gastrointestinal tract - physiology and
drug absorption
Marianne Ashford

The factors that influence the rate and extent of

CHAPTER CONTENTS absorption depend upon the route of administration.
As stated in Chapter 15, the intravenous route offers
Physiological factors influencing oral drug
absorption 217 direct access to the systemic circulation and the total
Physiology of the gastrointestinal tract 218
dose administered via this route is available in the
The oesophagus 219 plasma for distribution into other body tissues and
The stomach 220 the site(s) of action of the drug. Other routes will
The smalt intestine 220 require an absorption step before the drug reaches
The colon 222
the systemic circulation. Factors affecting this
The transit of Pharmaceuticals in the
gastrointestinal tract 222 absorption will depend on the physiology of the
Gastric emptying 223 administration site(s) and the membrane barriers
Small intestinal transit 223 present at those site(s), that the drug needs to cross
Colonic transit 223 in order to reach the systemic circulation. A
Barriers to drug absorption 224 summary of some of the properties of each route of
The environment within the lumen 224
Gastrointestinal pH 224 administration is given in Chapter 1.
Luminal enzymes 225 The GI tract is discussed in detail in this chapter
Influence of food in the gastrointestinal tract 225 and a detailed description of the physiology of some
Complexation of drugs with components in the
diet 225 of the other more important routes of administration
Alteration of pH 225 is given in Part 4. The oral route of delivery is by far
Alteration of gastric emptying 225 the most popular, mainly because it is natural and
Stimulation of gastrointestinal secretions 225 convenient for the patient and because it is relatively
Competition between food components and
drugs for specialized absorption easy to manufacture oral dosage forms. Oral dosage
mechanisms 226 forms do not need to be sterilized, are compact, and
Increased viscosity of gastrointestinal can be produced in large quantities by automated
contents 226
Food-induced changes in presystemic machines. This chapter and the next will therefore be
metabolism 226 confined to discussing the biopharmaceutical factors
Food-induced changes in blood flow 226 (that is, physiological, dosage form and drug factors)
Disease state and physiological disorders 226
The unstirred water layer 226
that influence oral drug absorption.
The gastrointestinal membrane 226
The structure of the membrane 226
Mechanisms of transport across the
membrane 227
Transcellutar pathways 227 PHYSIOLOGICAL FACTORS
Passive diffusion 227 INFLUENCING ORAL DRUG
Carrier-mediated transport 229 ABSORPTION
Endocytosis 230
Paracetlular pathway 231
Efflux of drugs from the intestine 231 The gastrointestinal tract is complex. Figure 16.1
Presystemic metabolism 232 shows a diagram of the gastrointestinal tract, outlin-
Gut-wall metabolism 232
Hepatic metabolism 232 ing some of the key structures involved in and key
Summary 232
physiological parameters that affect oral drug
References and bibliography 232
absorption. In order to gain an insight into the
numerous factors that can potentially influence the

217
 BIOPHARMACEUTICAL PRINCIPLES OF DRUG DELIVERY

Fig. 16.1 The gastrointestinal tract.

rate and extent of drug absorption into the systemic stomach empties the drug into the small intestine, the
circulation, a schematic illustration of the steps rate at which the drug is metabolized by enzymes in
involved in the release and absorption of a drug from the intestinal mucosal cells during its passage through
a tablet dosage form is presented in Figure 16.2. It them into the mesenteric blood vessels, and the rate of
can be seen from this that the rate and extent of metabolism of drug during its initial passage through
appearance of intact drug in the systemic circulation the liver, often termed the 'first-pass' effect.
depends on a succession of kinetic processes.
The slowest step in this series, which is known as
the rate-limiting step., controls the overall rate and
extent of appearance of intact drug in the systemic PHYSIOLOGY OF THE
circulation. The particular rate-limiting step will vary GASTROINTESTINAL TRACT
from drug to drug. For a drug which has a very poor
aqueous solubility the rate at which it dissolves in the The gastrointestinal tract is a muscular tube approx-
gastrointestinal fluids is often the slowest step, and imately 6 m in length with varying diameters. It
the bioavailability of that drug is said to be dissolu- stretches from the mouth to the anus and consists of
tion-rate limited. In contrast, for a drug that has a four main anatomical areas: the oesophagus, the
high aqueous solubility its dissolution will be rapid stomach, the small intestine and the large intestine
and the rate at which the drug crosses the gastroin- or colon. The luminal surface of the tube is not
testinal membrane may be the rate-limiting step smooth but very rough, thereby increasing the
(permeability limited). Other potential rate-limiting surface area for absorption.
steps include the rate of release of the drug from the The wall of the gastrointestinal tract is essentially
dosage form (this can be by design in the case of con- similar in structure along its length, consisting of
trolled-release dosage forms), the rate at which the four principal histological layers (Fig. 16.3):

218
 THE Gl TRACT - PHYSIOLOGY AND DRUG ABSORPTION

4. The mucosa, which is essentially composed of

three layers, the muscularis mucosa, which can
alter the local conformation of the mucosa, a
layer of connective tissue known as the lamina
propria, and the epithelium.
The majority of the gastrointestinal epithelium is
covered by a layer of mucus. This is a viscoelastic
translucent aqueous gel that is secreted throughout
the gastrointestinal tract, acting as a protective layer
and a mechanical barrier. Mucus is a constantly
changing mix of many secretions and exfoliated
epithelial cells. It has a large water component
(~95%). Its other primary components, which are
responsible for its physical and functional properties,
are large glycoproteins called mucins. Mucins
consist of a protein backbone approximately 800
amino acids long and oligosaccharide side chains
that are typically up to 18 residues in length.
The mucus layer ranges in thickness from 5 /-on to
500 /zm along the length of the gastrointestinal tract,
with average values of around 80 ^tm. The layer is
thought to be continuous in the stomach and duo-
denum, but may not be so in the rest of the small and
Fig. 16.2 Steps involved prior to a pharmacological effect after large intestines.
administration of a rapidly disintegrating tablet. Mucus is constantly being removed from the
luminal surface of the gastrointestinal tract through
abrasion and acidic and enzymatic breakdown, and
is continually replaced from beneath. Turnover time
has been estimated at 4-5 hours, but this may well
be an underestimate and is liable to vary along the
length of the tract.

The oesophagus
The mouth is the point of entry for most drugs (so-
called peroral - via the mouth - administration). At
this point contact with the oral mucosa is usually
Fig. 16.3 Cross-section through the gastrointestinal tract. brief. Linking the oral cavity with the stomach is the
oesophagus. This is composed of a thick muscular
1. The serosa, which is an outer layer of epithelium layer approximately 250 mm long and 20 mm in
and supporting connective tissue; diameter. It joins the stomach at the gastro-
2. The muscularis externa, which contains two oesophageal junction, or cardiac orifice as it is some-
layers of smooth muscle tissue, a thinner outer times known.
layer which is longitudinal in orientation, and a The oesophagus, apart from the lowest 20 mm
thicker inner layer, whose fibres are oriented in a which is similar to the gastric mucosa, contains a well
circular pattern. Contractions of these muscles differentiated squamous epithelium of non-prolifera-
provide the forces for movement of tive cells. Epithelial cell function is mainly protective:
gastrointestinal contents; simple mucous glands secrete mucus into the narrow
3. The submucosa, which is a connective tissue lumen to lubricate food and protect the lower part of
layer containing some secretory tissue and which the oesophagus from gastric acid. The pH of the
is richly supplied with blood and lymphatic oesophageal lumen is usually between 5 and 6.
vessels. A network of nerve cells, known as the Materials are moved down the oesophagus by the
submucous plexus, is also located in this layer; act of swallowing. After swallowing, a single peristaltic

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 BIOPHARMACEUTICAL PRINCIPLES OF DRUG DELIVERY

wave of contraction, its amplitude linked to the size

of the material being swallowed, passes down the
length of the oesophagus at the rate of 20-60 mm
per second, speeding up as it progresses. When swal-
lowing is repeated in quick succession, the subse-
quent swallows interrupt the initial peristaltic wave
and only the final wave proceeds down the length of
the oesophagus to the gastrointestinal junction, car-
rying material within the lumen with it. Secondary
peristaltic waves occur involuntarily in response to
any distension of the oesophagus and serve to move
sticky lumps of material or refluxed material to the
stomach. In the upright position the transit of mate-
rials through the oesophagus is assisted by gravity.
The oesophageal transit of dosage forms is
extremely rapid, usually of the order of 10—14
Fig. 14.4 The anatomy of the stomach.
seconds.

of gastrin is stimulated by peptides, amino acids

The stomach
and distension of the stomach;
The next part of the gastrointestinal tract to be • pepsins, which are secreted by the peptic cells in
encountered by both food and Pharmaceuticals is the form of its precursor pepsinogen. Pepsins are
the stomach. The two major functions of the peptidases which break down proteins to peptides
stomach are: at low pH. Above pH 5 pepsin is denatured;
• mucus, which is secreted by the surface mucosal
• to act as a temporary reservoir for ingested food
cells and lines the gastric mucosa. In the stomach
and to deliver it to the duodenum at a controlled
the mucus protects the gastric mucosa from
rate;
autodigestion by the pepsin-acid combination.
• to reduce ingested solids to a uniform creamy
consistency, known as chyme, by the action of Contrary to popular belief very little drug absorption
acid and enzymatic digestion. This enables better occurs in the stomach owing to its small surface area
contact of the ingested material with the mucous compared to the small intestine. The rate of gastric
membrane of the intestines and thereby facilitates emptying can be a controlling factor in the onset of
absorption. drug absorption from the major absorptive site, the
small intestine. Gastric emptying will be discussed
Another, perhaps less obvious, function of the
under gastrointestinal transit later in this chapter.
stomach is its role in reducing the risk of noxious
agents reaching the intestine.
The stomach is the most dilated part of the gas- The small intestine
trointestinal tract and is situated between the lower
The small intestine is the longest (4-5 m) and most
end of the oesophagus and the small intestine. Its
convoluted part of the gastrointestinal tract, extend-
opening to the duodenum is controlled by the
ing from the pyloric sphincter of the stomach to the
pyloric sphincter. The stomach can be divided into
ileocaecal junction where it joins the large intestine.
four anatomical regions (Fig. 16.4), namely the
Its main functions are:
fundus, the body, the antrum and the pylorus.
The stomach has a capacity of approximately • digestion: the process of enzymatic digestion,
1.5 L, although under fasting conditions it usually which began in the stomach, is completed in the
contains no more than 50 mL of fluid, which is small intestine.
mostly gastric secretions. These include: • absorption: the small intestine is the region where
most nutrients and other materials are absorbed.
• acid secreted by the parietal cells, which
maintains the pH of the stomach between 1 and The small intestine is divided into the duodenum,
3.5 in the fasted state; which is 200-300 mm in length, the jejunum, which
• the hormone gastrin, which itself is a potent is approximately 2 m in length, and the ileum, which
stimulator of gastric acid production. The release is approximately 3 m in length.

220
 THE Gl TRACT - PHYSIOLOGY AND DRUG ABSORPTION

The wall of the small intestine has a rich network

of both blood and lymphatic vessels. The gastroin-
testinal circulation is the largest systemic regional
vasculature and nearly a third of the cardiac output
flows through the gastrointestinal viscera. The blood
vessels of the small intestine receive blood from the
superior mesenteric artery via branched arterioles.
The blood leaving the small intestine flows into the
hepatic portal vein, which carries it via the liver to
the systemic circulation. Drugs that are metabolized
by the liver are degraded before they reach the sys-
temic circulation: this is termed hepatic presystemic
clearance, or first-pass metabolism.
The wall of the small intestine also contains
lacteals, which contain lymph and are part of the
lymphatic system. The lymphatic system is impor-
tant in the absorption of fats from the gastrointesti-
nal tract. In the ileum are areas of lymphoid tissue
close to the epithelial surface which are known as
Peyer's patches. These cells play a key role in the Fig. 16.5 Structure of a villus.
immune response as they transport macromolecules
and are involved in antigen uptake.
The surface area of the small intestine is increased • intestinal cells, which are present throughout the
enormously, by about 600 times that of a simple small intestine and secrete mucus and enzymes.
cylinder, to approximately 200 m2 in an adult, by The enzymes, hydrolases and proteases, continue
several adaptations which render the small intestine the digestive process;
such a good absorption site: • pancreatic secretions. The pancreas is a large
gland which secretes about 1-2 L of pancreatic
• Folds of Kerckring: these are submucosal folds juice per day into the small intestine via a duct.
which extend circularly most of the way around The components of pancreatic juice are sodium
the intestine and are particularly well developed bicarbonate and enzymes. The enzymes consist of
in the duodenum and jejunum. They are several proteases, principally trypsin, chymotrypsin and
millimetres in depth. carboxypeptidases, which are secreted as inactive
• Villi: these have been described as finger-like precursors or zymogens and converted to their
projections into the lumen (approximately active forms in the lumen by the enzyme
0.5-1.5 mm in length and 0.1 mm in diameter). enterokinase. Lipase and amylase are both
They are well supplied with blood vessels. Each secreted in their active forms. The bicarbonate
villus contains an arteriole, a venule and a blind- component is largely regulated by the pH of
ending lymphatic vessel (lacteal). The structure chyme delivered into the small intestine from the
of a villus is shown in Figure 16.5. stomach;
• Microvilli: approximately 600-1000 of these • bile, which is secreted by hepatocytes in the liver
brush-like structures (~ 1 ^tm in length and into bile canaliculi, concentrated in the
0.1 /mi in width) cover each villus, providing the gallbladder and hepatic biliary system by the
largest increase in surface area. These are covered removal of sodium ions, chloride and water, and
by a fibrous substance known as glycocalyx. delivered to the duodenum. Bile is a complex
The luminal pH of the small intestine increases to aqueous mixture of organic solutes (bile acids,
between about 6 and 7.5. The sources of the secre- phospholipids, particularly lecithin, cholesterol
tions that produce these pH values in the small and bilirubin) and inorganic compounds (plasma
intestine are: electrolytes; sodium and potassium). Bile
pigments, the most important of which is
• Brunner's glands, which are located in the bilirubin, are excreted in the faeces, but the bile
duodenum and are responsible for the secretion acids are absorbed by an active process in the
of bicarbonate which neutralizes the acid emptied terminal ileum. They are returned to the liver via
from the stomach; the hepatic portal vein and, as they have a high

221
 BIOPHARMACEUTICAL PRINCIPLES OF DRUG DELIVERY

hepatic clearance, are resecreted in the bile. This The colon is permanently colonized by an extensive
process is known as enterohepatic recirculation. number (about 1012 per gram of contents) and
The main functions of the bile are promoting the variety of bacteria. This large bacterial mass is
efficient absorption of dietary fat, such as fatty capable of several metabolic reactions, including
acids and cholesterol, by aiding its emulsification hydrolysis of fatty acid esters and the reduction of
and micellar solubilization, and the provision of inactive conjugated drugs to their active form. The
excretory pathways for degradation products. bacteria rely upon undigested polysaccharides in
the diet and the carbohydrate components of secre-
tions such as mucus for their carbon and energy
The colon sources. They degrade the polysaccharides to
The colon is the final part of the gastrointestinal produce short-chain fatty acids (acetic, proprionic
tract. It stretches from the ileocaecal junction to the and butyric acids), which lower the luminal pH, and
anus and makes up approximately the last 1.5 m of the gases hydrogen, carbon dioxide and methane.
the 6 m of the gastrointestinal tract. It is composed Thus the pH of the caecum is around 6-6.5. This
of the caecum (~85 mm in length), the ascending increases to around 7-7.5 towards the distal parts of
colon (-200 mm), the hepatic flexure, the transverse the colon.
colon (usually greater than 450 mm), the splenic Recently there has been much interest in the
flexure, the descending colon (~300 mm), the exploitation of the enzymes produced by these bac-
sigmoid colon (~400 mm) and the rectum, as shown teria with respect to targeted drug delivery to this
in Figure 16.6. The ascending and descending region of the gastrointestinal tract.
colons are relatively fixed, as they are attached via
the flexures and the caecum. The transverse and
sigmoid colons, however, are much more flexible.
The colon, unlike the small intestine has no spe- THE TRANSIT OF PHARMACEUTICALS
cialized villi. However, the microvilli of the absorp- IN THE GASTROINTESTINAL TRACT
tive epithelial cells, the presence of crypts, and the
irregularly folded mucosae serve to increase the As the oral route is the one by which the majority of
surface area of the colon by 10-15 times that of a Pharmaceuticals are administered, it is important to
simple cylinder. The surface area nevertheless know how these materials behave during their
remains approximately l/30th that of the small passage through the gastrointestinal tract. It is
intestine. known that the small intestine is the major site of
The main functions of the colon are: drug absorption, and thus the time a drug is present
in this part of the gastrointestinal tract is extremely
• the absorption of sodium ions, chloride ions and
significant. If sustained- or controlled-release drug
water from the lumen in exchange for
delivery systems are being designed, it is important
bicarbonate and potassium ions. Thus the colon
to consider factors that will affect their behaviour
has a significant homeostatic role in the body.
and, in particular, their transit times through certain
• the storage and compaction of faeces.
regions of the gastrointestinal tract.
In general, most dosage forms, when taken in an
upright position, transit through the oesophagus
quickly, usually in less than 15 seconds. Transit
through the oesophagus is dependent both upon the
dosage form and posture.
Tablets/capsules taken in the supine position,
especially if taken without water, are liable to lodge
in the oesophagus. Adhesion to the oesophageal wall
can occur as a result of partial dehydration at the site
of contact and the formation of a gel between the
formulation and the oesophagus. The chances of
adhesion will depend on the shape, size and type of
formulation. Transit of liquids, for example, has
always been observed to be rapid, and in general
faster than that of solids. A delay in reaching the
Fig. 16.6 The anatomy of the colon. stomach may well delay a drug's onset of action or

222
 THE Gl TRACT - PHYSIOLOGY AND DRUG ABSORPTION

cause damage or irritation to the oesophageal wall, these include the postural position, the composition
e.g. potassium chloride tablets. of the food, the effect of drugs and disease state. In
general, food, particularly fatty foods, delays gastric
emptying and hence the absorption of drugs.
Gastric emptying Therefore, a drug will reach the small intestine most
The time a dosage form takes to traverse the rapidly if it is administered with water to a patient
stomach is usually termed the gastric residence whose stomach is empty. Metoclopramide, which is
time, gastric emptying time or gastric empty- a drug that increases gastric emptying rate, has been
ing rate. shown to increase the rate of absorption of paraceta-
Gastric emptying of Pharmaceuticals is highly mol, whereas proprantheline, a drug which delays
variable and is dependent on the dosage form and gastric emptying, has been shown to delay its rate of
the fed/fasted state of the stomach. Normal gastric absorption (Nimmo et al 1973).
residence times usually range between 5 minutes and
2 hours, although much longer times (over 12 hours)
have been recorded, particularly for large single Small intestinal transit
units. In the fasted state the electrical activity in the There are two main types of intestinal movement,
stomach - the interdigestive myoelectric cycle, or propulsive and mixing. The propulsive movements
migrating myoelectric complex (MMC) as it is primarily determine the intestinal transit rate and
known - governs its activity and hence the transit of hence the residence time of the drug or dosage form
dosage forms. It is characterized by a repeating cycle in the small intestine. As this is the main site of
of four phases. absorption in the gastrointestinal tract for most drugs,
Phase I is a relatively inactive period of 40-60 the small intestinal transit time (that is, the time of
minutes with only rare contractions occurring. transit between the stomach and the caecum) is an
Increasing numbers of contractions occur in phase II, important factor with respect to drug bioavailability.
which has a similar duration to phase I. Phase III is Small intestinal transit has been found to be rela-
characterized by powerful peristaltic contractions tively constant, at around 3 hours. In contrast to the
which open the pylorus at the base and clear the stomach, the small intestine does not discriminate
stomach of any residual material. This is sometimes between solids and liquids, and hence between
called the housekeeper wave. Phase IV is a short dosage forms, or between the fed and the fasted state.
transitional period between the powerful activity of Small intestinal residence time is particularly
phase III and the inactivity of phase I. The cycle important for dosage forms that release their drug
repeats itself every 2 hours until a meal is ingested and slowly (e.g. controlled- sustained- prolonged-release
the fed state or motility is initiated. In this state, two systems) as they pass along the length of the gas-
distinct patterns of activity have been observed. The trointestinal tract; enteric-coated dosage forms
proximal stomach relaxes to receive food and gradual which release drug only when they reach the small
contractions of this region move the contents distally. intestine; drugs that dissolve slowly in intestinal
Peristalsis - contractions of the distal stomach - serve fluids; and drugs that are absorbed by intestinal
to mix and break down food particles and move them carrier-mediated transport systems.
towards the pyloric sphincter. The pyloric sphincter
allows liquids and small food particles to empty while
other material is retropulsed into the antrum of the Colonic transit
stomach and caught up by the next peristaltic wave for
The colonic transit of Pharmaceuticals is long and
further size reduction before emptying.
variable and depends on the type of dosage form,
Thus in the fed state liquids, pellets and disinte-
diet, eating pattern and disease state.
grated tablets will tend to empty with food, yet large
Contractile activity in the colon can be divided
sustained or controlled release dosage forms can be
retained in the stomach for long periods of time. In into two main types:
the fasted state the stomach is less discriminatory • Propulsive contractions or mass movements,
between dosage form types, with emptying appear- which are associated with the aboral (away from
ing to be an exponential process and being related to the mouth) movement of contents;
the point in the MMC at which the formulation is • Segmental or haustral contractions, which serve
ingested. to mix the luminal contents and result in only
Many factors influence gastric emptying, as well as small aboral movements. Segmental contractions
the type of dosage form and the presence of food: are brought about by contraction of the circular

223
 BIOPHARMACEUTICAL PRINCIPLES OF DRUG DELIVERY

muscle and predominate, whereas the propulsive riers can prevent some or all of the drug reaching the
contractions, which are due to contractions of the systemic circulation, and can therefore have a detri-
longitudinal muscle, occur only 3-4 times daily mental effect on its bioavailability.
in normal individuals.
Colonic transit is thus characterized by short bursts The environment within the lumen
of activity followed by long periods of stasis. The environment within the lumen of the gastroin-
Movement is mainly aboral, i.e. towards the anus. testinal tract has a major effect on the rate and extent
Colonic transit can vary from anything between 2 of drug absorption.
and 48 hours. In most individuals mouth-to-anus
transit times are longer than 24 hours.
Gastrointestinal pH
The pH of fluids varies considerably along the length
of the gastrointestinal tract. Gastric fluid is highly
BARRIERS TO DRUG ABSORPTION acidic, normally exhibiting a pH within the range
1-3.5 in healthy people in the fasted state. Following
Some of the barriers to absorption that a drug may the ingestion of a meal the gastric juice is buffered to
encounter once it is released from its dosage form a less acidic pH, which is dependent on meal com-
and has dissolved into the gastrointestinal fluids are position. Typical gastric pH values following a meal
shown in Figure 16.7. The drug needs to remain in are in the range 3-7. Depending on meal size the
solution and not become bound to food or other gastric pH returns to the lower fasted-state values
material within the gastrointestinal tract. It needs to within 2-3 hours. Thus only a dosage form ingested
be chemically stable in order to withstand the pH of with or soon after a meal will encounter these higher
the gastrointestinal tract, and it must be resistant to pH values. This may be an important consideration
enzymatic degradation in the lumen. The drug then in terms of the chemical stability of a drug, or in
needs to diffuse across the mucous layer, without achieving drug dissolution or absorption.
binding to it, across the unstirred water layer, and Intestinal pH values are higher than gastric pH
subsequently across the gastrointestinal membrane, values owing to the neutralization of the gastric acid
its main cellular barrier. After passing through this with bicarbonate ions secreted by the pancreas into
cellular barrier the drug encounters the liver before the small intestine. There is a gradual rise in pH
it reaches the systemic circulation. Any of these bar- along the length of the small intestine from the duo-

Fig. 16.7 Barriers to absorption.

224
 THE Gl TRACT - PHYSIOLOGY AND DRUG ABSORPTION

peptide drugs in the lumen. Other drugs that resem-

Table 16.1 pH in the small intestine in healthy
humans in the fasted and fed states ble nutrients, such as nucleotides and fatty acids,
may also be susceptible to enzymatic degradation.
Location Fasted state pH Fed state pH The Upases may also affect the release of drugs from
fat/oil-containing dosage forms. Drugs that are
Mid-distal duodenum 4.9 5.2 esters can also be susceptible to hydrolysis in the
6.1 5.4
6.3 5.1
lumen.
6.4 Bacteria, which are mainly localized within the
colonic region of the gastrointestinal tract, also
Jejunum 4.4-6.5 5.2-6.0
6.6 6.2 secrete enzymes which are capable of a range of reac-
tions. These enzymes have been utilized when
lleum 6.5 6.8-7.8
6.8-8.0 6.8-8.0 designing drugs or dosage forms to target the colon.
7.4 7.5 Sulphasalazine, for example, is a prodrug of 5-
aminosalicylic acid linked via an azo bond to sul-
Data from Gray and Dressman 1996. phapyridine. The sulphapyridine moiety makes the
drug too large and hydrophilic to be absorbed in the
upper gastrointestinal tract, and thus permits its
denum to the ileum. Table 16.1 summarizes some of transport intact to the colonic region, where the bac-
the literature values recorded for small intestinal pH terial enzymes reduce the azo bond and release the
in the fed and fasted states. The pH drops again in active drug, 5-aminosalycylic acid, for local action in
the colon., as the bacterial enzymes, which are local- colonic diseases such as inflammatory bowel disease.
ized in the colonic region, break down undigested
carbohydrates into short-chain fatty acids; this
Influence of food in the gastrointestinal tract
lowers the pH in the colon to around 6.5.
The gastrointestinal pH may influence the absorp- The presence of food in the gastrointestinal tract can
tion of drugs in a variety of ways. It may influence influence the rate and extent of absorption, either
the chemical stability of the drug in the lumen, its directly or indirectly via a range of mechanisms.
dissolution or its absorption, if the drug is a weak Complexation of drugs with components in the diet
electrolyte. Drugs are capable of binding to components within
Chemical degradation due to pH-dependent the diet. In general this only becomes an issue (with
hydrolysis can occur in the gastrointestinal tract. The respect to bioavailability) where an irreversible or an
result of this instability is incomplete bioavailability, insoluble complex is formed. In such cases the frac-
as only a fraction of the administered dose reaches tion of the administered dose that becomes com-
the systemic circulation in the form of intact drug. plexed is unavailable for absorption. Tetracycline, for
The extent of degradation of penicillin G (ben- example, forms non-absorbable complexes with
zylpenicillin), the first of the penicillins, after oral calcium and iron, and thus it is advised that patients
administration depends on its residence time in the do not take products containing calcium or iron,
stomach and gastric pH.This gastric instability tends such as milk, iron preparations or indigestion reme-
to preclude its oral use. The antibiotic erythromycin dies, at the same time of day as the tetracycline.
and proton pump inhibitors (e.g. omeprazole) However, if the complex formed is water soluble and
degrade rapidly at acidic pH values and therefore readily dissociates to liberate the 'free' drug, then
have to be formulated as enteric-coated dosage forms there may be little effect on drug absorption.
to ensure good bioavailability (see Chapter 17). Alteration of pH In general, food tends to
The effects of pH on the drug dissolution and increase stomach pH by acting as a buffer. This is
absorption processes are also discussed in Chapter 17. liable to decrease the rate of dissolution and subse-
quent absorption of a weakly basic drug and increase
that of a weakly acidic one.
Luminal enzymes
Alteration of gastric emptying As already men-
The primary enzyme found in gastric juice is pepsin. tioned, some foods, particularly those containing a
Lipases, amylases and proteases are secreted from high proportion of fat, and some drugs, tend to
the pancreas into the small intestine in response to reduce gastric emptying and thus delay the onset of
ingestion of food. These enzymes are responsible for action of certain drugs.
most of nutrient digestion. Pepsins and the proteases Stimulation of gastrointestinal secretions Gastro-
are responsible for the degradation of protein and intestinal secretions (e.g. pepsin) produced in

225
 BIOPHARMACEUTICAL PRINCIPLES OF DRUG DELIVERY

response to food may result in the degradation of variety of mechanisms. Drug-food interactions are
drugs that are susceptible to enzymatic metabolism, often classified into five categories: those that cause
and hence in a reduction in their bioavailability. The reduced, delayed, increased and accelerated absorp-
ingestion of food, particularly fats, stimulates the tion, and those on which food has no effect. The
secretion of bile. Bile salts are surface active agents reader is referred to reviews by Fleischer et al.
and can increase the dissolution of poorly soluble (1999), Welling (1996) and Evans (2000) for more
drugs, thereby enhancing their absorption. However, detailed information on the effect of food on the rate
bile salts have been shown to form insoluble and and extent of drug absorption.
hence non-absorbable complexes with some drugs,
such as neomycin, kanamycin and nystatin.
Disease state and physiological disorders
Competition between food components and drugs for
specialized absorption mechanisms In the case of Disease states and physiological disorders associated
those drugs that have a chemical structure similar to with the gastrointestinal tract are likely to influence
nutrients required by the body for which specialized the absorption and hence the bioavailability of orally
absorption mechanisms exist, there is a possibility of administered drugs. Local diseases can cause alter-
competitive inhibition of drug absorption. ations in gastric pH that can affect the stability, dis-
Increased viscosity of gastrointestinal contents The solution and/or absorption of the drug. Gastric
presence of food in the gastrointestinal tract provides surgery can cause drugs to exhibit differences in
a viscous environment which may result in a reduc- bioavailability than that in normal individuals. For
tion in the rate of drug dissolution. In addition, the example, partial or total gastrectomy results in drugs
rate of diffusion of a drug in solution from the lumen reaching the duodenum more rapidly than in normal
to the absorbing membrane lining the gastrointesti- individuals. This increased rate of presentation to the
nal tract may be reduced by an increase in viscosity. small intestine may result in an increased overall rate
Both of these effects tend to decrease the bioavail- of absorption of drugs that are primarily absorbed in
ability of drug. the small intestine. However, drugs that require a
Food-induced changes in presystemic metabolism period of time in the stomach to facilitate their dis-
Certain foods may increase the bioavailability of solution may show reduced bioavailability in such
drugs that are susceptible to presystemic intestinal patients.
metabolism by interacting with the metabolic
process. Grapefruit juice, for example, is capable of
inhibiting the intestinal cytochrome P450 (CYP3A
The unstirred water layer
family) and thus, taken with drugs that are suscepti- The unstirred water layer or aqueous boundary layer
ble to CYP3A metabolism, is likely to result in their is a more or less stagnant layer of water, mucus and
increased bioavailability. Clinically relevant inter- glycocalyx adjacent to the intestinal wall. It is
actions exist between grapefruit juice and the anti- thought to be created by incomplete mixing of the
histamine terfenadine, the immunosuppresant luminal contents near the intestinal mucosal surface,
cyclosporin, the protease inhibitor saquinavir and and to be around 30-100 /mi in thickness. This layer
the calcium channel blocker verapamil. can provide a diffusion barrier to drugs. Some drugs
Food-induced changes in blood flow Blood flow to are also capable of complexing with mucus, thereby
the gastrointestinal tract and liver increases shortly reducing their availability for absorption.
after a meal, thereby increasing the rate at which
drugs are presented to the liver. The metabolism of
some drugs (e.g. propranolol, hydralazine, dextro-
The gastrointestinal membrane
propoxyphene) is sensitive to their rate of presenta-
The structure of the membrane
tion to the liver: the faster the rate of presentation the
larger the fraction of drug that escapes first-pass The gastrointestinal membrane separates the lumen
metabolism. This is because the enzyme systems of the stomach and intestines from the systemic cir-
responsible for their metabolism become saturated by culation. It is the main cellular barrier to the absorp-
the increased rate of presentation of the drug to the tion of drugs from the gastrointestinal tract. The
site of biotransformation. For this reason, the effects membrane is complex in nature, being composed of
of food serve to increase the bioavailability of some lipids, proteins, lipoproteins and polysaccharides, and
drugs that are susceptible to first-pass metabolism. has a bilayer structure (Fig. 16.8).The barrier has the
It is evident that food can influence the absorption characteristics of a semipermeable membrane, allow-
of many drugs from the gastrointestinal tract by a ing the rapid transit of some materials and impeding

226
 THE Gl TRACT - PHYSIOLOGY AND DRUG ABSORPTION

Fig. 16.9 Mechanisms of permeability (absorptive).

tration gradient of the drug across the membrane.

The process initially involves the partitioning of the
drug between the aqueous fluids within the gastroin-
testinal tract and the lipoidal-like membrane of the
lining of the epithelium. The drug in solution in the
membrane then diffuses across the epithelial
Fig. 16.8 Structure of the memberane.
cell/cells within the gastrointestinal barrier to blood
in the capillary network in the lamina propria. Upon
reaching the blood the drug will be rapidly distrib-
or preventing the passage of others. It is permeable to uted, so maintaining a much lower concentration
arnino acids, sugars, fatty acids and other nutrients, than that at the absorption site. If the cell mem-
and impermeable to plasma proteins. The membrane branes and fluid regions making up the gastrointesti-
can be viewed as a semipermeable lipoidal sieve, nal-blood barrier can be considered as a single
which allows the passage of lipid-soluble molecules membrane, then the stages involved in gastrointesti-
across it and the passage of water and small nal absorption could be represented by the model
hydrophilic molecules through its numerous aqueous shown in Figure 16.10.
pores. In addition there are a number of transporter Passive diffusion of drugs across the gastrointesti-
proteins or carrier molecules that exist in the mem- nal-blood barrier can often be described mathemat-
brane and which, with the help of energy, transport ically by Pick's first law of diffusion. This states that
materials back and forth across it. the rate of diffusion across a membrane (dC/dt) is
proportional to the difference in concentration on
each side of that membrane. Therefore, the rate of
Mechanisms of transport across the membrane
appearance of drug in the blood at the absorption
There are two main mechanisms of drug transport site is given by:
across the gastrointestinal epithelium: transcellular,
i.e. across the cells, and paracellular, i.e. between the
cells. The transcellular pathway is further divided into where dC/dt is the rate of appearance of drug in the
simple passive diffusion, carrier-mediated transport blood at the site of absorption, k is the proportion-
(active transport and facilitated diffusion) and endo- ality constant, Cg is the concentration of drug in
cytosis. These pathways are illustrated in Figure 16.9. solution in the gastrointestinal fluid at the absorp-
tion site, and Cb is the concentration of drug in the
Transcellular pathways blood at the site of absorption.
Passive diffusion This is the preferred route of The proportionality constant k incorporates the
transport for relatively small lipophilic molecules diffusion coefficient of the drug in the gastrointesti-
and thus many drugs. In this process, drug mole- nal membrane (D), and the thickness (/z) and surface
cules pass across the lipoidal membrane via passive area of the membrane (A*).
diffusion from a region of high concentration in the
lumen to a region of lower concentration in the
blood. This lower concentration is maintained pri-
marily by blood flow. The rate of transport is deter- These equations indicate that the rate of gastroin-
mined by the physicochemical properties of the testinal absorption of a drug by passive diffusion
drug, the nature of the membrane and the concen- depends on the surface area of the membrane that is

227
 BIOPHARMACEUTICAL PRINCIPLES OF DRUG DELIVERY

Fig. 16.10 Diagrammatic representation of absorption via passive diffusion.

available for drug absorption. Thus the small intes- The passive absorption process is driven solely by
tine, primarily the duodenum, is the major site of the concentration gradient of the diffusable species
drug absorption, owing principally to the presence of of the drug that exists across the gastrointestinal-
villi and microvilli which provide such a large surface blood barrier. Thus Eqns 16.1 and 16.2 can be
area for absorption (see earlier). combined and written as:
Equation 16.1 also indicates that the rate of drug
absorption depends on a large concentration gradi-
ent of drug existing across the gastrointestinal mem-
brane. This concentration gradient is influenced by and because for a given membrane D, A and h can
the apparent partition coefficients exhibited by the be regarded as constants, Eqn 16.3 becomes:
drug with respect to the gastrointestinal mem-
brane/fluid interface and the gastrointestinal mem-
brane/blood interface. It is important that the drug Equation 16.4 is an expression for a first-order
has sufficient affinity (solubility) for the membrane kinetic process (see Chapter 7) and indicates that
phase that it can partition readily into the gastroin- the rate of passive absorption will be proportional
testinal membrane. In addition, after diffusing across to the concentration of absorbable drug in solution
the membrane the drug should exhibit sufficient sol- in the gastrointestinal fluids at the site of absorption,
ubility in the blood such that it can partition readily and therefore that the gastrointestinal absorption of
out of the membrane phase into the blood. most drugs follows first-order kinetics.
On entering the blood in the capillary network in It has been assumed in this description that the
the lamina propria, the drug will be carried away from drug exists solely in one single absorbable species.
the site of absorption by the rapidly circulating gas- Many drugs, however, are weak electrolytes that exist
trointestinal blood supply and will become diluted by in aqueous solution as two species, namely the
distribution into a large volume of blood (i.e. the sys- unionized species and the ionized species. Because it
temic circulation), distribution into body tissues and is the unionized form of a weak electrolyte drug that
other fluids, and by metabolism and excretion. In exhibits greater lipid solubility compared to the cor-
addition, the drug may bind to plasma proteins in the responding ionized form, the gastrointestinal mem-
blood which will further lower the concentration of brane is more permeable to the unionized species.
free (i.e. diffusable) drug in the blood. Consequently, Thus the rate of passive absorption of a weak elec-
the blood acts as a 'sink' for absorbed drug and trolyte is related to the fraction of total drug that
ensures that the concentration of drug in the blood at exists in the unionized form in solution in the gas-
the site of absorption is low in relation to that in the trointestinal fluids at the site of absorption. This
gastrointestinal fluids at the site of absorption, i.e. fraction is determined by the dissociation constant of
Cg » Cb. The 'sink' conditions provided by the sys- the drug (i.e. its pKa value) and by the pH of the
temic circulation ensure that a large concentration aqueous environment, in accordance with the
gradient is maintained across the gastrointestinal Henderson-Hasselbalch equations for weak acids
membrane during the absorption process. and bases (see Chapters 3 and 8). The gastrointesti-

228
 THE Gl TRACT - PHYSIOLOGY AND DRUG ABSORPTION

nal absorption of a weak electrolyte drug is enhanced There are a large number of carrier-mediated
when the pH at the site of absorption favours the for- active transport systems or membrane transporters
mation of a large fraction of the drug in aqueous in the small intestine, which can be present either
solution that is unionized. This forms the basis of the on the apical (brush border) or on the basolateral
pH-partition hypothesis (see Chapter 17). membrane. These include the peptide transporters,
Carrier-mediated transport As already stated, the the nucleoside transporters, the sugar transporters,
majority of drugs are absorbed across cells (i.e. trans- the bile acid transporters, the amino acid trans-
cellularly) via passive diffusion. However, certain porters, the organic anion transporters and the
compounds and many nutrients are absorbed trans- vitamin transporters.
cellularly by a carrier-mediated transport mecha- Many nutrients, such as amino acids, sugars, elec-
nism, of which there are two main types, active trolytes (e.g. sodium, potassium, calcium, iron, chlo-
transport and facilitated diffusion or transport. ride, bicarbonate), vitamins (thiamine (Bt), nicotinic
Active transport In contrast to passive diffusion, acid, riboflavin (B2), pyroxidine (B6) and B12) and
active transport involves the active participation by bile salts are actively transported. Each carrier
the apical cell membrane of the columnar absorption system is generally concentrated in a specific
cells. A carrier or membrane transporter is responsi- segment of the gastrointestinal tract. The substance
ble for binding a drug and transporting it across the that is transported by that carrier will thus be
membrane by a process illustrated in Figure 16.11. absorbed preferentially in the location of highest
Carrier-mediated absorption is often explained by carrier density. For example, the bile acid trans-
assuming a shuttling process across the epithelial porters are only found in the lower part of the small
membrane. The drug molecule or ion forms a intestine, the ileum. Each carrier/transporter has its
complex with the carrier/transporter in the surface of own substrate specificity with respect to the chemi-
the apical cell membrane of a columnar absorption cal structure of the substance that it will transport.
cell; the drug-carrier complex then moves across the Some carriers/transporters have broader specificity
membrane and liberates the drug on the other side of than others. Thus if a drug structurally resembles a
the membrane. The carrier (now free) returns to its natural substance which is actively transported, then
initial position in the surface of the cell membrane the drug is also likely to be transported by the same
adjacent to the gastrointestinal tract, to await the carrier mechanism.
arrival of another drug molecule or ion. Many peptide-like drugs, such as the penicillins,
Active transport is a process whereby materials cephalosporins, angiotensin-converting enzyme
can be transported against a concentration gradient inhibitors (ACE) inhibitors and renin inhibitors,
across a cell membrane, i.e. transport can occur from rely on the peptide transporters for their efficient
a region of lower concentration to one of higher con- absorption. Nucleosides and their analogues for
centration. Therefore, active transport is an energy- antiviral and anticancer drugs depend on the nucle-
consuming process. The energy arises either from the oside transporters for their uptake. L-dopa and a-
hydrolysis of ATP or from the transmembranous methyldopa are transported by the carrier-mediated
sodium gradient and/or electrical potential. process for amino acids. L-dopa has a much faster

Fig. 16.11 Diagrammatic representation of active transport of a drug across a cell membrane.

229
 BIOPHARMACEUTICAL PRINCIPLES OF DRUG DELIVERY

permeability rate than methyldopa, which has been • show temperature dependence;
attributed to the lower affinity of methyldopa for the • can be competitively inhibited by substrate
amino acid carrier. analogues.
Unlike passive absorption, where the rate of
absorption is directly proportional to the concentra- Active transport also plays an important role in the
tion of the absorbable species of the drug at the intestinal, renal and biliary excretion of many drugs.
absorption site, active transport proceeds at a rate Facilitated diffusion or transport This carrier-
that is proportional to the drug concentration only at mediated process differs from active transport in that
low concentrations. At higher concentrations the it cannot transport a substance against a concentra-
carrier mechanism becomes saturated and further tion gradient of that substance. Therefore, facilitated
increases in drug concentration will not increase the diffusion does not require an energy input but does
rate of absorption, i.e. the rate of absorption remains require a concentration gradient for its driving force,
constant. Absorption rate-concentration relation- as does passive diffusion. When substances are trans-
ships for active and passive processes are compared ported by facilitated diffusion they are transported
in Figure 16.12. down the concentration gradient but at a much
Competition between two similar substances for faster rate than would be anticipated based on the
the same transfer mechanism, and the inhibition of molecular size and polarity of the molecule. The
absorption of one or both compounds, are other process, like active transport, is saturable and is
characteristics of carrier-mediated transport. subject to inhibition by competitive inhibitors. In
Inhibition of absorption may also be observed with terms of drug absorption, facilitated diffusion seems
agents such as sodium fluoride, cyanide or dinitro- to play a very minor role.
phenol, which interfere with cell metabolism. More information on carrier-mediated transport
Some substances may be absorbed by simultane- of drugs within the intestines can be obtained from
ous carrier-mediated and passive transport reviews by Oh et al. (1999),Tsuji andTamia (1996)
processes. For example, certain pyrimidines, such as and Yang et al. (1999).
uracil and thymine, are absorbed both passively and Endocytosis Endocytosis is the process by which
via a carrier-mediated process. The contribution of the plasma membrane of the cell invaginates and the
the carrier-mediated process to the overall absorp- invaginations become pinched off, forming small
tion rate decreases with concentration, and at a intracellular membrane-bound vesicles that enclose a
sufficiently high concentration is negligible. volume of material. Thus material can be transported
In summary, active transport mechanisms: into the cell. After invagination the material is often
transferred to other vesicles or lysosomes and
• must have a carrier molecule;
digested. Some material will escape digestion and
• must have a source of energy;
migrate to the basolateral surface of the cell, where it
• can be inhibited by metabolic inhibitors such as
is exocytosed. This uptake process is energy depen-
dinitrophenol;
dent. Endocytosis can be further subdivided into four
main processes: fluid-phase endocytosis or pinocyto-
sis; receptor-mediated endocytosis; phagocytosis; and
transcytosis. Endocytosis is thought to be the primary
mechanism of transport of macromolecules. The
process and pathways of endocytosis are complex.
Pinocytosis Fluid-phase endocytosis or pinocyto-
sis is the engulfment of small droplets of extracellu-
lar fluid by membrane vesicles. The cell will
internalize material regardless of its metabolic
importance to that cell. The efficiency of this process
is low. The fat-soluble vitamins A, D, E and K are
absorbed via pinocytosis.
Receptor-mediated endocytosis Many cells within
the body have receptors on their cell surfaces that are
capable of binding with suitable ligands to form
Fig. 16.12 Relationship between rate of absorption and
ligand-receptor complexes on the cell surface. These
concentration at the absorption site for active and passive complexes cluster on the cell surface and then invagi-
processes. nate and break off from the membrane to form coated

230
 THE Gl TRACT - PHYSIOLOGY AND DRUG ABSORPTION

vesicles. The binding process between the ligand and The convective component is the rate at which the
the receptor on the cell surface is thought to trigger a compound is carried across the epithelium via the
conformational change in the membrane to allow this water flux.
process to occur. Once within the cytoplasm of the
cell the coated vesicles rapidly lose their coat, and the Efflux of drugs from the intestine
resulting uncoated vesicles will promptly deliver their It is now known that there are countertransport
contents to early endosomes. Within the endosomes efflux proteins that expel specific drugs back into
the ligands usually dissociate from their receptors the lumen of the gastrointestinal tract after they
many of which are then recycled to the plasma mem- have been absorbed. One of the key countertrans-
brane. The dissociated ligands and solutes are next port proteins is P-glycoprotein. P-glycoprotein is
delivered to prelysosomes and finally to lysosomes, expressed at high levels on the apical surface of
the end-stage of the endocytic pathway. Lysosomes columnar cells (brush border membrane) in the
are spherical or oval cell organelles surrounded by a jejunum. It is also present on the surface of many
single membrane. They contain digestive enzymes other epithelia and endothelia in the body, and on
which break down bacteria and large molecules, such the surface of tumour cells. P-glycoproteins were
as protein, polysaccharides and nucleic acids, which originally discovered because of their ability to
have entered the cell via endocytosis. cause multidrug resistance in tumour cells by pre-
Phagocytosis Phagocytosis can be defined as the venting the intracellular accumulation of many
engulfment by the cell membrane of particles larger cytotoxic cancer drugs by pumping the drugs back
than 500 nm. This process is important for the out of the tumours. Certain drugs with wide struc-
absorption of polio and other vaccines from the gas- tural diversity (Table 16.2) are susceptible to efflux
trointestinal tract. from the intestine via P-glyocprotein. Such efflux
Transcytosis Transcytosis is the process by which may have a detrimental effect on drug bioavail-
the material internalized by the membrane domain is ability. These countertransport efflux proteins pump
transported through the cell and secreted on the
opposite side.
Table 16.2 Examples of transport mechanisms of
Paracellular pathway i commonly used drugs across the gastrointestinal
The paracellular pathway differs from all the other absorptive epithelia (adapted from Bray den 1997)
absorption pathways as it is the transport of materials
in the aqueous pores between the cells rather than Route Examples Therapeutic class
across them. The cells are joined together via closely Transcellular Propranol j3-Blocker
fitting tight junctions on their apical side. The inter- passive Testosterone Steroid
cellular spaces occupy only about 0.01% of the total diffusion Ketoprofen Non-steroidal
surface area of the epithelium. The tightness of these anti-inflammatory
Cisapride Antispasmodic
junctions can vary considerably between different
Oestradiol Sex hormone
epithelia in the body. In general, absorptive epithelia, Naproxen Non-steroidal
such as that of the small intestine, tend to be leakier anti-inflammatory
than other epithelia. The paracellular pathway Paracellular Cimetidine H2 antagonist
decreases in importance down the length of the gas- Loperamide Antidiarrhoeal
trointestinal tract, and as the number and size of Atenolol 0-Blocker
pores between the epithelial cells decrease. Mannitot Sugar used as
paracellular marker
The paracellular route of absorption is important Tiludronate Bisphosphonate
for the transport of ions such as calcium and for the
Carrier mediated Cephalexin Anti-bacterial
transport of sugars, amino acids and peptides at con-
Captopril ACE inhibitor
centrations above the capacity of their carriers. Small Bestatin Anticancer
hydrophilic and charged drugs that do not distribute Levodopa Dopaminergic
into cell membranes cross the gastrointestinal epithe- Foscarnet Antiviral
lium via the paracellular pathway. The molecular Transcellular Cyclosporine Immunosuppressant
weight cut-off for the paracellular route is usually diffusion subject Nifedipine Calcium channel blocker
considered to be 200 Da, although some larger drugs to P-glycoprotein Verapamil Calcium channel blocker
efflux Paclitaxel Anticancer
have been shown to be absorbed via this route. Celiprolol j3-Blocker
The paracellular pathway can be divided into a Digoxin Cardiac glycoside
convective ('solvent drag') and diffusive component.

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 BIOPHARMACEUTICAL PRINCIPLES OF DRUG DELIVERY

drugs out of cells in a similar way to which nutri- to such an extent as to render the gastrointestinal
ents, and drugs are actively absorbed across the gas- route of administration ineffective, or to necessitate
trointestinal membrane. This process therefore an oral dose which is many times larger than the
requires energy, can work against a concentration intravenous dose, e.g. propranolol. Although propra-
gradient, can be competitively inhibited by struc- nolol is well absorbed, only about 30% of an oral
tural analogues or be inhibited by inhibitors of cell dose is available to the systemic circulation owing to
metabolism, and is a saturable process. the first-pass effect. The bioavailability of sustained-
Table 16.2 summarizes the main mechanisms of release propranolol is even less as the drug is pre-
drug transport across the gastrointestinal epithelia sented via the hepatic portal vein more slowly than
for a number of commonly used drugs. from an immediate-release dosage form, and the
liver is therefore capable of extracting and metabo-
lizing a larger portion. Other drugs which are sus-
Presystemic metabolism ceptible to a large first-pass effect are the anaesthetic
As well as having the ability to cross the gastroin- lidocaine, the tricyclic antidepressant imipramine
testinal membrane by one of the routes described, and the analagesic pentazocine.
drugs also need to be resistant to degradation/
metabolism during this passage. All drugs that are
absorbed from the stomach, small intestine and
upper colon pass into the hepatic portal system and SUMMARY
are presented to the liver before reaching the sys-
temic circulation. Therefore, if the drug is going to There are many physiological factors that influence
be available to the systemic circulation it must also the rate and extent of drug absorption; these are ini-
be resistant to metabolism by the liver. Hence, an tially dependent on the route of administration. For
oral dose of drug could be completely absorbed but the oral route the physiological and environmental
incompletely available to the systemic circulation factors of the gastrointestinal tract, the gastrointesti-
because of first-pass or presystemic metabolism nal membrane and presystemic metabolism can all
by the gut wall and/or liver. influence drug bioavailability.

Gut-wall metabolism
It is only relatively recently that the full extent of gut- REFERENCES AND BIBLIOGRAPHY
wall metabolism has been recognized. Watkins and
co-workers were the first to report that a major Benet, L.Z., Wu, C., Hevert, M.WacherV.J. (1996) Intestinal
drug metabolism and antitransport processes: a potential
cytochrome P450 enzyme, CYP3A, that is present in paradigm shift in oral drug delivery. J. Cont. Rel. 39,
the liver and is responsible for the hepatic metabo- 139-143.
lism of many drugs, is present in the intestinal Brayden, D. (1997) Human intestinal epithelial monolayers
mucosa and that intestinal metabolism may be as prescreens for oral drug delivery. Pharmaceutical News,
4 (1), 11-13.
important for substrates of this enzyme (Watkins et Evans A.M. (2000) Influence of dietary components on the
al. 1987, Kolars et al. 1992). This effect can also be gastrointestinal metabolism and transport of drugs. 22,
known as first-pass metabolism by the intestine. 131-136.
One drug that is susceptible to extensive gut metab- Fleisher, D. Cheng, L. Zhou,Y. Li-Heng, P and Karim, A
olism that results in a significant reduction in its (1999) Drug, meal and formulation interactions
influencing drug absorption after oral administration.
bioavailability is cyclosporin (Benet et al, 1996). Clin Pharmacokinet, 36, 233-254.
Gray, V. and Dressman J. (1996) Simulated intestinal fluid
TS - Change to pH 6.8. Pharmacopeial Forum 22,
Hepatic metabolism 1943-1945.
Kolars, J.C., Schmiedlin-Ren, P., Schuetz, J.D., Fang, C. and
The liver is the primary site of drug metabolism and Watkins, P.B. (1992) Identification of rifampicin-inducible
thus acts as a final barrier for oral absorption. This P450IIIA4 (GYP 3A4) in human bowel enterocytes.
first pass of absorbed drug through the liver may J. Clin. Invest. 90, 1871-1878.
result in extensive metabolism of the drug, and a Lennernas, H. (1998) Human intestinal permeability.
significant portion may never reach the systemic cir- J. Pharm Set., 87, 403-410.
Nimmo, J. Heading, R.C.,Tothill, P. and Prescott, L.F.
culation, resulting in a low bioavailability of those (1973) Pharmacological modification of gastric emptying:
drugs which are rapidly metabolized by the liver. The effects of propantheline and metoclopramide on
bioavailability of a susceptible drug may be reduced paracetamol absorption. Br. Med.J. 1, 587-589.

232
 THE Gl TRACT - PHYSIOLOGY AND DRUG ABSORPTION

Oh, D.M. Han, H.K. and Amidon, G.L. (1999) Drug transport inducible cytochromes P-450 in intestinal mucosa of rats
and targeting. Intest. Transport Pharml. Biotech. 12, 59-88. and man. J. Clin. Invest. 80, 1029-1036.
Tsuji, A. andTamia, I. (1996) Carrier-mediated intestinal Welling, P.G. (1996) Effects of food on drug absorption,
transport of drugs. Pharm. Res. 13, 963-977. Annu. Rev. Nutr., 16, 383-414.
Watkins, P.B., Wrighton, S.A., Schuetz, E.G., Molowa, D.T. Yang, C.Y., Dantzig, A H, Pidgeon, C. (1999) Pharm. Res.
and Guzelian, P.S. (1987) Identification of glucocorticoid- 16, 1331-43.

233
17
Bioavailability - physicochemical and dosage
form factors
Marianne Ashford

As discussed in Chapter 16, the rate and extent of

CHAPTER CONTENTS absorption are influenced by the physiological
factors associated with the structure and function of
Physicochemical factors influencing the GI tract. This chapter discusses the physico-
bioavailability 234
Dissolution and solubility 234 chemical properties of the drug and dosage form
Physiological factors affecting the dissolution rate factors that influence bioavailability. For a drug to be
of drugs 235 absorbed it needs to be in solution and, secondly, to
Drug factors affecting dissolution rate 236
Surface area and particle size 236 pass across the membrane; in the case of orally
Solubility !n the diffusion layer, Cs 237 administered drugs this is the gastrointestinal epithe-
Salts 237 lium. The physicochemical properties of the drug
Crystal form 239
Factors affecting the concentration of drug in that will influence its passage into solution and
solution in the gastrointestinal fluids 240 transfer across membranes include its dissolution
Complexation 240 rate, pKa) lipid solubility, chemical stability and com-
Micellar solubilization 240 plexation potential.
Adsorption 240
Chemical stability of the drug in the
gastrointestinal fluids 241
Poorly soluble drugs 241
Drug absorption 241
Drug dissociation and lipid solubility 241 PHYSICOCHEMICAL FACTORS
pH-partition hypothesis of drug absorption 241 INFLUENCING BIOAVAILABILITY
Limitations of the pH-partition hypothesis 242
Lipid solubility 243
Molecular size and hydrogen bonding 243 Dissolution and solubility
Summary 244 Solid drugs need to dissolve before they can be
Dosage form factors influencing absorbed. The dissolution of drugs can be described
bioavailability 244
Introduction 244 by the Noyes-Whitney equation (Eqn 17.1). This
Influence of type of dosage form 244 equation, first proposed in 1897, describes the rate
Aqueous solutions 245 of dissolution of spherical particles when the disso-
Aqueous suspensions 245
Liquid-filled capsules 246 lution process is diffusion controlled and involves no
Powder-filled capsules 247 chemical reaction:
Tablets 248
Uncoated tablets 248
Coated tablets 249
Enteric-coated tablets 249
Influence of excipients for conventional dosage where dC/dt is the rate of dissolution of the drug par-
forms 250 ticles, D is the diffusion coefficient of the drug in
Diluents 250
Surfactants 250 solution in the gastrointestinal fluids, A is the effec-
Lubricants 251 tive surface area of the drug particles in contact with
Djsintegrants 251 the gastrointestinal fluids, h is the thickness of the
Viscosity-enhancing agents 251
diffusion layer around each drug particle, Cs is the
Summary 252 saturation solubility of the drug in solution in the
References 252 diffusion layer and C is the concentration of the drug
Bibliography 252 in the gastrointestinal fluids.

234
 BIOAVAILABILITY - PHYSICOCHEMICAL AND DOSAGE FORM FACTORS

Table 17.1 Physicochemical and physiological factors affecting drug dissolution in the gastrointestinal tract (adapted
from Dressman et at, 1998)

Factor Physicochemical parameter Physiological parameter

Effect surface area of drug Particle size, wettability Surfactants in gastric juice and bile
Solubility in diffusion layer Hydrophilicity, crystal structure, solubilization pH, buffer capacity, bile,
food components
Amount of drug already dissolved Permeability, transit
Diffusivity of drug Molecular size Viscosity of luminal contents
Boundary layer thickness Motility patterns and flow rate
Volume of solvent available Gastrointestinal secretions,
co-administered fluids

The limitations of the Noyes-Whitney equation in tion (Eqn 17.1) and hence the dissolution rate of a
describing the dissolution of drug particles are dis- drug. For instance, the diffusion coefficient, £), of the
cussed in Chapter 2. Despite these limitations, the drug in the gastrointestinal fluids may be decreased
equation serves to illustrate and explain how various by the presence of substances that increase the vis-
physicochemical and physiological factors can cosity of the fluids. Hence the presence of food in the
influence the rate of dissolution in the gastrointesti- gastrointestinal tract may cause a decrease in disso-
nal tract. These are summarized in Table 17.1 and lution rate of a drug by reducing the rate of diffusion
are discussed in more detail in the next section. of the drug molecules away from the diffusion layer
Figure 17.1 illustrates the dissolution of a spheri- surrounding each undissolved drug particle.
cal drug particle in the gastrointestinal fluids. Surfactants in gastric juice and bile salts will affect
both the wettability of the drug, and hence the effec-
tive surface area, A, exposed to gastrointestinal
Physiological factors affecting the dissolution
fluids, and the solubility of the drug in the gastroin-
rate of drugs
testinal fluids via micellization. The thickness of the
The environment of the gastrointestinal tract can diffusion layer, h, will be influenced by the degree of
affect the parameters of the Noyes-Whitney equa- agitation experienced by each drug particle in the

Fig. 17.1 Schematic representation of the dissolution of a drug particle in the gastrointestinal fluids.

235
 BIOPHARMACEUTICAL PRINCIPLES OF DRUG DELIVERY

gastrointestinal tract. Hence an increase in gastric of drug absorbed in humans. Many poorly soluble,
and/or intestinal motility may increase the dissolu- slowly dissolving drugs are routinely presented in
tion rate of a sparingly soluble drug by decreasing micronized form to increase their surface area.
the thickness of the diffusion layer around each drug Examples of drugs where a reduction in particle
particle. The concentration, C, of drug in solution in size has been shown to improve the rate and extent of
the bulk of the gastrointestinal fluids will be oral absorption and hence bioavailability are shown
influenced by such factors as the rate of removal of in Table 17.2. Such improvements in bioavailability
dissolved drug by absorption through the gastroin- can result in an increased incidence of side-effects,
testinal-blood barrier, and by the volume of fluid thus for certain drugs it is important that the particle
available for dissolution, which will be dependent on size is well controlled, and many Pharmacopoeia
the position of the drug in the gastrointestinal tract state the requirements of particle size.
and the timing with respect to meal intake. In the For some drugs, particularly those that are
stomach the volume of fluid will be influenced by the hydrophobic in nature, micronization and other dry
intake of fluid in the diet. According to the particle size-reduction techniques can result in aggre-
Noyes-Whitney equation a low value of C will favour gation of the material, with a consequent reduction in
more rapid dissolution of the drug by virtue of the effective surface area exposed to the gastrointesti-
increasing the value of the term (Cs - C). In the case nal fluids and hence their dissolution rate and
of drugs whose absorption is dissolution-rate bioavailability. Aspirin, phenacetin and phenobarbi-
limited, the value of C is normally kept very low by tone are all prone to aggregation during particle size
absorption of the drug. Hence dissolution occurs reduction; one approach that may overcome this
under sink conditions, that is, under conditions such problem is to micronize or mill the drug with a
that the value of (Cs - C) approximates to Cs. Thus wetting agent or hydrophilic carrier. To overcome
for the dissolution of a drug from the gastrointestinal aggregation and to achieve particle sizes in the nano-
tract under sink conditions the Noyes-Whitney size region, wet milling in the presence of stabilizers
equation can be expressed as: has been used. The relative bioavailability of danazol
has been increased 400% by administering particles
DACr
dCfdt = (17.2) in the nano- rather than the micrometre size range.
As well as milling with wetting agents the effective
surface area of hydrophobic drugs can be increased
Drug factors affecting dissolution rate by the addition of a wetting agent to the formulation.
The presence of polysorbate-80 in a fine suspension
Drug factors that can influence the dissolution rate
of phenacetin (particle size less than 75 jum) greatly
are the particle size, the wettability, the solubility and
improved the rate and extent of absorption of the
the form of the drug (whether a salt or a free form,
phenacetin in human volunteers compared to the
crystalline or amorphous).
Surface area and panicle size According to Eqn
17.1, an increase in the total surface area of drug in
Table 17.2 Examples of drugs where a reduction in
contact with the gastrointestinal fluids will cause an particle size has led to improvements in bioavailability
increase in dissolution rate. Provided that each par-
ticle of drug is intimately wetted by the gastrointesti- Drug Therapeutic class
nal fluids, the effective surface area exhibited by the
drug will be directly proportional to the particle size Digoxin Cardiac glycoside
of the drug. Hence the smaller the particle size, the Nitrofurantoin Antifungal
greater the effective surface area exhibited by a given Medoxyprogesterone Hormone
mass of drug, and the higher the dissolution rate. acetate
Particle size reduction is thus likely to result in Danazol Steroid
increased bioavailability, provided the absorption of
Tolbutamide Antidiabetic
the drug is dissolution-rate limited.
One of the classic examples of particle size effects Aspirin Analgesic
on the bioavailability of poorly soluble compounds is Sulphadiazine Antibacterial
that of griseofulvin, where a reduction of particle size Naproxen Non-steroidal anti-inflammatory
from about 10 ^tm (specific surface area = 0.4 m2 g"1) Ibuprofen Non-steroidal anti-inflammatory
to 2.7 /itm (specific surface area = 1.5 m2 g'1) was
Phenacetin Analgesic
shown to produce approximately double the amount

236
 BIOAVAILABILITY - PHYSICOCHEMICAL AND DOSAGE FORM FACTORS

same-size suspension without a wetting agent. differences in dissolution rate will be expected in dif-
Polysorbate-80 helps by increasing the wetting and ferent regions of the gastrointestinal tract.
solvent penetration of the particles and by minimiz- The solubility of weakly acidic drugs increases with
ing aggregation of suspended particles, thereby pH, and so as a drug moves down the gastrointestinal
maintaining a large effective surface area. Wetting tract from the stomach to the intestine, its solubility
effects are highly drug specific. will increase. Conversely, the solubility of weak bases
If an increase in the effective surface area of a drug decreases with increasing pH, i.e. as the drug moves
does not increase its absorption rate it is likely that down the gastrointestinal tract. It is important there-
the dissolution process is not rate limiting. For drugs fore for poorly soluble weak bases to dissolve rapidly in
such as penicillin G and erythromycin, which are the stomach, as the rate of dissolution in the small
unstable in gastric fluids, their chemical degradation intestine will be much slower. The antifungal drug
will be minimized if they remain in the solid state. ketoconazole, a weak base, is particularly sensitive to
Thus particle size reduction would not only serve to gastric pH. Dosing ketoconazole 2 hours after the
increase their dissolution rate, but would also administration of the H2 blocker cimetidine, which
increase chemical degradation and therefore reduce reduces gastric acid secretion, results in a significantly
the amount of intact drug available for absorption. reduced rate and extent of absorption (van der Meer et
Solubility in the diffusion layer, Cs The dissolution al 1980). Similarly, in the case of the antiplatelet
rate of a drug under sink conditions, according to the dipyrimidole, pretreatment with the H2 blocker famo-
Noyes-Whitney equation, is directly proportional to its tidine reduces the peak plasma concentration by a
intrinsic solubility in the diffusion layer surrounding factor of up to 10 (Russell et al 1994).
each dissolving drug particle, Cs. The aqueous solubil- Salts The dissolution rate of a weakly acidic drug
ity of a drug is dependent on the interactions between in gastric fluid (pH 1-3.5) will be relatively low. If the
molecules within the crystal lattice, intermolecular pH in the diffusion layer could be increased, then the
interactions with the solution in which it is dissolving, solubility, Cs, exhibited by the acidic drug in this layer,
and the entropy changes associated with fusion and and hence its dissolution rate in gastric fluids, would
dissolution. In the case of drugs that are weak elec- be increased even though the bulk pH of gastric fluids
trolytes, their aqueous solubilities are dependent on remained at the same low value. The pH of the diffu-
pH (see Chapter 2). Hence in the case of an orally sion layer would be increased if the chemical nature of
administered solid dosage form containing a weak the weakly acidic drug were changed from that of the
electrolyte drug, the dissolution rate of the drug will be free acid to a basic salt, for example the sodium or
influenced by its solubility and the pH in the diffusion potassium form of the free acid. The pH of the diffu-
layer surrounding each dissolving drug particle. The sion layer surrounding each particle of the salt form
pH in the diffusion layer - the microclimate pH - for a would be higher (e.g. 5-6) than the low bulk pH
weak electrolyte will be affected by the pKa and solu- (1-3.5) of the gastric fluids because of the neutralizing
bility of the dissolving drug and the pKa and solubility action of the strong anions (Na+ or K+) ions present in
of the buffers in the bulk gastrointestinal fluids. Thus the diffusion layer (Fig. 17.2).

Fig. 17.2 Schematic representation of the dissolution process of a salt form of a weakly acidic drug in gastric fluid.

237
 BIOPHARMACEUTICAL PRINCIPLES OF DRUG DELIVERY

Because the salt form of the weakly acidic drug has absorbed faster and is more effective in newer indi-
a relatively high solubility at the elevated pH in the cations, such as mild to moderate pain (Sevelius et al
diffusion layer, dissolution of the drug particles will 1980).
take place at a faster rate. When dissolved drug dif- Conversely, strongly acidic salt forms of weakly
fuses out of the diffusion layer into the bulk of the basic drugs, for example chlorpromazine hydrochlo-
gastric fluid, where the pH is lower than that in the ride, dissolve more rapidly in gastric and intestinal
diffusion layer, precipitation of the free acid form is fluids than do the free bases (e.g. chlorpromazine).
likely to occur. This will be a result of the overall sol- The presence of strongly acidic anions (e.g. Cl~ ions)
ubility exhibited by the drug at the lower bulk pH. in the diffusion layer around each drug particle
Thus the free acid form of the drug in solution, which ensures that the pH in that layer is lower than the
is in excess of its solubility at the bulk pH of gastric bulk pH in either the gastric or the intestinal fluid.
fluid, will precipitate out, leaving a saturated (or near- This lower pH will increase the solubility of the drug
saturated) solution of free acid in gastric fluid. Often Cs in the diffusion layer. The oral administration of a
this precipitated free acid will be in the form of very salt form of a weakly basic drug in a solid oral dosage
fine, non-ionized wetted particles which exhibit a form generally ensures that dissolution occurs in the
very large total effective surface area in contact with gastric fluid before the drug passes into small intes-
gastric fluids. This large total effective surface area tine, where pH conditions are unfavourable. Thus
will facilitate rapid redissolution of the precipitated the drug should be delivered to the major absorption
particles of free acid when additional gastric fluid site, the small intestine, in solution. If absorption is
becomes available as a consequence of either dis- fast enough, precipitation of the dissolved drug is
solved drug being absorbed, additional fluid accumu- unlikely to significantly affect bioavailability. It is
lating in the stomach, or the fine precipitated important to be aware that hydrochloride salts may
particles being emptied from the stomach to the experience a common ion effect owing to the pres-
intestine. This rapid redissolution will ensure that the ence of chloride ions in the stomach (see Chapter 8).
concentration of free acid in solution in the bulk of The in vitro dissolution of a sulphate salt of an HIV
the gastric fluids will be at or near to saturation. protease inhibitor analogue is significantly greater in
Thus the oral administration of a solid dosage hydrochloric acid than that of the hydrochloride salt.
form containing a strong basic salt of a weakly acidic The bioavailability of the sulphate salt is more than
drug would be expected to give a more rapid rate of three times greater than that of the hydrochloride
drug dissolution and (in the case of drugs exhibiting salt. These observations are attributed to the
dissolution rate limited absorption) a more rapid rate common ion effect of the hydrochloride (Loper et al
of drug absorption than the free acid form of the 1999).
drug. The sodium salts of acidic drugs and the
Many examples can be found of the effects of salts hydrochloride salts of basic drugs are by far the most
improving the rate and extent of absorption. The dis- common. However, many other salt forms are
solution rate of the oral hypoglycaemic tolbutamide increasingly being employed (see Chapter 8). Some
sodium in 0.1 M HC1 is 5000 times faster than that salts have a lower solubility and dissolution rate than
of the free acid. Oral administration of a non-disin- the free form, for example aluminium salts of weak
tegrating disc of the more rapidly dissolving sodium acids and palmoate salts of weak bases. In these
salt of tolbutamide produced a very rapid decrease in cases insoluble films of either aluminium hydroxide
blood sugar level (a consequence of the rapid rate of or palmoic acid are found to coat the dissolving
drug absorption), followed by a rapid recovery. In solids when the salts are exposed to a basic or an
contrast, a non-disintegrating disc of the tolbu- acidic environment, respectively. In general, poorly
tamide free acid produced a much slower rate of soluble salts delay absorption and may therefore be
decrease of blood sugar (a consequence of the slower used to sustain the release of the drug. A poorly
rate of drug absorption) that was maintained over a soluble salt form is generally employed for suspen-
longer period of time. The barbiturates are often sion dosage forms.
administered in the form of sodium salts to achieve Although salt forms are often selected to improve
a rapid onset of sedation and provide more pre- bioavailability, other factors, such as chemical stabil-
dictable effects. ity, hygroscopicity, manufacturability and crys-
The non-steroidal anti-inflammatory drug tallinity, will all be considered during salt selection
naproxen was originally marketed as the free acid for and may preclude the choice of a particular salt. The
the treatment of rheumatoid and osteoarthritis. sodium salt of aspirin, sodium acetylsalicylate, is
However, the sodium salt (naproxen sodium) is much more prone to hydrolysis than is aspirin,

238
 BIOAVAILABILITY - PHYSICOCHEMICAL AND DOSAGE FORM FACTORS

acetylsalicylic acid, itself. One way to overcome Amorphous solids In addition to different poly-
chemical instabilities or other undesirable features of morphic crystalline forms, a drug may exist in an
salts is to form the salt in situ or to add basic/acidic amorphous form (see Chapter 9). Because the amor-
excipients to the formulation of a weakly acidic or phous form usually dissolves more rapidly than the
weakly basic drug. The presence of the basic excipi- corresponding crystalline form(s), the possibility
ents in the formulation of acidic drugs ensures that a exists that there will be significant differences in the
relatively basic diffusion layer is formed around each bioavailabilities exhibited by the amorphous and
dissolving particle. The inclusion of the basic ingre- crystalline forms of drugs that show dissolution-rate
dients aluminium dihydroxyaminoacetate and mag- limited bioavailability.
nesium carbonate in aspirin tablets was found to A classic example of the influence of amorphous
increase their dissolution rate and bioavailability. versus crystalline forms of a drug on its gastroin-
testinal bioavailability is provided by that of the
Crystal form antibiotic novobiocin. The more soluble and rapidly
Polymorphism Many drugs can exist in more than dissolving amorphous form of novobiocin was
one crystalline form, e.g. chloramphenicol palmitate, readily absorbed following oral administration of an
cortisone acetate, tetracyclines and sulphathiazole. aqueous suspension to humans and dogs. However,
This property is referred to as polymorphism and the less soluble and slower-dissolving crystalline
each crystalline form is known as a polymorph (see form of novobiocin was not absorbed to any
Chapter 9). As discussed in Chapter 2, a metastable significant extent. The crystalline form was thus
polymorph usually exhibits a greater dissolution rate therapeutically ineffective. A further important
than the corresponding stable polymorph. observation was made in the case of aqueous sus-
Consequently, the metastable polymorphic form of a pensions of novobiocin. The amorphous form of
poorly soluble drug may exhibit an increased novobiocin slowly converts to the more thermody-
bioavailability compared to the stable polymorphic namically stable crystalline form, with an accompa-
form. nying loss of therapeutic effectiveness. Thus unless
A classic example of the influence of polymor- adequate precautions are taken to ensure the stabil-
phism on drug bioavailability is provided by chlo- ity of the less stable, more therapeutically effective
ramphenicol palmitate. This drug exists in three amorphous form of a drug in a dosage form, then
crystalline forms designated A, B and C. At normal unacceptable variations in therapeutic effectiveness
temperature and pressure A is the stable polymorph, may occur.
B is the metastable polymorph and C is the unstable Several delivery technologies for poorly soluble
polymorph. Polymorph C is too unstable to be drugs rely on stabilizing the drug in its amorphous
included in a dosage form, but polymorph B, the form to increase its dissolution and bioavailability.
metastable form, is sufficiently stable. The plasma Solvates Another variation in the crystalline form
profiles of chloramphenicol from orally administered of a drug can occur if the drug is able to associate
suspensions containing varying proportions of the with solvent molecules to produce crystalline forms
polymorphic forms A and B were investigated. The known as solvates. When water is the solvent, the
extent of absorption of chloramphenicol increases as solvate formed is called a hydrate. Generally the
the proportion of the polymorphic form B of chlo- greater the solvation of the crystal, the lower are the
ramphenicol palmitate is increased in each suspen- solubility and dissolution rate in a solvent identical
sion. This was attributed to the more rapid in vivo to the solvation molecules. As the solvated and non-
rate of dissolution of the metastable polymorphic solvated forms usually exhibit differences in dissolu-
form, B, of chloramphenicol palmitate. Following tion rates, they may also exhibit differences in
dissolution, chloramphenicol palmitate is hydrolysed bioavailability, particularly in the case of poorly
to give free chloramphenicol in solution, which is soluble drugs that exhibit dissolution-rate limited
then absorbed. The stable polymorphic form A of bioavailability.
chloramphenicol palmitate dissolves so slowly and A valuable example is that of the antibiotic ampi-
consequently is hydrolysed so slowly to chloram- cillin: the faster-dissolving anhydrous form of ampi-
phenicol in vivo that this polymorph is virtually inef- cillin was absorbed to a greater extent from both hard
fective. The importance of polymorphism to the gelatin capsules and an aqueous suspension than was
gastrointestinal bioavailability of chloramphenicol the slower-dissolving trihydrate form. The anhydrous
palmitate is reflected by a limit being placed on the form of the hydrochloride salt of an HIV protease
content of the inactive polymorphic form, A, in inhibitor, an analogue of indinavir, has a much faster
Chloramphenicol Palmitate Mixture. dissolution rate than the hydrated form in water; this

239
 BIOPHARMACEUTICAL PRINCIPLES OF DRUG DELIVERY

is reflected by a significantly greater rate and extent of cyclodextrin molecule to form reversible complexes,
absorption and overdoubling of the bioavailability of although other stoichiometries are possible. For
the anhydrous form (Loper et al 1999). example the antifungal miconazole shows poor oral
bioavailability owing to its poor solubility. However,
in the presence of cyclodextrin the solubility and
Factors affecting the concentration of drug in
dissolution rate of miconazole are significantly
solution in the gastrointestinal fluids
enhanced (by up to 55- and 255-fold, respectively).
The rate and extent of absorption of a drug depend This enhancement of dissolution rate resulted in a
on the effective concentration of that drug, i.e. the more than doubling of the oral bioavailability in a
concentration of drug in solution in the gastroin- study in rats (Terjarla et al 1998).There are numer-
testinal fluids which is in an absorbable form. ous examples in the literature of drugs whose solu-
Complexation, micellar solubilization, adsorption bility and hence bioavailability have been increased
and chemical stability are the principal physico- by the use of cyclodextrins: they include piroxicam,
chemical properties that can influence the effective itraconazole, indamethacin, pilocarpine, naproxen,
drug concentration in the gastrointestinal fluids. hydrocortisone, diazepam and digitoxin. The first
Complexation Complexation of a drug may occur product on the UK market containing a cyclodex-
within the dosage form and/or in the gastrointestinal trin is the poorly soluble antifungal itraconazole,
fluids, and can be beneficial or detrimental to which has been formulated as a liquid dosage form
absorption. with the more soluble derivative of ^-cyclodextrin,
Mucin, a normal component of gastrointestinal hydroxypropyl-jS-cyclodextrin.
fluids, complexes with some drugs. The antibiotic Micellar solubization Micellar solubilization can
streptomycin binds to mucin, thereby reducing the also increase the solubility of drugs in the gastroin-
available concentration of the drug for absorption. It testinal tract. The ability of bile salts to solubilize
is thought that this may contribute to its poor drugs depends mainly on the lipophilicity of the
bioavailability. Another example of Complexation is drug (Naylor et al 1995). Further information on
that between drugs and dietary components, as in solubilization and complex formation can be found
the case of the tetracyclines, which is discussed in in Florence and Attwood (1998).
Chapter 16. Adsorption The concurrent administration of
The bioavailability of some drugs can be reduced drugs and medicines containing solid adsorbents
by the presence of excipients within the dosage (e.g. antidiarrhoeal mixtures) may result in the
forms. The presence of calcium (e.g. from the diluent adsorbents interfering with the absorption of drugs
dicalcium phosphate) in the dosage form of tetracy- from the gastrointestinal tract. The adsorption of a
cline reduces its bioavailability via the formation of a drug on to solid adsorbents such as kaolin or char-
poorly soluble complex. Other examples of com- coal may reduce its rate and/or extent of absorption,
plexes that reduce drug bioavailability are those owing to a decrease in the effective concentration of
between amphetamine and sodium carboxymethyl- the drug in solution available for absorption. A con-
cellulose, and between phenobarbitone and polyeth- sequence of the reduced concentration of free drug
ylene glycol 4000. Complexation between drugs and in solution at the site of absorption will be a reduc-
excipients probably occurs quite often in liquid tion in the rate of drug absorption. Whether there is
dosage forms. also a reduction in extent of absorption will depend
Complexation is sometimes used to increase drug on whether the drug-absorbent interaction is readily
solubility, particularly of poorly water-soluble reversible. If the absorbed drug is not readily
drugs. One class of complexing agents that is released from the solid absorbent in order to replace
increasingly being employed is the cyclodextrin the free drug that has been absorbed from the gas-
family. Cyclodextrins are enzymatically modified trointestinal tract, there will also be a reduction in
starches. They are composed of glucopyranose units the extent of absorption from the gastrointestinal
which form a ring of either six (a-cyclodextrin), tract.
seven (/3-cyclodextrin) or eight (y-cyclodextrin) Examples of drug-adsorbent interactions that give
units. The outer surface of the ring is hydrophilic reduced extents of absorption are promazine-
and the inner cavity is hydrophobic. Lipophilic mol- charcoal and linomycin-kaopectate. The adsorbent
ecules can fit into the ring to form soluble inclusion properties of charcoal have been exploited as an anti-
complexes. The ring of /3-cyclodextrin is the correct dote in drug intoxification.
size for the majority of drug molecules, and nor- Care also needs to be taken when insoluble excip-
mally one drug molecule will associate with one ients are included in dosage forms to check that the

240
 BIOAVAILABILITY- PHYSICOCHEMICAL AND DOSAGE FORM FACTORS

drug will not adsorb to them. Talc, which can be of drugs, such as the HIV protease inhibitors, the
included in tablets as a glidant, is claimed to inter- glycoprotein Ilb/IIIa inhibitors, and many anti-infec-
fere with the absorption of cyanocobalamin by virtue tive and anticancer drugs. Medicinal chemists are
of its ability to adsorb this vitamin. using approaches such as introducing ionizable
Further details of the biopharmaceutical implica- groups, reducing melting points, changing poly-
tions of adsorption can be found in Florence and morphs or introducing prodrugs to improve solubil-
Attwood (1998). ity. Further information on these approaches can be
Chemical stability of the drug in the gastrointestinal obtained from reviews by Lipinski et al (1997) and
fluids If the drug is unstable in the gastrointestinal Panchagnula and Thomas (2000). Pharmaceutical
fluids the amount of drug that is available for absorp- scientists are also applying a wide range of formula-
tion will be reduced and its bioavailability reduced. tion approaches to improve the dissolution rate of
Instability in gastrointestinal fluids is usually caused poorly soluble drugs. These include formulating in
by acidic or enzymatic hydrolysis. When a drug is the nano-size range; formulating in a solid solution
unstable in gastric fluid its extent of degradation or dispersion or self-emulsifying drug delivery
would be minimized (and hence its bioavailability system; stabilizing the drug in the amorphous form
improved) if it exhibited minimal dissolution in or formulating with cyclodextrins. Many drug
gastric fluid but still rapid dissolution in intestinal delivery companies thrive on technologies designed
fluid. The concept of delaying the dissolution of a to improve the delivery of poorly soluble drugs.
drug until it reaches the small intestine has been
employed to improve the bioavailability of ery-
thromycin in the gastrointestinal tract. Enteric
Drug absorption
coating of tablets containing the free base ery- Once the drug has successfully passed into solution
thromycin is one method that has been used to it is available for absorption. In Chapter 16 many
protect this drug from gastric fluid. The enteric physiological factors were shown to influence drug
coating resists gastric fluid but disrupts or dissolves absorption. Absorption, and hence the bioavailability
at the less acid pH range of the small intestine (see of a drug once in solution, is also influenced by many
later and Chapter 28). An alternative method of pro- drug factors, in particular its pK,, lipid solubility,
tecting a susceptible drug from gastric fluid, which molecular weight, the number of hydrogen bonds in
has been employed in the case of erythromycin, is the molecule and its chemical stability.
the administration of chemical derivatives of the
parent drug. These derivatives, or prodrugs, exhibit
limited solubility (and hence minimal dissolution) in
Drug dissociation and lipid solubility
gastric fluid but, once in the small intestine, liberate The dissociation constant and lipid solubility of a
the parent drug to be absorbed. For instance, ery- drug, and the pH at the absorption site, often
thromycin stearate, after passing through the influence the absorption characteristics of a drug
stomach undissolved, dissolves and dissociates in the throughout the gastrointestinal tract. The inter-
intestinal fluid, yielding the free base erythromycin relationship between the degree of ionization of a
that is absorbed. weak electrolyte drug (which is determined by its
Instability in gastrointestinal fluids is one of the dissociation constant and the pH at the absorption
reasons why many peptide-like drugs are poorly site) and the extent of absorption is embodied in the
absorbed when delivered via the oral route. pH-partition hypothesis of drug absorption, first
proposed by Overton in 1899. Although it is an over-
simplification of the complex process of absorption,
Poorly soluble drugs
the pH-partition hypothesis provides a useful frame-
Poorly water-soluble drugs are increasingly becom- work for understanding the transcellular passive
ing a problem in terms of obtaining the satisfactory route of absorption, which is that favoured by the
dissolution within the gastrointestinal tract that is majority of drugs.
necessary for good bioavailability. It is not only exist- pH-partition hypothesis of drug absorption According
ing drugs that cause problems, but it is the challenge to the pH-partition hypothesis, the gastrointestinal
of medicinal chemists to ensure that new drugs are epithelia acts as a lipid barrier towards drugs which
not only active pharmacologically but have enough are absorbed by passive diffusion, and those that are
solubility to ensure fast-enough dissolution at the lipid soluble will pass across the barrier. As most
site of administration, often the gastrointestinal drugs are weak electrolytes, the unionized form of
tract. This is a particular problem for certain classes weakly acidic or basic drugs (i.e. the lipid-soluble

241
 BIOPHARMACEUTICAL PRINCIPLES OF DRUG DELIVERY

form) will pass across the gastrointestinal epithelia, weak acids are still quite well absorbed from the
whereas the gastrointestinal epithelia is impermeable small intestine. In fact, the rate of intestinal absorp-
to the ionized (i.e. poorly lipid-soluble) form of such tion of a weak acid is often higher than its rate of
drugs. Consequently, according to the pH-partition absorption in the stomach, even though the drug is
hypothesis, the absorption of a weak electrolyte will unionized in the stomach. The significantly larger
be determined chiefly by the extent to which the surface area that is available for absorption in the
drug exists in its unionized form at the site of small intestine more than compensates for the high
absorption. degree of ionization of weakly acidic drugs at intesti-
The extent to which a weakly acidic or basic drug nal pH values. In addition, a longer small intestinal
ionizes in solution in the gastrointestinal fluid may residence time and a microclimate pH, that exists at
be calculated using the appropriate form of the the surface of the intestinal mucosa and is lower than
Henderson-Hasselbalch equation (see Chapter 3). that of the luminal pH of the small intestine, are
For a weakly acidic drug having a single ionizable thought to aid the absorption of weak acids from the
group (e.g. aspirin, phenylbutazone, salicylic acid) small intestine.
the equation takes the form of: The mucosal unstirred layer is another recognized
component of the gastrointestinal barrier to drug
absorption that is not accounted for in the pH-parti-
tion hypothesis. During absorption drug molecules
where pKa is the negative logarithm of the acid dis- must diffuse across this layer and then on through
sociation constant of the drug, and [HA] and [A~] the lipid layer. Diffusion across this layer is liable to
are the respective concentrations of the unionized be a significant component of the total absorption
and ionized forms of the weakly acidic drug, which process for those drugs that cross the lipid layer very
are in equilibrium and in solution in the gastroin- quickly. Diffusion across this layer will also depend
testinal fluid. pH refers to the pH of the environment on the relative molecular weight of the drug.
of the ionized and unionized species, i.e. the gas- The pH-partition hypothesis cannot explain the fact
trointestinal fluids. that certain drugs (e.g. quaternary ammonium com-
For a weakly basic drug possessing a single ioniz- pounds and tetracyclines) are readily absorbed despite
able group (e.g. chlorpromazine) the analogous being ionized over the entire pH range of the gastro-
equation is: intestinal tract. One suggestion for this is that the gas-
trointestinal barrier is not completely impermeable to
ionized drugs. It is now generally accepted that ionized
forms of drugs are absorbed in the small intestine but
where [BH+] and [B] are the respective concentra- at a much slower rate than the unionized form.
tions of the ionized and unionized forms of the weak Another possibility is that such drugs interact with
basic drug, which are in equilibrium and in solution endogenous organic ions of opposite charge to form
in the gastrointestinal fluids. an absorbable neutral species - an ion pair - which is
Therefore, according to these equations a weakly capable of partitioning into the lipoidal gastrointesti-
acidic drug, pKa 3.0, will be predominantly unionized nal barrier and be absorbed via passive diffusion.
in gastric fluid at pH 1.2 (98.4%) and almost totally Another, physiological, factor that causes devia-
ionized in intestinal fluid at pH 6.8 (99.98%), whereas tions from the pH-partition hypothesis is convec-
a weakly basic drug, pKa 5, will be almost entirely tiveflow or solvent drag. The movement of water
ionized (99.98%) at gastric pH of 1.2 and predom- molecules into and out of the gastrointestinal tract
inantly unionized at intestinal pH of 6.8 (98.4%).This will affect the rate of passage of small water-soluble
means that, according to the pH-partition hypothesis, molecules across the gastrointestinal barrier. Water
a weakly acidic drug is more likely to be absorbed movement occurs because of differences in osmotic
from the stomach where it is unionized, and a weakly pressure between blood and the luminal contents,
basic drug from the intestine where it is predom- and differences in hydrostatic pressure between the
inantly unionized. However, in practice, other factors lumen and the perivascular tissue. The absorption of
need to be taken into consideration. water-soluble drugs will be increased if water flows
Limitations of the pH-partition hypothesis The from the lumen to the blood, provided that the drug
extent to which a drug exists in its unionized form is and water are using the same route of absorption;
not the only factor determining the rate and extent this will have greatest effect in the jejunum, where
of absorption of a drug molecule from the gastroin- water movement is at its greatest. Water flow also
testinal tract. Despite their high degree of ionization, effects the absorption of lipid-soluble drugs. It is

242
 BIOAVAILABILITY - PHYSICOCHEMICAL AND DOSAGE FORM FACTORS

thought that this is because the drug becomes more The lipophilicity of a drug is critical in the drug dis-
concentrated as water flows out of the intestine, covery process. Polar molecules, i.e. those that are
thereby favouring a greater drug concentration gra- poorly lipid soluble (log P < 0) and relatively large,
dient and increased absorption. such as gentamicin, ceftriaxone, heparin and strep-
Lipid solubility A number of drugs are poorly tokinase, are poorly absorbed after oral administra-
absorbed from the gastrointestinal tract despite the tion and therefore have to be given by injection.
fact that their unionized forms predominate. For Smaller molecules that are poorly lipid soluble, i.e.
example, the barbiturates, barbitone and thiopen- hydrophilic in nature, such as the /3-blocker atenolol,
tone, have similar dissociation constants - pKa 7.8 can be absorbed via the paracellular route. Lipid-
and 7.6, respectively - and therefore similar degrees soluble drugs with favourable partition coefficients
of ionization at intestinal pH. However, thiopentone (i.e. log P > 0) are usually absorbed after oral admin-
is absorbed much better than barbitone. The reason istration. Drugs which are very lipid soluble (log P >
for this difference is that the absorption of drugs is 3) tend to be well absorbed but are also more likely to
also affected by the lipid solubility of the drug. be susceptible to metabolism and biliary clearance.
Thiopentone, being more lipid soluble than barbi- Although there is no general rule that can be applied
tone, exhibits a greater affinity for the gastrointestinal across all drug molecules, within a homologous series
membrane and is thus far better absorbed. drug absorption usually increases as the lipophilicity
An indication of the lipid solubility of a drug, and rises. This has been shown for a series of barbiturates
therefore whether that drug is liable to be transported by Schanker (1960) and for a series of /3-blockers by
across membranes, is given by its ability to partition Taylor et al (1985).
between a lipid-like solvent and water or an aqueous Sometimes, if the structure of a compound cannot
buffer. This is known as the drug's partition be modified to yield lipid solubility while maintain-
coefficient, and is a measure of its lipophilicity. The ing pharmacological activity, medicinal chemists
value of the partition coefficient P is determined by may investigate the probability of making lipid pro-
measuring the drug partitioning between water and a drugs to improve absorption. A prodrug is a chemi-
suitable solvent at constant temperature. As this ratio cal modification, frequently an ester of an existing
normally spans several orders of magnitude it is drug, which converts back to the parent compound
usually expressed as the logarithmn. The organic as a result of metabolism by the body. A prodrug has
solvent that is usually selected to mimic the biological no pharmocological activity itself. Examples of pro-
membrane, because of its many similar properties, is drugs which have been successfully used to improve
octanol. the lipid solubility and hence absorption of their
parent drugs are shown in Table 17.3.
concentration of drug Molecular size and hydrogen bonding Two other
„ .. -,, . in organic phase drug properties that are important in permeability
Partition coefficient =
concentration in are the number of hydrogen bonds within the mole-
aqueous phase cule and the molecular size
The effective partition coefficient, taking into For paracellular absorption the molecular weight
account the degree of ionization of the drug, is should ideally be less than 200 Da; however, there
known as the distribution coefficient and again is are examples where larger molecules (up to molecu-
normally expressed as the logarithm (log D); it is lar weights of 400 Da) have been absorbed via this
given by the following equations for acids and bases:
For acids:
Table 17.3 Prodrugs with improved lipid solubility
and oral absorption

Parent drug Prodrug Ester

Ampicillin Pivampicillin Pivaloyloxymethyl

Ampicillin Bacampicillin Carbonate
For bases:
CarbenicJIlin Indanylcarbenicillin Indanyl
Cefuroxime Cefuroxime axetil Acetylethyl
Enalaprilat Enalapril Ester of 1 -carboxylic acid
Terbutaline Ibuterol Dibutyl

243
 BIOPHARMACEUTICAL PRINCIPLES OF DRUG DELIVERY

route. Shape is also an important factor for paracel- influenced by many physiological factors and by
lular absorption. many physicochemical properties associated with the
In general, for transcellular passive diffusion a drug itself. The bioavailability of a drug can also be
molecular weight of less than 500 Da is preferable. influenced by factors associated with the formulation
Drugs with molecular weights above this may be and production of the dosage form. Increasingly
absorbed less efficiently. There are few examples of many dosage forms are being designed to affect the
drugs with molecular weights above 700 Da being release and absorption of drugs, for example con-
well absorbed. trolled-release systems (see Chapter 20) and delivery
Too many hydrogen bonds within a molecule are systems for poorly soluble drugs. This section focuses
detrimental to its absorption. In general, no more than on summarizing how the type of dosage form and the
five hydrogen bond donors and no more than 10 excipients used in conventional oral dosage forms can
hydrogen bond acceptors (the sum of nitrogen and affect the rate and extent of drug absorption.
oxygen atoms in the molecule is often taken as a rough
measure of hydrogen bond acceptors) should be
present if the molecule is to be well absorbed. The large Influence of the type of dosage form
number of hydrogen bonds within peptides is one of
the reasons why peptide drugs are poorly absorbed. The type of dosage form and its method of prepara-
tion or manufacture can influence bioavailability.
Thus, whether a particular drug is incorporated and
Summary administered in the form of a solution, a suspension
There are many properties of the drug itself that will or solid dosage form can influence its rate and/or
influence its passage into solution in the gastrointesti- extent of absorption from the gastrointestinal tract.
nal tract and across the gastrointestinal membrane, The type of oral dosage form will influence the
and hence its overall rate and extent of absorption. number of possible intervening steps between
administration and the appearance of dissolved drug
in the gastrointestinal fluids, i.e. the type of dosage
form will influence the release of drug into solution
in the gastrointestinal fluids (Fig. 17.3).
DOSAGE FORM FACTORS INFLUENCING
In general, drugs must be in solution in the gas-
BIOAVAILABILITY
trointestinal fluids before absorption can occur.
Thus the greater the number of intervening steps,
Introduction the greater will be the number of potential obstacles
The rate and/or extent of absorption of a drug from to absorption and the greater will be the likelihood of
the gastrointestinal tract have been shown to be that type of dosage form reducing the bioavailability

Fig. 17.3 Schematic outline of the influence of the dosage form on the appearance of drug in solution in the gastrointestinal tract.

244
 BIOAVAILABILITY - PHYSICOCHEMICAL AND DOSAGE FORM FACTORS

exhibited by the drug. Hence the bioavailability of a • Complexation, i.e. the formation of a complex
given drug tends to decrease in the following order between the drug and an excipient included to
of types of dosage form: aqueous solutions > increase the aqueous solubility, the chemical
aqueous suspensions > solid dosage forms (e.g. hard stability of the drug or the viscosity of the dosage
gelatin capsules or tablets). Although this ranking is form;
not universal, it does provide a useful guideline. In • Solubilization, i.e. the incorporation of the drug
general, solutions and suspensions are the most suit- into micelles in order to increase its aqueous
able for administering drugs intended to be rapidly solubility;
absorbed. However, it should be noted that other • The viscosity of a solution dosage form, particularly
factors (e.g. stability, patient acceptability etc.) can if a viscosity-enhancing agent has been included.
also influence the type of dosage form in which a
drug is administered via the gastrointestinal route. Information concerning the potential influence of
each of the above factors was given earlier. Further
details concerning the formulation of oral solution
Aqueous solutions dosage forms are given in Chapter 21.
For drugs that are water soluble and chemically
stable in aqueous solution, formulation as a solution Aqueous suspensions
normally eliminates the in vivo dissolution step and
An aqueous suspension is a useful dosage form for
presents the drug in the most readily available form
administering an insoluble or poorly water-soluble
for absorption. However, dilution of an aqueous solu-
drug. Usually the absorption of a drug from this type
tion of a poorly water-soluble drug whose aqueous
of dosage form is dissolution-rate limited. The oral
solubility had been increased by formulation tech-
administration of an aqueous suspension results in a
niques such as cosolvency, complex formation or sol-
large total surface area of dispersed drug being
ubilization can result in precipitation of the drug in
immediately presented to the gastrointestinal fluids.
the gastric fluids. Similarly, exposure of an aqueous
This facilitates dissolution and hence absorption of
solution of a salt of a weak acidic compound to
the drug. In contrast to powder-filled hard gelatin
gastric pH can also result in precipitation of the free
capsule and tablet dosage forms, dissolution of all
acid form of the drug. In most cases the extremely
drug particles commences immediately on dilution
fine nature of the resulting precipitate permits a more
of the suspension in the gastrointestinal fluids. A
rapid rate of dissolution than if the drug had been
drug contained in a tablet or hard gelatin capsule
administered in other types of oral dosage forms,
may ultimately achieve the same state of dispersion
such as aqueous suspension, hard gelatin capsule or
in the gastrointestinal fluids, but only after a delay.
tablet. However, for some drugs this precipitation can
Thus a well formulated, finely subdivided aqueous
have a major effect on bioavailability. The same dose
suspension is regarded as being an efficient oral drug
of an experimental drug was given to dogs in three
delivery system, second only to a non-precipitating
different solution formulations, a polyethlyene glycol
solution-type dosage form.
solution and two different concentrations of hydroxy-
Factors associated with the formulation of aqueous
propyl-/3-cyclodextrin. Bioavailabilities of 19%, 57%
suspension dosage forms that can influence the
and 89% were obtained for polyethylene glycol, the
bioavailabilities of drugs from the gastrointestinal
lower concentration and the higher concentration of
tract include:
hydroxypropyl-/3-cyclodextrin, respectively. The dif-
ference in bioavailability of the three solutions was • The particle size and effective surface area of the
attributed to the difference in precipitation rates of dispersed drug;
the candidate drug from the three solutions on dilu- • The crystal form of the drug;
tion. The experimental drug was observed to precipi- • Any resulting complexation, i.e. the formation of
tate most quickly from the polyethylene glycol a non-absorbable complex between the drug and
solution, and slowest from the most concentrated an excipient such as the suspending agent;
hydroxypropyl-/3-cyclodextrin solution. • The inclusion of a surfactant as a wetting,
Factors associated with the formulation of flocculating or deflocculating agent;
aqueous solutions that can influence drug bioavail- • The viscosity of the suspension.
ability include:
Information concerning the potential influence of
• The chemical stability exhibited by the drug in the above factors on drug bioavailability is given in
aqueous solution and the gastrointestinal fluids; earlier sections. Further information concerning the

245
 BIOPHARMACEUTICAL PRINCIPLES OF DRUG DELIVERY

formulation and uses of suspensions as dosage forms Many poorly water-soluble drugs have been found
is given in Chapter 23. to exhibit greater bioavailabilities from liquid-filled
capsule formulations. The cardiac glycoside digoxin,
when formulated as a solution in a mixture of poly-
Liquid-filled capsules
ethylene glycol, ethanol and propylene glycol in a
Liquids can be filled into capsules made from soft or soft gelatin capsule, has been shown to be absorbed
hard gelatin. Both types combine the convenience of a faster than the standard commercial tablets.
unit dosage form with the potentially rapid drug More recently, far more complex capsule formula-
absorption associated with aqueous solutions and sus- tions have been investigated to improve the absorption
pensions. Drugs encapsulated in liquid-filled capsules of poorly soluble drugs. Cyclosporin is a hydrophobic
for peroral administration are dissolved or dispersed in drug with poor solubility in gastrointestinal fluids. It
non-toxic, non-aqueous vehicles. Such vehicles may be showed low and variable oral bioavailability from its
water immiscible (i.e. lipophilic) or water miscible (i.e. original liquid-filled soft gelatin capsule formulation
hydrophilic). Vegetable oils are popular water-immisci- (Sandimmun) and was particularly sensitive to the
ble vehicles, whereas polyethylene glycols and certain presence of fat in diet and bile acids. In its new for-
non-ionic surfactants (e.g. polysorbate-80) are water mulation (Sandimmun Neoral), which is a complex
miscible. Sometimes the vehicles have thermal proper- mixture of hydrophilic and lipophilic phases, surfac-
ties such that they can be filled into capsules while hot, tants, cosurfactants and a cosolvent, it forms a non-
but are solids at room temperature. precipitating microemulsion on dilution with
The release of the contents of gelatin capsules is gastrointestinal fluids. It has a significantly improved
effected by dissolution and splitting of the flexible bioavailability with reduced variability that is indepen-
shell. Following release, a water-miscible vehicle dis- dent of the presence of food (Drewe et al 1992).
perses and/or dissolves readily in the gastrointestinal Many protease inhibitors (antiviral drugs) are
fluids, liberating the drug (depending on its aqueous peptidomimetic in nature. They have high molecular
solubility) as either a solution or a fine suspension, weights and low aqueous solubility, are susceptible
which is conducive to rapid absorption. In the case of to degradation in the lumen and extensive hepatic
gelatin capsules containing drugs in solution or sus- metabolism, and consequently have poor bioavail-
pension in water-immiscible vehicles, release of the ability (Barry et al 1997). Saquinavir has recently
contents will almost certainly be followed by disper- been reformulated from a powder-filled hard gelatin
sion in the gastrointestinal fluids. Dispersion is facili- capsule (Invirase) to a complex soft gelatin formula-
tated by emulsifiers included in the vehicle, and also tion (Fortovase). The latter shows a significant
by bile. Once dispersed, the drug may end up as an improvement in bioavailability (3-4 times) over the
emulsion, a solution, a fine suspension or a nano/ standard hard gelatin formulation, and as a conse-
microemulsion. Well formulated liquid-filled capsules quence, a significantly greater viral load reduction
aimed at improving the absorption of poorly soluble (Perry and Noble 1998)
drugs will ensure that no precipitation of drug occurs Factors associated with the formulation of liquid-
from the nano- or microemulsion in the gastrointesti- filled gelatin capsules which can influence the bioavail-
nal fluids. If the lipophilic vehicle is a digestible oil and abilities of drugs from this type of dosage form include:
the drug is highly soluble in the oil, it is possible that
the drug will remain in solution in the dispersed oil • the solubility of the drug in the vehicle (and
phase and be absorbed (along with the oil) by fat gastrointestinal fluids);
absorption processes. For a drug that is less lipophilic • the particle size of the drug (if suspended in the
or is dissolved in a non-digestible oil, absorption prob- vehicle);
ably occurs following partitioning of the drug from the • the nature of the vehicle, i.e. hydrophilic or
oily vehicle into the aqueous gastrointestinal fluids. In lipophilic (and whether a lipophilic vehicle is a
this case the rate of drug absorption appears to digestible or a non-digestible oil);
depend on the rate at which drug partitions from the • the inclusion of a surfactant as a
dispersed oil phase. The increase in interfacial area of wetting/emulsifying agent in a lipophilic vehicle
contact resulting from dispersion of the oily vehicle in or as the vehicle itself;
the gastrointestinal fluids will facilitate partition of the • the inclusion of a suspending agent (viscosity-
drug across the oil/aqueous interface. For drugs sus- enhancing agent) in the vehicle;
pended in an oily vehicle release may involve dissolu- • the complexation, i.e. formation, of a non-
tion in the vehicle, diffusion to the oil/aqueous absorbable complex between the drug and any
interface and partition across the interface. excipient.

246
 BIOAVAILABILITY - PHYSICOCHEMICAL AND DOSAGE FORM FACTORS

Powder-filled capsules
appears to be a complex function of the rates of dif-
Generally the bioavailability of a drug from a well ferent processes, such as the dissolution rate of the
formulated powder-filled hard gelatin capsule gelatin shell, the rate of penetration of the gastroin-
dosage form will be better than or at least equal to testinal fluids into the encapsulated mass, the rate at
that from the same drug in a compressed tablet. which the mass deaggregates (i.e. disperses) in the
Provided the hard gelatin shell dissolves rapidly in gastrointestinal fluids, and the rate of dissolution of
the gastrointestinal fluids and the encapsulated mass the dispersed drug particles.
disperses rapidly and efficiently, a relatively large The inclusion of excipients (e.g. diluents, lubricants
effective surface area of drug will be exposed to the and surfactants) in a capsule formulation can have a
gastrointestinal fluids, thereby facilitating dissolu- significant effect on the rate of dissolution of drugs,
tion. However, it is incorrect to assume that a drug particularly those that are poorly soluble and
formulated as a hard gelatin capsule is in a finely hydrophobic. Figure 17.4 shows that a hydrophilic
divided form surrounded by a water-soluble shell, diluent (e.g. sorbitol, lactose) often serves to increase
and that no bioavailability problems can occur. The the rate of penetration of the aqueous gastrointestinal
overall rate of dissolution of drugs from capsules fluids into the contents of the capsule, and to aid the

In gastrointestinal fluids, hard gelatin capsule shell dissolves, thereby exposing contents to fluids

Fig. 17.4 Diagrammatic representation of how a hydrophilic diluent can increase the rate of dissolution of a poorly soluble,
hydrophobic drug from a hard gelatin capsule.

247
 BIOPHARMACEUTICAL PRINCIPLES OF DRUG DELIVERY

dispersion and subsequent dissolution of the drug in administration of a tablet. Because the effective surface
these fluids. However, the diluent should exhibit no area of a poorly soluble drug is an important factor
tendency to adsorb or complex with the drug, as either influencing its dissolution rate, it is especially impor-
can impair absorption from the gastrointestinal tract. tant that tablets containing such drugs should disinte-
Both the formulation and the type and conditions grate rapidly and completely in the gastrointestinal
of the capsule-filling process can affect the packing fluids if rapid release, dissolution and absorption are
density and liquid permeability of the capsule con- required. The overall rate of tablet disintegration is
tents. In general, an increase in packing density (i.e. influenced by several interdependent factors, which
a decrease in porosity) of the encapsulated mass will include the concentration and type of drug, diluent,
probably result in a decrease in liquid permeability binder, disintegrant, lubricant and wetting agent, as
and dissolution rate, particularly if the drug is well as the compaction pressure (see Chapter 27).
hydrophobic, or if a hydrophilic drug is mixed with a The dissolution of a poorly soluble drug from an
hydrophobic lubricant such as magnesium stearate. intact tablet is usually extremely limited because of
If the encapsulated mass is tightly packed and the the relatively small effective surface area of drug
drug is hydrophobic in nature, then a decrease in dis- exposed to the gastrointestinal fluids. Disintegration
solution rate with a concomitant reduction in parti- of the tablet into granules causes a relatively large
cle size would be expected, unless a surfactant had increase in effective surface area of drug and the dis-
been included to facilitate liquid penetration. solution rate may be likened to that of a coarse,
In summary, formulation factors that can aggregated suspension. Further disintegration into
influence the bioavailabilities of drugs from hard small, primary drug particles produces a further
gelatin capsules include: large increase in effective surface area and dissolu-
tion rate. The dissolution rate is probably compara-
• the surface area and particle size of the drug
ble to that of a fine, well dispersed suspension.
(particularly the effective surface area exhibited
Disintegration of a tablet into primary particles is
by the drug in the gastrointestinal fluids);
thus important, as it ensures that a large effective
• the use of the salt form of a drug in preference to
surface area of a drug is generated in order to facili-
the parent weak acid or base;
tate dissolution and subsequent absorption.
• the crystal form of the drug;
However, simply because a tablet disintegrates
• the chemical stability of the drug (in the dosage
rapidly this does not necessarily guarantee that the
form and in gastrointestinal fluids);
liberated primary drug particles will dissolve in the
• the nature and quantity of the diluent, lubricant
gastrointestinal fluids, and that the rate and extent of
and wetting agent;
absorption are adequate. In the case of poorly soluble
• drug-excipient interactions (e.g. adsorption,
drugs the rate-controlling step is usually the overall
complexation);
rate of dissolution of the liberated drug particles in
• the type and conditions of the filling process;
the gastrointestinal fluids. The overall dissolution rate
• the packing density of the capsule contents;
and bioavailability of a poorly soluble drug from an
• the composition and properties of the capsule
uncoated conventional tablet is influenced by many
shell (including enteric capsules);
factors associated with the formulation and manufac-
• interactions between the capsule shell and its
ture of this type of dosage form. These include:
contents.
• the physicochemical properties of the liberated
drug particles in the gastrointestinal fluids, e.g.
Tablets wettability, effective surface area, crystal form,
chemical stability;
Uncoated tablets Tablets are the most widely used
• the nature and quantity of the diluent, binder,
dosage form. When a drug is formulated as a com-
disintegrant, lubricant and any wetting agent;
pressed tablet there is an enormous reduction in the
• drug-excipient interactions (e.g. complexation),
effective surface area of the drug, owing to the granu-
the size of the granules and their method of
lation and compression processes involved in tablet
manufacture;
making. These processes necessitate the addition of
• the compaction pressure and speed of
excipients, which serve to return the surface area of the
compression used in tabletting;
drug back to its original precompressed state.
• the conditions of storage and age of the tablet.
Bioavailability problems can arise if a fine, well dis-
persed suspension of drug particles in the gastroin- Because drug absorption and hence bioavailability
testinal fluids is not generated following the are dependent upon the drug being in the dissolved

248
 BIOAVAILABILITY - PHYSICOCHEMICAL AND DOSAGE FORM FACTORS

state, suitable dissolution characteristics can be an ble film-coating materials, such as ethylcellulose or
important property of a satisfactory tablet, particu- certain acrylic resins, are used (see Chapter 28), the
larly if it contains a poorly soluble drug. On this resulting film coat acts as a barrier which delays
basis, specific in vitro dissolution test conditions and and/or reduces the rate of drug release. Thus these
dissolution limits are included in the British types of film-coating materials form barriers which
Pharmacopoeia for tablets (and hard gelatin capsules) can have a significant influence on drug absorption.
containing certain drugs, e.g. digoxin. That a partic- Although the formation of such barriers would be
ular drug product meets the requirements of a com- disadvantageous in the case of film-coated tablets
pendial dissolution standard provides a greater intended to provide rapid rates of drug absorption,
assurance that the drug will be released satisfactorily the concept of barrier coating has been used (along
from the formulated dosage form in vivo and be with other techniques) to obtain more precise control
absorbed adequately (see also Chapter 18). over drug release than is possible with conventional
Coated tablets Tablet coatings may be used simply uncoated tablets (see Chapter 20). In this context,
for aesthetic reasons to improve the appearance of a film coating has been used to provide limited control
tablet or to add a company logo, or may be employed over the site at which a drug is released from a tablet
to mask an unpleasant taste or odour or to protect an into the gastrointestinal tract.
ingredient from decomposition during storage. Enteric-coated tablets The use of barrier coating to
Currently the most common type of tablet coat is film; control the site of release of an orally administered
however, several older preparations, such as vitamins drug is well illustrated by enteric-coated tablets. An
and ibuprofen, still have sugar coats. The presence of a enteric coat is designed to resist the low pH of gastric
coating presents a physical barrier between the tablet fluids but to disrupt or dissolve when the tablet enters
core and the gastrointestinal fluids: coated tablets the higher pH of the duodenum. Polymers such as
therefore not only possess all the potential bioavailabil- cellulose acetate phthalate, hydroxypropyl methylcel-
ity problems associated with uncoated conventional lulose phthalate, the copolymers of methacrylic acid
tablets, but are subject to the additional potential and their esters and polyvinyl acetate phthalate, can
problem of being surrounded by a physical barrier. In be used as enteric coatings. These materials do not
the case of a coated tablet which is intended to disin- dissolve over the gastric pH range but dissolve rapidly
tegrate and release drug rapidly into solution in the at the less acid pH (about 5) values associated with
gastrointestinal fluids, the coating must dissolve or the small intestine. Enteric coating should preferably
disrupt before these processes can occur. The physico- begin to dissolve at pH5 in order to ensure the avail-
chemical nature and thickness of the coating can thus ability of drugs which are absorbed primarily in the
influence how quickly a drug is released from a tablet. proximal region of the small intestine. Enteric coating
In the process of sugar coating the tablet core is thus provides a means of delaying the release of a drug
usually sealed with a thin continuous film of a poorly until the dosage form reaches the small intestine.
water-soluble polymer such as shellac or cellulose Such delayed release provides a means of protecting
acetate phthalate. This sealing coat serves to protect drugs which would otherwise be destroyed if released
the tablet core and its contents from the aqueous fluids into gastric fluid. Hence, enteric coating serves to
used in the subsequent steps of the sugar-coating improve the oral bioavailability exhibited by such
process. Hence the presence of this water-imperme- drugs from uncoated conventional tablets. Enteric
able sealing coat can potentially retard drug release coating also protects the stomach against drugs which
from sugar-coated tablets. In view of this potential can produce nausea or mucosal irritation (e.g. aspirin,
problem, annealing agents such as polyethylene glycols ibuprofen) if released at this site.
or calcium carbonate, which do not substantially In addition to the protection offered by enteric
reduce the water impermeability of the sealing coat coating, the delayed release of drug also results in a
during sugar coating, but which dissolve readily in significant delay in the onset of the therapeutic
gastric fluid, may be added to the sealer coat in order response of a drug. The onset of the therapeutic
to reduce the barrier effect to rapid drug release. response is largely dependent on the residence time of
The coating of a tablet core by a thin film of a the enteric-coated tablet in the stomach. Gastric emp-
water-soluble polymer, such as hydroxypropyl methy- tying of such tablets is an all-or-nothing process, i.e.
cellulose, should have no significant effect on the rate the tablet is either in the stomach or in the duodenum.
of disintegration of the tablet core and subsequent Consequently, drug is either not being released or
drug dissolution, provided that the film coat dissolves being released. The residence time of an intact
rapidly and independently of the pH of the gastroin- enteric-coated tablet in the stomach can vary from
testinal fluids. However, if hydrophobic water-insolu- about 5 minutes to several hours (see Chapter 16).

249
 BIOPHARMACEUTICAL PRINCIPLES OF DRUG DELIVERY

Hence there is considerable intra- and intersubject ability is provided by the Australian outbreak of
variation in the onset of therapeutic action exhibited phenytoin intoxication which occurred in epileptic
by drugs administered as enteric-coated tablets. patients as a consequence of the diluent in sodium
The formulation of an enteric-coated product in phenytoin capsules being changed. Many epileptic
the form of small individually enteric-coated granules patients who had been previously stabilized with
or pellets (multiparticulates) contained in a rapidly sodium phenytoin capsules containing calcium sul-
dissolving hard gelatin capsule or a rapidly disinte- phate dihydrate as the diluent, developed clinical
grating tablet, largely eliminates the dependency of features of phenytoin overdosage when given sodium
this type of dosage form on the all-or-nothing gastric phenytoin capsules containing lactose as the diluent
emptying process associated with intact (monolith) even though the quantity of drug in each capsule for-
enteric coated tablets. Provided the coated granules mulation was identical. It was later shown that the
or pellets are sufficiently small (less than 1 mm diam- excipient calcium sulphate dihydrate had been
eter), they will be able to empty from the stomach responsible for decreasing the gastrointestinal
with liquids. Hence enteric-coated granules and absorption of phenytoin, possibly because part of the
pellets exhibit a gradual but continual release from administered dose of drug formed a poorly
the stomach into the duodenum. This type of release absorbable calcium-phenytoin complex. Hence,
also avoids the complete dose of drug being released although the size of dose and frequency of adminis-
into the duodenum, as occurs with an enteric-coated tration of the sodium phenytoin capsules containing
tablet. The intestinal mucosa is thus not exposed calcium sulphate dihydrate gave therapeutic blood
locally to a potentially toxic concentration of drug. levels of phenytoin in epileptic patients, the
Further information on coated tablets and multi- efficiency of absorption of phenytoin had been
particulates is given in Chapter 28. lowered by the incorporation of this excipient in the
hard gelatin capsules. Hence, when the calcium sul-
phate dihydrate was replaced by lactose without any
Influence of excipients for conventional alteration in the quantity of drug in each capsule, or
dosage forms in the frequency of administration, an increased
Drugs are almost never administered alone but bioavailability of phenytoin was achieved. In many
rather in the form of dosage forms that generally patients the higher plasma levels exceeded the
consist of a drug (or drugs) together with a varying maximum safe concentration for phenytoin and pro-
number of other substances (called excipients}. duced toxic side-effects.
Excipients are added to the formulation in order to
facilitate the preparation, patient acceptability and
Surfactants
functioning of the dosage form as a drug delivery
system. Excipients include disintegrating agents, Surfactants are often used in dosage forms as
diluents, lubricants, suspending agents, emulsifying emulsifying agents, solubilizing agents, suspension
agents, flavouring agents, colouring agents, chemical stabilizers or wetting agents. However, surfactants in
stabilizers etc. Although historically excipients were general cannot be assumed to be 'inert' excipients as
considered to be inert in that they themselves should they have been shown to be capable of either increas-
exert no therapeutic or biological action, or modify ing, decreasing or exerting no effect on the transfer
the biological action of the drug present in the of drugs across biological membranes.
dosage form, they are now regarded as having the Surfactant monomers can potentially disrupt the
ability to influence the rate and/or extent of absorp- integrity and function of a biological membrane.
tion of the drug. For instance, the potential influence Such an effect would tend to enhance drug penetra-
of excipients on drug bioavailability has already been tion and hence absorption across the gastrointestinal
illustrated by virtue of the formation of poorly barrier, but may also result in toxic side-effects.
soluble, non-absorbable drug-excipient complexes Inhibition of absorption may occur as a consequence
between tetracyclines and dicalcium phosphate, of a drug being incorporated into surfactant
amphetamine and sodium carboxymethylcellulose, micelles. If such surfactant micelles are not
and phenobarbitone and polyethylene glycol 4000. absorbed, which appears usually to be the case, then
solubilization of a drug may result in a reduction of
the concentration of 'free' drug in solution in the
Diluents
gastrointestinal fluids that is available for absorption.
The classic example of the influence that excipients Inhibition of drug absorption in the presence of
employed as diluents can have on drug bioavail- micellar concentrations of surfactant would be

250
 BIOAVAILABILITY - PHYSICOCHEMICAL AND DOSAGE FORM FACTORS

expected to occur in the case of drugs that are nor- cant during tablet compression and capsule-filling
mally soluble in the gastrointestinal fluids, i.e. in the operations. Its hydrophobic nature often retards
absence of surfactant. Conversely, in the case of liquid penetration into capsule ingredients, so that
poorly soluble drugs whose absorption is dissolu- after the shell has dissolved in the gastrointestinal
tion-rate limited, the increase in saturation solubility fluids a capsule-shaped plug often remains, especially
of the drug by solubilization in surfactant micelles when the contents have been machine-filled as a con-
could result in more rapid rates of dissolution and solidated plug (Chapter 29). Similar reductions in
hence absorption. dissolution rate may be observed when magnesium
The release of poorly soluble drugs from tablets stearate is included in tablets. However, these effects
and hard gelatin capsules may be increased by the can usually be overcome by the simultaneous
inclusion of surfactants in their formulations. The addition of a wetting agent (i.e. a water-soluble
ability of a surfactant to reduce the solid/liquid inter- surfactant) and the use of a hydrophilic diluent.
facial tension will permit the gastrointestinal fluids
to wet the solid more effectively, and thus enable it
Disintegrants
to come into more intimate contact with the solid
dosage forms. This wetting effect may thus aid the Disintegrants are required to break up capsules,
penetration of gastrointestinal fluids into the mass of tablets and granules into primary powder particles in
capsule contents that often remains when the hard order to increase the surface area of the drug
gelatin shell has dissolved, and/or reduce the ten- exposed to the gastrointestinal fluids. A tablet that
dency of poorly soluble drug particles to aggregate in fails to disintegrate or disintegrates slowly may result
the gastrointestinal fluids. In each case, the resulting in incomplete absorption or a delay in the onset of
increase in the total effective surface area of drug in action of the drug. The compaction force used in
contact with the gastrointestinal fluids would tend to tablet manufacture can affect disintegration: in
increase the dissolution and absorption rates of the general, the higher the force the slower the disinte-
drug. It is interesting to note that the enhanced gas- gration time. Even small changes in formulation may
trointestinal absorption of phenacetin in humans result in significant effects on dissolution and
resulting from the addition of polysorbate-80 to an bioavailability. A classic example is that of tolbu-
aqueous suspension of this drug was attributed to tamide, where two formulations, the commercial
the surfactant preventing aggregation and thus product and the same formulation but with half the
increasing the effective surface area and dissolution amount of disintegrant, were administered to healthy
rate of the drug particles in the gastrointestinal volunteers. Both tablets disintegrated in vitro within
fluids. 10 minutes meeting pharmacopoeial specifications,
The possible mechanisms by which surfactants but the commercial tablet had a significantly greater
can influence drug absorption are varied and it is bioavailability and hypoglycaemic response.
likely that only rarely will a single mechanism
operate in isolation. In most cases the overall effect
Viscosity-enhancing agents
on drug absorption will probably involve a number
of different actions of the surfactant (some of which Viscosity-enhancing agents are often employed in
will produce opposing effects on drug absorption), the formulation of liquid dosage forms for oral use in
and the observed effect on drug absorption will order to control such properties as palatability, ease
depend on which of the different actions is the over- of pouring and, in the case of suspensions, the rate of
riding one. The ability of a surfactant to influence sedimentation of the dispersed particles. The viscos-
drug absorption will also depend on the physico- ity-enhancing agent is often a hydrophilic polymer.
chemical characteristics and concentration of the There are a number of mechanisms by which a
surfactant, the nature of the drug and the type of viscosity-enhancing agent may produce a change in
biological membrane involved. the gastrointestinal absorption of a drug. Complex
formation between a drug and a hydrophilic polymer
could reduce the concentration of drug in solution
Lubricants
that is available for absorption. The administration of
Both tablets and capsules require lubricants in their viscous solutions or suspensions may produce an
formulation to reduce friction between the powder increase in viscosity of the gastrointestinal contents.
and metal surfaces during their manufacture. This could lead to a decrease in dissolution rate
Lubricants are often hydrophobic in nature. and/or a decrease in the rate of movement of drug
Magnesium stearate is commonly included as a lubri- molecules to the absorbing membrane.

251
 BIOPHARMACEUTICAL PRINCIPLES OF DRUG DELIVERY

Normally, a decrease in the rate of dissolution estimate the solubility and permeability in drug discovery
would not be applicable to solution dosage forms and development settings. Adv. Drug Del. Rev. 23, 3-29.
Loper, A., Hettrick, L., Novak, L., Landis, E.,Yeh, S.,
unless dilution of the administered solution in the gas- Asgharnejad, M., Gehret, J. and Ostovic, D. (1999) Factors
trointestinal fluids caused precipitation of the drug. influencing the absorption of an HIV protease inhibitor
In the case of suspensions containing drugs with analogue of indinavir in beagle dogs. AAPS Pharm. Sci,
bioavailabilities that are dissolution-rate dependent, 4243.
Naylor, L.J. et al. (1995) Dissolution of steroids in bile salt
an increase in viscosity could also lead to a decrease and lecithin solutions, with references to bile salt
in the rate of dissolution of the drug in the gastroin- concentrations in the GI tract. Eur. J. Pharm. Biopharm.,
testinal tract. 41, 346-353.
Panchagnula, R. and Thomas, N.S. (2000) Biopharmaceutics
and pharmacokinetics in drug research. Int. J. Pharm.., 201,
Summary 131-150.
Perry, C.M. Noble, S. (1998) Saquinavir soft-gel capsule
As well as physiological and drug factors, the dosage formulation. A review of its use in patients with HIV
form can play a major role in influencing the rate and infection. Drugs (3) 461-486.
extent of absorption. Often this is by design. Russell T.L. et al (1994). Influence of gastric pH and emptying
on dipyridamole absorption. Pharm. Res., 11; 136-143.
However, even with conventional dosage forms it is Sevelius, H. et al. (1980); Bioavailability of naproxen sodium
important to consider whether changing the dosage and its relationship to clinical analgesic effects. Br. J. Clin.
form or excipients will affect the bioavailability of the Pharmacol., 10, 259.
drug. Some drugs will be more susceptible to Taylor, D.C., Pownall, R., Burke, W. (1985). Absorption of
changes in rate and extent of absorption through beta-adrenoceptor antagonists in the rat in situ small
intestine. J. Pharm. Pharmacol., 37, 280-283.
dosage form changes than others: this will depend on Terjarla, S., Puranjoti, P., Kasina, P., Mandal, J. (1998)
the biopharmaceutical properties of the drug (see Preparation, characterisation and evaluation of
Chapter 18). miconazole-cyclodextrin complexes for improved oral and
topical delivery. J. Pharm. Sci., 87; 425-429.

REFERENCES
BIBLIOGRAPHY
Barry, M., Gribous, Back D., Mulcahy F. (1997) Protease
inhibitors in patients with HIV disease. Clinically Brayden, D. (1997) Human intestinal epithelial monolayers
important pharmacokinetic considerations. Clin as prescreens for oral drug delivery. Pharm. News, 4 (1).
Pharmacokinet 32 (3) 194-209. 11-13.
Dressman, J.B., Amidon, G.L., Reppas, C., Shah, V.P. (1998). Dressman, J.B., Amidon, G.L., Reppas, C., Shah, V.P. (1998).
Dissolution testing as a prognostic tool for oral drug Dissolution testing as a prognostic tool for oral drug
absorption; immediate release dosage forms. Pharm. Res, absorption; immediate release dosage forms. Pharm. Res,
15, 11-22. 15, 11-22.
Drewe, J., Meier, R., Vonderscher, J., Kiss, D., Posanki, U., Lennernas, H. (1998) Human intestinal permeability.
Kissel,T, Gyr, K. (1992). Br. J. Clin. Pharmacol., 34, 60. J. Pharm. Sci., 87, 403-410.
Florence, A.T. and Attwood, D. (1998). Physicochemical vander Meer, J.W., Keuning, J.J., Scheijgrond, H.W.,
principles of Pharmacy, 3rd edn. Macmillan Press. Heykants, J., Van Cutsem J., Brugmans, J. (1980) The
Lipinski, C.A., Lombardo, F., Dominy, B.W. and Feeney, P.J. influence of gastric acidity on the bioavailability of
(1997) Experimental and computational approaches to ketoconazole. Antimicrob. Chemother, 6 (4). 552-554.

252
18
Assessment of biopharmaceutical properties

Marianne Ashford

CHAPTER CONTENTS INTRODUCTION

Introduction 253
Biopharmaceutics is involved with factors that
Measurement of key biopharmaceutical influence the rate and extent of drug absorption. As
properties 254
Release of drug from its dosage form into discussed in Chapters 16 and 17, the factors that
solution 254 affect the release of a drug from its dosage form, its
Stability in physiological fluids 255 dissolution into physiological fluids, its stability
Permeability 256
Partition coefficients 256
within those fluids, its permeability across the rele-
Cell culture techniques 257 vant biological membranes and its presystemic
Tissue techniques 259 metabolism will all influence its rate and extent of
Perfusion studies 260 absorption (Fig. 18.1). Once the drug is absorbed
Assessment of permeability in humans 261
Intestinal perfusion studies 261 into the systemic circulation, its distribution within
Non-invasive approaches 262 the body tissues (including to its site of action), its
Presystemic metabolism 262 metabolism and elimination are described by the
Assessment of bioavailability 262 pharmacokinetics of the compound. The pharmaco-
Plasma concentration-time profiles 262 kinetics of the compound influence the length and
Minimum effective (or therapeutic) plasma
concentration 263 magnitude of the therapeutic effect or the response
Maximum safe concentration 263 of the compound, i.e. its pharmacodynamics (see
Therapeutic range or window 264 Chapter 15).
Onset 264
Duration 264 The key biopharmaceutical properties that can be
Peak concentration 264 quantified and therefore give an insight into the
Time of peak concentration 264 absorption of a drug are its:
Area under the plasma concentration-time
curve 264 • release from its dosage form into solution at the
The use of plasma concentration-time curves in absorption site;
bioavailability studies 264
Cumulative urinary drug excretion curves 265 • stability in physiological fluids;
The use of urinary drug excretion curves in • permeability;
bioavailability studies 266 • susceptibility to presystemic clearance.
Absolute and relative bioavailability 267
Absolute bioavailability 267 As most drugs are delivered via the mouth, these
Relative bioavailability 269 properties will be discussed with respect to the
Bioequivalence 270
peroral route. The bioavailability of a compound is
Assessment of site of release in vivo 271
an overall measure of its availability in the systemic
The Biopharmaceutical Classification Scheme 273 circulation, and so the assessment of bioavailability
Class I drugs 273
Class II drugs 273
will also be discussed. Other methods of assessing
Class 111 drugs 273 the performance of dosage forms in vivo will also
Class IV drugs 273 be briefly mentioned. The Biopharmaceutical
Summary 273 Classification Scheme, which classifies drugs accord-
ing to two of their key biopharmaceutical properties,
References 273 solubility and permeability, is outlined.

253
 BIOPHARMACEUTICAL PRINCIPLES OF DRUG DELIVERY

Fig. 18.1 Key biopharmaceutical properties affecting drug absorption.

use of animals to evaluate formulations and the size

MEASUREMENT OF KEY and number of costly clinical studies to assess
BIOPHARMACEUTICAL PROPERTIES
bioavailability.
An in vitro/in vivo correlation may only be possi-
Release of drug from its dosage form ble for those drugs where dissolution is the rate-lim-
into solution iting step in the absorption process. Determining full
As discussed in the Chapter 17 and Part 4 of this dissolution profiles of such drugs in a number of dif-
book, a dosage form is normally formulated to aid the ferent physiologically representative media will aid
release of drug from it. For example, for an immedi- the understanding of the factors affecting the rate
ate-release tablet, the tablet needs to disintegrate to and extent of dissolution. The profiles can also be
give the primary drug particles. Further, a suspension used to generate an in vitro/in vivo correlation. To
should not be so thick that it impedes the diffusion of achieve this, at least three batches that differ in their
dissolving drug away from the solid particles. in vivo as well as their in vitro behaviour should be
The solubility of a drug across the gastrointestinal available. The differences in the in vivo profiles need
pH range will be one of the first indicators as to to be mirrored by the formulations in vitro.
whether dissolution is liable to be rate limiting in the Normally, the in vitro test conditions can be
absorption process. A knowledge of the solubility modified to correspond with the in vivo data to
across the gastrointestinal pH range can be determined achieve a correlation. Very often a well designed in
by measuring the equilibrium solubility in suitable vitro dissolution test is found to be more sensitive
buffers or by using an acid or a base titration method. and discriminating than the in vivo test. From a
Methods of measuring the dissolution rate of both quality assurance perspective a more discriminative
a drug itself (intrinsic dissolution rate) and of dissolution method is preferred because the test will
various dosage forms are discussed in Chapters 8 indicate possible changes in the product before the
and 2, respectively. in vivo performance is affected.
The aim of dissolution testing is to find an in vitro A dilute hydrochloric acid-based solution at pH
characteristic of a potential formulation that reflects its 1.2 can simulate gastric fluid, and phosphate-
in vivo performance. Historically, dissolution tests have buffered solution at pH 6.8 can mimic intestinal
been developed mainly for quality control purposes fluid. However, dissolution media more closely rep-
and as a guide in the development of new formula- resenting physiological conditions may well provide
tions, rather than to predict the in vivo performance of more relevant conditions. Dressman et al (1998)
the product. The tests tend to be carried out with stan- studied in detail a range of physiological parameters
dard procedures (volumes, agitation rates etc.) and and suggested four more appropriate media for sim-
under sink conditions. These conditions are not repre- ulated gastric and intestinal conditions in the fed
sentative of physiological conditions and are therefore and fasted states. Each of these media takes into
liable to correlate poorly with the in vivo situation. account not only the pH of the fluids in the different
When designing a dissolution test to assess drug states, but their ionic composition, surface tension,
release from a biopharmaceutical perspective, it is buffer capacity and bile and lecithin contents. The
important to mimic as closely as possible the condi- proposed composition for gastric fluid in the fasted
tions of the gastrointestinal tract. Clinical scientists state and intestinal fluids in the fed and fasted states
increasingly want to rely on dissolution tests to are shown in Tables 18.1-18.3.
establish in vitro/in vivo correlations between the In the fed state the conditions in the stomach are
release of drug from the dosage form and its absorp- highly dependent on the composition of the meal
tion. If this can be successfully achieved, it is possi- eaten and therefore difficult to simulate. In trying to
ble that the dissolution test could replace some of the produce an in vitro/in vivo correlation it has been
in vivo studies that need to be performed during suggested that a more appropriate way of simulating
product development and registration. Such correla- the fed-state gastric fluids is to homogenize the meal
tions should have the benefit of reducing both the to be used in clinical studies and then dilute it with

254
 ASSESSMENT OF BIOPHARMACEUTICAL PROPERTIES

diction of the permeability properties of the drug is

Table 18.1 Dissolution medium to simulate gastric
conditions in the fasted state (proposed by Dressman beneficial. If, for example, the drug is absorbed from
et al 1998) the upper intestine and is likely to be dosed in the
fasted state, the most appropriate dissolution condi-
Component Concentration/amount tions may be a short test (~ 15-30 minutes) in a
medium simulating gastric fluid in the fasted state
Hydrochloric acid 0.01-0.05 M
(see Table 18.1). Alternatively, if it is advised that a
Sodium lauryl sulphate 2.5 g drug should be administered with food, and it is
Sodium chloride 2g known to be well absorbed throughout the length of
Distilled water qs to 1000 ml the gastrointestinal tract, a far longer dissolution
test, perhaps several hours in duration, with a range
of media such as, initially, simulated gastric fluid for
the fed state, simulated intestinal fluid for the fed
Table 18.2 Dissolution medium to simulate intestinal and then the fasted states, may be more appropriate.
conditions in the fasted state (proposed by Dressman The volumes in, and agitation of, the stomach and
| eta! 1998) intestines vary enormously, particularly between the
fed and the fasted states, and so it is difficult to
Component Concentration/amount choose a representative volume and degree of agita-
Potassium dihydrogen phosphate 0.029 M tion. The latest Guidance for Industry on the disso-
lution testing of immediate-release solid oral dosage
Sodium hydroxide qs to pH 6.8
forms from the Food and Drug Administration
Sodium taurocholate (bile salt) 5 mM (1997) suggests volumes of 500, 900 or 1000 mL
Lecithin 1.5 mM and gentle agitation conditions.
Potassium chloride 0.22 M
Distilled water qs to 1000 ml. Stability in physiological fluids
pH = 6.8, osmolarity = 280-310 mOSm. The stability of drugs in physiological fluids (in the
Buffer capacity = 10 ± 2 mEq/L/pH. case of orally administered drugs, the gastrointesti-
nal fluids) depends on two factors: the chemical sta-
bility of the drug across the gastrointestinal pH
range, i.e. the drug's pH-stability profile between pH
Table 18.3 Dissolution medium to simulate intestinal 1 and pH 8, and its susceptibility to enzymatic
conditions in the fed state (proposed by Dressman breakdown by the gastrointestinal fluids. Means of
et al 1998)
assessing the chemical stability of a drug are dis-
Component Concentration/amount cussed in Chapters 7 and 8. The stability of a drug in
gastrointestinal fluids can be assessed by simulated
Acetic acid 0.144 M gastric and intestinal media or by obtaining gas-
Sodium hydroxide qs to pH 5 trointestinal fluids from humans or animals. The
Sodium taurocholate (bile salt) 15 mM
latter provides a harsher assessment of gastrointesti-
nal stability but is more akin to the in vivo setting. In
Lecithin 4 mM general the drug is incubated with either real or sim-
Potassium chloride 0.19 M ulated fluid at 37°C for a period of 3 hours and the
Distilled water qs to 1000 mL drug content analysed. A loss of more than 5% of
drug indicates potential instability. Many of the per-
pH = 5, osmolarity = 485-535 mOSm. meability methods described below can be used to
Buffer capacity = 76 ±2 mEq/L/pH
identify whether gastrointestinal stability is an issue
for a particular drug.
For drugs that will still be in the gastrointestinal
water. Long-life milk has also been used to simulate lumen when they reach the colonic region, resistance
gastric conditions in the fed state. to the bacterial enzymes present in this part of the
It has been proposed that the duration of the dis- intestine need to be considered. The bacterial
solution test should depend on the site of absorption enzymes are capable of a whole host of reactions.
of the drug and its timing of administration. Thus, in There may be a significant portion of a poorly
designing a dissolution test some knowledge or pre- soluble drug still in the gastrointestinal tract by the

255
 BIOPHARMACEUTICAL PRINCIPLES OF DRUG DELIVERY

time it reaches the colon. If the drug is absorbed across membranes that are used to gain an assess-
along the length of the gastrointestinal tract, and is ment of oral absorption in humans. These range
susceptible to degradation or metabolism by the bac- from computational (in silico) predictions and both
terial enzymes within the tract, its absorption and physicochemical and biological methods. The bio-
hence its bioavailability is liable to be reduced. logical methods can be further subdivided into in
Similarly, for sustained- or controlled-release prod- vitro, in situ and in vivo methods. In general, the
ucts that are designed to release their drug along the more complex the technique the more information
length of the gastrointestinal tract, the potential of that can be gained and the more accurate is the
degradation or metabolism by bacterial enzymes assessment of oral absorption in humans. The range
should be assessed. If the drug is metabolized to a of techniques is summarized in Table 18.4. Some of
metabolite which can be absorbed the potential tox- the more popular ones are discussed below.
icity of this metabolite should be considered.
Partition coefficients
Permeability One of the first properties of a molecule that can be
There is a wealth of techniques available for either predicted or measured is its partition coefficient
estimating or measuring the rate of permeation between an oil and a water phase (log P). This gives
I
i Table 18.4 Some of the models available for predicting or measuring drug absorption
Model type Model Description

Computational cLogP Commercial software that calculates octanol/water partition coefficient

based on fragment analysis, known as the Leo-Hansch method
mLogP Method of calculating log P, known as the Moriguchi method (see text)
Physicochemical Partition coefficient Measure of lipophilicity of drug, usually measured between octanol
and aqueous buffer via a shake-flask method
Immobilized artificial membrane Measures partition into more sophisticated lipidic phase on an HPLC
column
Cell culture Caco-2 monolayer Measures transport across monolayers of differentiated human colon
adenocarcinoma cells
HT-29 Measures transport across polarized cell monolayer with
mucin-producing cells
Excised tissues Cells Measures uptake into cell suspensions, e.g. erythrocytes
Freshly isolated cells Measures uptake into enterocytes; however, the cells are difficult to
prepare and are short-lived
Membrane vesicles Measures uptake into brush border membrane vesicles prepared from
intestinal scrapings or isolated enterocytes
Everted sacs Measures uptake into intestinal segments/sacs
Everted intestinal rings Studies the kinetics of uptake into the intestinal mucosa
Isolated sheets Measures the transport across sheets of intestine
In situ studies In-situ perfusion Measures drug disappearance from either closed or open loop
perfusate of segments of intestine of anaesthetized animals
Vascularly perfused intestine Measures drug disappearance from perfusate and its appearance
in blood
In vivo studies Intestinal loop Measures drug disappearance from perfusate of loop of intestine
in awake animal
Human data Loc-l-Gut Measures drug disappearance from perfusate of human intestine
High-frequency capsule Non-invasive method; measures drug in systemic circulation
InteliSite capsule Non-invasive method; measures drug in systemic circulation.
Bioavailability Deconvolution of pharmacokinetic data

256
 ASSESSMENT OF BIOPHARMACEUTICAL PROPERTIES

a measure of the lipophilicity of a molecule, which ment to overall lipophilicity (often called the
can be used as a prediction as to how well it will be cLogP). Another method used to calculate log P is
able to cross a biological membrane. As discussed in the Moriguchi method, which uses 13 parameters
Chapter 17, octanol is usually chosen as the solvent for hydrophobic and hydrophilic atoms, proximity
for the oil phase as it has similar properties to bio- effects, unsaturated bonds, intramolecular bonds,
logical membranes. If the aqueous phase is at a par- ring structures, amphoteric properties and several
ticular pH, the distribution coefficient at that pH is specific functionalities to obtain a value for the par-
measured (log D); this then accounts for the ioniza- tition coefficient. This is often called the mLogP.
tion of the molecule at that pH. In the case of a The advantages of these methods are in drug dis-
weakly acidic or a weakly basic drug, the log D mea- covery, where an estimate of the lipophilicity of
sured at an intestinal pH (e.g. 6.8) is liable to give a many molecules can be obtained before they are
better prediction of the drug's ability to cross the actually synthesized.
lipid gastrointestinal membrane than its partition Another more sophisticated physicochemical
coefficient, log P, which does not take the degree of means of gaining a view as to how well a drug will
ionization into account. partition into a lipophilic phase is by investigating
One of the most common ways of measuring par- how well the molecule can be retained on a high-
tition coefficients is to use the shake flask method. performance liquid chromatography column
This relies on the equilibrium distribution of a drug (HPLC). HPLC columns can be simply coated with
between an oil and an aqueous phase. Prior to the octanol to mimic octanol-aqueous partition, or more
experiment the aqueous phase should be saturated elaborately designed to mimic biological membranes,
with the oil phase and vice versa. The experiment for example the Immobilized Artificial Membrane
should be carried out at constant temperature. The (LAM). This technique provides a measure of how
drug should be added to the aqueous phase and the well a solute (i.e. the drug) in the aqueous phase will
oil phase which, in the case of octanol, as it is less partition into biological membranes (i.e. be retained
dense than water, will sit on top of the water. The on the column). Good correlations between these
system is mixed and then left to reach equilibrium methods and biological in vitro methods of estimat-
(usually at least 24 hours). The two phases are sepa- ing transcellular passive drug absorption have been
rated and the concentration of drug is measured in obtained.
each phase and a partition coefficient calculated
(Fig. 18.2). As discussed in Chapter 17, within a
Cell culture techniques
homologous series increasing lipophilicity (log PID)
tends to result in greater absorption. A molecule is Cell culture techniques for measuring the intestinal
unlikely to cross a membrane (i.e. be absorbed via absorption of molecules have been increasingly used
the transcellular passive route) if it has a log P less over recent decades and are now a well accepted
than 0. model for absorption.
Instead of measuring log P computational The cell line that is most widely used is Caco-2.
methods can be used to estimate it, and there are a Caco-2 cells are a human colon carcinoma cell line
number of software packages available to do this. that was first proposed and characterized as a model
There is a reasonably good correlation between the for oral drug absorption by Hidalgo in 1989. In
calculated and the measured values. Log P can be culture, Caco-2 cells spontaneously differentiate to
estimated by breaking down the molecule into frag- form a monolayer of polarized enterocytes. These
ments and calculating the contribution of each frag- enterocytes resemble those in the small intestine, in
that they contain microvilli and many of the trans-
port systems present in the small intestine, for
example those for sugars, amino acids, peptides and
the P-glycoprotein efflux transporter. Adjacent
Caco-2 cells adhere through tight junctions.
However, the tightness of these junctions is more like
those of the colon than those of the leakier small
intestine.
There are many variations on growing and carrying
out transport experiments with Caco-2 monolayers.
Fig. 18.2 Diagram of the shake-flask method for determining In general the cells are grown on porous supports,
partition coefficient. usually for a period of 15-21 days in typical cell

257
 BIOPHARMACEUTICAL PRINCIPLES OF DRUG DELIVERY

culture medium, Dulbecco's Modified Eagle Medium

supplemented with 20% fetal bovine serum, 1 % non-
essential amino acids and 2mM L-glutamine.The cells
are grown at 37°C in 10% carbon dioxide at a relative
humidity of 95%. The culture medium is replaced at
least twice each week. Transport experiments are
carried out by replacing the culture medium with
buffers, usually Hanks Balanced Salt Solution
adjusted to pH 6.5 on the apical surface and Hanks
Balanced Salt Solution adjusted to pH 7.4 on the
basolateral surface (Fig. 18.3).
After a short incubation period - usually about 30 Fig. 18.4 The relationship between the fraction absorbed in
minutes - when the cells are maintained at 37°C in humans and the apparent permeability coefficient in Caco cells.
a shaking water bath, the buffers are replaced with
fresh buffers and a dilute solution of drug is intro- apparent permeability coefficient in Caco-2 cells. As
duced to the apical chamber. At regular intervals the cells are biological systems, and as small changes in
concentration of the drug in the basolateral chamber their source, method of culture and the way in which
is determined. The apparent permeability coefficient the transport experiment is carried out will affect the
across cells can be calculated as follows: apparent permeability of a drug, this curve can shift
significantly to the right or left or alter its steepness.
Therefore, when carrying out Caco-2 experiments it
where Papp is the apparent permeability coefficient is important always to standardize the procedure
(cm/s), dQIdt is the rate of drug transport (/Ag/s), C0 within a particular laboratory, and ensure that this
is the initial donor concentration (/xg/mL) and, A is procedure is regularly calibrated with a set of stan-
the surface area of the monolayer (cm2). dard compounds.
To check that the monolayer has maintained its Caco-2 monolayers can also be used to elucidate
integrity throughout the transport process, a marker the mechanism of permeability. If the apparent per-
for paracellular absorption, such as mannitol, which meability coefficient is found to increase linearly
is often radiolabelled for ease of assay, is added to the with increasing concentration of drug (i.e. the trans-
apical surface. If less than 2% of this crosses the port is not saturated), is the same whether the drug
monolayer in an hour then the integrity of the mono- transport is measured from the apical to basolateral
layer has been maintained. Another way to check the or the basolateral to apical direction, and is indepen-
integrity of the monolayer is by measuring the dent of pH, it can be concluded that the transport is
transepithelial resistance, or TEER. a passive and not an active process. If the transport
To use the Caco-2 cells as an absorption model a in the basolateral to apical direction is significantly
calibration curve needs to be generated. This is done greater than that in the apical to basolateral direc-
for compounds for which the absorption in humans tion, then it is likely that the drug is actively effluxed
is known. Figure 18.4 shows the general shape of the from the cells by a countermembrane transporter
curve of fraction absorbed in humans versus the such as P-glycoprotein. If the transport of the drug is

Fig. 18.3 Diagram of a Caco-2 cell culture system for determining apparent permeability.

258
 ASSESSMENT OF BIOPHARMACEUTICAL PROPERTIES

also inhibited by the presence of compounds that are layer. HT-29-18C1, a subclone of a human intestinal
known inhibitors of P-glycoprotein, such as vera- adenocarcinoma cell line, can differentiate in culture
pamil, this gives a further indication that the drug is to produce both absorptive cells containing a
susceptible to P-glycoprotein efflux. microvillus structure and mucus secreting goblet
To help elucidate whether other membrane trans- cells. It also has a resistance similar to that of the
porters are involved in the absorption of a particu- small intestine, and so it can be argued that this cell
lar drug, further competitive inhibition studies can line is preferable to Caco-2 in that it will give better
be carried out with known inhibitors of the particu- information about the transcellular and paracellular
lar transporter. For example, the dipeptide glycosyl- routes of absorption. However, this cell line has yet
sarcosine can be used to probe whether the to be well characterized as an absorption model, and
dipeptide transporter is involved in the absorption therefore its use is not widespread.
of a particular drug. Further information on the use of Caco-2 mono-
To evaluate whether a compound is absorbed via layers as an absorption model can be obtained from
the paracellular or the transcellular pathway, the Artusson et al (1996).
tight junctions can be artificially opened with com-
pounds such as EDTA, which chelates calcium.
Tissue techniques
Calcium is involved in keeping the junctions
together. If the apparent permeability of a com- A range of tissue techniques have been used as
pound is not affected by the opening of these junc- absorption models (Table 18.4). Two of the more
tions, which can be assessed by using a paracellular popular ones are the use of isolated sheets of intesti-
marker such as mannitol, one can assume the drug nal mucosa and of everted intestinal rings. These are
transport is via a transcellular pathway. discussed in more detail below.
If the disappearance of drug on the apical side of Isolated sheets of intestinal mucosa are prepared by
the membrane is not mirrored by its appearance on cutting the intestine into strips; the musculature is
the basolateral side, and/or the mass balance at the then removed and the sheet mounted and clamped in
end of the transport experiment does not account for a diffusion chamber or an Ussing chamber filled with
100% of the drug, there may be a problem with appropriate biological buffers (Fig. 18.5). The
binding to the membrane porous support. This will transepithelial resistance is measured across the tissue
need investigation, or the drug may have a stability to check its integrity. The system is maintained at
issue. The drug could be susceptible to enzymes 37°C and stirred so that the thickness of the unstirred
secreted by the cells and/or to degradation by water layer is controlled and oxygen provided to the
hydrolytic enzymes as it passes through the cells, or tissue. The drug is added to the donor chamber and
it may be susceptible to metabolism by cytochrome
P450 within the cell. Thus the Caco-2 cells are not
only capable of evaluating the permeability of drugs
but have value in investigating whether two of the
other potential barriers to absorption, stability and
presystemic metabolism, are likely to affect the
overall rate and extent of absorption.
Caco-2 cells are very useful tools for understand-
ing the mechanism of absorption of drugs and have
furthered significantly our knowledge of the absorp-
tion of a variety of drugs. Other advantages of Caco-
2 cells are that they are a non-animal model, require
only small amounts of compound for transport
studies, can be used as a rapid screening tool to
assess the permeability of large numbers of com-
pounds in the discovery setting, and can be used to
evaluate the potential toxicity of compounds to cells.
The main disadvantages of Caco-2 monolayers as
an absorption model are that, because of the tight-
ness of the monolayer, they are more akin to the
paracellular permeability of the colon rather than
that of the small intestine, and that they lack a mucus Fig. 18.5 Diagram of a diffusion chamber.

259
 BIOPHARMACEUTICAL PRINCIPLES OF DRUG DELIVERY

the amount accumulating in the receiver chamber is Caco-2 model. A similarly shaped curve for the per-
measured as a function of time. The permeability centage of drug absorbed in humans versus apparent
across the tissue can then be calculated. permeability or uptake (mole per weight of tissue)
Similar to cell monolayers, the two sides of the for the isolated sheet and everted ring methods,
tissue can be sampled independently and thus fluxes respectively, is obtained.
from mucosal to serosal and from serosal to mucosal
can be measured. Any pH dependence of transport
Perfusion studies
can be determined by altering the pH of the buffers
in the donor and/or receiver chambers. This system Many variations of intestinal perfusion methods have
can also therefore be used to probe active transport. been used as absorption models over the years. Again,
One advantage of this technique over cell culture in general, because of its relative ease of use and sim-
techniques is that permeability across different ilarity to the permeability of the human intestine, the
regions of the intestine can be assessed. It is particu- rat model is preferred. In situ intestinal perfusion
larly helpful to be able to compare permeabilities models have the advantage that the whole animal is
across intestinal and colonic tissue, especially when used, with the nerve, lymphatic and blood supplies
assessing whether a drug is suitable for a controlled- intact, and therefore there should be no problem with
release delivery system. In addition, different animal tissue viability and all the transport mechanisms
tissues can be used, which permits an assessment of present in a live animal should be functional.
permeability in different preclinical models. The rat The animal is anaesthetized and the intestine
intestine is usually preferred for absorption studies exposed. In the open loop method a dilute solution of
as its permeability correlates well with that of human drug is pumped slowly through the intestine and the
intestine. Human tissue and cell monolayers have difference in drug concentration between the inlet
also been used in this system. and outlet concentrations is calculated (Fig. 18.6).
Everted intestinal rings use whole intestinal seg- An absorption rate constant or effective permeability
ments rather than just sheets. The musculature is coefficient across the intestine can be calculated as
therefore intact. Intestinal segments are excised, follows:
again usually from rats; the segment is then tied at
Peff = Q . In (Q - C0)/277r/ (18.2)
one end and carefully everted by placing it over a
glass rod, and cut into small sections or rings. These where Peff is the effective permeability coefficient
rings are incubated in stirred oxygenated drug- (cm/s), Q is the flow rate in mL/s, Q is the initial
containing buffer at 37°C. After a set period of time, drug concentration, C0 is the final drug concentra-
drug uptake is quenched by quickly rinsing the ring tion, r is the radius of the intestinal loop (cm), and,
with ice-cold buffer and carefully drying it. The ring / is the length of intestinal loop (cm).
is then assayed for drug content and the amount of In the closed loop method a dilute solution of
drug taken up per gram of wet tissue over a specific drug is added to a section of the intestine and the
period of time is calculated (mol g"1 time"1). The
advantage of using intestinal rings is that the test is
relatively simple and quick to perform. A large
number of rings can be prepared from each segment
of intestine, which allows each animal to act as its
own control. In addition, the conditions of the exper-
iment can be manipulated and so provide an insight
into the mechanisms of absorption.
The disadvantages of this system are that it is bio-
logical and that care must be taken to maintain the
viability of the tissue for the duration of the experi-
ment. As the drug is taken up into the ring, the tissue
needs to be digested and the drug extracted from it
before it is assayed, which results in lengthy sample
preparation and complicates the assay procedure. In
addition, as this is an uptake method no polarity of
absorption can be assessed.
Both these absorption models can be calibrated
with a standard set of compounds similar to the Fig. 18.6 Diagram of an in situ rat perfusion.

260
 ASSESSMENT OF BIOPHARMACEUTICAL PROPERTIES

intestine closed. The intestine is then excised and liver, and determining the relative importance of the
drug content analysed immediately and after an intestine and liver in presystemic metabolism.
appropriate time or time intervals, depending on the The disadvantages of these perfusion systems is
expected rate of absorption. Again, assuming a first- that as they become more complex, a larger number
order rate process and hence an exponential loss of of animals are required to establish suitable perfusion
drug from the intestine, an absorption rate constant conditions and the reproducibility of the technique.
and effective permeability can be calculated. Like the However, in general, as the complexity increases so
intestinal ring method, the closed loop in situ perfu- does the amount of information obtained.
sion model requires a lengthy digestion, extraction
and assay procedure to analyse the drug remaining
Assessment of permeability in humans
in the intestinal loop.
There is a lot of fluid moving in and out of the intes- Intestinal perfusion studies Until relatively recently
tine, and so the drug concentrations in both these in the most common way to evaluate the absorption of
situ perfusion methods need to be corrected for fluid drugs in humans was by performing bioavailability
flux. This is normally done by gravimetric means or by studies and deconvoluting the data available to cal-
using a non-absorbable marker to assess the effect of culate an absorption rate constant. This rate con-
fluid flux on the drug concentration. As with other stant, however, is dependent on the release of the
absorption models, correlations have been made with drug from the dosage form, and is affected by ifttesti-
standard compounds where the fraction absorbed in nal transit and presystemic metabolism. Therefore,
humans is known, and similar-shaped curves have very often it does not reflect the true intrinsic intesti-
been obtained (Fig. 18.4). In these models the 'absorp- nal permeability of a drug.
tion rate' is calculated by measuring the disappearance Extensive studies have been carried out using a
of the drug from the lumen and not its accumulation regional perfusion technique which has afforded a
in the plasma. It is therefore important to check that greater insight into human permeability (Loc-I-
the drug is not degraded in the lumen or intestinal Gut). The Loc-I-Gut is a multichannel tube system
wall, as drug that has disappeared will be erroneously with a proximal and a distal balloon (Fig. 18.7).
assumed to have been absorbed. These balloons are 100 mm apart and allow a
More sophisticated techniques are those involving segment of intestine 100 mm long to be isolated and
vascular perfusion. In these techniques, either a pair perfused. Once the proximal balloon passes the liga-
of mesenteric vessels supplying an intestinal ment of Treitz both balloons are filled with air
segment or the superior mesenteric artery and thereby preventing mixing of the luminal contents in
portal vein perfusing almost the entire intestine are the segment of interest with other luminal contents.
cannulated.The intestinal lumen and sometimes the A non-absorbable marker is used in the perfusion
lymph duct are also cannulated for the collection of solution to check that the balloons work to occlude
luminal fluid and lymph, respectively. This model, the region of interest. A tungsten weight is placed in
although complicated, is very versatile as drug can front of the distal balloon to facilitate its passage
be administered into the luminal or the vascular per- down the gastrointestinal tract.
fusate. When administered to the intestinal lumen, Drug absorption is calculated from the rate of dis-
drug absorption can be evaluated from both its dis- appearance of the drug from the perfused segment.
appearance from the lumen and its appearance in This technique has afforded greater control in human
the portal vein. Using this method both the rate and intestinal perfusions, primarily because it isolates the
extent of absorption can be estimated, as well as
carrier-mediated transport processes. Collection of
the lymph allows the contribution of lymphatic
absorption for very lipophilic compounds to be
assessed. One of the other advantages of this system
is the ability to determine whether any intestinal
metabolism occurs before or after absorption.
A further extension of this model is to follow the
passage of drugs from the intestine through the liver,
and several adaptations of rat intestinal-liver perfu-
sion systems have been investigated. Such a com-
bined system gives the added advantage of assessing
the first-pass or presystemic metabolism through the Fig. 18.7 Diagram of the Loc-I-Gut.

261
 BIOPHARMACEUTICAL PRINCIPLES OF DRUG DELIVERY

luminal contents of interest, and has greatly facilitated lism. Drugs are incubated with either brush border
the study of permeability mechanisms and the metab- membrane preparations or gut wall homogenate at
olism of drugs and nutrients in the human intestine 37°C and the drug content analysed.
(Knutson et al 1989, Lennernas et al 1992). Various liver preparations, for example subcellular
Non-invasive approaches There is concern that fractions such as microsomes, isolated hepatocytes
the invasive nature of perfusion techniques can affect and liver slices, are used to determine hepatic metab-
the function of the gastrointestinal tract, in particu- olism in vitro. Microsomes are prepared by high-
lar the fluid content, owing to the intubation process speed centrifugation of liver homogenates (100 000 g)
altering the absorption and secretion balance. To and are composed mainly of fragments of the endo-
overcome this problem, several engineering-based plasmic reticulum. They lack cystolic enzymes and
approaches have been developed to evaluate drug cofactors and are therefore only suitable to evaluate
absorption in the gastrointestinal tract. These some of the metabolic processes the liver is capable of,
include high-frequency (HF) capsules (Fuhr et al known as phase I metabolism. Hepatocytes must be
1994) and the InteliSite capsule (Wilding 1997). freshly and carefully prepared from livers and are only
The transit of the high-frequency capsule down the viable for a few hours. It is therefore difficult to obtain
gastrointestinal tract is followed by X-ray fluoroscopy. human hepatocytes. Hepatocytes are very useful for
Once the capsule reaches its desired release site drug hepatic metabolism studies as it is possible to evaluate
release is triggered by a high-frequency signal, which most of the metabolic reactions, i.e. both phase I and
leads to rupturing of a latex balloon that has been II metabolism. Whole liver slices again have the ability
loaded with drug. Concerns about X-ray exposure to evaluate both phase I and II metabolism. Because
and the difficulties of loading the drug into the they are tissue slices rather than cell suspensions, and
balloon have limited the use of this technique. because they do not require enzymatic treatment in
The InteliSite capsule is a more sophisticated their preparation, this may be why a higher degree of
system for measuring drug absorption. Either a in vivo correlation can be achieved with liver slices
liquid or a powder formulation can be filled into the than with hepatocytes and microsomes. The reader is
capsule, the transit of which is followed by gamma- referred to a review by Carlile et al (1997).
scintigraphy (see later). Once the capsule reaches its
desired release site it is activated by exposure to a
radiomagnetic field, which induces a small amount
of heat in the capsule's electronic assembly. The heat ASSESSMENT OF BIOAVAILABILITY
causes some shape-memory alloys to straighten,
rotating the inner sleeve of the capsule with respect The measurement of bioavailability gives the net
to an outer sleeve and allowing a series of slots in the result of the effect of the release of drug into solution
two sleeves to become aligned and the enclosed drug in the physiological fluids at the site of absorption, its
to be released. For both these systems blood samples stability in those physiological fluids, its permeability
need to be taken to quantify drug absorption. and its presystemic metabolism on the rate and extent
of drug absorption by following the concentration-
Presystemic metabolism time profile of drug in a suitable physiological fluid.
The concentration-time profile also gives informa-
Presystemic metabolism is the metabolism that occurs tion on other pharmacokinetic parameters, such as
before the drug reaches the systemic circulation. the distribution and elimination of the drug. The
Therefore, for an orally administered drug this most commonly used method of assessing the
includes the metabolism that occurs in the gut wall and bioavailability of a drug involves the construction of
the liver. As discussed above, perfusion models that a blood plasma concentration-time curve, but urine
involve both the intestines and the liver allow an eval- drug concentrations can also be used and are
uation of the presystemic metabolism in both organs. discussed below.
In other models it is sometimes possible to design mass
balance experiments that will assess whether presys-
temic intestinal metabolism is likely to occur. Plasma concentration-time curves
Intestinal cell fractions, such as brush border When a single dose of a drug is administered orally
membrane preparations which contain an abun- to a patient, serial blood samples are withdrawn and
dance of hydrolytic enzymes, and homogenized the plasma assayed for drug concentration at specific
preparations of segments of rat intestine, can also be periods of time after administration, a plasma con-
used to determine intestinal presystemic metabo- centration-time curve can be constructed.

262
 ASSESSMENT OF BIOPHARMACEUTICAL PROPERTIES

Figure 18.8 shows a typical plasma concentra- exceeds the rate absorption. Therefore, the concen-
tion-time curve following the administration of an tration of the drug in the plasma declines.
oral tablet. Eventually drug absorption ceases when the
At zero time, when the drug is first administered, bioavailable dose has been absorbed, and the con-
the concentration of drug in the plasma will be zero. centration of drug in the plasma is now controlled
As the tablet passes into the stomach and/or intestine only by its rate of elimination by metabolism and/or
it disintegrates, the drug dissolves and absorption excretion. This is sometimes called the elimination
occurs. Initially the concentration of drug in the phase of the curve. It should be appreciated,
plasma rises, as the rate of absorption exceeds the rate however, that elimination of a drug begins as soon as
at which the drug is being removed by distribution it appears in the plasma.
and elimination. Concentrations continue to rise until Several parameters based on the plasma
a maximum (or peak) is attained. This represents the concentration-time curve which are important in
highest concentration of drug achieved in the plasma bioavailability studies are shown in Figure 18.9, and
following the administration of a single dose, and is are discussed below.
often termed the Crmax
n . It is reached when the rate of Minimum effective (or therapeutic) plasma concentra-
appearance of drug in the plasma is equal to its rate of tion It is generally assumed that some minimum
removal by distribution and elimination. concentration of drug must be reached in the plasma
The ascending portion of the plasma concentration- before the desired therapeutic or pharmacological
time curve is sometimes called the absorption effect is achieved. This is called the minimum effec-
phase. Here the rate of absorption outweighs the tive (or therapeutic) plasma concentration. Its
rate of removal of drug by distribution and elimina- value not only varies from drug to drug but also from
tion. Drug absorption does not usually stop abruptly individual to individual, and with the type and sever-
at the time of peak concentration, but may continue ity of the disease state. In Figure 18.9 the minimum
for some time into the descending portion of the effective concentration is indicated by the lower line.
curve. The early descending portion of the curve can Maximum safe concentration The concentration
thus reflect the net result of drug absorption, distri- of drug in the plasma above which side-effects or
bution, metabolism and elimination, but in this toxic effects occur is known as the maximum safe
phase the rate of drug removal from the blood concentration.

Fig. 18.8 A typical blood plasma concentration-time curve obtained following the peroral administration of a single dose of a drug in
a tablet.

263
 BIOPHARMACEUTICAL PRINCIPLES OF DRUG DELIVERY

The use of plasma concentration-time curves in

bioavailability studies
In order to illustrate the usefulness of plasma
concentration-time curves in bioavailability studies
to assess the rate and extent of absorption, the
administration of single equal doses of three differ-
ent formulations, A, B and C, of the same drug to
the same healthy individual by the same route of
administration on three separate occasions can be
considered. The assumption is made that sufficient
time was allowed to elapse between the administra-
tion of each formulation such that the systemic cir-
culation contained no residual concentration of drug
and no residual effects from any previous adminis-
trations. It is also assumed that the kinetics and
Fig. 18.9 Relationship between the plasma concentration-time
curve obtained following a single extravascular dose of a drug
pattern of distribution of the drug, its binding phe-
and parameters associated with the therapeutic or nomena, the kinetics of elimination and the experi-
pharmacological response. mental conditions under which each plasma
concentration-time profile was obtained, were the
same on each occasion. The plasma concentration-
Therapeutic range or window A range of plasma time profiles for the three formulations are shown in
drug concentrations is also assumed to exist, over Figure 18.10. The differences between the three
which the desired response is obtained yet toxic curves are attributed solely to differences in the rate
effects are avoided. This range is called the thera- and/or extent of absorption of the drug from each
peutic range or window. The intention in clinical formulation.
practice is to maintain plasma drug concentrations The three plasma profiles in Figure 18.10 show
within this range. that each of the three formulations (A, B and C) of
Onset The onset may be denned as the time the same dose of the same drug results in a different
required to achieve the minimum effective plasma peak plasma concentration. However, the areas
concentration following administration of the dosage under the curves for formulation A and B are
form. similar, and this indicates that the drug is absorbed
Duration The duration of the therapeutic effect to a similar extent from these two formulations.
of the drug is the period during which the concen- Consideration of the times at which the peak plasma
tration of drug in the plasma exceeds the minimum concentrations occur for formulations A and B show
effective plasma concentration. that the drug is absorbed faster from A than from B,
Peak concentration This represents the highest meaning that formulation A shows a fast onset of
concentration of the drug achieved in the plasma, therapeutic action, but as its peak plasma concentra-
which is often referred to as the C_Pmax
D . tion exceeds the maximum safe concentration it is
Time of peak concentration This is the period of likely that this formulation will result in toxic side-
time required to achieve the peak plasma concentra- effects. Formulation B, which gives a slower rate of
tion of drug after the administration of a single dose. absorption than A, shows a slower therapeutic onset
This parameter is related to the rate of absorption of than A, but its peak plasma concentration lies within
the drug and can be used to assess that rate. It is the therapeutic range. In addition, the duration of
often referred to as the T"max. action of the therapeutic effect obtained with formu-
Area under the plasma concentration—time curve lation B is longer than that obtained with A. Hence
This is related to the total amount of drug absorbed formulation B appears to be superior to formulation
into the systemic circulation following the adminis- A from a clinical viewpoint, in that its peak plasma
tration of a single dose, and is often known as the concentration lies within the therapeutic range of the
AUG. However, changes in the area under the drug and the duration of the therapeutic effect is
plasma concentration-time curve need not necessar- longer.
ily reflect changes in the total amount of drug Formulation C gives a much smaller area under
absorbed, but can reflect modifications in the kinet- the plasma concentration-time curve, indicating that
ics of distribution, metabolism and excretion. a lower proportion of the dose has been absorbed.

264
 ASSESSMENT OF BIOPHARMACEUTICAL PROPERTIES

Fig. 18.10 Plasma concentration-time curves for three different formulations of the same drug administered in equal single doses by
the same extravascular route.

This, together with the slower rate of absorption ent rates of absorption, metabolism, excretion and
from formulation C (the time of peak concentration distribution, different distribution patterns and dif-
is longer than for formulations A and B), results in ferences in their binding phenomena, all of which
the peak plasma concentration not reaching the would influence the concentration-time curve.
minimum effective concentration, i.e. formulation C Therefore it would be extremely difficult to attribute
does not produce a therapeutic effect and conse- differences in the concentration-time curves
quently is clinically ineffective as a single dose. obtained for different drugs presented in different
This simple hypothetical example illustrates how formulations to differences in their bioavailabilities.
differences in bio availability exhibited by a given drug
from different formulations can result in a patient
being either over, under, or correctly medicated.
Cumulative urinary drug excretion
It is important to realize that the study of bioavail-
curves
ability based on drug concentration measurements Measurement of the concentration of intact drug
in the plasma (or urine or saliva) is complicated by and/or its metabolite(s) in the plasma can also be
the fact that such concentration-time curves are used to assess bioavailability.
affected by factors other than the biopharmaceutical When a suitable specific assay method is not avail-
factors of the drug product itself. Factors such as able for the intact drug in the urine, or the specific
body weight, sex and age of the test subjects, disease assay method available for the parent drug is not
states, genetic differences in drug metabolism, excre- sufficiently sensitive, it may be necessary to assay the
tion and distribution, food and water intake, con- principal metabolite or intact drug plus its metabo-
comitant administration of other drugs, stress and lite (s) in the urine to obtain an index of bioavailabil-
time of administration of the drug are some of the ity. Measurements involving metabolite levels in the
variables that can complicate the interpretation of urine are only valid when the drug in question is not
bioavailability studies. As far as possible, studies subject to metabolism prior to reaching the systemic
should be designed to control these factors. circulation. If an orally administered drug is subject to
Although plots such those in as Figure 18.10 can intestinal metabolism or first-pass liver metabolism,
be used to compare the relative bioavailability of a then measurement of the principal metabolite, or of
given drug from different formulations, they cannot intact drug plus metabolites, in the urine would give
be used indiscriminately to compare different drugs. an overestimate of the systemic availability of that
It is quite usual for different drugs to exhibit differ- drug. It should be remembered that the definition of

265
 BIOPHARMACEUTICAL PRINCIPLES OF DRUG DELIVERY

bioavailability is in terms of the extent and the rate at

which intact drug appears in the systemic circulation
after the administration of a known dose.
The assessment of bioavailability by urinary excre-
tion is based on the assumption that the appearance
of the drug and/or its metabolites in the urine is a
function of the rate and extent of absorption. This
assumption is only valid when a drug and/or its
metabolites are extensively excreted in the urine, and
where the rate of urinary excretion is proportional to
the concentration of the intact drug in the blood
plasma. This proportionality does not hold if:
• the drug and/or its metabolites are excreted by an
active transport process into the distal kidney
tubule;
• the intact drug and/or its metabolites are weakly
acidic or weakly basic (i.e. their rate of excretion Fig. 18.11 Corresponding plots showing the plasma
is dependent on urine pH); concentration-time curve (upper curve) and the cumulative
• the excretion rate depends on the rate of urine urinary excretion curve (lower curve) obtained following the
flow. administration of a single dose of a drug by the peroral route

The important parameters in urinary excretion

studies are the cumulative amount of intact drug
The use of urinary drug excretion curves in
and/or metabolites excreted, and the rate at which
bioavailability studies
this excretion takes place. A cumulative urinary
excretion curve is obtained by collecting urine In order to illustrate how cumulative urinary excre-
samples (resulting from total emptying of the tion curves can be used to compare the bioavailabil-
bladder) at known intervals after a single dose of the ities of a given drug from different formulations, let
drug has been administered. Urine samples must be us consider the urinary excretion data that would
collected until all drug and/or its metabolites has have been obtained following the administration of
been excreted (this is indicated by the cumulative single equal doses of the three different formula-
urinary excretion curve becoming parallel to the tions, A, B and C, of the same drug to the same
abscissa) if a comparison of the extent of absorption healthy individual by the same extravascular route
of a given drug from different formulations or dosage on three different occasions, and giving the plasma
forms is to be made. A typical cumulative urinary concentration-time curves shown in Figure 18.10.
excretion curve and the corresponding plasma con- The corresponding cumulative urinary excretion
centration-time curve obtained following the admis- curves are shown in Figure 18.12.
sion of a single dose of a given drug by the oral route The cumulative urinary excretion curves show that
to a subject is shown in Figure 18.11. the rate at which drug appeared in the urine (i.e. the
The initial segments (X-Y) of the curves reflect slope of the initial segment of each urinary excretion
the 'absorption phase' (i.e. where absorption is the curve) from each formulation decreased in order A >
dominant process) and the slope of this segment of B > C. Because the slope of the initial segment of the
the urinary excretion curve is related to the rate of urinary excretion curve is related to the rate of drug
absorption of the drug into the blood. The total absorption, the cumulative urinary excretion curves
amount of intact drug (and/or its metabolite) indicate that the rates of absorption of drug from the
excreted in the urine at point Z corresponds to the three formulations decrease in the order A > B > C.
time at which the plasma concentration of intact Inspection of the corresponding plasma concentra-
drug is zero and essentially all the drug has been tion-time curves in Figure 18.10 shows that this is the
eliminated from the body. The total amount of drug case, i.e. peak concentration times (which are
excreted at point Z may be quite different from the inversely related to the rate of drug absorption) for the
total amount of drug administered (i.e. the dose), three formulations increase in the order A > B > C.
either because of incomplete absorption on because Although Figure 18.12 shows that the rate of appear-
of the drug being eliminated by processes other than ance of drug in the urine from formulation A is faster
urinary excretion. than from B, the total amount of drug eventually

266
 ASSESSMENT OF BIOPHARMACEUTICAL PROPERTIES

Fig. 18.12 Cumulative urinary excretion curves corresponding to the plasma concentration-time curves shown in Fig. 18.10 for three
different formulations of the same drug administered in equal single doses by the same extravascular route.

excreted from these two formulations is the same, i.e. curve than do formulations A and B. Thus one can
the cumulative urinary excretion curves for formula- conclude that cumulative urinary excretion curves
tions A and B eventually meet and merge. As the total may be used to compare the rate and extent of
amount of intact drug excreted is assumed to be absorption of a given drug presented in different for-
related to the total amount absorbed, the cumulative mulations, provided that the conditions mentioned
urinary excretion curves for formulations A and B previously apply.
indicate that the extent of drug absorption from these
two formulations is the same. This is confirmed by the
Absolute and relative bioavailability
plasma concentration-time curves for formulations A
and B in Figure 18.10, which exhibit similar areas
Absolute bioavailability
under their curves.
Thus both the plasma concentration-time curves The absolute bioavailability of a given drug from a
and the corresponding cumulative urinary excretion dosage form is the fraction (or percentage) of the
curves for formulations A and B show that the extent administered dose which is absorbed intact into the
of absorption from these formulations is equal, systemic circulation. Absolute bioavailability may be
despite being at different rates from the respective calculated by comparing the total amount of intact
formulations. drug that reaches the systemic circulation after the
Consideration of the cumulative urinary excretion administration of a known dose of the dosage form
curve for C shows that this formulation not only via a route of administration, with the total amount
results in a slower rate of appearance of intact drug that reaches the systemic circulation after the admin-
in the urine, but also that the total amount of drug istration of an equivalent dose of the drug in the
that is eventually excreted is much less than from the form of an intravenous bolus injection. An intra-
other two formulations. Thus the cumulative urinary venous bolus injection is used as a reference to
excretion curve suggests that both the rate and compare the systemic availability of the drug admin-
extent of drug absorption are reduced in the case of istered via different routes, because when a drug is
formulation C.This is confirmed by the plasma con- delivered intravenously the entire administered dose
centration-time curve shown in Figure 18.10 for for- is introduced directly into the systemic circulation,
mulation C, i.e. formulation C exhibits a longer peak i.e. it has no absorption barriers to cross and is there-
concentration time and a smaller area under the fore considered to be totally bioavailable.

267
 BIOPHARMACEUTICAL PRINCIPLES OF DRUG DELIVERY

The absolute bioavailability of a given drug using where Dabs is the size of the single dose of drug
plasma data may be calculated by comparing the administered via the absorption site, and Div is the
total areas under the plasma concentration-time size of the dose of the drug administered as an intra-
curves obtained following the administration of venous bolus injection. Sometimes it is necessary to
equivalent doses of the drug via an absorption site use different dosages of drugs via different routes.
and via the intravenous route in the same subject on Often the dose administered intravenously is lower
different occasions. Typical plasma concentration- to avoid toxic side-effects and for ease of formula-
time curves obtained by administering equivalent tion. Care should be taken when using different
doses of the same drug by the intravenous route dosages to calculate bioavailability data, as some-
(bolus injection) and the gastrointestinal route are times the pharmacokinetics of a drug are non-linear
shown in Figure 18.13. and different doses will then lead to an incorrect
For equivalent doses of administered drug: figure for the absolute bioavailability calculated
using a simple ratio, as in Eqn 18.4.
Absolute bioavailability using urinary excretion
data may be determined by comparing the total
where (AUCT)abs is the total area under the plasma cumulative amounts of unchanged drug ultimately
concentration-time curve following the administration excreted in the urine following administration of the
of a single dose via an absorption site and (AUCT)iv is drug via an absorption site and the intravenous route
the total area under the plasma concentration-time (bolus injection), respectively, on different occasions
curve following administration by rapid intravenous to the same subject.
injection. For equivalent doses of administered drug:
If different doses of the drug are administered by
both routes, a correction for the sizes of the doses
can be made as follows:
where (Xu)abs and (Xu)iv are the total cumulative
amounts of unchanged drug ultimately excreted in
the urine following administration of equivalent

Fig. 18.13 Typical plasma concentration-time curves obtained by administering equivalent doses of the same drug by intravenous
bolus injection and by the peroral route.

268
 ASSESSMENT OF BIOPHARMACEUTICAL PROPERTIES

single doses of drug via an absorption site and as an the same route of administration to the same subject
intravenous bolus injection, respectively. on different occasions, may be calculated from the
If different doses of drug are administered, corresponding plasma concentration-time curves as
follows:

The absolute bioavailability of a given drug from a

particular type of dosage form may be expressed as a
fraction or, more commonly, as a percentage.
Measurements of absolute bioavailability obtained areas under me plasma concentration-time curves
by administering a given drug in the form of a simple following the administration of a single dose of the
aqueous solution (that does not precipitate on dilu- test dosage form and of the standard dosage form,
tion with gastrointestinal fluids) by both the oral and respectively.
the intravenous routes provide an insight into the When different doses of the test and standard
effects that factors associated with the oral route may dosage forms are administered, a correction for the
have on bioavailability, e.g. presystemic metabolism size of dose is made as follows:
by the intestine or liver, the formation of complexes
between the drug and endogenous substances (e.g.
mucin) at the site of absorption and drug stability in
the gastrointestinal fluids.
It should be noted that the value calculated for where Dlest and Atandard are me §izes of the single doses
of the test and standard dosage forms, respectively.
the absolute bioavailability will only be valid for
Like absolute bioavailability, relative bioavailabil-
the drug being examined if the kinetics of elimina-
ity may be expressed as a fraction or as a percentage.
tion and distribution are independent of the route
Urinary excretion data may also be used to
and time of administration, and also of the size of
measure relative bioavailability as follows:
dose administered (if different doses are adminis-
tered by the intravenous route and absorption
site). If this is not the case, one cannot assume that
the observed differences in the total areas under
the plasma concentration-time curves or in the where (Xu)test and (Xu)standard are the total cumulative
total cumulative amounts of unchanged drug amounts of unchanged drug ultimately excreted in
ultimately excreted in the urine are due entirely to the urine following the administration of single doses
differences in bio availability. of the test dosage form and the standard dosage
form, respectively.
If different doses of the test and standard dosage
Relative bioavailability
forms are administered on separate occasions, the
In the case of drugs that cannot be administered by total amounts of unchanged drug ultimately
intravenous bolus injection, the relative (or compar- excreted in the urine per unit dose of drug must be
ative) bioavailability is determined rather than the used in the above equation.
absolute bioavailability. In this case the bioavailabil- It should be noted that measurements of relative
ity of a given drug from a 'test' dosage form is com- and absolute bioavailability based on urinary excre-
pared to that of the same drug administered in a tion data may also be made in terms of either the
'standard' dosage form, which is either an orally total amounts of principal drug metabolite or of
administered solution (from which the drug is unchanged drug plus its metabolites ultimately
known to be well absorbed) or an established com- excreted in the urine. However, the assessment of
mercial preparation of proven clinical effectiveness. relative and absolute bioavailability in terms of
Hence relative bioavailability is a measure of the urinary excretion data is based on the assumption
fraction (or percentage) of a given drug that is that the total amount of unchanged drug (and/or its
absorbed intact into the systemic circulation from a metabolites) ultimately excreted in the urine is a
dosage form relative to a recognized (i.e. clinically reflection of the total amount of intact drug entering
proven) standard dosage form of that drug. the systemic circulation (as discussed in the earlier
The relative bioavailability of a given drug admin- section on cumulative urinary excretion curves).
istered as equal doses of a test dosage form and a Relative bioavailability measurements are often used
recognized standard dosage form, respectively, by to determine the effects of dosage form differences on

269
 BIOPHARMACEUTICAL PRINCIPLES OF DRUG DELIVERY

the systemic bioavailability of a given drug. Numerous time and/or cumulative urinary excretion curves
dosage form factors can influence the bioavailability of would be superimposable. In such a case there
a drug. These include the type of dosage form (e.g. would be no problem in concluding that these prod-
tablet, solution, suspension, hard gelatin capsule), dif- ucts were bioequivalent. Nor would there be a
ferences in the formulation of a particular type of problem in concluding bioinequivalence if the para-
dosage form, and manufacturing variables employed meters associated with the plasma concentration-
in the production of a particular type of dosage form. time and/or cumulative urinary excretion profiles
A more detailed account of the influence of these for the test differed from the standard product by,
factors on bioavailability is given in Chapter 17. for instance, 50%. However, a problem arises in
deciding whether the test and standard drug
products are bioequivalent when such products
Bioequivalence
show relatively small differences in their plasma
An extension of the concept of relative bioavailability, concentration-time curves and/or cumulative
which essentially involves comparing the total urinary excretion curves.
amounts of a particular drug that are absorbed intact The problem is how much of a difference can be
into the systemic circulation from a test and a recog- allowed between two chemically equivalent drug
nized standard dosage form, is that of determining products and still permit them to be considered
whether test and standard dosage forms containing bioequivalent. Should this be 10%, 20%, 30% or
equal doses of the same drug are equivalent or not in more? The magnitude of the difference that could
terms of their rates and extents of absorption (i.e. sys- be permitted will depend on the significance of
temic availabilities). This is called bioequivalence. such a difference on the safety and therapeutic
Two or more chemically equivalent products (i.e. efficacy of the particular drug. This will depend on
products containing equal doses of the same thera- such factors as the toxicity, the therapeutic range
peutically active ingredient (s) in identical types of and the therapeutic use of the drug. In the case of
dosage form which meet all the existing physico- a drug with a wide therapeutic range, the toxic
chemical standards in official compendia) are said to effects of which occur only at relatively high plasma
be bioequivalent if they do not differ significantly in concentrations, chemically equivalent products
their bioavailability characteristics when adminis- giving quite different plasma concentration-time
tered in the same dose under similar experimental curves (Fig. 18.14) may still be considered satisfac-
conditions. Hence in those cases where bioavailabil- tory from a therapeutic point of view, although they
ity is assessed in terms of plasma concentration-time are not strictly bioequivalent.
curves, two or more chemically equivalent drug In the case of the hypothetical example shown in
products may be considered bioequivalent if there is Figure 18.14, provided that the observed difference
no significant difference between any of the follow- in the rates of absorption (as assessed by the times of
ing parameters: maximum plasma concentrations peak plasma concentration), and hence in the times
(Cmax), time to peak height concentration (T"max) and of onset, for formulations X and Y is not considered
areas under the plasma concentration-time curves to be therapeutically significant, both formulations
(AUC). may be considered to be therapeutically satisfactory.
In conducting a bioequivalence study it is usual However, if the drug in question was a hypnotic, in
for one of the chemically equivalent drug products which case the time of onset for the therapeutic
under test to be a clinically proven, therapeutically response is important, then the observed difference
effective product which serves as a standard against in the rates of absorption would become more
which the other 'test' products may be compared. If important.
a test product and this standard product are found to If the times of peak plasma concentration for for-
be bioequivalent then it is reasonable to expect that mulations X andY were 0.5 and 1.0 hour, respec-
the test product will also be therapeutically effective, tively, it is likely that both formulations would still be
i.e. the test and the reference products are therapeu- deemed to be therapeutically satisfactory despite a
tically equivalent. Bioequivalence studies are there- 100% difference in their times of peak plasma con-
fore important in determining whether chemically centration. However, if the times of peak plasma
equivalent drug products manufactured by different concentration for formulations X andY were 2 and
companies are therapeutically equivalent, i.e. 4 hours, respectively, these formulations might no
produce identical therapeutic responses in patients. longer be regarded as being therapeutically equiva-
If two chemically equivalent drug products are lent even though the percentage difference in their
absolutely bioequivalent, their plasma concentration- peak plasma concentration was the same.

270
 ASSESSMENT OF BIOPHARMACEUTICAL PROPERTIES

Fig. 18.14 Plasma concentration-time curves for two chemically equivalent drug products administered in equal single doses by the
same extravascular route.

It is difficult to quote a universally acceptable per- these parameters differed by more than 20% then
centage difference that can be tolerated before two there might have been a problem with the bioequiv-
chemically equivalent drug products are regarded alence of the test product (s) with respect to the stan-
as being bioinequivalent and/or therapeutically dard product. However, recently some regulatory
inequivalent. In the case of chemically equivalent authorities have been adopting more stringent
drug products containing a drug which exhibits a requirements for bioequivalence, involving statistical
narrow range between its minimum effective plasma models and considerations of average, population
concentration and its maximum safe plasma concen- and individual pharmacokinetics.
tration (e.g. digoxin), the concept of bioequivalence A further crucial factor in establishing bioequiva-
is fundamentally important, as in such cases small lence, or in determining the influence of the type of
differences in the plasma concentration-time curves dosage form, the route of administration etc., have on
of chemically equivalent drug products may result in the bioavailability of a given drug, is the proper design,
patients being overmedicated (i.e. exhibiting toxic control and interpretation of such experimental
responses) or undermedicated (i.e. experiencing studies.
therapeutic failure). These two therapeutically unsat-
isfactory conditions are illustrated in Figure 18.15a
& b respectively. ASSESSMENT OF SITE OF RELEASE IN
Despite the problems of putting a value on the VIVO
magnitude of the difference that can be tolerated
before two chemically equivalent drug products are There are many benefits of being able to assess the
deemed to be bioinequivalent, a value of 20% for the fate of a dosage form in vivo and the site and release
tolerated difference used to be regarded as suitable pattern of the drug. Particularly for drugs that show
as a general criterion for determining bioequiva- poor oral bioavailability, or in the design and devel-
lence. Thus if all the major parameters in either the opment of controlled- or sustained-release delivery
plasma concentration—time or cumulative urinary systems, the ability to follow the transit of the
excretion curves for two or more chemically equiva- dosage form and the release of drug from it is
lent drug products differed from each other by less advantageous. The technique of gamma scintigra-
than 20%, these products would have been judged to phy is now used extensively and enables a greater
be bioequivalent. However, if any one or more of knowledge and understanding of the transit and fate

271
 BIOPHARMACEUTICAL PRINCIPLES OF DRUG DELIVERY

Fig. 18.15 Plasma concentration-time curves for chemically equivalent drug products administered in equal single doses by the
same extravascular route, showing potential consequences of bioinequivalence for a drug having a narrow therapeutic range, i.e.,
(a) overmedication and (b), undermedication. (After Chodos and Di Santo 1973.)

of pharmaceuticals in the gastrointestinal tract to be The signals are assembled by computer software to
gained. form a two-dimensional image of the dosage form in
Gamma scintigraphy is a versatile, non-invasive the gastrointestinal tract. The anatomy of the
and ethically acceptable technique which is capable gastrointestinal tract can be clearly seen from liquid
of obtaining information both quantitatively and dosage forms, and the site of disintegration of solid
continuously. The technique involves the radio- dosage forms identified. The release of the radiolabel
labelling of a dosage form with a gamma-emitting from the dosage form can be measured by following
isotope of appropriate half-life and activity. the intensity of the radiation. By co-administration
Technetium-99m is often the isotope of choice for of a radiolabelled marker and a drug in the same
pharmaceutical studies because of its short half-life dosage form, and simultaneous imaging and taking
(6 hours). The radiolabelled dosage form is of blood samples, the absorption site and release
administered to a subject who is positioned in front rate of a drug can be determined (for example with
of a gamma camera. Gamma radiation emitted from the InteliSite capsule; see earlier). When used in
the isotope is focused by a collimator and detected this way, the technique is often referred to as
by a scintillation crystal and its associated circuitry. pharmacoscintigraphy.

272
 ASSESSMENT OF BIOPHARMACEUTICAL PROPERTIES

absorption (see earlier). Examples of class II drugs

THE BIOPHARMACEUTICAL are the non-steroidal anti-inflammatory drug keto-
CLASSIFICATION SCHEME profen and the antiepileptic carbamazepine. This
class of drug should be amenable to formulation
A biopharmaceutical classification scheme has been approaches to improve the dissolution rate and
proposed which classifies drugs into four classes hence oral bioavailability.
according to their solubility across the gastrointesti- Class III drugs Class III drugs are those that dis-
nal pH range and their permeability across the gas- solve rapidly but which are poorly permeable; exam-
trointestinal mucosa (Amidon et al 1995). Two of the ples are the H2-antagonist ranitidine and the
four potential barriers to absorption are thus jS-blocker atenolol. It is important that dosage forms
addressed by the scheme (see Fig. 18.1). containing class III drugs release them rapidly, in
The scheme was originally proposed for the order to maximize the amount of time these drugs,
identification of immediate-release solid oral prod- which are slow to permeate the gastrointestinal
ucts for which in vivo bioequivalence tests may not epithelium, are in contact with it.
be necessary, but it is also useful to classify drugs and Class IV drugs Class IV drugs are those that are
predict bioavailability issues that may arise during classed as poorly soluble and poorly permeable.These
the various stages of the development process. The drugs are liable to have poor oral bioavailability, or the
four classes are: oral absorption may be so low that they cannot be
given by the oral route. The diuretics hydrochloroth-
• Class I: high solubility/low permeability
iazide and frusemide are examples of class IV drugs.
• Class II: low solubility/high permeability Forming prodrugs of class IV compounds or finding
• Class III: high solubility/low permeability an alternative route of delivery are approaches that
• Class IV: low solubility/low permeability. have to be adopted to significantly improve their
A drug is considered to be highly soluble where the absorption into the systemic circulation.
highest dose strength is soluble in 250 mL or less of
aqueous media over the pH range 1-8. The volume is
derived from the minimum volume anticipated in the
stomach when a dosage form is taken in the fasted SUMMARY
state with a glass of water. If the volume of aqueous
media taken to dissolve the drug in pH conditions This chapter discusses the range of current approaches
ranging from 1 to 8 is greater than 250 mL then the to assessing the biopharmaceutical properties of drugs
drug is considered to have low solubility. The that are intended for oral administration. Methods of
classification therefore takes into account the dose of measuring and interpreting bioavailability data are
the drug as well as its solubility. A drug is considered described. The concepts of bioequivalence and the bio-
to be highly permeable when the extent of absorption pharmaceutical classification of drugs are introduced.
in humans is expected to be greater than 90% of the It is imperative that the biopharmaceutical properties
administered dose. Permeability can be assessed of drugs are fully understood, both in the selection of
using one of the methods discussed earlier which has candidate drugs during the discovery process and in
been calibrated with known standard compounds or the design and development of efficacious immediate-
by pharmacokinetic studies. and controlled-release dosage forms.
Class I drugs Class I drugs will dissolve rapidly
when presented in immediate-release dosage forms,
and are also rapidly transported across the gut wall.
Therefore, unless they form insoluble complexes, REFERENCES
are unstable in gastric fluids or undergo presys-
temic clearance, it is expected that such drugs will Amidon, G.L., Lennernas, H., Shah, V.P. and Crison, J.R.A.,
be rapidly absorbed and thus show good bioavail- (1995) Theoretical basis for a biopharmaceutic drug
classification: the correlation of in vitro drug product
ability. Examples of class I drugs are the /3-blockers dissolution and in vivo bioavailability. Pharm. Res., 12,
propranolol and metoprolol. 413-420.
Class II drugs In contrast, for drugs in class II Artusson, P., Palm, K., Luthman, K., (1996) Caco-2
the dissolution rate is liable to be the rate-limiting monolayers in experimental and theoretical predictions of
drug transport. Adv. Drug Del. Rev., 22, 67-84.
step in oral absorption. For class II drugs, there- Carlile, D.J., Zomorodi, K., Houston, J.B. (1997) Scaling
fore, it should be possible to generate a strong cor- factors to relate drug metabolic clearance in heptaic
relation between in vitro dissolution and in vivo microsomes, isolated hepatocytes and the intact liver -

273
 BIOPHARMACEUTICAL PRINCIPLES OF DRUG DELIVERY

studies with induced livers involving diazepam. Drug Metab. Hidalgo, I.J., Raub,TJ., Borchardt, R.T. (1989)
Dispos. 25, 903-911. Characterization of the human colon carcinoma cell line
Chodos, DJ. and Di Santo, A.R. (1973) Basis of (Caco-2) as a model system for intestinal epithelium
Bioavailability. The Upjohn Company, Kalamazoo, permeability. Gastroenterology, 96, 736-749.
Michigan. Knutson, L., Odlind, B., Hallgren, R. (1989) A new
Dressman, J.B., Amidon, G.L., Reppas, C. and Shah,V.P. technique for segmental jejunal perfusion in man. Am. J.
(1998) Dissolution testing as a prognostic tool for oral Gastroenterol, 84, 1278-1284.
drug absorption: immediate release dosage forms. Pharm. Lennernas, H., Abrenstedt, O., Hallgren, R., Knutson L.,
Res., 15, 11-22. Ryde, M., Paalzow, L.K. (1992) Regional jejunal perfusion,
Fuhr U, Staib, A.M., Harder, S. et al. (1994) Absorption of a new in vivo approach to study oral drug absorption in
ipsapirone along the human gastrointestinal. Br. J. Clin. amn. Pharm. Res., 9, 1243-1251.
Pharmacol, 38, 83-86. Wilding (1997) Non invasive techniques to study human
drug absorption. Eur.J. Pharm. Sci., 5 518-519.

274
19
Dosage regimens

Stuart Proudfoot (updated by John Collett)

CHAPTER CONTENTS DOSAGE REGIMENS: THEIR INFLUENCE

ON THE CONCENTRATION-TIME
Dosage regimens: their influence on the PROFILE OF A DRUG IN THE BODY
concentration-time profile of a drug in the
body 275
The subject of dosage regimens is concerned with
One-compartment open model of drug disposition the dose, time of administration and drug plasma
in the body 276 levels factors associated with multiple dosing of a
Rate of drug input versus rate of drug output 276
Elimination rate constant and biological half-life of a drug. The influence that physiological factors, the
drug 277 physicochemical properties of a drug and dosage
Concentration-time curve of a drug in the body form factors can have in determining whether a
following the peroral administration of equal therapeutically effective concentration of a drug is
doses of a drug at fixed intervals of time 278 achieved in the plasma following peroral adminis-
Important factors influencing steady-state plasma tration of a single dose of drug has been discussed
drug concentrations 281 previously in Chapters 16, 17 and 18.
Dose size and frequency of administration 281 Some drugs, such as hypnotics, analgesics and
Size of dose 281 antiemetics, may provide effective treatment follow-
Interval between successive equal doses 281
Summary of the effects of dose size and ing the administration of a single dose. However,
frequency of administration 282 the duration of most illnesses is longer than the
The concept of loading doses' 284 therapeutic effect produced by the administration
Influence of changes in the apparent elimination of a single dose of a drug in a conventional dosage
rate constant of a drug: the problem of patients
with renal impairment 28S
form, i.e. a dosage form which is formulated to give
Influence of the 'overnight no-dose period' 286 rapid and complete drug release. In such cases
Concluding comments 287 doses are usually administered on a repetitive basis
over a period of time determined by the nature of
Bibliography 288 the illness. For instance, one 250 mg ampicillin
capsule may be administered every 6 hours for a
period of 5 days to treat a bacterial infection. Such
a regimen, in which the total dose of drug (i.e. in
this example 5 g) administered over 5 days is given
in the form of multiple doses (i.e. each of 250 mg)
at given intervals of time (i.e. every 6 hours) is
known as a multiple-dosage regimen.
The proper selection of both the dose size and the
frequency of administration is an important factor
that influences whether a satisfactory therapeutic
plasma concentration is achieved and maintained
over the prescribed course of treatment. Thus the
design of a multiple-dosage regimen is crucial to
successful drug therapy.

275
 BIOPHARMACEUTICAL PRINCIPLES OF DRUG DELIVERY

in the gastrointestinal fluids at the site(s) of absorp-

ONE-COMPARTMENT OPEN MODEL OF tion, i.e. the effective concentration, Ce, of drug at
DRUG DISPOSITION IN THE BODY time t. Hence:

In order to understand how the design of a dosage

regimen can influence the time course of a drug in and
the body, as measured by its plasma concentration-
time curve, consider that the complex kinetic
processes of drug input, output and distribution in where ka is the apparent absorption rate constant.
the body may be represented by the pharmacokinetic The negative sign in Eqn 19.2 indicates that the
model of drug disposition, the one-compartment effective concentration of drug at the absorption
open model, shown in Figure 19.1. In this case the site(s) decreases with time. The apparent absorption
drug is considered to be distributed instantly rate constant gives the proportion (or fraction) of
throughout the whole body following its release drug that enters the body compartment per unit
and absorption from the dosage form. Thus the time. Its units are time"1, e.g. rr1.
body behaves as a single compartment in Unlike the rate of drug input into the body com-
which absorbed drug is distributed so rapidly that partment, the apparent absorption rate constant, &a,
a concentration equilibrium exists at any given is independent of the effective concentration of drug
time between the plasma, other body fluids, at the absorption site(s). Because the rate of drug
and the tissues into which the drug has become input is proportional to the effective drug concentra-
distributed. tion, it will be maximal following the administration
To assume that the body behaves as one- of a dose contained in a peroral dosage form which
compartment open model does not necessarily gives rapid and complete drug release. The rate of
mean that the drug concentrations in all drug input will decrease gradually with time as a
body tissues at any given time are equal. The model consequence of the effective drug concentration at
does assume, however, that any changes that the absorption site(s) decreasing progressively with
occur in the plasma reflect quantitatively changes time, chiefly as a result of absorption into the body
occurring in the concentration of drug at the site(s) compartment. Other processes, such as chemical
of action. degradation and movement of drug away from the
absorption site(s), will also contribute to the gradual
decrease in the effective drug concentration with
Rate of drug input versus rate of drug time.
output In the case of a one-compartment open model, the
In a one-compartment open model, the overall rate of drug output or elimination is a first-order
kinetic processes of drug input and drug output are process. Consequently, the magnitude of this para-
described by first-order kinetics. In the case of a meter at any given time is dependent on the concen-
perorally administered dosage form, the process of tration of drug in the body compartment at that
drug input into the body compartment involves drug time. Immediately following administration of the
release from the dosage form and passage of the first dose of a peroral dosage form, the rate of drug
drug across the cellular membranes constituting the output from the body will be low as little of the drug
gastrointestinal barrier. The rate of input or absorp- will have been absorbed into the body compartment.
tion represents the net result of all these processes. However, as absorption proceeds - initially at a
The rate of input (absorption) at any given time is higher rate than the rate of drug output - the net
proportional to the concentration of drug, which concentration of drug in the body will increase with
is assumed to be in an absorbable form, in solution time. Likewise, the rate of drug output from the

Fig. 19.1 One-compartment open model of drug disposition for a perorally administered drug.

276
 DOSAGE REGIMENS

body compartment will also increase with time. As a single dose of drug. This interplay explains why
the rate of drug output is increasing with time while increases in dose size and formulation changes in
the rate of input into the body compartment is dosage forms which produce increases in the effec-
decreasing with time, the situation is eventually tive concentration of drug at the absorption site(s),
reached when the rate of drug output just exceeds result in higher peak plasma and body concentra-
that of drug input. Consequently, the net concentra- tions being obtained for a given drug. It should
tion of drug in the body compartment will reach a also be noted that any unexpected decrease in the
peak value and then begin to fall with time. The rate of drug output relative to that of drug input,
ensuing decreases in the net concentration of drug in which may occur as the result of renal impairment,
the body will also cause the rate of drug output to is also likely to result in higher plasma and body
decrease with time. concentrations of drug than expected, and the pos-
These changes in the rates of drug input and sibility of the patient exhibiting undesirable side-
output relative to each other with time are responsi- effects. The adjustment of dosage regimens in
ble for the characteristic shape of the concentra- cases of patients having severe renal impairment is
tion-time course of a drug in the body shown in considered later in this chapter.
Figure 19.2 following peroral administration of a
single dose of drug.
Elimination rate constant and biological
It is evident from the above discussion and
Figure 19.2, that the greater the rate of drug input
half-life of a drug
relative to that of drug output from the body com- In the case of a one-compartment open model the
partment over the net absorption phase, the higher rate of elimination or output of a drug from the body
will be the peak concentration achieved in the compartment follows first-order kinetics (Chapter 7)
body or plasma following peroral administration of and is related to the concentration of drug, Ct,

Fig. 19.2 Concentration-time course of a drug in the body following peroral administration of a single dose of drug which confers
one-compartment open model characteristics on the body.

277
 BIOPHARMACEUTICAL PRINCIPLES OF DRUG DELIVERY

remaining in the body compartment at time t, by the

Table 19,2 The biological half-life ranges for
following equation: i phenobarbitone, digoxin and theophylline

Drug Biological half-life (h)

where ke is the apparent elimination rate constant.
The negative sign in Eqn 19.3 indicates that elimi- Phenobarbitone 50-120
nation is removing drug from the body compart- Digoxin 36-51
ment. Theophylline 3-8
The apparent elimination rate constant of a drug
gives the proportion or fraction of that drug which is
eliminated from the body per unit time. Its units are
in terms of time^1. The apparent elimination con- the body over the time interval between successive
doses in a multiple-dosage regimen. Biological half-
stant of a given drug therefore provides a quantita-
life varies from drug to drug and, even for a given
tive index of the persistence of that drug in the body.
An alternative parameter used is the biological or drug, from patient to patient. Some biological half-
lives for various drugs are given in Table 19.2.
elimination half-life of the drug, r1/2. This is the time
For a drug whose elimination follows first-order
required for the body to eliminate 50% of the drug
kinetics, the biological half-life, r1/2, is related to the
that it contained. Thus, the larger the biological half-
apparent elimination rate constant, ke, of that drug
life exhibited by a drug, the slower will be its elimi-
according to the following equation:
nation from the body or plasma.
For a drug whose elimination follows first-order
kinetics, the value of its biological half-life is inde-
pendent of the concentration of drug remaining in
the body or plasma. Hence, if a single dose of a drug Thus the biological half-life of a drug will be
having a biological half-life of 4 hours was adminis- influenced by any factor that influences the appar-
tered perorally, then after the peak plasma concen- ent elimination rate constant of that drug. This
tration had been reached the plasma concentration explains why factors such as genetic differences
of drug would fall by 50% every 4 hours until all the between individuals, age and disease can affect
drug had been eliminated or a further dose was the biological half-life exhibited by a given drug.
administered. The relationship between the numbers Biological half-life is an important factor that
of half-lives elapsed and the percentage of drug elim- influences the plasma concentration-time curve
inated from the body following administration of a obtained following peroral administration of a
single dose is given in Table 19.1. multiple-dosage regimen.
An appreciation of the relationship between the
percentage of drug eliminated from the body and the
number of biological half-lives elapsed is useful Concentration-time curve of a drug in
when considering how much drug is eliminated from the body following the peroral
administration of equal doses of a drug
at fixed intervals of time
Table 19.1 Relationship between the amount of drug
• eliminated and the number of half-lives elapsed In discussing how the design of multiple peroral
dosage regimen can influence the concentration-
Number of half-lives Percentage of drug time course of a drug in the body, the following
elapsed eliminated assumptions have been made:
0.5 29.3 1. The drug confers upon the body the
1.0 50.0 characteristics of a one-compartment open
2.0 75.0 model.
3.0 87.5
3.3 90.0 2. The values of the apparent absorption rate and
4.0 94.0 apparent elimination rate constants for a given
4.3 95.0 drug do not change during the period for which
5.0 97.0 the dosage regimen is administered to a patient.
6.0 98.4
6.6 99.0
3. The fraction of each administered dose which is
7.0 99.2 absorbed by the body compartment remains
constant for a given drug.

278
 DOSAGE REGIMENS

4. The aim of drug therapy is to achieve promptly tion of the previous dose, then the resulting plasma
and maintain a concentration of drug at the concentration-time curve exhibits the characteristic
appropriate site(s) of action which is both profile shown in Figure 19.4.
clinically efficacious and safe for the desired Figure 19.4 shows that at the start of this multiple-
duration of treatment. This aim is assumed to be dosage regimen the maximum and minimum plasma
achieved by the prompt attainment and concentrations of drug observed during each
maintenance of plasma concentrations of drug dosing time interval tend to increase with succes-
which lie within the therapeutic range of that sive doses. This increase is because the time inter-
drug. val between successive doses is less than that
required for complete elimination of the previous
If the interval between each perorally administered absorbed dose. Consequently, the total amount of
dose is longer than the time required for complete the drug remaining in the body compartment at
elimination of the previous dose, then the plasma any time after a dose is equal to the sum of that
concentration-time profile of a drug will exhibit a remaining from all the previous doses. The accumu-
series of isolated single-dose profiles, as shown in lation of drug in the body and plasma with succes-
Figure 19.3. sively administered doses does not continue
Consideration of the plasma concentration-time indefinitely. Provided drug elimination follows first-
profile shown in Figure 19.3 in relation to the order kinetics, the rate of elimination will increase as
minimum effective and maximum safe plasma con- the average concentration of drug in the body (and
centrations (MEG and MSC, respectively) for the plasma) rises. If the amount of drug supplied to the
drug reveals that the design of this particular dosage body compartment per unit dosing time interval
regimen is unsatisfactory. The plasma concentration remains constant, then a situation is eventually
only lies within the therapeutic concentration range reached when the overall rate of elimination from
of the drug for a relatively short period following the the body over the dosing time interval becomes
administration of each dose, and the patient remains equal to the overall rate at which drug is being
undermedicated for relatively long periods. If the supplied to the body compartment over that inter-
dosing time interval is reduced so that it is now val, i.e. the overall rate of elimination has effectively
shorter than the time required for complete elimina- caught up with the overall rate of supply. This effect

Fig. 19.3 Plasma concentration-time curve following peroral administration of equal doses of a drug at time intervals that allow
complete elimination of the previous dose. (MSC, maximum safe plasma concentration of the drug; MEC, minimum effective plasma
concentration of the durg.)

279
 BIOPHARMACEUTICAL PRINCIPLES OF DRUG DELIVERY

Fig. 19.4 Plasma concentration-time curve following peroral administration of equal doses, D, of a drug every 4 hours. (MSC,
maximum safe plasma concentration of the drug; MEC, minimum effective plasma concentration of the drug.)

is due to the elimination rate increasing as the steady-state value corresponding to the particular
residual concentration of drug in the plasma rises multiple dosage regimen is 4.3 times the biological
(as elimination is first order here). half-life of the drug. The corresponding figure for
When the overall rate of drug supply equals 99% is 6.6 times. Therefore, depending on the mag-
the overall rate of drug output from the body nitude of the biological half-life of the drug being
compartment, a steady state is reached with respect administered, the time taken to attain the average
to the average concentration of drug remaining in steady-state plasma concentration may range from a
the body over each dosing time interval. At steady few hours to several days.
state, the amount of drug eliminated from the body From a clinical viewpoint the time required to
over each dosing time interval is equal to the amount reach steady state is important, because for a prop-
that was absorbed into the body compartment fol- erly designed multiple-dosage regimen the attain-
lowing administration of the previous dose. ment of steady state corresponds to the achievement
Figure 19.5 shows that the amount of drug in the and maintenance of maximal clinical effectiveness of
body, as measured by the plasma concentration, the drug in the patient.
fluctuates between maximum and minimum values It should be noted that for a drug such as pheny-
which remain more or less constant from dose to toin, whose elimination is not described by first-
dose. At steady state the average concentration of order kinetics, the peroral administration of equal
drug in the plasma, Q*erage, over successive dosing doses at fixed intervals may not result in the attain-
time intervals remains constant. ment of steady-state plasma levels. If the concentra-
For a drug administered repetitively in equal doses tion of such drug in the body rises sufficiently
and at equal time intervals, the time required for the following repetitive administration, the pathway
average plasma concentration to attain the corre- responsible for its elimination may become satu-
sponding steady-state value is a function only of the rated. If this occurred the rate of elimination would
biological half-life of the drug, and is independent of become maximal and could not increase to cope
both the size of the dose administered and the length with any further rises in the average concentration of
of the dosing time interval. The time required for the drug in the body. Hence the overall rate of elimina-
average plasma concentration to reach 95% of the tion would not become equal to the overall rate of

280
 DOSAGE REGIMENS

Fig. 19.5 Fluctuation of concentration of drug in the plasma at steady state resulting from repetitive peroral administration of equal
doses, D, of drug at a fixed interval of time, T. C^ax, C^in and C|verage represent the maximum, minimum and average plasma
concentrations of drug, respectively, achieved at steady state.

supply over each dosing time interval, and the con- of the administered dose is increased, the higher
dition necessary for the attainment of steady state are the corresponding maximum, minimum and
would not be achieved. If repetitive administration average plasma drug levels, Q£ax, C^in and C^erage,
continued at the same rate, the average concentra- respectively, achieved at steady state. What may not
tion of drug in the body and plasma would tend to be so well appreciated is that the larger the dose the
continue to accumulate, rather than to reach a larger is the fluctuation between C^ax and C^in
plateau. during each dosing time interval. Large fluctua-
tions between C^ax and C^in can be hazardous,
particularly with a drug such as digoxin, which has
a narrow therapeutic range. In such cases, it is
IMPORTANT FACTORS INFLUENCING possible that C^ax could exceed the maximum safe
STEADY-STATE PLASMA DRUG plasma concentration. Figure 19.6 also illustrates
CONCENTRATIONS that the time required to attain steady-state plasma
concentrations is independent of the size of the
Dose size and frequency of administered dose.
administration
In designing a multiple-dosage regimen that bal- Interval between successive equal doses
ances patient convenience with the achievement and
maintenance of maximal clinical effectiveness, only Figure 19.7 illustrates the effects of constant doses
two parameters can be adjusted for a given drug: the administered at various dosing intervals, which are
size of dose and the frequency of administration. multiples of the biological half-life of the drug r1/2.
Consider how the maximum, minimum and average The uppermost plasma concentration-time curve in
steady-state plasma concentrations of drug are Figure 19.7 shows that the repetitive administration
influenced by these parameters. of doses at a time interval which is less than the bio-
logical half-life of the drug results in higher steady-
state plasma drug concentrations being obtained.
Size of dose This is a consequence of the extent of elimination of
Figure 19.6 illustrates the effects of changing the the drug from the body over a dosing time interval
dose size on the concentration of drug in the equal to 0.5 tl/2 being smaller than that which is
plasma following repetitive administration of eliminated when the dosing time interval is equal to
peroral doses at equal intervals of time. As the size r1/2 (see Table 19.1).

281
 BIOPHARMACEUTICAL PRINCIPLES OF DRUG DELIVERY

Fig. 19.6 Diagrammatic representation of the effect of dose size on the plasma concentration-time curve obtained following peroral
administration of equal doses of a given fixed drug at fixed intervals of time equal to the biological half-life of the drug. Curve A, dose ;
250 mg. Curve B, dose = 100 mg. Curve C, dose = 40 mg.

Figure 19.7 also shows that repetitive administra- concentration, following repetitive peroral adminis-
tion of doses at intervals greater than the biological tration of equal doses, have revealed the following
half-life of the drug results in the lower steady-state relationships:
plasma drug concentrations being obtained. This is a
1. The magnitude of the fluctuations between the
consequence of a greater proportion of the drug
maximum and minimum steady-state amounts
being eliminated over a dosing time interval equal to
of drug in the body is determined by the size of
2r1/2> compared to that which is eliminated when the
dose administered or, more accurately, by the
dosing time interval is equal to r1/2.
amount of drug absorbed following each dose
administered.
2. The magnitude of the fluctuations between the
Summary of the effects of dose size and
maximum and minimum steady-state plasma
frequency of administration
concentrations are an important consideration
Consideration of the effects of dose size and the for any drug that has a narrow therapeutic
dosage interval on the amount of a given drug range, e.g. digoxin. The more frequent
achieved in the body, as measured by the plasma administration of smaller doses is a means of

282
 DOSAGE REGIMENS

Fig. 19.7 Diagrammatic representation of the effect of changing the dosing time interval, T, on the plasma concentration-time curve
obtained following repetitive peroral administration of equal size doses of a given drug. Curve A, dosing time interval = 3 hours (0.5tL).
Curve B, dosing time interval = 6 hours (t,_). Curve C, dosing time = 12 hours (2fL).

reducing the steady-state fluctuations without 5. If the maximum safe and minimum effective
altering the average steady-state plasma plasma drug concentrations are represented by
concentration. For example, a 500 mg dose the dashed lines shown in Figures 19.6 and
given every 6 hours will provide the same C^erage 19.7, respectively, then it is evident that the
value as a 250 mg dose of the same drug given proper selection of dose size and dosage time
every 3 hours, whereas the Cmax and Cmin interval are important with respect to achieving
fluctuation for the latter dose will be decreased and maintaining steady-state plasma
by half. concentrations that lie within the therapeutic
The average maximum and minimum amounts range of the particular drug being administered.
of drug achieved in the body at steady state are
influenced by either the dose size, the dosage It is evident from the preceding discussion that the
time interval in relation to the biological half-life proper selection of the dose size and the dosage time
of the drug, or both. The greater the dose size interval is crucial in ensuring that a multiple-dosage
and the smaller the dosage time interval relative regimen provides steady-state concentrations of
to the biological half-life of the drug, the greater drug in the body which are both clinically efficacious
are the average, maximum and minimum steady- and safe.
state amounts of drug in the body. Mathematical relationships that predict the values
For a given drug, the time taken to achieve of the various steady-state parameters achieved in
steady state is independent of dose size and the body following repetitive administration of doses
dosage time interval. at constant intervals of time have been used to assist

283
 BIOPHARMACEUTICAL PRINCIPLES OF DRUG DELIVERY

the design of clinically acceptable multiple dosage where the average steady-state plasma concentration
regimens. For example, a useful equation for pre- of drug, Coverage? is 16 mg L"1, the fraction of each
dicting the average amount of drug achieved in the administered dose absorbed, F = 0.9, the size of
body at steady state, /^average? following repetitive administered dose, D = 250 mg, the biological half-
peroral administration of equal doses, D, at a fixed life of the drug, r1/2 - 3 h, and the apparent volume of
time interval, T is: distribution, VA = 0.2 L kg"1 of patient's body weight.
Hence, for a patient weighing 76 kg the value of

where F is the fraction of drug absorbed following

the administration of a dose, D, of drug; thus F • D
To calculate the dosage time interval, T, requires sub-
is the bioavailable dose of drug, and tl/2 is the bio-
stitution of the above values into Eqn 19.7, which
logical half-life of that drug. The average amount of
gives:
a given drug in the body at steady state, -Overage is
related to the corresponding average plasma concen-
tration of the drug by the factor known as the
apparent volume of distribution, i.e.:

where Vd is the apparent volume of distribution of

the drug and Ca*erage is the average steady-state
plasma concentration. Equation 19.5 can be rewrit-
ten in terms of the average steady-state plasma con-
centration of the drug as follows:
Thus one 250 mg tablet should be administered
every 4 hours in order to achieve the required
averaged average steady-state plasma concentration.
If the value of the average body amount or the Mathematical equations which predict the
average plasma concentration of a given drug at maximum or minimum steady-state plasma concen-
steady state which gives a satisfactory therapeutic trations of a drug achieved in the body followed by
response in a patient is known, then Eqns 19.5 or repetitive administration of equal doses at a fixed
19.7 can be used respectively to estimate either the interval of time are also available for drugs whose
size of dose that should be administered repetitively time course in the body is described by the one-
at a preselected constant dosage time interval, or the compartment open pharmacokinetic model.
dosage time interval at which a preselected dose
should be administered repetitively. In order to illus-
trate a dosage regimen calculation, based on the
average steady-state plasma concentration of a drug,
The concept of 'loading doses'
consider the following worked example. As discussed earlier, the time required for a given
An antibiotic is to be administered on a repetitive drug to reach 95% of the average steady-state
basis to a male patient weighing 76 kg. The antibiotic plasma concentration is 4.3 biological half-lives,
is commercially available in the form of tablets, each when equal doses of the drug are administered
containing 250 mg of the drug. The fraction of the repetitively at equal intervals of time. Thus, for a
drug that is absorbed following peroral administration drug with a long half-life of 24 hours it would take
of one 250 mg tablet is 0.9. The antibiotic has been more than 4 days for the average concentration in
found to exhibit a biological half-life of 3 hours and the plasma to reach 95% of its steady-state value.
the patient has an apparent volume of distribution of Because the attainment of steady-state plasma con-
0.2 L kg"1 of body weight. What dosage time interval centrations is normally associated with the attain-
should be selected to administer this drug on a repet- ment of maximal clinical effectiveness of the drug, it
itive basis so that a therapeutic average steady-state is conceivable that a number of days could elapse
plasma concentration of 16 mg L"1 will be achieved? before a patient experienced the full therapeutic
Using Eqn 19.7: benefit of a drug having a long half-life. To reduce
the time required for onset of the full therapeutic
effect, a large single dose of the drug may be admin-

284
 DOSAGE REGIMENS

istered initially in order to achieve a peak plasma

Influence of changes in the apparent
concentration that lies within the therapeutic range
elimination rate constant of a drug: the
of the drug and is approximately equal to the value
problem of patients with renal
of C^ax required. This is known as the loading dose
impairment
or priming dose. Whereas the loading dose, maintenance dose and
Thereafter smaller, equal doses are administered dosage time interval may be varied in order to design
repetitively at suitable fixed intervals so as to main- a clinically efficacious multiple dosage regimen, one
tain the plasma concentrations of drug at the factor cannot normally be adjusted. This is the appar-
maximum, minimum and average state levels that ent elimination rate constant exhibited by the particu-
provide the patient with the full therapeutic benefit. lar drug being administered. However, the elimination
These are known as maintenance doses. As a rate constant of a given drug does vary from patient to
general rule, the loading dose should be twice the patient, and is influenced by whether the patient has
size of the maintenance dose if the selected dosage normal or impaired renal function.
time interval corresponds to the biological half-life of Figure 19.9 indicates the effects produced by
the drug. changes in the apparent elimination rate constant on
Figure 19.8 illustrates how rapidly therapeutic the plasma concentration-time curve obtained fol-
steady-state plasma concentrations of drug are lowing repetitive, peroral administration of equal
achieved when the dosage regimen consists of an doses of a given drug at equal intervals of time. Any
initial loading dose followed by equal maintenance reduction in the apparent elimination rate constant
doses at fixed intervals, compared to a 'simple' mul- will produce a proportional increase in the biological
tiple-dosage regimen consisting of doses that are half-life exhibited by the drug. This reduction, in turn,
equal in size and are administered at the same will result in a greater degree of accumulation of the
dosage time intervals as the maintenance doses. drug in the body following repetitive administration

Fig. 19.8 Diagrammatic representation of how the initial administration of a loading dose followed by equal maintenance doses at
fixed intervals of time ensure rapid attainment of steady-state plasma levels for a drug having a long biological half-life of 24 hours.
Curve A represents the plasma concentration-time curve obtained following peroral administration of a loading dose of 500 mg
followed by a maintenance dose of 250 mg every 24 hours. Curve B represents the plasma concentration-time curve obtained
following peroral administration of a 250 mg dose every 24 hours.

285
 BIOPHARMACEUTICAL PRINCIPLES OF DRUG DELIVERY

Fig. 19.9 Diagrammatic representation of the effect of changing the biological half-life of a given drug on the plasma
concentration-time curve exhibited by the drug following peroral administration of one 250 mg dose every 6 hours. Curve A, biological
half-life of drug = 6 hours. Curve B, biological half-life of drug = 12 hours.

before steady-state drug levels are achieved. The In order to illustrate this concept, consider that
greater degree of drug accumulation is a conse- curves A and B in Figure 19.9 correspond to the
quence of a smaller proportion of the drug being plasma concentration-time curves obtained for a
eliminated from the body over each fixed dosage given drug in patients having normal renal function
time interval when the biological half-life of the drug and severe renal impairment, respectively, and that
is increased. the upper and lower dashed lines represent the
Patients who develop severe renal impairment maximum safe and minimum effective plasma con-
normally exhibit smaller apparent elimination rate centrations, respectively. It is thus evident that the
constants and consequently longer biological half- administration of a drug according to a multiple-
lives for drugs which are eliminated substantially by dosage regimen which produces therapeutic steady-
renal excretion than do patients with normal renal state plasma levels in patients with normal renal
function. For instance, the average apparent elimina- function, will give plasma concentrations that exceed
tion rate constant for digoxin may be reduced from the maximum safe plasma concentration of the drug
0.021 h"1 in patients with normal renal function to in patients with severe renal impairment. Hence the
0.007 h"1 severe renal impairment. The average adjustment of multiple-dosage regimens in terms or
steady-state amount of drug in the body is only dose size, frequency of administration or both is nec-
achieved and maintained when the overall rate of essary if patients suffering with renal disease are to
supply equals the overall rate of elimination over suc- avoid the possibility of overmedication.
cessive dosing time intervals. Any reduction in the
overall rate of elimination of a drug as a result of
renal disease, without a corresponding compen-
Influence of the 'overnight no-dose
satory reduction in the overall rate of supply, will
period'
result in increased steady-state amounts of drug in So far we have considered that multiple-dosage reg-
the body. This effect in turn may lead to side-effects imens comprise of doses being administered at
and toxic effects if the increased steady-state levels uniform time intervals around the clock, but in prac-
exceed the maximum safe concentration of the drug. tice this is unusual. If a multiple-dosage regimen

286
 DOSAGE REGIMENS

requires a dose to be administered 'four times a day' maximum and minimum values over successive
it is unlikely that a dose will be administered at dosage time intervals, as would occur if the doses
6-hourly intervals around the clock. Instead, the four were administered every 4 hours around the clock.
doses are likely to be administered during 'waking' Furthermore, Figure 19.11 shows that even if a
hours, e.g. 10 am-2 pm -6 pm-10 pm or 9 am-1 loading dose of 120 mg were included in the dosage
pm-5 pm-9 pm.The significant feature of both these regimen to ensure that a true steady state was
schedules is that the patient will experience an obtained before the first overnight no-dose period, the
overnight no-dose period of 12 hours. Although steady state would not be re-established after the first
this will undoubtedly give the patient periods of overnight no-dose period. If the upper and lower
undisturbed sleep, it may also cause problems in dashed lines in Figures 19.10 and 19.11 represent the
maintaining therapeutic steady-state plasma concen- therapeutic range of the drug, then the patient would
trations of drug in the body. experience periods during which the level of drug in
It is conceivable that overnight no-dose periods of the plasma and body would fall below that necessary
8-12 hours could result in substantial decreases in to elicit the therapeutic effect. Hence, unless the ther-
the amount of a drug in the plasma and body, par- apeutic range of the drug is sufficiently large to
ticularly for drugs having biological half-lives which accommodate the fluctuations in concentration asso-
are relatively short compared to the overnight no- ciated with overnight no-dose periods, problems
dose period. For instance, in the case of a drug could arise with regard to maintaining therapeutic
having a biological half-life of 4 hours, an overnight drug levels in patients. The potential problems associ-
no-dose period of 12 hours would correspond to the ated with overnight no-dose periods are even further
elapse of three biological half-lives and consequently complicated by patients who forget to take one of their
a large reduction in the amount of drug in the body. daytime doses.
The potential problems of overnight no-dose
periods with respect to maintaining therapeutic
steady-state drug levels is illustrated in Figure 19.10.
Concluding comments
This shows that for a drug having a biological half- This chapter explains the interrelationship between
life of 4 hours, a multiple-dosage regimen compris- the rate at which drug enters the body and the rate
ing one 60 mg dose administered perorally four at which it leaves. It also discusses how, in turn, this
times each day according to the timetable 9 am-1 balance influences the concentration of drug in the
pm-5 pm-9 pm does not permit a true steady state plasma at any given time. It is clearly important for
to be attained. Thus the concentration of drug in the pharmaceutical scientists to come to terms with this
plasma does not fluctuate between constant problem and then overcome it by finding ways of

Fig. 19.10 Diagrammatic representation of the variation in the concentration of a drug in the plasma accompanying the peroral
administration of a single dose of 60 mg four times a day according to the time schedule 9 am-1 pm-5 pm-9 pm. The biological half-
life of the drug is 4 hours.

287
 BIOPHARMACEUTICAL PRINCIPLES OF DRUG DELIVERY

Fig. 19.11 Diagrammatic representation of the variation in the concentration of drug in the plasma accompanying the peroral
administration of a loading dose of 120 mg followed by single maintenance doses of 60 mg four times a day according to the time
schedule 9 am-1 pm-5 pm-9 pm. The biological half-life of the drug is 4 hours.

maintaining therapeutic drug levels appropriate to a

particular disease state. This can be achieved by the BIBLIOGRAPHY
careful design of the appropriate drug delivery
Gibaldi, M. (1991) Biopharmaceutics and Clinical
system. This aspect of the design and formulation of Pharmacokinetics, 4th edn. Lea & Febiger.
modified-release drug delivery systems is discussed Rowland, M. and Tozer, T.N. (1995) Clinical Pharmacokinetics:
fully in Chapter 20. Concepts and Applications, 3rd edn. Lea & Febiger.

288
20
Modified-release peroral dosage forms

John Collett, Chris Moreton

CHAPTER CONTENTS

Maintenance of therapeutic drug concentrations Hydrophilic colloid matrix systems 299

by modified-release peroral dosage forms 290 Principle of design of hydrophilic
Repeat-action versus sustained-action drug matrices 299
therapy 291 Types of hydrophilie matrix 299
Modified release 291 Advantages of hydrophilic matrix
Kinetic pattern of drug release required for the ideal systems 300
modified controlled-release perorat dosage Disadvantages of hydrophilic matrix delivery
form 292 systems 300
Formulation methods of achieving modified drug Components of hydrophilic matrix delivery
release 293 systems 300
Potential advantages of modified-release dosage Lubricants for hydrophilic delivery
forms over conventional dosage forms 294 systems 301
Potential limitations of peroral modified-release Drug release from hydrophilic colloid
dosage forms 294 matrices 301

Design of peroral modified-release drug delivery Membrane-controlled drug delivery systems 302
systems 295 Components of a membrane-controlled
Factors influencing design strategy 295 system 302
The physiology of the gastrointestinal tract and Core 302
drug absorption 295 Coating 302
Physicochemical properties of the drug 295 Single-unit systems 302
Choice of the dosage form 296 Core formulation for single-unit systems 302
Drug-release mechanisms 296 Multiple-unit systems 303
Constant release 296 Release-controlling membrane 303
Declining release 296 Advantages of membrane-controlled
Bimodal release 296 systems 303
Disadvantages of membrane-controlled
Formulation of modified-release dosage systems 304
forms 296 Osmotic pump systems 304
Components of a modified-release delivery Components of osmotic pump systems 304
system 296 Advantages of osmotic pump systems 304
Monolithic matrix delivery systems 297 Disadvantages of osmotic pump systems 304
Lipid matrix systems 297 Delivery systems for targeting to specific sites in
Principle of design 297 the gastrointestinal tract 304
Matrix formers 298 Gastric retentive systems 304
Chanelling agents 298 Colonic delivery systems 305
Solubilizers and pH modifiers 298
Antiadherent/glidant 298 References 305
Insoluble polymer matrix systems 298
Drug release from insoluble matrices 298 Acknowledgement 305

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 BIOPHARMACEUTICAL PRINCIPLES OF DRUG DELIVERY

regimens requiring frequent administration of

MAINTENANCE OF THERAPEUTIC DRUG conventional dosage forms, is often an important
CONCENTRATIONS BY MODIFIED- reason for therapeutic inefficiency or failure.
RELEASE PERORAL DOSAGE FORMS Clearly, not even a peroral dosage regimen
which has been designed to perfection can
For many disease states the ideal dosage regimen is achieve and maintain clinically efficacious
that by which an acceptable therapeutic concentra- concentrations of a drug at its site(s) of action if
tion of drug at the site(s) of action is attained imme- the patient does not comply with it.
diately and is then maintained constant for the These limitations and requirements led pharmaceu-
desired duration of the treatment. It is evident from tical scientists to consider presenting therapeutically
the preceding chapter that, provided dose size and active molecules in 'extended-release' preparations.
frequency of administration are correct, therapeutic In reality the scientists were attempting to take the
'steady-state' plasma concentrations of a drug can be control of medication away from the patient, and to
achieved promptly and maintained by the repetitive some extent the physician, and to place it in the drug
administration of conventional peroral dosage forms. delivery system.
However, there are a number of potential limitations Over the years there has been an enormous
associated with this. In the context of this section a amount of work put into designing drug delivery
'conventional' peroral oral dosage form is assumed
systems that can eliminate or reduce the cyclical
to be one that is designed to release rapidly the com- plasma concentrations seen after conventional drug
plete dose of drug contained therein immediately delivery systems are administered to a patient
following administration. In addition, the released according to a specified dosage regimen.
drug is assumed to be in a form which is therapeuti-
One of the first commercially available products to
cally active and immediately available for absorption provide sustained release of a drug was Dexedrine
into the systemic circulation. Spansules®, made by Smith Kline & French. After
These limitations are:
this many more sustained-release products came to
the market, some successful, others potentially
1. The concentration of drug in the plasma and lethal. Each delivery system was aimed at eliminating
hence at the site(s) of action of the drug the cyclical changes in plasma drug concentration
fluctuates over successive dosing intervals, even seen after the administration of a conventional deliv-
when the so-called 'steady-state' condition is ery system. A variety of terms was used to describe
achieved. Hence it is not possible to maintain a these systems:
therapeutic concentration of drug which
remains constant at the site(s) of action for the • Delayed release indicates that the drug is not
duration of treatment. At best, the mean value of being released immediately following
the maximum and minimum plasma administration but at a later time, e.g. enteric-
concentrations associated with each successive coated tablets, pulsatile-release capsules.
dose remains constant for the period of drug • Repeat action indicates that an individual dose
treatment. is released fairly soon after administration, and
2. The inevitable fluctuations of steady-state second or third doses are subsequently released
concentrations of drug in the plasma, and hence at intermittent intervals.
at the site(s) of action, can lead to a patient • Prolonged release indicates that the drug is
being over- or undermedicated for periods of provided for absorption over a longer period of
time if the values of C^ax and C^in (Chapter 19) time than from a conventional dosage form.
rise or fall, respectively, beyond the therapeutic However, there is an implication that onset is
range of the drug. delayed because of an overall slower release rate
3. For drugs with short biological half-lives from the dosage form.
frequent doses are required to maintain steady- • Sustained release indicates an initial release of
state plasma concentrations within the drug sufficient to provide a therapeutic dose soon
therapeutic range. For such drugs the after administration, and then a gradual release
maintenance of therapeutic plasma over an extended period.
concentrations is particularly susceptible to the • Extended release (ER) dosage forms release
consequence of forgotten doses and the drug slowly, so that plasma concentrations are
overnight no-dose period. Lack of patient maintained at a therapeutic level for a prolonged
compliance, which is more likely in the case of period of time (usually between 8 and 12 hours).

290
 MODIFIED-RELEASE PERORAL DOSAGE FORMS

• Controlled release (CR) dosage forms

release drug at a constant rate and provide
plasma concentrations that remain invariant with
time.
• Modified release (MR) dosage forms are
denned by the USP as those whose drug release
characteristics of time course and/or location are
chosen to accomplish therapeutic or convenience
objectives not offered by conventional forms,
whereas an extended-release (ER) dosage form
allows a twofold reduction in dosing frequency or
increase in patient compliance or therapeutic
performance. It is interesting to note that the
USP considers that the terms controlled release,
prolonged release and sustained release are Time following peroral administration of ONE dosage form
interchangeable with extended release. From a
Fig. 20.1 Plasma concentration-time curves obtained following
biopharmaceutical perspective this is not strictly peroral administration of (a) one repeat-action dosage form
a concern. containing two doses, and (b) one MR dosage form containing
the same drug. MSC = maximum safe concentration, MEC =
minimum effective concentration (see Chapter 19).
Repeat-action versus sustained-action
drug therapy
A repeat-action tablet or hard gelatin capsule may tration of a 'single dose'. Although all MR products
be distinguished from its sustained-released coun- could be described literally as controlled-release
terpart by the fact that the repeat-action product systems, the term 'controlled release' will only be
does not release the drug in a slow controlled used in this chapter to describe a peroral sustained-
manner, and consequently does not give a plasma release product which is able to maintain a constant
concentration-time curve which resembles that of a therapeutic steady-state concentration of drug in
sustained-release product. A repeat-action tablet the plasma, the tissues, or at the site of action. This
usually contains two doses of drug, the first being use of the term is in accordance with the proposals
released immediately following peroral administra- of Chien (1995).
tion in order to provide a rapid onset of the thera- The degree of precision of control over the rate
peutic response. The release of the second dose is of drug release from an MR dosage form varies
delayed, usually by means of an enteric coat. according to the particular formulation technique
Consequently, when the enteric coat surrounding employed. Consequently, depending on the
the second dose is breached by the intestinal fluids, degree of control over release (and consequently
the second dose is released immediately. Figure over drug absorption) that is achieved, peroral
20.1 shows that the plasma concentration-time MR products are generally designed to provide
curve obtained following the administration of one either:
repeat-action preparation exhibits the 'peak and
1. the prompt achievement of a plasma
valley' profile associated with the intermittent
concentration of drug that remains essentially
administration of conventional dosage forms. The
constant at a value within the therapeutic range
primary advantage provided by a repeat-action
of the drug for a satisfactorily prolonged period
tablet over a conventional one is that two (or occa-
of time, or
sionally three) doses are administered without the
2. the prompt achievement of a plasma
need to take more than one tablet.
concentration of drug which, although not
remaining constant, declines at such a slow rate
Modified release that the plasma concentration remains within the
therapeutic range for a satisfactorily prolonged
The term modified release (MR) will be used in
period of time.
this chapter to describe peroral dosage forms that
continuously release drugs at rates which are Typical drug plasma concentration-time profiles
sufficiently controlled to provide periods of pro- corresponding to the above criteria for modified-
longed therapeutic action following each adminis- release products are shown in Figure 20.2.

291
 BIOPHARMACEUTICAL PRINCIPLES OF DRUG DELIVERY

Fig. 20.2 Typical plasma concentration - time profiles for MR peroral products which, following rapid attainment of a therapeutic
plasma concentration of drug, provide a period of prolonged therapeutic action by either (a) maintaining a constant therapeutic plasma
concentration (curve A) or, (b) ensuring that the plasma concentration of drug remains within the therapeutic range for a satisfactorily
prolonged period of time (curve B).

Kinetic pattern of drug release required release and subsequent absorption of the initial
for the ideal modified controlled-release priming dose is the rapid attainment of a therapeutic
peroral dosage form concentration of drug in the body. This priming dose
provides a rapid onset of the desired therapeutic
If it is assumed that the drug which is to be incorpo-
response in the patient.
rated into the ideal MR dosage form confers upon
Following this period of rapid drug release, the
the body the characteristics of a one-compartment
portion Dm of drug remaining in the dosage form
open model, then the basic kinetic design of such a
is released at a slow but defined rate (see step 3 in
product may be represented diagrammatically as
Fig. 20.3). In order to maintain a constant plasma
shown in Figure 20.3.
level of drug, the maintenance dose, Dm, must be
To achieve a therapeutic concentration promptly
released by the dosage form according to zero-order
in the body and then to maintain that concentration
kinetics. It thus follows that the rate of release of
for a given period of time requires that the total drug
drug will remain constant and be independent of the
in the dosage form consists of two portions, one that
amount of the maintenance dose remaining in the
provides the initial priming/loading dose, Di3 and
dosage form at any given time. The rate of release of
one that provides the maintenance or sustained
the maintenance dose may be characterized by the
dose, Dm.
zero-order rate constant k^.
The initial priming dose of drug Di is released
Two further conditions must be fulfilled in order
rapidly into the gastrointestinal fluids immediately
to ensure that the therapeutic concentration of drug
following administration of the MR dosage form (see
in the body remains constant.
step 1 in Fig. 20.3). The released dose is required to
be absorbed into the body compartment rapidly fol- 1. The zero-order rate of release of drug from the
lowing a first-order kinetic process that is character- maintenance dose must be rate determining
ized by the apparent absorption rate constant, kla with respect to the rate at which the released
(see step 2 in Fig. 20.3). The aim of this initial rapid drug is subsequently absorbed into the body.

292
 MODIFIED-RELEASE PERORAL DOSAGE FORMS

Fig. 20.3 A one-compartment open model of drug disposition in which the source of drug input is an ideal MR peroral drug product.
Dj is the initial priming dose of drug in dosage form; Dm is the maintenance dose of drug in the dosage form; /r1a is the first-order
apparent absorption rate constant of drug from the priming dose; /t°m is the zero-order release rate constant of drug from the
maintenance dose.

The kinetics of absorption of the maintenance simply as MR products and may be differentiated
dose will thus be characterized by the same from their ideal counterparts by the following
zero-order release rate constant, k^ (step 3 in definition. A modified-release product/dosage form
Fig. 20.3). is a system in which a portion (the initial priming
2. The rate at which the maintenance dose is dose) of the drug is released immediately in order to
released from the dosage form, and hence the achieve the desired therapeutic response promptly.
rate of absorption (input) of drug into the body, The remaining dose of drug (the 'maintenance'
must be equal to the rate of drug output from dose) is then released slowly, thereby resulting in a
the body when the concentration of drug in the therapeutic drug/tissue drug concentration which is
body is at the required therapeutic value (see prolonged but not maintained constant.
step 4 in Fig. 20.3).
In practice, the design of an ideal modified- or Formulation methods of achieving
controlled-release product, which is capable of modified drug release
releasing the maintenance dose at a precise con-
trolled rate which is in mass balance with the rate of It is evident from the preceding discussion that for-
drug elimination corresponding to the required mulation techniques that permit rapid release of the
therapeutic concentration of drug in the plasma, is priming dose, followed by slow release of the main-
difficult to achieve. There are problems in achieving tenance dose, are required in order to design peroral
and maintaining zero-order release and absorption MR products. All MR formulations use a chemical
of the maintenance dose of drug in the presence of or physical 'barrier' to provide slow release of the
all the variable physiological conditions associated maintenance dose. Many formulation techniques
with the gastrointestinal tract (see Chapter 16). In have been used to 'build' the barrier into the peroral
addition, the apparent elimination rate constant of a dosage form. These include the use of coatings,
given drug varies from patient to patient, depending embedding of the drug in a wax or plastic matrix,
on such factors as genetic differences, age differ- microencapsulation, chemical binding to ion-
ences and differences in the severity of disease. exchange resins, and incorporation in an osmotic
Consequently it is likely that most peroral MR pump. The initial rapidly releasing priming dose may
products in current use will not fall into the cate- be provided by incorporating that portion of the
gory of ideal MR/controlled-release peroral dosage drug in a separate, rapidly releasing form in the
forms. However, such products may be referred to dosage form, for instance as uncoated, rapidly releas-

293
 BIOPHARMACEUTICAL PRINCIPLES OF DRUG DELIVERY

ing granules or pellets in a tablet or hard gelatin Potential limitations of peroral modified-
capsule. Alternatively, immediate and rapid release release dosage forms
of the priming dose has been achieved by that
portion of the drug being positioned at the surface of 1. Variable physiological factors, such as
a porous wax or plastic matrix. gastrointestinal pH, enzyme activities, gastric
and intestinal transit rates, food and severity of
disease, which often influence drug
Potential advantages of modified-release bioavailability from conventional peroral dosage
dosage forms over conventional dosage forms, may also interfere with the precision of
forms control of release and absorption of drugs from
peroral MR dosage forms. The achievement and
1. Improved control over the maintenance of maintenance of prolonged drug action depends
therapeutic plasma drug concentration of drugs on such control.
permits: 2. The rate of transit of MR peroral products along
(a) improved treatment of many chronic the gastrointestinal tract limits the maximum
illnesses where symptom breakthrough period for which a therapeutic response can be
occurs if the plasma concentration of drug maintained following administration of a 'single
drops below the minimum effective dose' to approximately 12 hours, plus the length
concentration, e.g. asthma, depressive of time that absorbed drug continues to exert its
illnesses; therapeutic activity.
(b) maintenance of the therapeutic action of a 3. MR products, which tend to remain intact, may
drug during overnight no-dose periods, e.g. become lodged at some site along the
overnight management of pain in terminally gastrointestinal tract. If this occurs, slow release
ill patients permits improved sleep; of the drug may produce a high localized
(c) a reduction in the incidence and severity of concentration that causes local irritation to the
untoward systemic side-effects related to high gastrointestinal mucosa. MR products which are
peak plasma drug concentrations; formulated to disperse in the gastrointestinal
(d) a reduction in the total amount of drug fluids are less likely to cause such problems.
administered over the period of treatment. 4. There are constraints on the types of drugs that
This contributes to the reduced incidence of are suitable candidates for incorporation into
systemic and local side-effects observed in peroral MR formulations. For instance, drugs
the cases of many drugs administered in MR having biological half-lives of 1 hour or less are
formulations. difficult to formulate for modified release. The
2. Improved patient compliance, resulting from high rates of elimination of such drugs from the
the reduction in the number and frequency of body mean that an extremely large maintenance
doses required to maintain the desired dose would be required to provide 8-12 hours of
therapeutic response, e.g. one peroral MR continuous therapy following a single
product every 12 hours contributes to the administration. Apart from the potential hazards
improved control of therapeutic drug of administering such a large dose, the physical
concentration achieved with such products. size of the MR dosage form could make it
3. There is a reduction in the incidence and difficult to swallow. Drugs having biological half-
severity of localized gastrointestinal side-effects lives between 4 and 6 hours make good
produced by 'dose dumping' of irritant drugs candidates for inclusion in MR formulations.
from conventional dosage forms, e.g. potassium Factors other than the biological half-life can
chloride. The more controlled, slower release of also preclude a drug from being formulated as
potassium chloride from its peroral MR an MR product. Drugs that have specific
formulations minimizes the build-up of localized requirements for their absorption from the
irritant concentrations in the gastrointestinal gastrointestinal tract are poor candidates. In
tract. Consequently, potassium chloride is now order to provide a satisfactory period of
administered perorally almost exclusively in MR prolonged drug therapy, a drug is required to be
form. well absorbed from all regions as the dosage
4. It is claimed that cost savings are made from the form passes along the gastrointestinal tract.
better disease management that can be achieved 5. MR products normally contain a larger total
with MR products. amount of drug than the single dose normally

294
 MODIFIED-RELEASE PERORAL DOSAGE FORMS

administered in a conventional dosage form. The aqueous solubility and intestinal permeability
There is the possibility of unsafe overdosage if of drug compounds are of paramount importance. A
an MR product is improperly made and the total classification has been made (Amidon et al 1995)
drug contained therein is released at one time or whereby drugs can be considered to belong to one of
over too short a time interval. Consequently, it four categories:
may be unwise to include very potent drugs in
• high solubility and high permeability (best case);
such formulations.
• high solubility and low permeability;
6. As a general rule, MR formulations cost more
• low solubility and high permeability;
per unit dose than conventional dosage forms
• low solubility and low permeability (worst case).
containing the same drug. However, fewer 'unit
doses' of an MR formulation should be required. This is now codified as the Biopharmaceutical
Classification System (see Chapter 18 for further
details).
Consider first the influence of solubility. A drug
DESIGN OF PERORAL MODIFIED- that is highly soluble at intestinal pH and absorbed
RELEASE DRUG DELIVERY SYSTEMS by passive diffusion (i.e. not site-specific absorption)
would probably present the ideal properties for
Factors influencing design strategy inclusion in an MR dosage form. However, there
may be some problems associated with the choice of
Having made the decision that a drug is to be actual formulation. At the other end of the scale,
included in a modified-release delivery system compounds that have a low aqueous solubility (< 1 mg
intended for oral administration, it is necessary to mL^1) may already posses inherent sustained-release
take account of the physiology of the gastrointestinal potential as a result of their low solubility. The innate
tract; the physicochemical properties of the drug; the advantages of low aqueous solubility in relation to
design of the dosage form; the drug release mecha- modified release would be negated if the drug also
nism; the particular disease factors; and the biologi- had low membrane permeability.
cal properties of the drug. All of these can influence Having achieved dissolution of the drug in the gas-
or interact with one another. trointestinal tract then permeability considerations
become important. An indication of drug permeabil-
The physiology of the gastrointestinal tract and ity values can be obtained using Caco-2 tissue
drug absorption culture models (see Chapter 18). More than 90%
absorption in vivo may be expected for compounds
The influence of gastrointestinal physiology on drug with permeability, P, values > 4 x 10~6 mm s"1,
delivery is discussed in detail in Chapter 16. It whereas less than 20% absorption is expected when
should also be noted that the residence time of a P is <0.5 x 10~6 mm s'1 (Bailey et al 1996). Drug
dosage form in the gastrointestinal tract is influenced candidates with a permeability <0.5 x 10^6 mm s*1
by both stomach emptying time and intestinal transit are likely to be unsuitable for presentation as MR
time. It has been reported that:
preparations.
• solution and pellets (<2 mm) leave the stomach Drug compounds that satisfy the solubility and
rapidly; permeability requirements should also ideally have:
• single dose units (>7 mm) can stay in the • a biological half-life of between two and six
stomach for up to 10 hours if the delivery system
hours so that accumulation in the body does not
is taken with a heavy meal; occur
• the transit time through the small intestine is
• a lack of capability to form pharmacologically
approximately 3 hours. active metabolites by, for example, first-pass
metabolism. Modified release is actually used for
Physicochemical properties of the drug drugs which undergo first-pass metabolism but
Several physicochemical properties of the active this should not be to such an extent that only
drug can influence the choice of dosage form. This is inactive metabolites are left after absorption
discussed fully in Chapter 17; these properties • a dosage not exceeding 125-325 mg in order to
include aqueous solubility and stability; pK^, parti- limit the size of the delivery system. There are a
tion coefficient (or, more appropriately, permeability few examples where this dose is exceeded, e.g.
values) and salt form. Brufen Retard.

295
 BIOPHARMACEUTICAL PRINCIPLES OF DRUG DELIVERY

Choice of the dosage form Bimodal release Although constant drug release
may be ideal, this may not always be the case. If the
The first decision to be made is whether to formu- gastrointestinal tract behaves as a one-compartment
late the active ingredient as a single or a multiple model (Chapter 19), i.e. the different segments are
unit system. Single-unit dosage forms include homogeneous, then the situation is ideal. However,
tablets, coated tablets, matrix tablets and some cap- we know from Chapter 16 that absorption rate is not
sules. A multiple-unit dosage form includes gran- invariant along the gastrointestinal tract. So, whatever
ules, beads, capsules and microcapsules. happens, the rate of release from the dosage form
Modified-release dosage forms include inert insol- must regulate drug absorption - in other words,
uble matrices, hydrophilic matrices, ion-exchange release rate must always be slower than absorption
resins, osmotically controlled formulations and rate. This situation may not be easy to achieve: a
reservoir systems. release rate suited to absorption from the intestine
The selection of the appropriate dosage form will may be far too great for that required in the stomach
need to take account of an acceptable level of vari- or colon. One possible solution to this problem is to
ability of performance, the influence of GI tract prepare a dosage form that provides a rapid initial
structure and function on the delivery system, and delivery of drug followed by a slower rate of delivery
the release mechanism and release profile of the and then an increased rate at a later time.
dosage form.

Drug-release mechanisms
The two basic mechanisms controlling drug release
FORMULATION OF MODIFIED-RELEASE
are dissolution of the active drug component and the
DOSAGE FORMS
diffusion of dissolved or solubilized species. Within
the context of these mechanisms there are four
For convenience of description oral modified release
processes operating:
delivery systems can be considered under the follow-
• Hydrating of the device (swelling of the ing headings:
hydrocolloid or dissolution of the channelling
• Monolithic or matrix systems
agent)
• Reservoir or membrane-controlled systems
• Diffusion of water into the device
• Osmotic pump systems.
• Dissolution of the drug
• Diffusion of the dissolved (or solubilized) drug These are the main classes of delivery system and
out of the device. they are considered in turn below. However, there
are other systems and the above is not an exhaustive
These mechanisms may operate independently,
list.
together or consecutively.
There is a basic principle that governs all these
Drug delivery systems can be designed to have
systems. In a solution, drug diffusion will occur from
either continuous release, a delayed gastrointestinal
a region of high concentration to a region of low
transit while continuously releasing, or delayed release.
concentration. This concentration difference is the
Drug release may be constant, declining or bimodal.
driving force for drug diffusion out of a system.
Constant release The general belief has been that Water diffuses into the system in an analogous
the ideal MR system should provide and maintain manner. There is an abundance of water in the sur-
constant drug plasma concentrations. This led to
rounding medium and the system should allow water
considerable effort being put into developing
penetration. The inside of the system normally has a
systems that release drugs at a constant rate.
lower water content initially than the surrounding
(Although with the advent of chronotherapy, i.e.
medium.
drug delivered at both the appropriate time and rate,
zero-order release may not be such a desirable goal
in the future.) In general these systems rely on diffu- Components of a modified-release
sion of the drug or, occasionally, osmosis. delivery system
Declining release Drug release from these systems These include:
is commonly a function of the square root of time or
follows first-order kinetics. These systems cannot • active drug;
maintain a constant plasma drug concentration but • release-controlling agent(s): matrix formers,
can provide sustained release. membrane formers;

296
 MODIFIED-RELEASE PERORAL DOSAGE FORMS

a solvent enters the matrix and dissolves the

Table 20.1 Suitable excipients for modified-release
dosage forms categorized as inert, lipid or hydrophilic particles (lipid matrices and insoluble
polymer matrices}.
Inert excipients
Drugs dispersed in a soluble matrix rely on a slow
Dibasic calcium phosphate
Ethyl cellulose dissolution of the matrix to provide sustained
Methacrylate copolymer release. Excipients used to provide a soluble matrix
Polyamide often are those used to make soluble film coatings.
Polyethylene Alternatively, slowly dissolving fats and waxes can be
Polyvinyl acetate
used. Synthetic polymers, such as polyorthoesters
Lipid excipients and polyanhydrides, have been used. These undergo
Carnauba wax
Cetyl alcohol
surface erosion with little or no bulk erosion. If the
Hydrogenated vegetable oils matrix is presented with a conventional tablet geom-
Microcrystalline waxes etry, then on contact with dissolution media the
Mono- and triglycerides surface area of the matrix decreases with time, with
PEG monostearate a concomitant decrease of drug release.
PEG
Hydrophilic excipients Drug particles may be incorporated into an insol-
Alginates uble matrix. Drug release from these matrices
Carbopol follows penetration of fluid, followed by dissolution
Gelatin of the drug particles and diffusion through fluid-
Hydroxypropylcellulose
Hydroxypropyl methylcellulose filled pores. This type of delivery system would not
Methylcellulose be suitable for the release of compounds that are
insoluble or which have a low aqueous solubility.
Excipients used in the preparation of insoluble
• matrix or membrane modifier, such as channelling matrices include hydrophobic polymers, such as
agents for wax matrices and solubilizers, and polyvinyl acetate, ethylcellulose and some waxes.
wicking agents for hydrophilic matrices; It is useful to consider each of the matrix systems
• solubilizer, pH modifier and/or density modifiers; mentioned above separately.
• lubricant and flow aid, such as magnesium
stearate, stearic acid, hydrogenated vegetable oil,
sodium stearyl fumarate, talc, colloidal silicon Lipid matrix systems
dioxide; Principle of design Wax matrices are a simple
• supplementary coatings to extend lag time, concept. They are easy to manufacture using stan-
further reduce drug release, etc.; dard direct compression, roller compaction or hot-
• density modifiers (if required). melt granulation.
These types of components are virtually the same for The matrix compacts are prepared from blends of
all oral solid MR dosage forms. The differences are powdered components. The active compound is con-
in the excipients, how they are incorporated into the tained in a hydrophobic matrix that remains intact
formulation and what role they play. during drug release. Release depends on an aqueous
The delivery systems may also be classified as medium dissolving the channelling agent, which
inert, lipid or hydrophilic, depending on the nature of leaches out of the compact so forming a porous
the excipients used. Suitable excipients for modified- matrix of tortuous capillaries. The active agent dis-
release dosage systems are listed in Table 20.1. solves in the aqueous medium and, by way of the
water-filled capillaries, diffuses out of the matrix.
Monolithic matrix delivery systems Wax matrices are a simple unsophisticated delivery
system with a fairly coarse control of rate and extent
These systems can be considered as two groups: of drug release. The release is generally not zero order
• Those with drug particles dispersed in a soluble and there are few opportunities to modify it.
matrix, with drug becoming available as the These matrices are not now in common usage, but
matrix dissolves or swells and dissolves the concept is worth considering. A typical formula-
(hydrophilic colloid matrices}; tion consists of:
• Those with drug particles dispersed in an • active drug
insoluble matrix, with drug becoming available as • wax matrix former

297
 BIOPHARMACEUTICAL PRINCIPLES OF DRUG DELIVERY

• channelling agent ticles. The concept of using inert matrices as drug

• solubilizer and pH modifier delivery systems was considered in the late 1950s
• antiadherent/glidant and led to the development of Duretter (Astra
• lubricant. Hassle) and Gradumet (Abbott) technologies, and
Matrix formers Hydrophobic materials that are products such as Ferro-Gradumet (Abbott). There
solid at room temperature and do not melt at body have been concerns that residual catalysts and initia-
temperature are used as matrix formers. These tors used in the preparation of the polymer(s) of the
include hydrogenated vegetable oils, cottonseed, oil, matrix could be leached along with active drug. The
soya oil, microcrystalline wax and carnauba wax. In matrices remain intact during gastrointestinal
general such waxes form 20-40% of the formulation. transit, and there have also been concerns that
Channelling agents Channelling agents are impaction may occur in the large intestine and that
chosen to be soluble in the gastrointestinal tract and patients may be concerned to see the matrix 'ghosts'
to leach from the formulation, so leaving tortuous in stools. More recently there has been renewed
capillaries through which the dissolved drug may interest in this type of matrix, and polymers such as
diffuse in order to be released. The drug itself can be ethylcellulose are finding favour.
a channelling agent, but a water-soluble pharmaceu- The release rate of a drug from an inert matrix can
tically acceptable solid material is more likely to be be modified by changes in the porosity and tortuos-
used. Typical examples include sodium chloride, ity of the matrix, i.e. its pore structure. The addition
sugars and polyols. The choice will depend on the of pore-forming hydrophilic salts or solutes will have
drug and the desired release characteristics. These a major influence, as can the manipulation of pro-
agents can be 20-30% of the formulation. cessing variables. Compression force controls the
Solubilizers and pH modifiers It is often necessary porosity of the matrix, which in turn controls drug
to enhance the dissolution of the drug. This may be release. Generally a more rigid and less porous
achieved by the inclusion of solubilizing agents, such matrix will release drug more slowly than a less con-
as PEGs, polyols or surfactants. If the drug is ioniz- solidated matrix.
able then the inclusion of buffers or counter-ions The addition of excipients, such as lubricants,
may be appropriate. On occasions the dissolution fillers etc., is a necessary part of the formulation
enhancer may also be the channelling agent. process. However, the presence of excipients is likely
Antiadherent/glidant Heat generated during com- to influence drug release. It may be anticipated that
paction of the matrix can cause melting of the wax water-soluble excipients will enhance the wetting of
matrix-forming compound and sticking to the the matrix, or increase its tortuosity and porosity on
punches. Something is needed to cope with the stick- dissolution. Insoluble excipients will tend to
ing; suitable antiadherents include talc and colloidal decrease the wettability of the matrix and reduce the
silicon dioxide. penetration of the dissolving medium.
These materials also act as glidants and improve The particle size of the insoluble matrix compo-
the flow of formulations on the tablet machine. The nents influences release rate, larger particles leading
typical amounts used will depend on the antiadher- to an increase in release rate. This is attributed to
ent used, for example 0.5-1% for colloidal silicon these coarser particles producing matrices with a
dioxide and 4-6% for talc. more open pore structure.
This type of formulation usually does not need a An increase in drug loading tends to enhance
lubricant per se, as the fats are themselves liquid-film release rate, but the relationship between the two is
lubricants (i.e. they melt during compaction). not clearly defined. One possible explanation may be
Magnesium stearate, if added, can also act as an a decrease in the tortuosity of the matrix. As may be
antiadherent. expected, release rate can be related to drug solubility.
Drug release from insoluble matrices The release
Insoluble polymer matrix systems of drugs from insoluble matrices has been investi-
gated and four types of drug matrix system can be
An inert matrix system is one in which a drug is considered:
embedded in an inert polymer which is not soluble
• Drug molecularly dissolved in the matrix and
in the gastrointestinal fluids. Drug release from inert
drug diffusion occurs by a solution-diffusion
matrices has been compared to the leaching from a
mechanism;
sponge. The release rate depends on drug molecules
• Drug dispersed in the matrix and then, after
in aqueous solution diffusing through a network of
dissolution of the drug, diffusion occurs via a
capillaries formed between compacted polymer par-
solution-diffusion mechanism;

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 MODIFIED-RELEASE PERORAL DOSAGE FORMS

• Drug dissolved in the matrix and diffusion occurs On contact with water the hydrophilic colloid compo-
through water-filled pores in the matrix; nents swell to form a hydrated matrix layer. This then
• Drug dispersed in the matrix and then, after controls the further diffusion of water into the matrix.
dissolution, diffusion occurs through water-filled Diffusion of the drug through the hydrated matrix
pores. layer controls its rate of release. The outer hydrated
matrix layer will erode as it becomes more dilute; the
The amount of drug released from matrix dosage
rate of erosion depends on the nature of the colloid.
forms is normally proportional to the square root of
Hydrophilic colloid gels can be regarded as a
the time of exposure to the dissolution medium:
network of polymer fibrils that interlink in some way.
There is also a continuous phase in the interstices
between the fibrils through which the drug diffuses.
where Mt is the amount of drug released with time r,
These interstices connect together and are analo-
and K is a constant.
gous to the tortuous capillaries seen in wax matrices.
The amount of drug released decreases with time of
The tortuosity of the diffusion path and the 'micro-
exposure to the dissolution medium. The reason for
viscosity' and interactions within the interstitial con-
this is that the drug is released initially from the
tinuum govern the diffusion of the drug through the
surface region, and there is then only a short diffusion
hydrated gel layer, and hence the release of the drug.
pathway. As the period of dissolution progresses, the
area of drug exposed to dissolution medium
Types of hydrophilic matrix
decreases. Also, an ever-increasing 'zone of depletion'
True gels These systems interact in the presence
is formed within the matrix as the drug dissolves, and
of water to form a crosslinked polymeric structure
so the diffusion pathway increases in length.
with a continuous phase trapped in the interstices of
A simple exponential relationship has been used to
the gel network. The crosslinks are more than just
characterize drug release from non-swelling delivery
random hydrogen bonds between adjacent polymer
svstems:
chains (e.g. alginic acid in the presence of di or triva-
lent cations, gelatin): here they limit the mobility of
the polymer chains and give a structure to the gel
where MJMa is the fractional solute release, K is a (Fig. 20.4). The crosslinks can be chemical bonds or
constant and n is the diffusional exponent. physical bonds, e.g. triple-helix formations in gelatin
The numerical value of the diffusional exponent is gels which are based on hydrogen bonds. The por-
indicative of the release mechanism and is influenced tions of the polymer chains between crosslinks can
by the matrix aspect ratio (i.e. diameter:length move, but the crosslinks restrict the overall move-
ratio). If the matrix is presented as a thin film a value ment of the chains.
of n = 0.5 would be indicative of Fickian diffusion, Viscous or 'Viscolized' matrices Not all matrix
whereas values of n not equal to 0.5 are indicative of systems form 'true' gels: in reality some are more
anomalous or non-Fickian process. Zero-order
release is considered to be happening if n - 1.0. In
other words, the rate of surface erosion is controlling
the rate of drug release and not its rate of diffusion
within the matrix.

Hydrophilic colloid matrix systems

These delivery systems are also called swellable- Fig. 20.4. Representation of a 'true' gel matrix.
soluble matrices. In general they comprise a com-
pressed mixture of drug and water-swellable
hydrophilic polymer. The systems are capable of
swelling, followed by gel formation erosion and dis-
solution in aqueous media. Their behaviour is in
contrast to a true hydrogel, which swells on hydra-
tion but does not dissolve.
Principle of design of hydrophilic matrices The
system comprises a mixture of drug, hydrophilic
colloid, any release modifiers and lubricant/glidant. Fig. 20.5 Representation of a 'viscolized' matrix.

299
 BIOPHARMACEUTICAL PRINCIPLES OF DRUG DELIVERY

• Uses readily available pharmaceutical

Table 20.2 Comparison of different types of
hydrocoffoid matrix manufacturing equipment;
• Possible to obtain different types of release
True gels Viscous matrices profile: zero order, first order, biomodal etc.
Disadvantages of hydrophilic matrix delivery systems
The diffusion pathway is The diffusion pathway is
via the continuous phase via the continuous phase • Release of the drug is dependent on two
in the interstices of the gel trapped between the diffusion processes, penetration of the water
adjacent polymeric chains through the hydrated matrix into the non-
The crosslinks are more There are no 'fixed' hydrated core, and diffusion of the dissolved drug
or less 'fixed' after the gel cross-links through the hydrated matrix.
has formed • If the outer layer of the hydrated matrix erodes,
The bulk viscosity of the gel The bulk viscosity is this can complicate the release profile.
is derived from the structure related to the • Requires batch-to-batch consistency in the
of the crosslinked polymeric entanglement of adjacent matrix-forming materials, other components and
chains with a contribution polymer chains which are
from the continuous phase free to move within the process parameters.
continuous phase • Scale-up of manufacture can be a problem.
Bulk viscosity generally Bulk viscosity may
• Need optimal rate-controlling polymers for
does not correlate well correlate with diffussion different actives.
with diffusion These matrices are comparatively simple in concept.
Diffusion in the gel correlates However, the events following hydration can be quite
with 'microviscosity' complex.
The key is that there are two diffusion processes
(water in and then drug out). The drug will only
diffuse through a hydrated gel layer. This really only
properly described as very viscous solutions. In the applies to drugs that are solid at room temperature.
presence of water these systems form a matrix in Liquid drugs may diffuse in the non-hydrated state
which the increased viscosity occurs as a result of and would not be suitable for some types of system.
simple entanglement of adjacent polymer chains, Components of hydrophilic matrix delivery systems
but without proper crosslinking (Fig. 20.5). It is a • Active drug
dynamic structure. The chains are able to move rel- • Hydrophilic colloid (s)
ative to one another and the drug diffuses through • (Matrix modifier)
the interstitial continuum, but the pathway is not • (Solubilizer and/or pH modifier)
fixed. Examples are hydroxypropyl methylcellulose • Compression aid
and sodium alginate in water. • Lubricant
Comparison of different types of hydrocolloid matrix • (Glidant).
The differences between the various different types Those components listed in parentheses are optional
of hydrocolloid matrix are summarized in Table and not always necessary.
20.2. It should be appreciated that these are Matrix-forming agents for hydrophilic matrices
simplifications. In general bulk viscosity is not a good Hydrophilic colloids which, on contact with water,
test for the functionality of either system. It may be form a hydrated gel that remains 'sufficiently intact'
satisfactory as a quality control test for the matrix- during passage through the gastrointestinal tract are
forming materials. suitable matrix-forming agents for hydrophilic
Advantages of hydrophilic matrix systems matrices. Examples of hydrophilic colloids include:
• Comparatively simple concept; • Hydroxypropyl methylcellulose (high-viscosity
• Excipients are generally cheap and are usually grades)
GRAS (generally regarded as safe); • Sodium carboxymethyl cellulose
• Capable of sustaining high drug loadings; • Alginates
• Erodible, so reducing the possibility of 'ghost' • Xanthan gum
matrices; • Xanthan gun/locust bean gum combinations
• Easy to manufacture using commonly available • Carbopol.
equipment, by direct compression, wet These agents generally occupy 20-80% of the mass;
granulation or roller compaction; the actual amount will depend on the drug and the
• Well established technology; desired release characteristics.

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 MODIFIED-RELEASE PERORAL DOSAGE FORMS

Hydration and swelling are the key factors in the Lubricants for hydrophilic delivery systems As with
functioning of a hydrophilic matrix, as has already any tablet compacted on a tablet machine, a lubricant
been stated. is necessary. Lubricants can have four functions:
Gel modifiers for hydrophilic matrix delivery systems
These are materials that are incorporated into the • Reduce interparticulate friction during
matrix to modify the diffusional characteristics of the compression and compaction;
gel layer, very often to enhance drug diffusion and • Reduce die-wall friction;
hence release of the drug. Examples include sugars, • Prevent sticking to the punches;
polyols and soluble salts. • Improve flow of the formulation on to the
The type of modifier will depend very much on machine and into the die.
the chemical nature of the hydrocolloid(s) used. The requirement for lubricants for hydrophilic
They may also modify the rate and extent of hydra- matrix tablets are no different from those for any
tion of the hydrophilic matrix material. other tablet, and are thus analogous to those for con-
Gel modifiers can have a number of other func- ventional immediate-release tablets and capsules.
tions. For example, they may act: Generally the choice is not governed by the same
• to allow more complete, more uniform hydration constraints as in immediate release. For example,
of the gel matrix; overblending or excess magnesium stearate may not
• to allow more rapid hydration of the gel matrix; be a major problem here.
• to associate with the matrix molecules and thus It is not essential that the lubricant is soluble.
to influence the interactions at a molecular level, Such lubricants are available but are generally not
e.g. crosslinking; very effective and tend to be reserved for efferves-
• to modify the environment in the interstices of the cent products.
gel, either to speed up or slow down diffusion; Suitable lubricants and recommended concentra-
• to suppress or promote the ionization of ionizable tions to be included in the formulation are listed in
polymers. Table 20.3.
Drug release from hydrophilic colloid matrices The
Few materials will have only a single action. It is classic description of the events following immersion
more likely that they will work in several ways. of a matrix in aqueous media are as follows:
Solubilizers and pH modifiers for drugs in
hydrophilic matrices Many drugs will not dissolve • Surface drug (if water soluble) dissolves and
sufficiently in gastrointestinal fluids to allow them gives a 'burst effect'.
to be released from a hydrophilic colloid matrix. • The hydrophilic polymer hydrates and an outer
Dissolution can be improved by the inclusion of gel layer forms.
solubilizing agents (e.g. PEGs, polyols, surfactants • The gel layer becomes a barrier to uptake of
etc.). The only restriction is that the formulation further water and to the transfer of drug.
can be formed into a tablet and that the material is
acceptable. Many drugs are ionizable. The inclu- Table 20.3 Concentration of lubricants used in
sion of appropriate counter-ions can facilitate hydrophilic matrix systems
release from the system. Some materials can act as
both dissolution enhancer and matrix modifier: the Lubricants %
amount of excipient needed will be determined by
Hydrophobia lubricants
the amount of drug. Magnesium stearate 0.25-2
The above relates to the drug molecule, rather Calcium stearate 0.25-2
than the matrix material. It is necessary for any drug Stearic acid 1-4
to be in solution for diffusion to occur. For insoluble Hydrogenated vegetable oil 1-4
drugs, solubilization is therefore an important con- Hydrophilic lubricants (the latter two examples are only
sideration. partially soluble in water)
With some gel materials the use of certain ions Glyceryl palmitostearate 0.5-5
Glyceryl behenate 2-5
causes changes in the nature of the gel matrix. Sodium stearyl fumarate 0.25-2
The solubilizers and pH modifiers might also
Inorganic lubricants
influence the release process through a direct effect Colloidal silicon dioxide 0.05-0.25 as glidant
on the matrix. Different materials could augment 0.2-0.5 as antiadherent
crosslinking, whereas others might perhaps weaken Talc 1-4 as antiadherent
the crosslinks.

301
 BIOPHARMACEUTICAL PRINCIPLES OF DRUG DELIVERY

• Drug (if soluble) release occurs by diffusion Aqueous medium diffusing into the system and
through the gel layer; insoluble drug is released forming a continuous phase through the membrane
by erosion followed by dissolution. initiates drug diffusion and release.
• Following erosion the new surface becomes The essential difference between a membrane
hydrated and forms a new gel layer. and a matrix system is that in the former the
polymer membrane is only at the surface of the
It may be anticipated that the relative importance of
system, whereas in the latter the polymer is through-
each release mechanism will depend on the physico-
out the whole system. In both cases the hydration of
chemical properties of the gel layer; the aqueous sol-
the polymer is the step that allows the drug to
ubility of the drug; and the mechanical attrition of
diffuse. With the classic membrane system there are
the matrix in the aqueous environment.
the two diffusion processes: 'water in' followed by
When a drug/glassy polymer matrix is placed in an
'drug out'.
aqueous environment, the water penetrates the
The delivery systems may be presented either as
polymer network. As the amount of water increases a
single or as multiple unit.
transition from a glassy to a rubbery state occurs as
the glass transition temperature is decreased by the
presence of water to the temperature of the medium. Components of a membrane-controlled system
The intake of solvent (water) induces stresses within Core
the matrix polymer. Eventually the matrix polymer • Active drug
relaxes, and this manifests itself as swelling. It is pos- • Filler or substrate
sible to differentiate three 'fronts' during hydration: • (Solubilizer)
eroding, diffusing and swelling. • Lubricant/glidant.
The actual drug release mechanism depends on
the relative contributions of swelling and dissolu- The exact composition of the core formulation will
tion. Drug release from swellable, soluble matrices depend on the formulation approach adopted.
is constant when swelling and eroding fronts syn- Coating
chronize, but is non-linear when this is not the case. • Membrane polymer
The release of sodium diclofenac from PVA and • Plasticizer
from HPMC matrices has been investigated. It was • (Membrane modifier)
noted that if the fronts synchronized then the gel • (Colour/opacifier).
layer thickness was constant and zero-order release
was observed. When synchronization did not take Single-unit systems
place the gel layer tended to increase in thickness
This is essentially a tablet formulation, but with dif-
and there was a decrease in the amount released,
ferences from conventional dosage forms in that
providing non-linear kinetics.
modified-release tablet cores should not disintegrate
but dissolve; and a formulation is required that
Membrane-controlled drug delivery allows water to penetrate and the drug to dissolve so
systems that diffusion can occur.
Membrane-controlled delivery systems function as Core formulation for single-unit systems Generally,
follows. The rate-controlling part of the system is a water-insoluble materials that compact by brittle
membrane through which the drug must diffuse. To fracture are not suitable if used alone. Suitable
allow the drug to diffuse out, the membrane has to fillers include lactose, microcrystalline cellulose,
become permeable, e.g. through hydration by water dextrose, sucrose and polyols (mannitol, sorbitol,
normally present in the gastrointestinal tract, or by xylitol etc.).
the drug being soluble in a membrane component, Care is needed in the choice of soluble fillers to
such as the plasticizer. Unlike hydrophilic matrix minimize osmotic effects. An inappropriate choice
systems, the membrane polymer does not swell on will result in increased internal osmotic pressure fol-
hydration to form a hydrocolloid matrix, and does lowed by rupture of the release-controlling mem-
not erode. brane. The choice of solubilizer (if required) will be
A drug reservoir, e.g. a tablet or multiparticulate governed by the solubility characteristics of the drug.
pellet, is coated with a membrane. The drug should Materials that have been used include buffers, sur-
not diffuse in the solid state, although loading of the factants, polyols and PEGs.
membrane might be an advantage if an initial release Because single-unit cores are most often com-
on contact with dissolution medium is desired. pressed tablets, a satisfactory lubricant system will

302
 MODIFIED-RELEASE PERORAL DOSAGE FORMS

also be required. Again, this is the same as for any choice of plasticizer will probably be a compromise
tablet except that soluble lubricants may not be nec- of all these different requirements.
essary. Suitable lubricants are listed in Table 20.3. Examples of suitable plasticizers for ethyl cellu-
lose films include dibutyl phthalate, diethyl phtha-
late, dibutyl sebecate and citric acid esters. These
Multiple-unit systems
are water-insoluble materials; a water-soluble plasti-
As the name implies, this type of dosage unit com- cizer might increase the permeability of the mem-
prises more than one discrete unit. Typically, such brane excessively. The amount of plasticizer
systems comprise coated spheroids (pellets approxi- required will depend on the several factors men-
mately 1 mm in diameter) filled into a hard gelatin tioned above, but is typically 10-25% of the
capsule shell or, less commonly, compressed into a polymer dry weight.
tablet. The smallest amount of plasticizer is used that will
There are two main approaches that can be adapted produce the most consistent result, i.e. complete
to the manufacture of drug-containing multiple units: coalescence of the droplets to form the film without
making it too elastic, plastic, soft or permeable. The
• The use of inert sugar spheres ('nonpareils')
plasticizer is not present only for processing but is
coated first with drug and then with the release-
added to have an effect on the mechanical properties
controlling membrane;
of the film, i.e. film flexibility should be induced and
• The formulation of small spheroids containing
maintained. Plasticizers should be permanent to
the drug using an extrusion/spheronization
avoid stability problems.
process (see Chapter 25). This approach is better
It may be necessary to add components to the
if a high drug loading is required.
coating formulation to modify the release character-
Typical formulations comprise drug with combina- istics of the film, particularly to increase the rate of
tions of lactose and microcrystalline cellulose. Other release. Typically this will be a less hydrophobic,
materials can be used. A typical formulation for a wet water-soluble component. Examples of such materi-
mass for extrusion/spheronization might comprise: als include polyethylene glycols, propylene glycol,
glycerol or other polyols, and water-soluble poly-
Parts by weight mers. Some of these may also act as plasticizers. It
Active drug 1-20 is important to recognize that many materials can
Lactose 60 have different functions in a formulation, and also
Microcrystalline cellulose 40 to understand what the implications of these differ-
Binder 2-4 ent functionalities are for the finished product.
Water 40 Advantages of membrane-controlled systems
After spheronization the material is dried prior to • For multiple-unit systems the gastrointestinal
coating. transit of small particulates is more consistent
Release-controlling membrane The membrane is a than that of a larger single-unit system.
critical part of the formulation as it controls the • Multiple-unit systems are also less likely to suffer
release of the drug. The requirement is that the from the problems associated with total dose
polymer remain intact for the period of release, i.e. dumping due to overall catastrophic failure of a
there should be no swelling or subsequent erosion, as film around a monolith (tablet), which would
seen in hydrophilic matrices. Typical polymers used then release the whole dosage.
include ethyl cellulose, acrylic copolymers, e.g. • In addition, multiple-unit systems allow the
Eudragit RL and RS grades, shellac and zein. Shellac release mechanism to be optimized for individual
and zein are natural products and their quality can drugs in a system delivering two or more active
vary. components.
The release-controlling polymer is film-coated on Disadvantages of membrane-controlled systems
to the system. For the coating to be successful the • Dose dumping can occur from single-unit system
coating droplets must coalesce. The plasticizer is as a result of film failure.
used to lower the glass transition temperature (T"g) of • Multiple-unit systems can be difficult to retain in
the film (see Chapter 28). The choice of plasticizer the higher gastrointestinal tract.
will depend on the polymer used, the active drug and • The control of the membrane characteristics in
the desired release characteristics. In addition, the film-coated membranes can be difficult.
plasticizer may modify the diffusional characteristics • Filling of the multiunit spheroids into capsules can
of the membrane with respect to the drug. The final be a problem owing to build-up of static charge.

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 BIOPHARMACEUTICAL PRINCIPLES OF DRUG DELIVERY

Osmotic pump systems • They are suitable for a wide range of drugs.
• The coating technology is straightforward.
In one sense osmotic pump systems are another • They typically give a zero-order release profile
form of membrane-controlled release drug delivery
after an initial lag.
system and work in the following way. A drug is
Disadvantages of osmotic pump systems
included in a tablet core which is water soluble, and
• Size of hole is critical.
which will solubilize (or suspend) the drug in the
• Laser drilling is capital intensive.
presence of water. The tablet core is coated with a • Integrity and consistency of the coating is
semipermeable membrane which will allow water to
essential:
pass through into the core, which then dissolves. As - If the coating process is not well controlled
the core dissolves, a hydrostatic pressure builds up
there is a risk of film defects, which could
and forces (pumps) drug solution (or suspension)
result in dose dumping.
through a hole drilled in the coating. The rate at - The film droplets or particles must be induced
which water is able to pass in through the mem- to coalesce into a film with consistent
brane, and how quickly the drug solution (or sus-
properties.
pension) can pass out of the hole, govern the rate of
release.
The rate at which the drug solution/suspension is
Delivery systems for targeting to
forced out can be modified by changes in the viscos- specific sites in the gastrointestinal tract
ity of the solution formed inside the system. The
essential difference between an osmotic pump Systems that target specific sites in the gastrointesti-
system and a 'classic' membrane-controlled system is nal tract are a form of modified-release delivery
that for the osmotic pump only one diffusion process system and are considered briefly here. Targeting of
is required (in this case, 'water in'). As mentioned drugs in the gastrointestinal tract is considered
above, in the 'classic' system two processes are key: useful as a means of taking advantage of and/or over-
water in, drug out. coming efflux systems (Chapter 16) and intestinal
cell metabolism; specific carrier mechanisms; and
cell recognition sites. It can be achieved by gastric
Components of osmotic pump systems retentive delivery systems and by colonic drug deliv-
Core This consists of the active drug, a filler or
ery systems.
substrate, a (viscosity modifier), (solubilizer) and,
lubricant/glidant.
Coating Coatings contain a membrane polymer, Gastric retentive systems
a plasticizer, a (membrane modifier) and (colour/ The advantages of using these drug delivery systems
opacifier). include reduced variability of drug release, local
This is the same list of components as for matrix- drug delivery and action, and enhanced bioavailabil-
controlled systems, and the types of excipient used ity for those drugs with a restricted absorption
are essentially similar. However, it is important to window in the gastrointestinal tract.
remember that the diffusing species is only water; an Methods to achieve gastric retention are:
agent must be included in the core which is soluble
enough to generate the osmotic pressure; and there • the addition of passage-delaying agents, such as
must be a hole through which the drug solution/sus- food material, for example triethanolamine
pension can be pumped out. Otherwise, the same myristate, or drugs, for example propantheline;
considerations apply for the formulation of the core • the use of high-density materials: high-density
as with other membrane-controlled systems. The particles (>2.5g/cm3) have prolonged gastric
coating must also be fully coalesced and be free from residence times. This can be achieved by the
unintentional pinholes, and it should act as a semi- addition of materials such as barium sulphate;
permeable membrane. • modification of the size/shape of delivery system
Advantages of osmotic pump systems by the use of unfolding polymer sheets, swelling
• They are well characterized and understood. hydrogel balloons, or polymer units that are too
• The diffusing species is water. large to pass through the pyloric sphincter.
• Modification of the rate of water diffusion is • bioadhesive systems. Systems have been used
more straightforward than for many drugs. which will adhere to surfaces such as the mucosa.
• The release mechanism is not dependent on the The problems when these systems are used for
drug. gastrointestinal delivery are that first, high local

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 MODIFIED-RELEASE PERORAL DOSAGE FORMS

concentrations of drug may result, and second, colonic bacteria. The principle here is to coat the
there is a turnover of mucosa, leading to drug/delivery system with a polymer that is
detachment of the delivery system; sensitive to bacteria in the colon. Degradation of
the use of floating dosage forms. These systems the polymer permits release of the active drug.
resist gastric emptying by floating on the stomach Polymers used include glassy amylase (mixed
contents. They should not alter the intrinsic with ethylcellulose); or pectin as a thick
emptying rate of the stomach and their specific compression coat, crosslinked with calcium, with
gravity should be less than that of the stomach different degrees of methoxylation or amidation,
contents. Systems used are (a) hydrodynamically or mixed with ethylcellulose.
balanced systems; (b) carbon dioxide-generating
systems; (c) freeze-dried systems.
REFERENCES
Colonic delivery systems Amidon, G.L., Lenneras, H, Shah, V.P. and Crison, J.R.
Applications for these systems include local delivery (1995) Pharm. Res., 10, 413.
Bailey, C.A., Bryla, P. and Malick, A.W. (1996) Adv. Drug
for the treatment of inflammatory diseases, infec- Dev. Rev., 22, 85.
tions, and diarrhoea; and systemic delivery. ChienY.W. (1995) Novel drug delivery systems. Marcel
Design principles for these delivery systems make Dekker, New York.
use of:
• the specific pH of the colon: pH-sensitive
polymers are used in their manufacture, e.g. ACKNOWLEDGEMENT
combinations of Eudragit 100-55 (pH 5.5) with
Eudragit S (pH 7.0). The principle is that drug is The authors wish to thank, Dr L.G. Martini and Dr
released at a specific pH environment; P.B. Geraghty (Glaxo SmithKline Pharmaceuticals,
• small-intestine transit time. These depend on Harlow, UK) for their assistance and advice in the
timed release of the active drug; preparation of this chapter.

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