“CONTROLLED AND SUSTAINED RELEASE DOSAGE FORMS”

DRUG DELIVERY SYSTEM:-

 A drug delivery system (DDS) is defined as a device that enables the introduction of therapeutic substance in
the body and improves its efficacy and safety by controlling the rate, time and place of release of drug in the
body.
 A drug delivery system acts as the interface between the drug and the patient.
 The design of any DDS should be primarily aimed to achieve the more predictability or reproducibility to
control the drug release, drug concentration in the target tissue & optimization of therapeutic effect of drug
by controlling its release in the body with lower & less frequent dose.
 An ideal drug delivery system should deliver the drug at a rate dictated by the needs of the body over aa
specified period of treatment.This idealized objective points to the two aspects most important to drug
delivery:-
 Temporal drug delivery:- It refers to the process of controlling the rate or specific time of drug delivery to
the target site.
 Spatial drug delivery:- It refers to the process of targeting the drugs to specific organs, cells, tissues, or even
sub cellular compartments.

CONTROLLED DRUG DELIVERY SYSTEM:-

 Controlled release dosage forms covers a wide range of pharmaceutical formulations which provide
continuous release of their active ingredients at a predetermined rate & for a predetermined time.
 The Controlled release system is designed to deliver a constant supply of drug in a quantity equivalent to the
amount eliminated from the body,usually at a zero-order rate, by continuously releasing it for a certain
period of time.
 Most of the controlled release systems are passive pre- programmed (Rate of release is predetermined & is
not influenced by external biological environment).
SUSTAINED DRUG DELIVERY SYSTEM
 Sustained release dosage form is defined as the type of dosage form in which a portion i.e. (loading dose) of
the drug is released immediately,in order to achieve desired therapeutic response more promptly, & the
remaining (Maintenance dose) is then released slowly, thereby, achieving a therapeutic effect which is
prolonged, but not constant.
 The rate of release of maintenance dose in SRDF’s is designed so that the amount of drug loss from the body
by elimination is constantly replaced.
 The primary objective of SRDF’s is to achieve steady state blood level for an extended period of time.
 Drug release in SRDF’s may or may not be controlled.

PLASMA CONCENTRATION-TIME PROFILE:-

Fig: A hypothetical plasma concentration-time profile from conventional multiple dosing & single doses of
sustained&controlled delivery formulations.

RATIONALE OF DEVELOPING SR & CR DOSAGE FORMS:-

1. To overcome the short-comings of conventional dosage forms:-

  Drugs with short half-life require frequent administration,which increases chances of missing dose of drug
leading to poor patience compliance.
 A typical peak-valley plasma concentration time profile is obtained which makes attainment of steady state
condition difficult.
 The unavoidable fluctuations in the drug concentration may lead to under-medication or over-medication as
the Css value rise or fall beyond the therapeutic range.
 The fluctuating drug levels may lead to precipitation of adverse effects especially of drugs with small
therapeutic index,whenever over-medication occurs.

The controlled drug delivery is designed to perform following tasks :-

 Sustain drug action at predetermined rate by maintaining a relatively constant, effective drug level in the
body with concomitant minimization of undesirable side effects associated with saw-tooth kinetic pattern.
 Localize drug action by spatial placement of a controlled release system adjacent to or in the desired tissue
or organ.
 Targeted drug action by using carriers or chemical derivatives to deliver the drugs to a particular target cell
type.
 Provide a physiologically/ therapeutically based drug delivery system.The amount and rate of release are
determined by the physiological/therapeutic needs of the body.

TERMINOLOGY:-

 Delayed release dosage forms-

These are the dosage forms that utilize repetitive, intermittent dosing of a drug from one or more immediate
release units incorporated into a single dosage form.
for e.g:- enteric coated tablets.
  Prolonged action dosage forms:-
These are the dosage forms which are designed to release the drug slowly so as to provide a continuous
supply of drug over an extended period.They prevent very rapid absorption of the drug,which could result in
extremely high peak plasma drug concentration.
 Repeat action dosage forms:-
These are the dosage forms that are designed to release a dose of drug initially followed by second dose of
drug at a later time.
 Targeted drug delivery system:-
A targeted drug delivery system is the one which delivers the drug only to its site of action & not to the non-
target organs or tissues.
 Extended release:-
Pharmaceutical dosage forms that release the drug slower- than- normal manner at a predetermined rate and
necessarily reduces the dosage frequency by two folds.

ADVANTAGES OF SR & CR DOSAGE FORMS:-

 Frequency of drug administration is reduced.
 Patient compliance can be improved.
 More consistent & prolonged therapeutic effect.
 Reduction in dose.
 Decreased incidence of adverse effects & toxicity.
 Reduction in health care cost.
 Better drug utilization
 Increased bioavailability of some drugs.
 Reduced fluctuations in circulating drug levels.
 Safety margin of potent drug is increased by technically excellent designing of formulation.
 Improved efficacy in treatment which is achieved by:-
Cure or control of condition.
Patient care time is reduced.
 Night time dosing can be avoided for patient convenience.
Product life time is increased in sustained release formulations.As the particles of drug are coated with
matrix or entire product is matrix coated which avoid exposure of drug to the environment & render it stable.
Make use of specific effects like SR Aspirin for morning relief of arthritis.

DISADVANTAGES OF CR & SR DOSAGE FORMS:-

 Toxicity due to dose dumping.
 Increased variability among dosage units.
 Increased cost.
 Need for additional patient education & counselling.
 Stability problems.
 Termination of therapy is difficult in case of toxicity, poisoning or hypersensitivity reactions.
 Dose adjustment is difficult.
 Longer time to achieve therapeutic blood concentrations due to incomplete release, increased first – pass
metabolism, increased instability, pH-dependent solubility etc.
 Poor in-vivo in-vitro correlation (IVIVC).

DIFFERENCE BETWEEN CONTROLLED RELEASE & SUSTAINED RELEASE DOSAGE FORMS:-

Sustained Release Controlled Release

 Constitutes dosage form that provides Constitutes dosage form that maintains constant
medication over extended period of time. drug levels in blood or tissues.

 These dosage forms do not attain zero Maintains constant drug levels in the blood or target tissue
order release kinetics. by releasing the drug in zero order pattern.

 SRDF do not contain methods to promote These dosage forms contain methods to promote the
localization of the drug at the active site. localization of the drug at active site.
  Drug release may or may not be controlled. Drug release is controlled.

FACTORS INFLUENCING THE DESIGN OF SR & CR DOSAGE FORMS

 Physicochemical properties of drug:-

Drug properties like Stability, solubility, partition coefficient & protein binding, play a dominant role in the
design and performance of controlled release systems.
 Route of Administration:
On chronic administration,some routes exert a negative influence on drug efficacy, therefore, route of
delivery
of drug should be taken into account. Performance of the controlled release systems may also be influenced
by physiological constraints,imposed by particular route,such as first-pass metabolism,GI motility,blood
supply
and sequestration of small foreign particles by the liver and spleen.
 Target Sites:-
Unwanted side effects can be minimized by delivering the maximum fraction of applied dose to the target
site.This can be partially achieved by the local administration or by the use of carriers.
 Acute/Chronic therapy:-
Consideration of whether one expects to achieve cure or control of a condition and the expected length of
drug therapy are important factors in designing CR systems.
For e.g:- Attempts to generate a one-year contraceptive implant presents significantly different problems in
design than does an antibiotic for acute infections.
 The disease:-
Pathological changes during the course of a disease can play a significant role in the design of a suitable
drug delivery system
.For e.g:- While designing ocular controlled-release product for an external inflammation,the time course of
changes in protein content in ocular fluids and in the integrity of ocular barriers would have to taken into
consideration.
 One can take advantages of the unique manifestations of the disease state. For e.g:- the higher plasminogen
activator levels in some tumor cells can lead to preferential bioconversion of peptidyl prodrugs in these cells.
 The Patient:-
Whether the patient is ambulatory or bedridden,young or old,obese or guant,etc can influence the design of
a controlled release product.
For e.g:- An implant or i.m injection of a drug to bedridden patient with little muscle movement may
perform
in a manner significantly different from that of an ambulatory patient.

BIOPHARMACEUTICAL FACTORS INFLUENCING FABRICATION OF CR & SR DOSAGE FORMS:-

The performance of a drug presented as a controlled-release system depends upon its:-
 Release from the formulation,
 Movement within the body during its passage to the site of action.
The former depends upon the fabrication of the formulation & the physico-chemical properties of the drug while
the latter element is dependent upon pharmacokinetics of drug.

Physicochemical factors:-
 AQUEOUS SOLUBILITY & pKa
 PARTITION COEFFICIENT
 DRUG STABILITY
 PROTEIN BINDING
 MOLECULAR SIZE & DIFFUSIVITY
 DOSE SIZE

AQUEOUS SOLUBILITY:-
 Aqueous solubility is an important consideration while designing the controlled or sustained release dosage
forms. The aqueous solubility exerts its control on the absorption process in two ways:-
1. By influencing dissolution rate of a compound, which establishes the drug concentration in solution.
2. By having an effect on the drug’s ability to penetrate tissues.
 Dissolution rate is related to aqueous solubility by the Noyes Whitney equation under the sink
condition(( CGIT»C).

dc/ dt= KD ACS

Where, dc/dt –Dissolution rate

KD - Dissolution rate constant
A-Total surface area of drug particles.
CS- Aqueous saturation solubility.

 The lower limit of solubility of a drug to be formulated as CRDDS is 0.1mg/ml.

 Drugs with low aqueous solubility (0.1mg/ml) have low dissolution rate and usually suffer oral
bioavailability problems, because of limited GI transit time of undissolved drug particles & limited solubility
at the absorption site.
For e.g:-Tetracycline dissolves to a greater extent in the stomach than in intestine,although it is best absorbed
in the intestine.
 Drugs with high aqueous solubility tend to release the dosage form in a burst & thus, is absorbed quickly
leading to a sharp increase in the blood drug concentration.
 It is often very difficult to incorporate a highly water- souble drug in the dosage form & retard the drug
release, especially when the dose is high.
 Slightly soluble drugs are also poor candidates for diffusion controlled systems,since the driving force for
drug release i.e drug’s concentration in solution will be low.
 Drugs which are aqueous soluble & depicts pH-independent solubility serves as a good candidate for CDDS
& SRDDS. e.g:- Pentoxyphylline.
 Drugs with pH-dependent aqueous solubility,e.g:-Phenytoin and drugs which are soluble in non-aqueous
solvents,e.g:- steroids are also good candidate for parenteral controlled drug delivery system.Upon injection,
the drug precipitates at the injection site and its release is slowed down due to change in pH or contact with
aqueous body fluids.

pka:-
 The degree of ionization (pKa) of a drug is a unique physicochemical property that control its ionization
state when it is in solution.
 The absorption of the unionized drug occurs rapidly as compared to ionized drugs from the biological
membranes.Generally,the highly ionized drug are poor candidates for CDDS & SRDDS. For e.g:-
Hexamethonium
 Most of the drugs are weakly acidic & weakly basic in nature. The Henderson-Hasselbach equation provides
an estimate of ionized & unionized drug concentration, by function of pH.
 FOR WEAKLY ACIDIC DRUG:-

pH=pKa+log ([ionized]/[unionized])

 FOR WEAKLY BASIC DRUGS:-

pH= pka+log([unionized]/[ionized])

 The pKa range for acidic & basic drugs, whose ionization is pH sensitive is 3.0-7.5 and 7.0- 11.0,
respectively.
 In drug delivery design, it is important to calculate the degree of ionization to otain an indication of whether
absorption from a particular site or transport can be assumed to be unrestricted in case of passive diffusion.
 For the optimum absorption by passive diffusion, the percentage of unionized drug at that site should be
between 0.1-5%.

PARTITION COEFFICIENT:-
 The partition coefficient is defined as the fraction of drug in an oil phase to that of an adjacent aqueous
phase.
 It influences not only the penetration of drug across the biological membranes, but also influences its
diffusion across the rate limiting membrane or matrix.
 Between the time of administration of drug & its elimination, it diffuses through several biological
membranes that act primarily as lipid-like barrier’s.
 Oil/Water partition coefficient plays a major role in evaluating the relative lipophilicity of drug. It is
expressed as follows:-
K= Co/Cs
Where,Co= Equilibrium concentration in organic phase.
Cs= Equilibrium concentration in aqueous phase.

 High partition coefficient compounds are predominantly lipid soluble and have very low aqueous solubility.
These compounds can penetrate biological membranes very easily, but cannot proceed further.
 Drugs that are very lipid soluble or very water-soluble i.e extremes in partition coefficient, will demonstrate
either low flux into the tissues or rapid flux followed by accumulation in tissues.
 Both cases are undesirable for sustained release & controlled release dosage forms.

DRUG STABILITY :-
 The stability of drug in the environment to which it is exposed is another physicochemical factor to be
considered in the design of controlled/sustained release systems.
 Drugs that are unstable in gastric pH (rifampicin,rabeprazole etc) can be developed as slow release dosage
forms & drug release can be delayed until the dosage form reaches the intestine.
  Drugs that undergo gut wall metabolism & show instability in small intestine ( captopril, ranitidine etc) are
not suitable for CR & SR system due to decreased bioavailability problem.To overcome the problem
associated with these drugs, a different route of administration should be chosen. e.g:- Controlled release of
nitroglycerin.

PROTEIN BINDING:-
 It refers to the formation of complex of the blood proteins ( like albumin) with the absorbed drug. It is well-
known that many drugs bind to plasma proteins with a concomitant influence on their duration of action.
 The binding of a drug to plasma proteins will decrease its plasma to tissue concentration gradient, thereby
slowing the rate of transfer of the drug across the capillaries.
 Extensive binding to plasma proteins will result in enhanced biological half life of the drug for elimination &
prolonged duration of action. Thus, such drugs need not to be fabricated as sustained/controlled release
dosage form. E.g :- Amitriptyline etc.
 Drug-protein binding also influences the distribution of the drug i.e Drugs which are highly bound to the
plasma proteins may distribute less widely because they remain trapped in the peripheral vasculature.

MOLECULAR SIZE & DIFFUSIVITY

 In addition to diffusion through a variety of biological membranes, drugs in CRDDS have to diffuse through
a rate controlling membrane or matrix.
 The ability of a drug to pass through such membranes is called diffusivity.It is related to molecular size of
drug by the following equation:-
Log D = -Svlog V + Kv = -Smlog M+
Km, Sm, Sv , Kv = Constants in particular medium.
D= Diffusion coefficient i.e diffusivity.
M= Molecular mass.
V= Molecular volume.
  The value of Diffusion constant ( D) depends on molecular size of the drug as well as on the size & shape of
cavities of membrane.Generally,lower the molecular weight,faster & more complete is the diffusion.
 Drugs with high molecular weight are not considered as a good candidate for sustained release dosage form
because they are expected to show very slow release of medicament.e.g:- Phenothiazines.
 For drugs of intermediate molecular weight i.e 150-400 Daltons, diffusivities through flexible polymers are
typically of the order of 10-8 cm 2 / sec, but for drugs with molecular weight >500 Daltons, diffusion
coefficients in many polymers are frequently so small that they are difficult to quantify.

BIOLOGICAL FACTORS
 ABSORPTION:-
 The rate, extent and uniformity in the absorption of drug are some important factors which are to be
considered while formulating any sustained/controlled release dosage forms.
 To maintain constant blood or tissue level of the drug, it must be uniformly released from the controlled
release systems & then uniformly absorbed. So, it is desirable in CDDS to have the released drug completely
absorbed.
 Usually, the rate – limiting step in drug delivery from a controlled release product is the release from the
dosage form rather than absorption. Thus, rapid drug absorption, relative to drug release from a dosage form
(kr<<ka) ,is expected for the suitability of CDDS & SRDDS.
 If the GI transit time of the dosage form is about 8-12 hours,then the maximum biological half-life should be
approximately 3-4 hrs. Otherwise, the dosage form will pass out of absorptive region before the drug release
is complete.
 Therefore, the compounds with lower absorption rate constants are poor candidates for CDDS. For e.g:-Iron
is not uniformly absorbed along the length of the GIT as the greatest uptake of this drug occurs at upper part
of duodenum, with significantly reduced absorptive capacity in the lower segment of intestine.
 Drugs which are either absorbed from a specific area of GIT due to pH-related solubility(Gentamycin) or
show absoption by carrier-mediated transport (Riboflavin) also influence the design of CDDS & SRDDS.
METABOLISM:-
 Metabolism of a drug is a process resulting in either inactivate an active drug or convert an inactive drug to
an active metabolite.
 For optimal bioavailability, the route of drug administration may be dictated by the drug’s metabolic pattern.
 Drugs selected for controlled release system should be completely metabolized but the rate of metabolism
should not be too rapid. Two factors, associated with metabolism process, significantly affect the design of
controlled release drug product:-
 Nature of drug:-If a drug is liver enzyme inhibitor/ inducer, it will create problem in maintaining uniform
plasma concentration on chronic administration.
 Examples of enzyme inducers:- antiepileptics, barbiturates (phenobarbitone), Rifampin, Griseofulvin,
phenybutazone etc.
 Examples of enzyme inhibitors:-azithromycin, cimetidine, cyclosporine, metronidazole, valproic acid etc.
 Secondly, variations in blood drug level either through intestinal ( or other tissue) metabolism or through
first-pass effect will also make preparation of sustained release dug product difficult.
 Example:- Hydralazine, bromocriptine etc are drugs which suffers from reduced bioavalability problem due
the first-pass effect & are undesirable to be formulated as SRDDS.

BIOLOGICAL HALF-LIFE:-
 The biological half-life of a drug plays an indispensable role in the process of considering a drug for
controlled or sustained release.
 Drugs with short half-life i.e 2-5 hours (paracetamol, atropine, indomethacin etc) require frequent dosing to
minimize fluctuations in the blood level . Thus, they can be formulated as SRDF as dose frequency can be
reduced.
 Drugs with shorter half-life i.e below 2 hours (Aspirin, ampicillin, furosemide, lignocaine etc) cannot be
fabricated as sustained release drug product as they require faster rate of release at a larger dose.
 Drugs with longer half-life i.e >8 hours (Theophylline, thyroxin, imipramine etc) are also not used in
sustaining system,as their effect is already sustained.
 THERAPEUTIC INDEX:-
 Therapeutic index is most widely used to measure the margin of safety of a drug.It can be expressed as:-
 Therapeutic index= Median toxic dose/ Median effective dose.
 A drug is considered to be relatively safe with therapeutic index more than 10 i.e higher the therapeutic
index, more safer will be the drug.
 Drugs with very small values of therapeutic index are considered as the poor candidates for formulation into
controlled release products due to limitation of precised control over the release rates