Critical Reviews™ in Therapeutic Drug Carrier Systems, 28(1), 47–99 (2011)

Gastroretentive Floating Drug-Delivery

Systems: A Critical Review
Udaya K. Kotreka1 & Moji Christianah Adeyeye1,2*
1
Mylan School of Pharmacy, Graduate School of Pharmaceutical Sciences, Duquesne
University, Pittsburgh, PA; and 2Department of Biopharmaceutical Sciences College
of Pharmacy, Roosevelt University, Schaumburg, IL

*Address all correspondence to: Moji Christianah Adeyeye, PhD, Department of Biopharmaceutical Sciences, College
of Pharmacy, Roosevelt University, 1400 N. Roosevelt Blvd., Schaumburg, IL 60173; Tel: 847-330-4547; Fax: 847-619-
7294; madeyeye@[Link].

ABSTRACT: The oral delivery of drugs with a narrow absorption window in the gastrointes-
tinal tract (GIT) is often limited by poor bioavailability with conventional dosage forms due
to incomplete drug release and short residence time at the site of absorption. To overcome this
drawback and to maximize the oral absorption of these drugs, gastroretentive systems such
as mucoadhesive, high-density, expandable, and floating systems have been developed. These
systems provide controlled delivery of drugs with prolonged gastric residence time. However,
in humans, differences in various physiological and biological factors can affect the gastric
residence time and drug-delivery behavior from gastroretentive systems. Some floating drug-
delivery systems (FDDS) have shown the capability to accommodate these variations without
affecting drug release. This review mainly focuses on various physiological considerations
for development of FDDS, and highlights recent technological developments including new
dosage forms and their production techniques (e.g., holt-melt extrusion, melt pelletization, and
pulsed plasma-irradiation processes). Alternatives to the existing in vitro compendial methods
for evaluating floating dosage forms will be discussed, and a critical analysis of the existing
literature on FDDS, identifying the potential areas for future research, is provided.

KEY WORDS: gastric physiology; gastric retention; effervescent systems; buoyancy; dis-
solution; scintigraphy; imaging; holt-melt extrusion; melt pelletization

I. INTRODUCTION

Oral delivery accounts for the largest proportion of administered pharmaceuticals due to
the ease of administration, patient compliance, and flexibility in formulation. However,
the bioavailability of the drugs delivered by this route can vary greatly, especially if the
therapeutic agents are delivered using conventional or immediate-release dosage forms.
This limitation was generally attributed to inter- and intra-subject variability in gastroin-
testinal tract (GIT) physiology, GIT transit time, and in some cases to a region-specific
(i.e., narrow) absorption window of drugs in the GIT.1 The non-uniformity in drug absorp-
tion across the alimentary canal or a region-specific absorption window may be due to the
differences in pH, available surface area, level of expression of various enzymes and trans-
porters, and metabolism across different regions of the GIT.1-3 Biological factors such as
age, gender, posture, and disease state also contribute to GIT region-specific absorption.

0743-4863/11/$35.00 ©2011 Begell House, Inc. [Link] 47

48 Kotreka & Adeyeye

In addition, drug absorption from the GIT is widely documented to be dependent on

the drug’s contact time with the gastric mucosa and also on the state of stomach (fed or
fasted). Because the transit time for solid particles through the small intestine is reported
to be relatively constant,4,5 the time that a dosage form remains in the stomach becomes
the most significant factor in the overall GIT transit time. Therefore, dosage forms that
have prolonged residence time in the stomach are advantageous in delivering drugs for
extended periods of time. This results in reduced fluctuations in plasma drug levels,
higher bioavailability, reduced frequency in dosing, and a more uniform pharmacologi-
cal response.6 Although gastric residence time (GRT) is critical for drug absorption,
the intrinsic properties of the drug molecule, such as its solubility, permeability, and
stability at the target site of drug delivery, may also largely dictate the fate of the drug
molecule and its bioavailability.7
A controlled drug-delivery system with prolonged residence time in the stomach can
be of great practical importance for drugs with a narrow absorption window in the upper
small intestine. Examples of such drugs include ciprofloxacin,8 sotalol HCl,9 levodopa,10
furosemide,11 riboflavin,12 chlordiazepoxide HCl,13 and cimetidine.14 For drugs such as
acetohydroxamic acid and chlorpheniramine maleate,15 which act locally in the treat-
ment of Helicobactor pylori infections, longer residence time in the stomach is desired.
In addition, the pharmacotherapy of drugs that are unstable in the intestinal fluid, such
as captopril,16 or drugs that exhibit poor solubility in the intestinal fluid, such as diaz-
epam,17 verapamil HCl,18 cinnarizine,3 and chlordiazepoxide HCl.13 could also be greatly
improved if delivered with prolonged residence time in the stomach.
Per-oral gastroretentive drug-delivery systems (GRDDS) are designed to deliver
drugs in such a manner to the GIT in order to overcome the drawbacks associated with
conventional dosage forms. However, these delivery systems are not suitable for drugs
that are unstable in the strongly acidic gastric environment or those that may cause gas-
tric lesions, such as nonsteroidal anti-inflammatory agents. In addition, these systems do
not offer significant advantages over the conventional dosage forms for drugs that are
absorbed throughout the GIT.3
Because several factors affect a drug’s bioavailability and suitability for the gastro-
retentive system, a thorough understanding of the various physiological, biological, and
formulation factors affecting GIT transit and emptying pattern is imperative to ensure ra-
tional design and improved clinical efficacy. Several technological approaches to improv-
ing the gastric retention of a dosage form, including GRDDS, have been reported in the
literature. This includes mucoadhesive, high-density, expandable, and floating drug-deliv-
ery systems (FDDS).19 FDDS in particular are extensively researched because they do not
adversely affect the motility of the GIT. Such a system aims to prolong the gastric reten-
tion of dosage forms in the GIT and consequently result in improved local bioavailability,
therapeutic efficacy, and a possible reduction in dose size and dosing frequency. 20-23
This review focuses on various physiological considerations and available formula-
tion approaches for the development of GRDDS. Progress in the area of FDDS, with an
emphasis on recent technological advancements in production methods, dosage forms,
and in vitro and in vivo evaluation methodologies, is discussed in detail.

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Gastroretentive Floating Drug-Delivery Systems 49

II. PHYSIOLOGICAL CONSIDERATIONS FOR THE DEVELOPMENT OF GRDDS

II.A. Basic GIT Physiology

The stomach is anatomically situated in the upper left part of the abdominal cavity im-
mediately under the diaphragm and is composed of three regions: the fundus, the body,
and the antrum (Figure 1). It is made up of goblet cells, parietal cells, and chief cells,
which secrete mucus, hydrochloric acid, and pepsinogen, respectively, amounting to 2
to 3 L of gastric juice daily. The contraction forces of the stomach churn the chyme (a
milky mixture of food) and mix it with the digestive gastric juices. The proximal part
of the stomach, composed of the fundus and the body, acts as a reservoir for undigested
material and propulses chyme to the antrum. The antrum is the main site for trituration
and grinding of the food particles by mixing motions, and it also acts as a pump to regu-
late gastric emptying by its propelling actions. Sedimentation of particles or pellets that
are small enough (density of 1.3 g/cm3 or higher) to be entrapped in the rugae or folds
of the antrum may allow them to withstand the peristaltic waves of the stomach wall
and provide prolonged gastric retention. The average length of the stomach is about 0.2
mm, and the apparent absorbing surface area is about 0.1 mm2.24,25 The pylorus is an
anatomical sphincter between the antrum and duodenum. The human pyloric diameter is
12.8 ± 7 mm,26 and acts as both a sieve and a mechanical stricture to the passage of large
particles. Particles must be in the range of 1 to 2 mm in size to be able to pass through
the pyloric valve into the small intestine.27 Unfoldable and size-expandable GRDDS use
drug-particle sizes larger than the pyloric diameter upon administration to avoid prema-
ture gastric emptying and to prolong gastric retention.

FIGURE 1. Anatomy of the human stomach.28

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50 Kotreka & Adeyeye

II.B. Gastric pH

The physiologic gastric pH in humans is not constant and varies across different sections
of the GIT.29 It also exhibits large intra-and inter-subject variability due to differences in
the state of the stomach during measurement (fed or fasted) and other physiological and
biological factors. The mean value of gastric pH in fasted healthy subjects is reported
to be 1.1 ± 0.15.30 In the fed state, the pH initially falls below 5.0, and then gradually
reaches the fasting state values over a period of a few hours. The mean fed-state pH in
healthy males is reported to be 3.6 ± 0.4.31 Physiological changes in elderly people af-
fect gastric acid secretion, causing hypochlorhydria or achlorhydria, which increases
their basal pH value to more than 5.32 Pathological conditions such as pernicious anemia
and AIDS, and the presence of drugs such as H2-receptor antagonists and proton-pump
inhibitors, significantly reduce gastric acid secretion and elevate the gastric pH.25 Due to
such large differences in gastric pH, clinical trials involving GRDDS should entail strict
screening protocols to identify such factors and to adapt appropriate controls to reduce
bias and achieve more reliable results.

II.C. Gastric Emptying

Gastric emptying is a motility-driven process whereby the dosage form is emptied from
the stomach into the small intestine. In drug delivery, gastric emptying determines the
length of time that the dosage form remains in the stomach. Therefore, this process is
significant for drugs with a narrow absorption window that have their primary site of
absorption in the stomach and proximal small intestine. Any factors that affect gastric
emptying will also influence the time that the drug remains in contact with the target
site, and will therefore affect its oral bioavailability. Because gastric emptying is an
extremely variable process, the ability to control or regulate it can widen the stom-
ach’s potential as a drug-absorbing organ and also broaden the scope for the design
of novel controlled-release drug-delivery systems. The motility pattern of the stomach
is mostly contractile, and its functions include grinding of food into smaller particles,
mixing them with gastric juices, resulting in “chyme” formation, and emptying into the
small intestine.33
This motility varies between the fast and fed state of the stomach. During the fasting
state, an inter-digestive series of electrical events takes place through the stomach and
intestine every 2 to 3 hours. This process is called the inter-digestive migrating myo-
electric cycle (MMC), and its purpose is to clear the stomach and intestine of all the un-
digested food.25 Feeding disrupts this cycle, resulting in a period of irregular contractile
activity that may last for 3 to 4 hours. In the fed state, the onset of MMC is delayed due
to the lag time for the onset of gastric emptying, resulting in a slowing down of the gas-
tric-emptying rate.34 Therefore, in drug delivery, frequent feeding may delay the onset of
gastric emptying and offer the advantage of prolonged retention of the dosage form. The
state of the stomach, fed or fasted, in relation to drug administration is thus the primary
consideration for modulating GRT.

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Gastroretentive Floating Drug-Delivery Systems 51

Gastric motility has also been found to be affected by various biological factors and
pathological conditions in humans. Factors such as age, gender, posture, mental stress,
and disease states with intestinal involvement, such as gastroesophageal reflux, con-
genital heart disease, diabetes, and respiratory distress syndrome, are reported to affect
gastric emptying.35,36 Formulation factors such as density, shape, and size of the device
were also found to affect the gastric retention of dosage forms.
Researchers usually aim to develop a successful GRDDS that will not only provide
controlled delivery of the drug at the target site, but will also offer better control over
fluctuations in peak plasma concentrations. To achieve this, one or more of the above-
mentioned formulation factors affecting gastric retention of dosage forms have been
exploited to design different types of GRDDS; examples are high-density, low-density/
floating, mucoadhesion, and swelling/unfoldable systems.13,37,38

III. TYPES OF GRDDS

III.A. Mucoadhesive Systems

Mucoadhesive drug-delivery systems contain a mucoadhesive polymer that adheres it-

self to the gastric mucosal surface, more specifically the mucus gel layer, thus prolong-
ing its retention in the GIT. The capability to adhere to the mucus gel layer makes mu-
coadhesive polymers very useful excipients in GRDDS. These polymers can be natural,
such as gelatin, sodium alginate, and guar gum, or semi-synthetic/synthetic, such as
hydroxypropylmethyl cellulose (HPMC), Carbopol® 934, and sodium carboxymethyl
cellulose.39,40 Depending on the nature of the polymers used, mucoadhesion can be me-
diated by swelling and hydration, mechanical or chemical bonding, and activation of
specific receptors on gastric cells.25,41 Table 1 shows the types of mucoadhesive polymers
used in GRDDS. Most of these polymers are non-specific in their binding, and will stick
to various other surfaces that they come into contact with. This non-specificity in bind-
ing and the inherent risk of unintended adhesion or contact time to the esophagus upon
administration may result in drug-induced injuries resulting from mucosal irritation. In
addition, the efficiency of the unique mucoadhesive property of the GRDDS may be
limited by the turnover time of the gastric mucus and possible interactions with food.3

III.B. Expandable Systems

The presence of polymers in GRDDS promotes swelling to a size that prevents their pas-
sage through the pyloric sphincter, resulting in prolonged gastric retention. Expandable
systems are also referred to as “plug type systems” because they exhibit a tendency to
remain lodged at the pyloric sphincter. The mean diameter of the pylorus in humans is
about 12.8 ± 7 mm.26 The integrity of the dosage form against peristaltic movements of
the stomach determines its size and therefore its residence in the GIT. A non-disintegrat-
ing type of expandable system that is small enough for easy administration swells to a
size greater than the pylorus opening and is thus retained in the stomach for longer peri-

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TABLE 1. Mucoadhesive Polymers Used in GRDDS39-42

Anionic Polymers Nonionic Polymers
®
Carbopol Hydroxypropylmethyl cellulose
Chondroitin sulfate Hydroxyethyl cellulose
Carboxymethyl cellulose Hydroxypropyl cellulose
γ-Carrageenan Polyoxyethylene
Dextran sodium Poly(vinyl alcohol)
Hyaluronic acid Poly(vinyl pyrrolidone)

Polyacrylic acid Poly(ethylene oxide)

Poly(methacrylic acid) Guar gum
Pectins Cationic Polymers
Poly-L-aspartic acid Chitosan
Polycarbophil Polylysine
Polyvinyl sulfate Polybrene
Sodium alginate Polyvinyl methyl imidazole

ods of time. However, a balance between the rate and extent of swelling and the rate of
erosion of the polymer is crucial to achieving optimum benefits and avoiding unwanted
side effects. Generally, the success of the expandable GRDDS lies in its ability to with-
stand the powerful mechanical contractions that exist in the stomach and maintain its
integrity and strength. However, the drawback with these systems is the risk of being
permanently retained in the stomach due to their large size, which could lead to life-
threatening conditions upon multiple administrations as a consequence of drug-induced
mucosal surface injuries. However, a major advantage of these systems is their ability to
prolong gastric retention independently of the fed or fasted state of the stomach.3

III.C. High-Density Systems

GRDDS owe their increased retention in the stomach to a density higher than that of the
stomach contents (∼1.004 g/cm3). Higher densities (>1.3g/cm3) causes sedimentation
of the dosage form in the rugae of the folds of the stomach near the pyloric region, the
part of the organ with the lowest position in an upright posture, and prevents premature
emptying due to strong gastric propulsions. Except for significant gastric retention that
could occur, dosage form density in the range of 2.5 to 3.0 g/cm3 is necessary to with-
stand the peristaltic movements of the stomach wall for prolonged durations.43 Higher
densities are usually accomplished by coating the drug with a heavy inert material such
as barium sulfate, zinc oxide, titanium dioxide, or iron powder. The high-density system
is technically very difficult to manufacture, especially with drug loads greater than 50%,

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Gastroretentive Floating Drug-Delivery Systems 53

if high densities are to be maintained. Although the use of these systems has provided
encouraging results for veterinary applications,44,45 their effectiveness in human subjects
has not been proven because of differences in retention due to mobility and posture (i.e.,
upright vs. supine).46

III.D. Floating or Low-Density Systems

By virtue of their low densities (<1.004 g/cm3), FDDS remain afloat above the gastric
contents for prolonged periods of time and provide continuous release of the drug. These
systems in particular have been extensively studied because they do not adversely affect
the motility of the GIT.47-50 Their dominance over other types of GRDDS is also evident
from the large number of floating dosage forms being commercialized and marketed
world-wide (Table 2).7,19,49 Table 3 lists the drugs studied generally as candidates for
FDDS, and the various patents awarded for the different systems are summarized in
Table 4. Low-density FDDS will be reviewed in subsequent sections.

IV. GASTRORETENTIVE FDDS

IV.A. Formulation Types and Considerations

The density of gastroretentive FDDS must be less than that of the gastric contents (∼1.004
g/cm3). Low density can be achieved, for example, by the entrapment of air (e.g., hollow
chambers113) or by the incorporation of low-density materials (e.g., fatty substances or
oils114 or foam powders115-117). Floating systems are classified into effervescent or non-
effervescent based on their mechanism of buoyancy. In the former type, gas-generating
excipients such as bicarbonate salts and acidic ingredients are used, which can generate
CO2 in the presence of gastric acid. Also, volatile organic solvents have been used in
floating systems to generate gas at physiological temperatures. The gas entrapped in these
systems reduces its density and keeps it afloat over the gastric contents. Over a period
of time, the gas entrapped in the system and the drug are slowly released. There are no
reports in the literature about any possible side effects of the released gas to the patient.
In non-effervescent systems, a high level of swellable and gel-forming polymers is
used. When in contact with gastric juices, these polymers either swell or gel by entrap-
ping the air inside the gel network. This lowers the density of dosage form below that
of gastric contents, causing buoyancy or flotation. Table 5 lists some of the polymers
used in FDDS. The wide range of dosage forms developed as FDDS include single-and
multiple-unit dosage forms such as hollow microspheres, granules, powders, tablets,
capsules, pills, laminated films, and in situ gel-forming liquid preparations.19,53,118
There are several factors than can affect the normal functioning and gastric retention
of dosage forms in the GIT. All of these factors are briefly mentioned in the previous
sections. In the following section, the factors that largely affect the product performance
characteristics of FDDS, such as size, shape, and density of the dosage form, the pres-
ence of food, and other formulation variables, are discussed in detail.

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 54

TABLE 2. Marketed Preparations of FDDS19,49,50

Dosage Form/
Brand Name Delivery System Drug or API* Category Manufacturer
Effervescent
Pierre Fabre Drug,
Topalkan® floating alginate Aluminum-magnesium Antacid
France
suspension
Non-effervescent
Conviron® Ferrous sulfate Antianemic Ranbaxy, India
floating capsules
Effervescent float-
Cifran OD® Ciprofloxacin Antibiotic Ranbaxy, India
ing tablets
Non-effervescent
Valrelease® Diazepam CNS depressant Hoffman-LaRoche, USA
floating capsules
Non-effervescent Benserazide and
Madopar® HBS Anti-Parkinson’s Roche Products, USA
floating capsules L-Dopa
Non-effervescent
Gastric ulcer treat-
Cytotech® bilayer floating Misoprostol Pharmacia, USA
ment
capsules
Effervescent float- Aluminum hydroxide, mag-
Liquid Gaviscon® Antacid GlaxoSmithKline, India
ing alginate raft nesium carbonate
Non-effervescent Muscle relaxant
Baclofen GRS Baclofen Sun Pharma, India
floating capsules and antispastic
Glumetza™ Expandable tablets Metformin Antidiabetic Depomed, Inc., USA
ProQuin® XR Expandable tablets Ciprofloxacin Antibiotic Depomed, Inc., USA
*API = Active pharmaceutical ingredient

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Kotreka & Adeyeye
 TABLE 3. Drugs Formulated as FDDS
Tablets
Atenolol 3 Captopril51 Losartan52 Piretanide3
Ampicillin53 Diltiazem53 Metoprolol tartrate54 Prednisolone55
Amoxicillin trihydrate56 Domperidone57 Miocamycin58 Phenoporlamine HCl59

Volume 28, Number 1, 2011

Acetylsalicic acid13 Ethmozine60 Metformin HCl61 Quinidine gluconate62
Acetaminophen63 Furosemide64 Metronidazole65 Riboflavin-5’-phosphate66

Acyclovir67, 68 Fluorouracil69 Nimodipine70 Sotalol9

Chlorpheniramine maleate71 Gentamicin sulfate72 Ofloxacin73, 74 Theophylline38
Cinnarizine53 Isosorbide mononitrate75 p-Aminobenzoic acid76 Verapamil HCl77
Gastroretentive Floating Drug-Delivery Systems

Ciprofloxacin78 Isosorbide dinitrate76 Pentoxyfillin20

Capsules Granules In Situ Gel-Forming Liquids Microspheres/MultiparticulateSystems
13 79 80
Chlordiazepoxide HCl Diltiazem Amoxycillin Acetohydroxamic acid81, 82
Diazepam83 Diclofenac Sodium84 Acetohydroxamic acid85 Aspirin86
87 69 88
Furosemide Fluorouracil Clarithromycin Cefpodoxime proxetil89
Isradipine90 Prednisolone91 Aluminum hydroxide Famotidine92, 93
94 95
L-Dopa and benserazide Indomethacin and magnesium carbonate19 Fenoverine96
Misoprostol97 Quinidine gluconate98 Metformin99 Griseofulvin86
Nicardipine 100 Repaglinide101 Ranitidine102 Ibuprofen103
104
Propranolol HCl Ketoprofen105
Pepstatin106 p-Nitroaniline86
Salbutamol sulfate107 Rosiglitazone maleate108
53
Ursodeoxycholic acid Tranilast109
Verapamil110 Terfenaidine111
55
 56

TABLE 4. Various Patents on FDDS112

Title/Year Patent Number Inventor Company/Assignee
Levodopa dimethyl-substituted diester prodrugs, US 2010/0173992 (A1) Xiang JN, Zhou CX, Yao F, Xenoport Inc
compositions, and methods of use (2010) Nguyen MQ
Methods of treatment using a gastric retained ga- US 2010/0034895 (A1) Berner B, Eddie Hou SY, Gus- King & Spalding LLP
bapentin dosage (2010) ler, GM
Methods of administering tetrahydrobiopterin, as- US 7612073 (B2) Oppenheimer DI, Dorenbaum Biomarin Pharmaceutical
sociated compositions, and methods of measur- A Inc
ing (2009)
Gastroretentive sustained-release formulations US 2007/0269512 (A1) Wang WW, Ryan JJ Johnson & Johnson
(2007)
Gastroretentive formulations and manufacturing WO/2007/010400 Chaudhari M, Chandwani DO, Ethypharm
process thereof (2007) Yelegaonkar sustained-release
Pharmaceutical composition for controlled drug- US 7157100 (B2) Doshi MM, Joshi MD, Mehta J.B. Chemicals & Phar-
delivery system (2007) BP maceuticals Ltd
Novel floating dosage form (2006) US 2006/0013876 (A1) Lohray BB, Tiwary BS, Pai MR, Cadila Healthcare Ltd
Murthy TK, Mehta RP
Therapeutic system comprising amoxicillin and US 2006/0121106 (A1) Kerc J, Opara J, Osel JM Novartis
clavulanic acid (2006)
Gastroretentive drug-delivery system comprising US 2005/0249798 (A1) Hassan M Euro-Celtique SA
an extruded hydratable polymer (2005)
Methods and dosage forms for improving the bio- US 2003/0138486 (A1) Laure Patricia Njiki Ouadji King Pharmaceuticals
availability of therapeutic agents (2003) Research
Gastric floating system (2002) WO/2002/102415 Avachat KM, Dhamne GA Blue Cross Laboratories
Ltd
Orally administered controlled drug-delivery sys- US 6261601 (B1) Talwar N, Sen N, Staniforth JN Ranbaxy Laboratories
tem providing temporal and spatial control (2001) Ltd

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Kotreka & Adeyeye
 (continued)
TABLE 4. Various Patents on FDDS112
Title/Year Patent Number Inventor Company/Assignee
Hydrodynamically balanced oral drug-delivery WO/2001/010405 Talwar N, Staniforth NJ, Tobyn Ranbaxy Laboratories

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system (2001) JM Ltd
Multiple unit effervescent dosage form (2001) US 6284271 (B1) Lundberg PJ, Thune M AstraZeneca AB
Antacid compositions with prolonged GRT (1994) US 5288506 Spickett GWR, Vidal L FJ, Es- Walton SA
coi CJ
Sustained-release, bilayer buoyant dosage form US 5232704 Franz RM, Oth PM G.D. Searle & Co
(1993)
Gastroretentive Floating Drug-Delivery Systems

Buoyant controlled release powder formulation US 5169638 Dennis A, Timmins P, Lee K E.R. Squibb & Sons, Inc
(1992)
Granule remaining in stomach (1989) US 4844905 Ichikawa M, Watanabe S, Mi- Eisai Co Ltd
yake Y
Floating sustained-release therapeutic composi- US 4814179 Bolton S, Desai S St. John’s University
tions (1989)
Pharmaceutical preparations and a method of US 4702918 Ushimaru K, Nakamichi K Nippon Shinyaku Co Ltd
manufacturing them (1987)
Sustained-release oral medicinal delivery device US 4451260 Mitra BS Minnesota Mining & Man-
(1984) ufacturing Co
Sustained-release pharmaceutical capsules US 4126672 Sheth RP, Jacques Hoffmann-LaRoche, Inc
(1978)
57
 TABLE 5. Polymers Used in FDDS42,133
58

Name Structural Formula Name Structural Formula

Sodium alginate Poly(ethylene oxide)

Carboxymethyl cellulose Polyvinylpyrrolidone

Ethyl cellulose
HPMC

Eudragit Poly(acrylic acid)

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Gastroretentive Floating Drug-Delivery Systems 59

VI.B. Factors That Influence Gastric Retention of FDDS

1. Formulation Factors

Formulation parameters such as shape and size can affect the GRT of gastroreten-
tive FDDS.

a. Shape
In an in vivo study of healthy human subjects, Cadwill et al. investigated the effect of
shape on the gastric-retention potential of FDDS. Their results showed that the tetrahe-
dron- and ring-shaped devices offered greater retention and longer GRTs over the other
shapes (i.e., cloverleaf, string, pellet, and disk) due to their ability to achieve a size large
enough to be retained in the stomach and their flexibility to resist premature emptying
by the strong propulsive forces of the stomach.46-47

b. Size
The size of a dosage form, as discussed earlier, can also affect the duration of gastric reten-
tion. The human pylorus in a resting state has a diameter of 12.8 ± 7 mm, and functions as
a sieve for the emptying of gastric contents. Therefore, its diameter should be taken as a
critical value for gastric emptying of dosage forms of different sizes. Various gastric-emp-
tying times have been reported for non-disintegrating tablets of different sizes.119 Small-
sized tablets are emptied from the stomach during the digestive phase, but large ones are
usually emptied during the “housekeeping” waves. An FDDS, by virtue of its density
(<1.004 g/cm3), floats over the gastric contents and positions itself away from the pyloric
sphincter. This allows it to avoid premature emptying by the strong propulsive forces in
the antral region of the stomach wall and prolongs gastric retention in the stomach.
Timmermans et al.120 investigated the effect of size, buoyancy, posture, and the na-
ture of meals on the gastric-emptying process of capsules of different sizes using gamma
scintigraphy as an in vivo imaging tool. Floating and non-floating capsules of different
diameters, 4.8 mm (small units), 7.5 mm (medium units), and 9.9 mm (large units), were
administered to healthy subjects and monitored for their in vivo transit. Using scinti-
graphic images, it was observed that regardless of their sizes the floating dosage units
remained buoyant on the gastric contents throughout their residence in the stomach,
while non-floating units settled in the lower part of the stomach. It was also observed
that buoyancy prolonged the GRT of small- and medium-sized floating units, whereas
no significant difference was observed between the floating and non-floating large units
(9.9-mm diameter). This indicates there is a cut-off size over which flotation does not
significantly improve gastric retention.26

2. Patient Posture

Timmermans et al.120 observed that subjects who were administered floating units in the
supine position had prolonged retention of the dosage form. However, this prolonged

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60 Kotreka & Adeyeye

retention was predominantly influenced by the size of the dosage form, and buoyancy
no longer remained an advantage for gastric retention.121 This was due to the fact that in
the supine position, the floating dosage form is positioned close to the pyloric sphinc-
ter, which selectively empties the particles based on their size. Wilson et al.27 have also
demonstrated the role of posture on gastric emptying in patients lying on their backs
to sleep after taking floating dosage forms. They observed that an alginate floating raft
emptied more slowly than food in subjects lying on their backs on their right side. This
posture caused the raft to position itself in the greater curvature of the stomach and
prolonged its gastric retention. In contrast, when the subjects lay on their left sides, the
raft was presented to the pylorus ahead of the meal due to its buoyancy and therefore
emptied faster.

3. Effect of Food

In the presence of food in vivo, multiparticulate systems distribute freely throughout the
GIT and undergo emptying in more consistent manner. Conversely, single-unit systems
undergo an “all-or-nothing” type of emptying. Therefore, the use of multi-unit as op-
posed to single-unit formulations often results in reliable gastric-emptying patterns, re-
duced intersubject variability in absorption, and a lower probability of dose dumping.38
Several studies have been reported in literature on the effects of the state of the
stomach, the type of food, and the frequency of intake on the performance of FDDS.
The GRTs for non-disintegrating dosage forms in several studies were correlated with
the caloric intake of the subjects.49 Therefore, most of these studies shared a common
viewpoint that the presence of food, rather than buoyancy, is the most important factor
affecting GRT and that floating does not invariably increase GRT.38,49,90,122,123 In a study
comparing floating and non-floating capsules, gastric-emptying time for both capsules
was found to be shorter in fasted subjects (less than 2 hours) compared with prolonged
emptying times of 4 hours and above observed in subjects after a meal.122
Similarly, Muller-Lissner et al.83 demonstrated that a GRT of 4 to 10 hours could be
achieved after a test meal of fat and protein. Oth et al.97 reported that the average GRT
of a bilayered floating capsule of misoprostol was 199 ± 69 minutes after a single light
meal (breakfast) and 618 ± 208 minutes after a succession of meals. Iannuccelli et al.44
also reported prolonged GRT of floating units by about 9 hours over the controls after
successive meals. This can be explained based on the fact that gastric emptying depends
on the onset of MMC: GRT is significantly increased under fed conditions because the
onset of MMC is delayed. This prolongation of the GRT by food is also expected to
maximize drug absorption from a floating system due to increased dissolution of the
drug and longer residence at the most favorable sites of absorption. Thus, it is evident
that FDDS rely more on the presence of a meal to retard their emptying. However, an
optimized or ideal FDDS should be able to provide gastroretentive properties indepen-
dent of meal size and should be suitable for patients with a wide range of eating habits.
Therefore, it may be concluded that although FDDS possess an inherent ability to facili-
tate gastric retention, they rely more on the presence of a meal to retard their emptying.

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Gastroretentive Floating Drug-Delivery Systems 61

IV.C. Optimization Studies of FDDS Using Experimental Designs

The need for optimization of FDDS is underscored due to the diversity in design and the
influence of various formulation variables on performance. Depending upon the type of
system, floating dosage forms could be as simple as a tablet or capsule or as complex as
multilayered, multiparticulate microspheres. Formulation variables such as the levels of
gas-generating agents, release-modifying polymers, manufacturing aids such as lubri-
cants or glidants, and low-density excipients have been found to have a profound influ-
ence on the floating kinetics and gastric retention of the floating dosage forms.124-127 Op-
timization of these formulation variables using experimental designs allows for studying
various processing and formulation parameters influencing the selected responses with
the lowest number of experiments, thereby reducing the time required in the develop-
ment work.99 Accordingly, the modern formulation optimization approaches, employing
systematic Design of Experiments (DoE), have been extensively used in the develop-
ment of FDDS. These DoE methodologies are well known to improve the irregularities
of one-variable-at-a-time methods, with distinct advantages in terms of economics of
time, money, and effort, the flexibility to fix errors and pronounced reproducibility.128
Numerous types of experimental designs employed in drug-delivery optimization have
been reviewed previously.129 Table 6 provides a concise account of various literature
reports on DoE optimization of several FDDS. The experimental designs that have been
successfully employed include the Taguchi design,125 simplex lattice design,130 central
composite design,131 and the factorial design.132 The influential factors have invariably
been the FDDS constituents. The response variables that were employed for optimiza-
tion include lag time for flotation, buoyancy, floating duration, and drug-release char-
acteristics.

IV.D. Effervescent FDDS

Effervescent FDDS are predominantly matrix-type systems (i.e., tablets or capsules)

that are mainly composed of swellable polymers and gas-generating agents. The gas-
generating compounds include, effervescence-causing substances such as bicarbonate
salts and organic acids, that interact in the presence of gastric acid to generate CO2
gas.143,144-146 The gas bubbles generated get entrapped in the swollen gel matrix of the
polymer and reduce its specific gravity to that of gastric contents (i.e., <1.004 g/cm3).
This imparts buoyancy to the FDDS to remain afloat above the gastric contents. This
type of drug-delivery system is successfully employed in commercial floating dosage
forms (Table 2).
The mechanism of floating by effervescence can be adopted in a single-layered tablet
in which the gas-generating agents and polymer components are intimately mixed into
a matrix or in a bilayered, sustained-release tablet with gas-generating content in one
polymer layer and the active content plus a release-modifying polymer incorporated into
the other layer.11 Singh et al. developed floating-matrix tablets of metoclopramide HCl
using natural polymers such as guar gum and karaya gum alone and in combination with

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 62

TABLE 6. Literature Reports on Various FDDS Optimized Using ‘Design of Experiments’

Drug Type of Design Factors Employed Response Variables
Rosiglitazone maleate Simplex lattice mixture Different drug-polymer ratios % Cumulative drug release at different
floating microspheres108 design (3 factors, 3 time points
levels)
Calcium carbonate float- Taguchi design (3 factors, HPMC type, HPMC/Carbopol ratio, Maximum floating force, time to reach
ing capsules126 4 levels) and level of magnesium stearate maximum floating force, area under the
floating kinetics curve
Carbamazepine floating Simplex lattice design (3 Amounts of matrix and gas-generat- Floating lag time, time required for 50%
tablets130 factors, 3 levels) ing agent and floating enhancer and 80% drug dissolution
Calcium floating tablets131 Central, composite Box- Level of HPMC, citric acid and mag- Diffusion exponent, time for 50% drug
Wilson design nesium stearate release, drug release at 6 h, time to
reach maximum floating force, area
under the floating kinetics curve
Ibuprofen floating micro- Factorial design (2 fac- Volume of solvent and amount of Bulk density, pore volume, surface area,
spheres132 tors, 3 levels) drug drug release at 1, 2, and 3 h
Tramadol floating tab- Central composite design Amounts of Carbopol 971P and Drug released in 16 h, time to 75%
lets134 (2 factors, 3 levels) HPMC drug release, bioadhesive strength and
buoyancy time
Quetiapine floating tab- Full factorial design (2 Amounts of sodium alginate and Times required for 50% and 90% drug
lets135 factors, 3 levels) sodium carboxymethyl cellulose release, and floating lag time
Theophylline floating Full factorial design (2 HPMC viscosity and HPMC content Drug diffusion exponent and % drug
tablets136 factors, 3 levels) released at 1, 4, 6, and 12 hrs.
Metformin HCl floating Full factorial design (2 Amounts of sodium alginate and Times required for 50% and 90% drug
tablets61 factors, 3 levels) sodium carboxymethyl cellulose release, and floating lag time

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Kotreka & Adeyeye
Volume 28, Number 1, 2011
TABLE 6. (continued)
Drug Type of Design Factors Employed Response Variables
Dipyridamole floating Full factorial design (2 Viscosity of polymer and type of filler Diffusion exponent, release rate con-
tablets138 factors, 3 levels) stant, and % drug release at 1, 6, and
12 h
Dipyridamole floating Full factorial design (2 Polymer content and ratio of poly- Diffusion exponent, release rate con-
Gastroretentive Floating Drug-Delivery Systems

tablets139 factors, 3 levels) mers stant and % drug release at 1 and 6 h

Diltiazem HCl floating Full factorial design (2 Amounts of guar gum and cetyl Similarity factors f2 and Sd, % drug
tablets140 factors, 3 levels) alcohol release, and mean dissolution time
Ranitidine HCl floating Full factorial design (2 Coating composition and coating Lag time prior to drug release and %
tablets141 factors, 3 levels) level drug released in 7 h
Metformin in situ forming Full factorial design (3 Concentrations of sodium alginate, Drug release exponent, dissolution ef-
liquid99 factors, 3 levels) gellan gum, and metformin ficiency, drug release at 0.5, 4, and 8 h
Dipyridamole floating Central composite design Level of polyoxyethylene, sodium Similarity factor between the dissolution
osmotic pump system142 chloride, and pore former profiles and target dissolution profile
63
64 Kotreka & Adeyeye

HPMC, K15M, and gas-generating agents such as calcium carbonate and citric acid.147
They studied the effect of the excipients on the buoyancy and in vitro drug release from
the floating tablets, and observed that the gas-generating agents were necessary to make
the tablets float immediately and HPMC was required to maintain the integrity of the tab-
let and to sustain the drug release. Therefore, tablets made without gas-generating agents
did not float and those without HPMC eroded completely, exhibiting rapid drug release.
The carbonates typically used in effervescence-based floating systems to provide
buoyancy also provide the initial alkaline microenvironment to the polymers, which,
depending on their nature, may cause gelling of the system.71 In addition, the CO2 gas
released creates pores in the polymer matrix and accelerates the hydration of these poly-
mers to form a bioadhesive hydrogel, providing an additional mechanism for these sys-
tems to prolong the gastric retention by both floating and bioadhesion. A similar obser-
vation was made by Sangekar et al.,123 who indicated that the increase in retention time
offered by the hydrodynamically balanced system (HBS) developed in their laboratory
was due to the synergistic effects of floating and bioadhesion to the gastric mucosa,
rather than being the effect of floating alone. Asrani148 made use of this approach and
successfully developed a novel, bioadhesive FDDS of the model drug verapamil HCl.
The performance of this system was found to be purely dependent on the level of bicar-
bonate and the type of polymer used. During in vitro studies, optimized formulations
were found to be buoyant and capable of sustaining the drug release for 24 hours.
Jamini et al.149 developed a floating tablet of famotidine, a histaminic H2-receptor an-
tagonist indicated in the treatment of gastroesophageal reflux, based on an effervescent
floating matrix system (EFMS). The floating tablets contained Methocel® as a release-
modifying agent and sodium carbonate as a gas-generating agent. Different viscosity
grades of Methocel®, such as K100M and K15M, were evaluated to balance the floating
and drug-release characteristics of the tablets. In vitro flotation of famotidine tablets in
0.1N HCl measured using a United States Pharmacopeia (USP) paddle apparatus indi-
cated that the famotidine tablets made with low-viscosity grade Methocel® K100 floated
for longer times than tablets made using high-viscosity grade Methocel® K15M. This
is in contrast to the observation made by Gerogiannis et al.,150 who characterized differ-
ent grades of Methocel® in water and simulated meals using a resultant-weight floating
measurement apparatus. The placebo capsules containing Methocel® grades with higher
molecular weights and slower rates of hydration improved floating characteristics.
In the studies by Jamini et al.,149 the discrepancy in the observed results could have
been a result of using an inappropriate apparatus and floating measurement conditions.
Under fed conditions, the pH of the stomach is elevated; therefore, citric acid is used
along with sodium bicarbonate to provide an acidic medium for the formulation compo-
nents to interact and effervesce. Different combinations of sodium bicarbonate and citric
acid along with Methocel® have been evaluated to achieve optimum in vitro buoyancy
and floating duration. The level of citric acid has been found to have a greater influence
on drug release than the grade of Methocel®, because the CO2 gas that is released upon
the interaction between citric acid and sodium bicarbonate accelerated the hydration of
floating tablets through porous channels. Release of drug was faster from the floating

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Gastroretentive Floating Drug-Delivery Systems 65

tablets due to higher formation of gas and consequent higher porosity or volume inside
the swollen gel matrix. The drug release from the hydrophilic polymer matrix was ana-
lyzed using Korsemeyer-Peppas drug release model shown below in Equation 1151:

Mt
= kt n
(1)
M∞
where M t and M ∞ are cumulative amount of drug released at time t and infinity, re-
spectively; n is the release exponent indicative of mechanism of drug release; and k is a
constant incorporating structural and geometric characteristics of the system.
The magnitudes of release exponents obtained in all cases were in the range of 0.60
to 0.89. These values indicated the drug release to be non-Fickian or the anomalous type,
in which drug diffusion, polymer relaxation, and matrix erosion contributed to overall
drug release from the matrix tablets. Although in all cases the mechanism of drug release
was found to be a result of a combination of drug diffusion and polymer relaxation, their
individual contributions to drug release were not evaluated as a function of polymer
viscosity. Therefore, treating the drug-release data with the Peppas and Sahlin model
(Equation 2) would have provided a better understanding of any changes in the contri-
bution of the polymer relaxation and diffusion phenomenon (Equation 3) to the overall
drug release from the tablets containing different viscosity grade polymers.134, 152

Mt
= k1t n + k 2t 2 n (2)
M∞
Where M t and M ∞ are cumulative amount of drug released at time t and infinity,
respectively, and n is the release exponent indicative of mechanism of drug release. The
first term on the right side of the equation represents the Fickian diffusional contribution
(referred to as F), whereas the second term represents the case-II relaxation contribution
(referred to as R). The ratio of both contributions can be calculated as follows:

R k 2t n
= (3)
F k1
also, despite large difference (150 times) in the viscosity of the two polymer grades, the
tablets made with both low- and high-viscosity–grade Methocel® provided similar drug-
release profiles, with 85% to 98% of the drug released over a period of 8 to 10 hours.
This ambiguity in the observed results indicates that the dissolution testing method em-
ployed is non-discriminating and insensitive to changes in the level and type of polymer
in the formulation. However, the researchers did not perform any in vivo studies to cor-
relate their in vitro results and substantiate their claims.
Jang et al.153 used an EFMS to investigate floating tablets of a derivative of eupatilin,
DA-6034, indicated in the treatment of inflammatory bowel disease. The therapeutic

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66 Kotreka & Adeyeye

limitation of DA-6034 due to its poor solubility in gastric conditions was overcome by
the use of solubilizers. The EFMS was formulated using Carbopol® and Kollidon® CL
as swelling polymers, sodium bicarbonate as a gas-generating agent, Eudragit® L100-
55 as an erosion polymer, and Poloxamer® and sodium lauryl sulfate as solubilizers.
This mixture was either directly pressed or wet granulated with water to form tablets by
adding a lubricant. The wet granulation method was chosen over direct compression to
overcome the poor flowability of the drug. Upon contact with gastric fluids, the tablets
floated after a lag time of 1 to 2 minutes. The solubilizers were shown to improve the
drug solubility, and the use of an enteric polymer, which is insoluble in acidic pH, led to
the disruption of tablet after swelling and subsequent drug release. The combination of
swelling polymers was used in this case to optimize lag time for flotation and also to of-
fer better control over drug release, resulting in the drug release following a non-Fickian
mechanism in which it is a function of its diffusion and polymer relaxation.
The DA-6034 EFMS tablet was evaluated in vivo by oral administration to ulcer-in-
duced female beagle dogs three times per day after meals for 16 days. The ulcer-healing
effects were monitored periodically by gastric endoscopy, which revealed a statistically
significant (P < 0.05) improvement in the ulcer-healing and gastro-protective effects of
the DA-6034 EFMS tablet compared with an immediate-release control tablet. However,
such results should be used with caution, because the immediate-release control tablet
used in this study was different in its density and composition from the GRDF and there-
fore did not represent an appropriate control with which to demonstrate the effectiveness
of a gastroretentive dosage form (GRDF). Any therapeutic advantages observed may
have been the result of the sustained-release nature of the drug from the dosage form
due to the use of different swellable polymers rather than of the prolonged drug release
due to gastric retention by flotation. Moreover, these researchers did not study the effect
of the floating tablet in dogs in the fasted state. Therefore, the improved therapeutic ef-
ficacy due to prolonged gastric retention of the floating EFMS tablet might have had less
to do with flotation than to the presence of food affecting gastric emptying.49 Further,
beagle dogs may represent a reasonable species for screening, but these results must be
evaluated with certain reservations when extrapolating experimental gastric retention
data to what could be expected in humans. Convincing evidence for gastric retention
requires human data.29,59
Fukuda et al.15 investigated the potential of floating tablets made using the hot-melt
extrusion (HME) process as a GRDDS. The HME tablets containing the model drugs
acetohydroxamic acid or chlorpheniramine maleate were prepared from a powder blend
containing sodium bicarbonate and Eudragit® RS PO. The tablets remained buoyant in
the medium and possessed sustained-release properties. Eudragit® RS PO when melted
extruded at a temperature (100°C) above its glass-transition temperature (55°C–60°C)
functions to retard drug release. To have better control over the drug release, the gastric
acid–soluble polymer Eudragit® EPO was also used. However, the HME tablets did not
float when the polymers made up 75% (w/w) of the tablet weight due to the increase in
the tablet density over 1.0 g/cm3. The influence of sodium bicarbonate on the physico-
chemical properties of the controlled-release HME tablets was evaluated. Studies were

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Gastroretentive Floating Drug-Delivery Systems 67

performed to compare the effects of the tablet-processing method on drug release and
buoyancy of directly compressible tablets and HME tablets. Results from dissolution
testing indicated that the drug release from directly compressible tablets was rapid, with
no significant buoyancy observed over dissolution medium. The porous internal tablet
morphology that contributed to the buoyancy of the HME tablets was produced by the
evolution of CO2 gas upon thermal decomposition of sodium bicarbonate in softened
acrylic polymers at elevated temperatures during the extrusion process.
Nakagawa et al.154 developed novel, intra-gastric floating tablets of 5-fluorouracil
by pulsed plasma irradiation of the double-compressed tablet. This work was a continu-
ation of that reported previously on the development of theophylline floating tablets by
an argon plasma irradiation–induced cross-linking reaction on the tablet surface using
polymers with plasma–cross-linkable properties (i.e., polymers with functional groups
that form plasma heat flux–induced free radicals and facilitate particle-particle cross-
linking).155-157 In this study, a core material with outer layer composed of Povidone®
(polyvinyl pyrrolidone) and Eudragit® RL as plasma–cross-linkable polymers (enabled
by mono-substituted vinyl monomers in the component) and sodium bicarbonate as a
gas-generating agent were used. The plasma heat flux caused the thermal decomposi-
tion of sodium bicarbonate to generate CO2. The resultant gases were trapped in the
outer layer of the tablet to reduce its density to 0.88 g/cm3, lower than the density of the
gastric contents (∼1.004 g/cm3). This allowed the tablets to remain buoyant in the simu-
lated gastric fluid for a prolonged period of time. In addition, the release of 5-fluoroura-
cil from the tablet was sustained due to the formation of fibrous pore structures upon
CO2 evolution and the plasma-induced cross-linking reaction between Povidone®and
Eudragit® RL on the outer surface of the tablet. The release rate of 5-fluorouracil was
found to be well controlled by plasma operational conditions. The tablets produced in an
optimum composition of 68/17/15 weight ratio of Povidone®, Eudragit® RL, and sodium
bicarbonate offered suitable floating and sustained drug-release properties with enough
mechanical strength to sustain gastric motility. However, the in vivo effectiveness of
these tablets has yet to be demonstrated.
From the above discussions, it was evident that the dosage forms incorporating in
situ gas-generating mechanisms have greater buoyancy and improved drug-release char-
acteristics. However, in the case of the matrix formulations, optimization of one char-
acteristic is often achieved at the cost of the other. Therefore, it is sometimes necessary
to develop a formulation such as tablets or beads using a multilayer approach in which
each individual layer is vested with a different function. This facilitates control of the
buoyancy and drug-release characteristics of the formulation independent of one an-
other by simply making modifications in different layers during optimization studies.3

1. Multilayered Tablet Dosage Forms

Sungthongjeen et al.158 developed floating, multilayered, coated tablets of the model

drug anhydrous theophylline. The dosage form was composed of a core tablet contain-
ing the drug, a protective polymer coat, an effervescing or gas-generating layer, and a

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68 Kotreka & Adeyeye

gas-entrapped membrane, sequentially. The drug-containing cores were prepared either

with the direct compression method, using microcrystalline cellulose as a filler, or with
the traditional wet-granulation method and HPMC as the binder. HPMC was used as the
core protecting polymer layer to retard drug release and prevent direct contact with the
gas-generating agents (i.e., bicarbonates) in the effervescing layer. In preliminary stud-
ies, tablets without a gas-entrapping layer did not float due to dissolution of the HPMC
membrane and the absence of a gas-entrapping membrane. Therefore, a gas-entrapping
membrane (Eudragit® RL 30D) was chosen mainly based on factors such as its perme-
ability to the dissolution medium in order to facilitate an effervescent reaction with the
gas-generating layer, its impermeability to the generated gas to prevent its escape, and
its elongation value or flexibility and capacity to withstand the pressure of the generated
gas and avoid membrane rupturing. The large number of ammonium groups present in
this polymer enabled it to hydrate faster to initiate the effervescence reaction and offer
quick buoyancy. A higher level of bicarbonates in the effervescing layer, however, did
not affect the floating lag time, the increased drug-release rate due to higher porosity, or
the volume created in the polymeric membrane upon release of CO2. Results indicated
that drug release from core tablets made using the directly compressible method was
faster due to the disintegrating nature of microcrystalline cellulose and slower in those
made using wet granulation due to the use of HPMC as binder. Tablets in their optimum
composition provided quick buoyancy (lag time of 7 minutes) and remained afloat for
more than 8 hours, with continuous drug release. Using the multilayered approach as
opposed to a single-layer matrix tablet, it was thus possible to achieve rapid onset of
buoyancy and controlled drug release with prolonged flotation. However, such claims
need to be further substantiated with evidence of performance in animal models and
human subjects.
Zou et al.159 developed a pulsatile FDDS of verapamil HCl intended for chronophar-
macotherapy of ischemia. The floating pulsatile concept has been recently explored by
researchers to increase the gastric residence of the dosage form by having a lag phase
followed by a burst release.160-162 The FDDS consisted of three different parts: a core
tablet containing the active ingredient, an erodible outer shell, and a top cover buoyant
layer. The buoyant layer, which was composed of Methocel® K4M, Carbopol® 934P, and
sodium bicarbonate, provided rapid onset of buoyancy and prolonged flotation when it
came into contact with the gastric fluids, increasing the retention of the oral dosage form
in the stomach. In vitro floating studies showed a floating onset time of less than 1 min-
ute and floating duration of more than 12 hours. The pulsatile release layer of the tablet
composed of Methocel® E15 eroded in the aqueous medium with progressive modifica-
tion in terms of thickness and consistency. When the erosion reached a limiting thick-
ness, the shell ruptured under the pressure applied by the swelling of the core tablet, and
resulted in the drug release after a prolonged lag time. The lag time was observed to be
clearly dependent on the kind and amount of hydrophilic polymer applied to the core.
In vivo analysis of gamma-scintigraphic images in the volunteers administered a
layered, floating, pulsatile-release tablet in the half-fed state (i.e., 4 hours after dinner)
indicated in vivo lag time values (4.4 ± 0.4 hours) consistent with the corresponding

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Gastroretentive Floating Drug-Delivery Systems 69

in vitro lag times (4.1 ± 0.1 hours). The GRT of floating, pulsatile-release tablets com-
pared with non-floating control tablets was found to be in excess of 4 hours. Both the
pharmacokinetic data in beagle dogs and in vivo gamma-scintigraphic data in humans
suggest great potential for this approach in extending the residence time of the tablets in
the stomach and releasing drugs after a programmed lag time. Because in vivo studies in
the fasted state were not performed, it is ambiguous to claim that the prolonged gastric
retention was purely due to flotation rather than the presence of food in the fed state.49
Ozdemir et al.11 developed floating, bilayered tablets for the controlled release of fu-
rosemide. The limitations of oral delivery of the drug due to its poor aqueous solubility
was overcome by making a solid dispersion with β-cyclodextrin mixed in at a 1:1 ratio.
The first layer, vested with the function of providing instantaneous flotation, contained
a mixture of sodium bicarbonate and citric acid to cause effervescence and HPMC 4000
as a matrix polymer to retain the CO2 gas. The drug-releasing layer contained the drug-
cyclodextrin complex and HPMC 100 as hydrophilic matrix materials. The tablets were
compressed at varying compression forces.
In vitro floating studies revealed that the lesser the compression force, the lesser
the density of the tablet and the shorter the time it took for the onset of floating. Tablets
compressed at 15 MPa, were found to float at 20 minutes, whereas in those compressed
at a force of 32 MPa, the onset of flotation was prolonged to 45 minutes. To determine
the duration of gastric retention using radiography, labeled bilayered tablets were given
to human subjects with water and light breakfast. Although radiographs showed gastric
retention of floating bilayered tablets for 6 hours, it is not clear whether the retention
was due to dosage form flotation or the presence of food delaying the gastric empty-
ing of non-disintegrating dosage forms. The pharmacokinetic data obtained for floating
tablets in patients in the fasted state indicated higher bioavailability and prolonged peak
diuretic effects compared with control tablets (i.e., immediate-release Furomid® tablets).
Such pharmacokinetic differences may have been due to the controlled-drug-release
nature of the floating tablet rather than the floating mechanism itself. An in vivo phar-
macokinetic study coupled with image analysis using the floating tablet as a test product
and an identical tablet without effervescing substances as a control in human subjects in
the fed and fasted states would provide more information and a better understanding of
the mechanism of gastric retention and any pharmacokinetic differences.

2. In situ Stimuli-Responsive Gel/Raft-forming Systems

In situ gel-forming preparations are “stimuli-responsive” polymeric drug-delivery sys-

tems that are conveniently delivered orally as a liquid, followed by a transition into a gel
upon contact with the gastric fluids in the stomach. The effervescence-causing excipi-
ents, such as carbonates and bicarbonates, in these preparations generate CO2 bubbles
that get entrapped into the gel network and cause the gel to float over the gastric con-
tents. The stimuli-responsive polymers are dependent on both the polymer-solvent and
the polymer-polymer interactions. Parameters that can change and trigger this sol-gel
phase transition include pH, temperature, and ionic strength.163,164 Numerous types of

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70 Kotreka & Adeyeye

stimuli-responsive polymers used in drug-delivery systems have been reviewed previ-

ously.133,165,166 Table 7 provides a list of such “smart” polymers used in in situ gel-form-
ing preparations. These formulations use the novel idea of delivering drugs to patients
in a liquid dosage form, yet prolong the drug’s contact time at the site of absorption
and sustain its release for the desired duration. An example of a commercially avail-
able product is the stomach-specific antibiotic drug delivery employed in the in situ gel
system in Liquid Gaviscon® (GlaxoSmithKline), which has been reported to be highly
beneficial in the treatment of H. pylori infection in peptic ulcer disease.
Several researchers have investigated the local delivery of antibiotics as in situ gel-
forming formulations to the gastric mucosa. Rajinikanth et al. have investigated the ef-
ficacy of gellan gum–based in situ gel-forming liquid preparations of antibiotics such as
clarithromycin, amoxicillin, and acetohydroxamic acid over their corresponding liquid
suspensions in the eradication of H. pylori.80,85,88 The formulation contained gellan gum
as an ion-activated in situ–gelling polymer and calcium carbonate as an effervescing
agent. The calcium carbonate present in the formulation dissolved and released CO2 on
reaction with the stomach acid and the in situ–released calcium ions activated the sol-
gel phase transition. The carboxylate groups of gellan gum interacted with the calcium
ions and caused gelation. The mechanism of gellan gum gelation involved the formation
of double helical junction zones from random coil chains (coil-to-helix transition), fol-
lowed by aggregation of double helical segments to form a three-dimensional network
by complexation with calcium ions and hydrogen bonding with water.85,167 The released
CO2 was entrapped in the gel network of the formulation and caused it to float over the
gastric contents. Thus, drug in the in situ–formed gel was retained in the stomach for
a prolonged period of time. As a result, it was observed that the required amount of
antibiotics for eradication of H. pylori in Mongolian gerbils was far less in floating in

TABLE 7. List of ‘Stimuli-Responsive’ Polymers Used in in situ Gel-

Forming Preparations133,165,166
Polymer Stimulus
®
Poloxamers (e.g., Pluronic L44, F68, F127, F87, Temperature
F108)
Xyloglucan
Cellulose derivatives (e.g., methyl cellulose,
HPMC, ethyl hydroxyethyl cellulose)
Carbomers (e.g., polyacrylic acid, Carbopol® 910, pH
934, 940)
Pseudo latexes
Cellulose acetate phthalate latex
Gellan gum Ionic strength
Alginates
Carrageenan and chitosan Ionic strength + pH
Poloxamer and chitosan Temperature + pH
Poly(N-isopropylacrylamide) Temperature + pH

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Gastroretentive Floating Drug-Delivery Systems 71

situ–gelling systems than for the corresponding suspension. Formulation optimization

studies were performed to identify the optimum levels of gellan gum and effervescence
causing carbonates or bicarbonates to achieve optimum viscosity and gelling capacity.
The formulation with optimum viscosity allows for easy dispensing and swallowing as
a liquid, which then undergoes a rapid sol-gel transition due to ionic interaction in the
stomach. Gelling capacity and the drug release from these preparations was found to be
a function of the polymer concentration.
Similar studies were performed by Rohith et al., who investigated the use of so-
dium alginate as a polymer in the in situ–gelling ranitidine liquid formulation for the
treatment of gastric ulcers and gastroesophageal reflux disease.102 The observed results
indicated that the grades and concentrations of sodium alginate used in the formulation
had a significant effect on the viscosity of the preparations, and on the floating and drug-
release kinetics from the in situ–geling systems.
Nagarwal et al.99 investigated the feasibility of developing an in situ gel-forming
metformin preparation as an alternative to the single-unit dosage forms commercially
available. The formulation contained metformin as an anti-diabetic drug, a combina-
tion of sodium alginate and gellan gum as anionic polymers, and calcium bicarbonate
as an effervescence-causing agent. The formulations were optimized using a 33 factori-
al design to identify the optimum levels of gellan gum, sodium alginate, and metformin
to achieve dissolution efficiency and drug-release kinetics similar to the commercial
product. In this case, a combination of two polymers was required to minimize the
burst release of the drug from the formulation and achieve the desired drug-release
characteristics. The anionic nature of both polymers induced gelation by ionic interac-
tion. The drug release from the in situ gel systems was found to be a function of the
gellan gum-to-sodium alginate ratio. Incorporation of gellan gum as another source of
anionic polymer decreased the burst effect, and increasing the gellan gum-to-sodium
alginate ratio decreased the drug release from the hydrogel matrix. The mechanism of
drug release was determined using the Korsemeyer-Peppas kinetic model (Equation 1).
The release exponents for all formulations in the range of 0.40 to 0.67 indicated Fick-
ian drug diffusion to be the predominant mechanism of drug release, along with some
contribution of polymer relaxation. The optimized in situ gel formulation was found
to be a very good alternative to the single-unit solid-dosage form, because it is easy to
administer to both geriatric and pediatric patients, who constitute a large proportion of
the diabetic population.

3. Multiparticulate Dosage Forms

Hamdani et al.168 investigated the potential of melt pelletization as a short, one-step,

single-pot production process to develop sustained-release floating pellets. The pellets
were prepared in a high-shear mixer and coated with an outer matrix composed of ex-
cipients that offer prolonged flotation and sustained drug release from the pellets. The
inner core was composed of a mixture of Compritol® and Precirol® as a lipidic barrier
to offer sustained-release characteristics, sodium bicarbonate as a gas-generating agent,

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72 Kotreka & Adeyeye

and Methocel® K100 as a swellable membrane to entrap CO2 bubbles and impart buoy-
ancy. With the purpose of reducing the floating lag time, the pellet core was coated with
matrix composed of Precirol® and sodium bicarbonate to offer immediate flotation of
the pellets. The placebo pellets composed of lactose were evaluated for buoyancy using
either the counting method or the resultant weight method. The results indicated rapid
onset and prolonged buoyancy in the acidic medium (0.1N HCl, Polysorbate 20) with
75% of them floating for 23 hours. The presence of a gas-generating agent in both the
inner matrix and the outer coating of pellets allowed for rapid onset and continuous
buoyancy. Differences in floatability and drug-release characteristics of the pellets made
of three different model drugs, ciprofloxacin HCl, tetracycline HCl, and theophylline,
was attributed to differences in their physicochemical properties such as water solubil-
ity, particle size, and particle size distribution.
Goole et al.169 developed a new multiple-unit, sustained-release floating system of
the model drug levodopa using the process of melt granulation and compression into
mini-tablets. The objective was to develop a simple composition and production tech-
nique that was easily scalable and provided mini-tablets with good floating and sus-
tained drug-release characteristics. Precirol® ATO (glyceryl palmitostearate) was used
as meltable binder and sodium bicarbonate and calcium carbonate with tartaric acid
were used as gas-generating compounds. High drug-loading capacities were achieved
when the tablets were coated with a flexible and swellable polymer such as Eudragit®
RL 30D instead of a large amount of gel-forming polymer as a means of entrapping
the evolved gas from the effervescent system and imparting good floating character-
istics.76,168 High drug-loading capacities also resulted in fewer mini-tablets needed for
a given dose. This decrease in the number of tablets required resulted in a relatively
decreased total surface area available for exposure to the dissolution medium at any
given point in time, causing drug release for prolonged periods of time. The use of
acetyl triethyl citrate (Citroflex A2®) as a plasticizer helped to maintain the flexibility
and mechanical integrity of the coated film for durations as long as 20 hours. For-
mulation variables such as core composition and diameter and coating composition
are reported to largely influence the floatability and drug-release characteristics of
mini-tablets.
Atyabi et al. developed a novel floating gastric retentive system using ion-exchange
resins.170-172 In this study, the Dowex™ 2 × 10 ion-exchange resin beads were loaded
with bicarbonate as a gas-generating agent prior to loading of the drug theophylline.
Because this cationic drug has a tendency to replace the bicarbonate ions from the resin
beads, drug-loading concentrations were carefully optimized to minimize the probabil-
ity for such displacement. Drug-loaded resins were then coated with the semi-permeable
polymer Eudragit® RS using the coacervation phase-separation technique. In simulated
gastric medium, the polymer membrane not only facilitated diffusion of gastric fluids
into the resin beads to cause effervescence, but also prevented loss of CO2 gas generated
by entrapping it. The resultant decrease in density due to the entrapped gas provided
beads with the buoyancy to float over the medium and release the drug for prolonged
times. The drug-release process involved a complex mechanism of anion exchange, with

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Gastroretentive Floating Drug-Delivery Systems 73

drug diffusing into the beads and out into the bulk, along with particle diffusion. In vivo
studies were performed in human volunteers to compare the performance of drug-coat-
ed and uncoated resin beads administered after a light, fluid breakfast. Evidence from
gamma-scintigraphic imaging demonstrated the potential of drug-coated resin beads to
remain floating for longer durations in the GIT. In contrast, the uncoated beads sank
quickly and did not float.
In a similar study, Todd et al.173 developed a floating formulation using cholestyr-
amine as an anion-exchange resin that could bind to the excess level of bile acids in pa-
tients with conditions such as hypercholesterolemia, pruritus, and biliary gastritis. The
cholestyramine is believed to exchange chloride ions for the bile with which it binds to
form an insoluble complex that is excreted in the feces, thus preventing normal reab-
sorption of the bile salts. The formulation contained low-viscosity-grade alginic acid or
a sodium alginate polymer to regulate drug release and a combination of citric acid and
sodium carbonate to facilitate effervescence. The gas generated upon effervescence was
trapped by the gelled alginate matrix to provide flotation and ensure prolonged gastric
retention of cholestyramine.
Umezawa106 developed floating mini-capsules of pepstatin to reduce pepsin activity
in patients with gastric and duodenal ulcers. The center (core) of the mini-capsule was
comprised of granules of sodium bicarbonate mixed with lactose and polyvinyl pyrrol-
idone and coated with a 2% methanol solution of HPMC in a coating pan. The core was
then coated with pepstatin and the mini-capsule was further coated on the outer surface
with the water-soluble coating agent HPMC. The mini-capsules thus obtained were 0.1
to 2.0 mm in diameter. The CO2 gas generated when the core containing sodium bi-
carbonate came into contact with the HPMC coating and gastric acid caused the mini-
capsules to float and be retained in the stomach for longer times. Results demonstrated
sustained release of pepstatin from these capsules. When administered to patients with
gastric and duodenal ulcers immediately after a meal, these capsules remained for 3 to
5 hours in the stomach, and a single dose of 50 to 200 mg of pepstatin was enough to
suppress the pepsin activity.
Ichikawa et al.174 designed a novel capsule containing granules capable of floating
and providing different residence times in the stomach. The granules contained a drug
core with two layers of coating. The inner first layer was a foamable layer composed of
effervescing agents (sodium carbonate alone or with citric acid), and the outer layer was
a water-permeable, flexible polymer layer that allowed gastric fluid to permeate through
and react with effervescing agents to generate CO2 gas. The polymer chosen for these
capsules not only must be flexible and water permeable, but also impermeable or less
permeable to the generated CO2 gas to escape from the granules. Polymers such as poly-
vinyl acetate, shellac, acrylic resins, and HPMC can be used to form a water-permeable,
flexible polymer layer. The CO2 gas generated expands the flexible outer layer and gets
entrapped in it, causing the granules to float and remain buoyant over gastric contents
for longer times. Ichikawa et al. reported that this type of preparation can be widely ap-
plicable for various classes of drugs such as analgesics, anti-tussives, local anesthetics,
and anti-allergics, which are required to remain in the stomach for a prolonged period

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74 Kotreka & Adeyeye

of time for better therapeutic efficacy. In a follow-up study, Ichikawa et al.76 used the
same approach to develop a multi-unit floating tablet of the model drug p-aminoben-
zoic acid. The system contained sustained-release mini-tablets as seeds surrounded by
double layers. The inner effervescing layer was composed of sodium bicarbonate and
tartaric acid and was subdivided into two layers to avoid direct contact between them.
The outer layer was a swellable membrane containing polyvinyl acetate and purified
shellac. When immersed in a buffer solution maintained at 37°C, the solution diffused
through the outer permeable membrane and initiated reaction in the effervescing layer.
The CO2 gas thus generated was entrapped in the outer layer. This caused the spherical
mini-tablets to swell like balloons and float over the solution due the decrease in their
density to a value below 1 g/cm3. The lag time for flotation was found to be 10 minutes,
and approximately 80% of the mini-tablets remained afloat over a period of 5 hours ir-
respective of the pH or viscosity of the test medium.
Interestingly, adaptation of the multilayered approach in single- and multi-unit
effervescent systems shifted the drug-release kinetics from the diffusion-based clas-
sical Higuchi square root kinetics to near zero-order kinetics.76,110,175 This shift in the
drug-release behavior was a result of gas entrapment by the impermeable polymer
layer/membrane/coat and the barrier it offers for drug diffusion and matrix relax-
ation.110,176 In contrast, non-effervescent floating systems typically follow Higuchi
drug-release kinetics, indicating that diffusion is the predominant mechanism of drug
release.38,104,110,177

IV.E. Non-Effervescent FDDS

Non-effervescent floating dosage forms use low-density substances such as polymers

that swell or gel in the acidic medium and attain low density by themselves or by entrap-
ping other low-density excipients such as oils and fatty substances. The use of oils not
only reduces their density enough to float over the stomach contents, but also decreases
the rate of polymer hydration and prevents faster erosion.115
The majority of non-effervescent FDDS use a swellable or gel-forming type of hy-
drocolloid, polysaccharides, and matrix-forming polymers such as polycarbonate, poly-
acrylate, polymethacrylate, and polystyrene.19 The formulations made using these poly-
mers are usually a simple blend of the drug and polymer thoroughly mixed with other
manufacturing aids and made into either a capsule or a tablet. Many of the commercial
floating formulations use this type of drug-delivery system (Table 2). After oral ad-
ministration, the dosage form swells and gel in contact with gastric fluids and achieves
a bulk density lower than the gastric fluid, which enables it to remain afloat. The air
entrapped within the swollen gel matrix imparts buoyancy to the dosage forms. The gel
layer formed also acts as a barrier opposing the entry of gastric medium into the system
and concomitant drug transport out of the system. This results in a sustained release of
the drug over a period of time.56,63 In many cases, polymers are either used singly or in
combination with others mainly to modulate the swelling and erosion behavior of the
matrix and to achieve a desired drug-release pattern.48

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Gastroretentive Floating Drug-Delivery Systems 75

1. Single-Unit Dosage Forms

Ali et al.178 investigated a single-unit HBS of metformin, a drug used as an anti-hyper-

glycemic agent in patients with type 2 diabetes to improve their glucose tolerance. The
immediate-release tablet dosage form has poor oral bioavailability (50%–60%) due to
shorter contact time at the site of absorption, the proximal small intestine. Therefore, a
hydrodynamically balanced or floating system was developed by simply mixing metfor-
min and different-swelling polymers such as HPMC and polyethylene oxide in different
ratios and putting them into empty capsule shells. The capsule swells upon contact with
citrate phosphate buffer at pH 3.0. The air trapped by the swollen polymers reduces bulk
density to less than unity and confers buoyancy to the dosage form. Although the formula-
tions remained buoyant, the drug release was not sustained due to the high water solubil-
ity of metformin. Therefore, release modifiers such as ethyl cellulose or cellulose acetate
phthalate were added to the formulations to sustain the drug release. During optimization
studies, formulations containing HPMC K4M and were found to possess the best floating
and sustained-release properties. An HBS made with the optimum composition of drugs
and polymers provided the in vitro release of 97% of the drug in 12 hours. Whole-body
images taken during in vivo studies in rabbits using a gamma camera confirmed the pro-
longed retention of capsules in the stomach for more than 5 hours; however, it is uncer-
tain whether such retention was due to flotation or to the size of the capsule, because no
information about the size of the capsule was provided. Results of pharmacokinetic stud-
ies comparing HBS and immediate-release formulations demonstrated a 136% increase
in the extent of absorption and sustained release of metformin over 7 hours using HBS.
However, the use of an immediate-release capsule as a control is inappropriate for dem-
onstrating any pharmacokinetic differences observed with HBS because such differences
can simply be as a result of the controlled drug-release system rather than any significant
effect of buoyancy. Therefore, use of a controlled-release capsule containing no floating
excipients as a control would provide a basis to demonstrate any significant advantage
an HBS capsule may have. In addition to that, the rabbit is reportedly not an appropriate
animal model with which to evaluate floating dosage forms because of large physiologi-
cal differences from humans.29,49 Because swelling is a vital factor in maintaining the
buoyancy of these systems, optimization studies for the selection of the ideal drug/poly-
mer ratio should involve monitoring of swelling parameters to expose any differences in
swelling behavior. This can be done by conducting water-uptake measurements or simply
by taking photographs of the dosage form at predetermined time intervals and measur-
ing the increase in radial and axial size extensions using image-analysis software.179 The
differences in swelling behavior can then be analyzed by fitting the data into the kinetic
model (Equation 4) proposed by Therien-Aubin et al.180:

(
S = S max 1 − e − kt ) (4)

where S is the swelling at time t, Smax is the maximum swelling at t→∞, and k is the rate
of swelling.

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76 Kotreka & Adeyeye

2. Multiparticulate Dosage Forms

Kawashima et al.109 developed a new emulsion-solvent diffusion evaporation method

to prepare hollow microspheres capable of floating on GIT fluids. In this method, the
acrylic polymer Eudragit® S100 was used as a release-controlling enteric polymer, and
combination of ethanol and dichloromethane was used as the organic phase based on
polymer solubility in the solvent mixture and solvent diffusivity. The selection of di-
chloromethane (boiling point of 40°C) was based on its ability to evaporate at low tem-
perature and result in hollow microspheres. In this technique, the solution of the drug
tranilast and Eudragit® S100 made in a solvent mixture of ethanol and dichloromethane
(1:1) was slowly added to the agitated aqueous solution of poly(vinyl alcohol) at 40°C
to make an oil/water emulsion. This also results in ethanol rapidly diffusing out of the
dispersed organic phase into the aqueous phase. Because ethanol is a good solvent for
the polymer, its diffusion results in polymer solidification and precipitation around the
dichloromethane droplets as a thin film at the interface between the organic and aqueous
phase. The microspheres thus formed are collected by filtration and subsequently dried
at 50°C for 12 hours. The evaporation of entrapped dichloromethane leads to the forma-
tion of hollow microspheres (Figure 2).
Using this method, the particle yield and drug-loading efficiency was low. Also, the
drug release was inefficient at the low pH of the stomach due to the use of an enteric
polymer. Low yield of microspheres could have been for two possible reasons: (i) the
rapid preferential diffusion of ethanol from the organic phase into the aqueous phase
even before the formation of a stable emulsion may have caused precipitation of poly-
mer on the surface; or (ii) evaporation of dichloromethane (boiling point of 40°C) at the
employed experimental condition of 40°C immediately upon diffusion of ethanol from
the organic phase may have led to the formation of incomplete or broken microspheres.
Dichloromethane is a highly volatile solvent with the potential for acute inhalation haz-
ard. Also, it is not a member of the generally regarded as safe (GRAS) solvents that can

FIGURE 2. Formation of hollow microspheres by the emulsion-solvent diffusion and evaporation

process.109

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Gastroretentive Floating Drug-Delivery Systems 77

be used in the pharmaceutical products, so its use in products and processes should be
limited. In the study by Kawashima et al.,109 the authors dried the product at 50°C for
12 hours, thereby assuming complete evaporation of the entrapped dichloromethane.
However, considering its potential to cause health hazard, the investigators should have
quantitatively measured the residual levels in the product.
Lee et al.181 later addressed this issue and attributed the low drug-loading efficiency
to the solubility behavior of the drug in the solvent system. They adopted the same
method used by Kawashima et al.109 and investigated several drugs with different physi-
cochemical properties as model drugs for encapsulation and release tests. It was ob-
served that drugs with low solubility in dichloromethane and high solubility in both the
aqueous phase and ethanol had poor loading efficiency in microspheres. A drug’s prop-
erties also affected its release from microspheres in the dissolution medium. The yield
of microspheres was observed to be largely influenced by the diffusion rate of ethanol
in the organic phase. A high yield of microspheres in the range of 91% to 96% was ob-
served when a mixture of ethanol and isopropanol along with dichloromethane was used
instead of ethanol and dichloromethane alone due to the decrease in the diffusion rate of
the solvent system. Factors such as agitation speed and temperature were found to affect
the morphology and particle size of the microspheres, with optimum results observed
at 250 rpm and 25°C. Insignificant drug release in the gastric pH was observed when
the enteric polymer was used alone. To overcome this, several studies have instead used
a combination of polymers such as Eudragit® S and RL to improve drug release in the
acidic pH due to increased permeability of the polymer mixture.105 Alternatively, excipi-
ents such as low-density polypropylene foam powder alone48 or preloaded with drug182
and non-volatile oils183 were also used in some studies as a dispersed phase to provide
buoyant microspheres.
In a study by Sato et al.184,185 riboflavin microballoons were prepared using the same
emulsion-solvent diffusion method developed by Kawashima et al. In this case, drug re-
lease in the stomach region was controlled using the combination of the pH-independent
hydrophilic polymer HPMC and the enteric polymer Eudragit® S100 in the riboflavin
microballoon. To provide convincing evidence of sustained pharmacological action due
to improved gastric retention of floating riboflavin microballoons, technetium-99m–la-
beled microballoons and non-floating microspheres possessing riboflavin release pro-
files equivalent to those of riboflavin microballoons as a control were administered to
three healthy volunteers in both fed and fasted conditions. Riboflavin pharmacokinetics
and intra-gastric floating behavior of both of the administered dosage forms was simul-
taneously analyzed using urinary excretion data and gamma scintigraphic imaging. Al-
though urinary excretion of riboflavin from riboflavin microballoons was not sustained
in the fasted state, it was significantly sustained (t1/2 5.62 ± 0.51 hour) compared with
non-floating microspheres (t1/2 3.88 ± 0.08 hours) in the fed state. Such a marked differ-
ence in the pharmacokinetic parameters of riboflavin from riboflavin microballoons over
non-floating microspheres with drug-release profiles equivalent to those of riboflavin
microballoons was clearly a result of improved gastric retention of riboflavin microbal-
loons due to flotation. Moreover, simultaneous gamma-scintigraphic analysis provided a

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78 Kotreka & Adeyeye

way to establish a correlation between the observed pharmacokinetic differences and the
improved GRT due to flotation of riboflavin microballoons in the fed state.
Murata et al.186 developed calcium-induced alginate floating beads of metronidazole
for treatment of H. pylori using two techniques. In one method, alginate beads are pre-
pared by dropping the solution containing sodium alginate, drug, and vegetable oil into a
0.1M calcium pantothenate solution at room temperature. Instantaneous gelation on the
outer surface of the droplets occurred as insoluble calcium alginate beads were formed.
The resultant hydrogel beads were washed twice and used for in vitro evaluation. It was
observed during in vitro studies that beads with a vegetable oil content of 30% w/w did
not sink and remained buoyant due to entrapment of low-density vegetable oil in the
alginate gel matrix, whereas beads prepared without any oil settled at the bottom of the
vessel and beads with 10% to 20% w/w oil content initially sank but gradually floated,
with the continuous release of metronidazole. Beads at all levels of added vegetable oil
showed higher loading capacity of metronidazole than calcium alginate beads alone.
However, in vivo studies were not performed with the vegetable oil–loaded beads be-
cause they were too large for guinea pigs to swallow.
Using same method, alginate beads containing chitosan were prepared. The air en-
trapped during chitosan-based alginate bead formation provided buoyancy to float over
the dissolution medium. Chitosan content amounting to 5% w/w was found to be nec-
essary to allow the beads to remain buoyant, but its molecular weight or deacetylation
ratio did not affect buoyancy. Floating was not observed when polymers such as chitin,
curdlan, sodium dextran sulfate, and xylan were used instead of chitosan. The drug-
loading efficiency of beads (65%) reported using this method was not promising. In
vitro release of metronidazole from chitosan-based alginate beads was found to be faster
due to the highly porous nature of the chitosan used. Although drug release in vitro was
faster and complete within 90 minutes, the in vivo drug release in guinea pigs was found
to be sustained over a period of 4 hours. This ambiguity in drug-release pattern was not
explained, but could have been the result of inadequacy in in vitro testing to simulate
in vivo conditions. No information about the in vitro floating duration of beads was
provided; however, in the in vivo studies, chitosan-based alginate gel beads were found
to be buoyant until 4 hours, as confirmed by visual observation of excised stomach in
guinea pigs. The use of metronidazole solution as a control to demonstrate efficacy of a
floating-beads system often resulted in false positive results. Moreover, the guinea pig
(as opposed to dogs) is not the proper animal model with which to evaluate gastroreten-
tive floating dosage forms.
Whitehead et al.187 made a slight modification to the above method and developed
a multi-unit floating system from freeze-dried calcium alginate. In this method, labeled
placebo calcium alginate beads were prepared by extruding the sodium alginate solu-
tion dropwise into calcium chloride solution. The calcium cation in the solution mini-
mizes the electrostatic repulsion between the carboxylic functional groups on two suc-
cessive alginate strands in the polymer, as depicted in Figure 3, and results in a calcium
alginate gel. The drop volume and concentrations were adjusted to obtain beads that
were spherical and approximately 2.5 mm in diameter. Once gelation was complete,

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Gastroretentive Floating Drug-Delivery Systems 79

beads were separated from the solution and snap-frozen in liquid nitrogen before be-
ing freeze-dried overnight at –40°C. The porous system produced due to freeze-drying
provided a positive floating force for over 12 hours in the in vitro resultant-weight
measurements.
In a subsequent study, Whitehead et al. performed in vivo studies in male healthy
human subjects using gamma scintigraphy.188 The evaluation of floatability and gas-
tric retention under different fed conditions (i.e., the same type of food with different
amounts and energy content) in different human subjects was carried out by compar-
ing floating and non-floating radiolabeled calcium alginate beads made from identical
materials. The mean density of the floating and non-floating beads was 0.33 and 1.82
g/cm3, respectively. The relative height of each set of floating and non-floating beads
from the base of the stomach was calculated using gamma-scintigraphic images taken
at different times.
From these measurements, it was found that non-floating dosage forms rapidly
settled at the bottom of stomach and emptied with a mean onset emptying time of 1
hour. In the case of floating alginate beads, gamma images taken to track the position
of labeled floating beads indicated prolonged gastric retention, with GRTs ranging from
5.5 to 9 hours across seven different subjects. The relative height of each set of beads
calculated using images taken at different time points was found to increase with float-
ing beads after meal consumption. This observation, along with the positive floating
force values observed in in vitro buoyancy evaluations, provided reasonable justifica-
tion of the floating capabilities of the developed freeze-dried calcium alginate beads.
Despite such large variations in the observed in vivo GRT (5.5–9 hours), the investi-
gators’ claim of prolonged gastric retention due to flotation in humans independent of
meal size remains ambiguous. However, no studies were performed in the fasted state

FIGURE 3. Mechanism of formation of calcium alginate floating beads.

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80 Kotreka & Adeyeye

(dosage form administered with water) to substantiate the evidence of gastric retention
due to flotation alone. In addition to that, the effect of drug inclusion on the dosage
form performance needs to be investigated.
Stops et al.189 continued the work further and investigated the in vivo gastric reten-
tion of placebo calcium alginate beads labeled with isotope technetium-99m in healthy
humans in the fasted state using gamma scintigraphy. They observed that when radiola-
beled beads were administered to human volunteers in a fasted state with 100 mL of 1%
(w/v) citric acid as opposed to 100 mL of water, the gastric emptying was significantly
delayed and resulted in 50% higher gastric residence times. However, the GRTs achieved
were not significant compared with those reported in the fed state in the previous study.
The exact mechanism by which citric acid delays gastric retention has yet to be clarified,
but Hunt et al. postulated that sufficient oral intake of citric acid causes the pH of the
duodenal contents to fall below pH 6.0, initiating a negative feedback mechanism. As a
result, bicarbonate is secreted to neutralize the acidic environment and facilitate gastric
emptying to recommence. The time for neutralization of excess acid is believed to be
responsible for delaying gastric emptying.190
To study the effect of drug inclusion on the performance of calcium alginate beads,
Whitehead et al.191 used the water-soluble drug amoxicillin trihydrate as a potential
treatment for H. pylori infections. Drug was incorporated into the alginate beads either
in a dissolved (solution) or dispersed (suspension) form. In vitro drug release from
beads containing soluble drug was found to be slower than that of the raw drug, but
this was not sustained. However, the drug release was moderately retarded by the in-
corporation of insoluble amylose as filler. Although drug loading (% w/w) of beads was
decreased depending on the amount of amylose added, the drug release was sustained
but not sufficient to be commensurate with the GRTs observed due to floating. In vitro
resultant-weight measurements for beads incorporated with soluble drug and amylose
2% (w/w) indicated positive resultant-weight values for 20 hours. This was found to be
comparable with the floating times reported in the earlier study.188 Greater drug load-
ing was obtained when the drug was incorporated into the beads as a suspension, but
at the expense of more rapid drug release and reduced buoyancy. Drug-release data
obtained were analyzed by Higuchi model and relating the amount of drug released to
the square root of time. Based on the observed linearity in the Higuchi plots, the inves-
tigators justified the drug release from the beads as being limited by its diffusion from
the insoluble alginic acid layer formed upon interaction of calcium alginate with acidic
dissolution medium. However, they failed to show any results of such data treatment in
their report. In addition, the use of acidic dissolution medium (pH 1.2) alone was inap-
propriate in this case, because the drug release from beads containing a pH-sensitive
calcium alginate polymer could be affected at elevated pH conditions prevalent in the
stomach and small intestine in the fed state. Therefore, dosage forms made up of such
polymers should be characterized in vitro for their swelling and relaxation behavior
using physiologically relevant medium prior to any in vivo investigations. In addition,
in vivo studies in animal models and humans need to be performed to support these in
vitro results.

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Gastroretentive Floating Drug-Delivery Systems 81

IV.F. Evaluation of Floating Dosage Forms

As discussed in the previous sections, the success of an FDDS in improving therapeutic

efficacy is largely based on its buoyant capabilities in vivo. Faster onset and continuous
flotation of a floating dosage form in vivo results in prolonged gastric retention at the
site of absorption, maximizing drug absorption and increasing local bioavailability of
the drug. Therefore, a thorough characterization of the floating kinetics of the dosage
form in vitro would facilitate the development of an optimized drug product with the
desired characteristics.
The evaluation of parameters including lag time for flotation, changes in floating
strength with time, stability and durability of floating forces produced, and maximum
floating time will help to develop an optimized drug product with the desired floating
characteristics. Such an evaluation not only provides an opportunity to predict the fate of
the dosage form in vivo, but also helps to avoid any unanticipated variations in floating
capabilities that might occur during in vivo evaluation of the dosage form.

1. In Vitro Buoyancy Testing

Depending on the whether the floating dosage form is a single unit or is composed of
multiple units, different floating evaluation techniques have been reported in the lit-
erature. In formulations such as floating pellets, the “counting method” developed by
Ichikawa et al. is widely used.76 Using this method, Hamdani et al.168 performed in vitro
evaluation of the floating ability of the pellets prepared by melt pelletization. Pellets of
size fractions in the range of 1250 to 2000 μm amounting to 100 to 150 in number were
immersed in 70 mL of medium composed of 0.1N HCl and 0.05% w/v Polysorbate 20 in
a 100-mL beaker. The beaker was kept shaking horizontally at a speed of 100 cycles/min
for 23 hours at 37°C to simulate in vivo gastric contractions and to ensure a monolayer
of pellets floating on the surface. The number or weight of the pellets floating on the
surface of the medium at different intervals was estimated by photographing the liquid
surface in the beaker and counting the number of floating pellets in the picture. The per-
centage of the pellets floating at each time point was then calculated by a simple ratio
of the number of pellets floating at any time to the initial number of pellets. In a method
similar to this, researchers have also used the known weight of the floating micropar-
ticles and added this to different beakers containing simulated gastric fluid maintained
at 37°C. Floating particles were collected at 1, 2, 4, and 6 hours from different beakers
and dried in a desiccator until they reached a constant weight. The percentage of the
initial weight of the microparticles floating at each time point was then calculated by a
simple ratio.127 However, a simple measure of the number of units floating at a particular
time may not provide any mechanistic understanding of the floating force evolution and
variations with time, because the polymer in the dosage form continuously reacts with
the gastric fluid to release its contents.
Timmermans et al.192,193 developed a novel “resultant-weight” method for character-
izing the buoyant capabilities of floating dosage forms. This method involves the use

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82 Kotreka & Adeyeye

of a specially designed apparatus (shown in Figure 4) that contains a sample holder at-
tached to the resultant-weight measuring device to quantitatively measure the total force
acting vertically on an object immersed in a liquid. The magnitude and the direction of
this force floating as evident from Equation 5 given below, is a result of the vectorial
sum of the buoyancy (Fbuoy) and gravity (Fgrav) forces acting on the object:

(5)

where F is the total vertical force, g the acceleration of gravity, df the density of the fluid,
ds the density of the object, m the tablet mass and V the tablet volume. The resultant-
weight method depends on both the weight and buoyancy forces. Weight gain upon
water uptake by the dosage form should be compensated for by adequate swelling in
order to keep the dosage form buoyant over the medium. The more positive the resultant
force and the resultant weight, the better the object floats. A typical profile depicting
the change in resultant weight with time is shown in Figure 5. The step-like pattern of
decreasing resultant weight in the curve is due to the periodic release of air bubbles or
CO2 gas entrapped in the matrix upon substitution by the test medium. The crossing of
the zero baseline by the resultant-weight curve from positive toward negative values
indicates a transition of the dosage form from floating to non-floating conditions. The
point of intersection of the resultant-weight curve on the time axis corresponds to the
maximum floating time of the dosage form. This method provides a more rational ap-
proach to characterizing the floating capabilities of dosage forms, with a provision to
compare the dosage forms on a scale with the best and least floating capabilities instead
of a “yes or no” approach to flotation that was used in earlier methods.
Hamdani et al.168 also used this same method in conjunction with counting method
to characterize floatability of the pellets made using melt pelletization technique. The

FIGURE 4. Schematic view of the resultant-weight apparatus.168

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Gastroretentive Floating Drug-Delivery Systems 83

FIGURE 5. Effect of resultant weight during buoyancy on the floating tendency of FDDS.

pellets of size fractions in the range of 1250-2000 μm were placed in the sample basket
holder and the resultant weight apparatus monitored the total vertical force acting on
the immersed pellets for the entire duration of study. The resultant-weight values were
found to be positive with more than 60% of the pellets floating up to 800 minutes after
contact with acidic medium. Strubing et al.179 used the same technique but instead mea-
sured the force equivalent to F required to maintain the tablet totally submerged into the
dissolution medium. The floating strength of the matrix tablets of propranolol HCl was
then determined as the weight decrease on the analytical balance over time.
Li et al.125 developed a continuous floating monitoring system, a modification of the
method by Timmermans et al., to monitor the floating kinetics of the calcium carbonate
capsules. As can be seen from Figure 6, the setup consisted of an analytical balance that
measures the upward resultant floating force and transfer data online to a computer con-
nected to it. The floating kinetic curve was generated by plotting floating force versus
time data collected at every 30-second interval. The kinetic parameters characteristic of
the floatability of capsule, such as maximum floating force (Fmax), time to reach maximum
floating force (Tmax), residual floating force (Fr), and area under the floating kinetics curve
(AUCf), are determined from the curve. The floating strength was observed to be mainly
dependent on the balance between water uptake and swelling of the polymeric system.

2. In Vitro Dissolution Testing

In oral or per-oral dosage forms, in which absorption of the drug is necessary to achieve
the desired therapeutic outcome, dissolution of the drug from dosage form is a vital
step for absorption to take place. An in vitro dissolution testing apparatus with the ap-
propriate hydrodynamic conditions that can predict in vivo drug-release behavior is an
important product-performance tool; it is also a required product-quality control test in
the USP monographs for various oral dosage forms. According to the SUPAC (Scale Up

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84 Kotreka & Adeyeye

FIGURE 6. Schematic illustration of the setup for the continuous floating monitoring system.125

and Post Approval Changes) guidelines from the US Food and Drug Administration,
upon establishing a valid in vitro and in vivo correlation, in vitro dissolution testing
may be used in place of in vivo bioequivalence testing to approve certain post-approval
changes in formulation and manufacturing.194 This underscores the need for a robust and
reproducible in vitro dissolution-performance testing methods. Consequently, research-
ers have periodically reviewed and modified the existing dissolution methods for con-
ventional dosage forms with the goal of establishing a broad range of testing conditions
that allow flexibility in choosing conditions to test the drug release from novel dosage
forms such as GRDDS. Traditional in vitro dissolution methods have been shown to
be poor predictors of in vivo performance of floating dosage forms,34 possibly due to
inadequacy in simulating in vivo hydrodynamic conditions that are prevalent with float-
ing systems, which will not allow for accurate determination of drug-release kinetics.
Therefore, the conventional dissolution testing methods have either been replaced with
new procedures or modifications to the existing apparatus are done to accommodate the
testing of the novel dosage forms such as FDDS.
Traditionally, tablet dissolution was assessed using standard USP type I (basket) and
type II (paddle) devices. The recommended compendial stirring speeds for the basket
and paddle apparatus were 100 and 50 rpm, respectively. The traditionally used paddle
apparatus for evaluating floating dosage forms poses a lot of experimental issues. These
include adherence of dosage form to the paddle shaft or sample withdrawal aids, incom-
plete exposure to the dissolution medium, hydrodynamic conditions causing formation
of a stagnant region of disintegrated particles below the surface of the paddle, and failure
to mimic in vivo conditions.195-198 The formation of such a stagnant region of particles
is believed to be the cause for incomplete dissolution and variability in drug release.
Such drawbacks have forced researches to modify certain design aspects of the testing
apparatus. The use of “peak” vessels or a larger “mega” paddle is believed to disperse
the stagnant layer and provide an efficient stirring system.199,200

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Gastroretentive Floating Drug-Delivery Systems 85

The floating delivery systems need special modification with regard to the usual
dissolution methods stated above, because the hydrodynamic conditions offered by the
standard paddle or basket methods described in the official pharmacopoeia are inad-
equate in providing either sufficient mixing to immediately disperse for rapid release of
the component or sufficient mechanical forces to cause erosion of the sustained-release
delivery system. To overcome this, Burns et al.201 developed and validated a sensitive,
discriminating in vitro dissolution method for floating dosage forms based on the stan-
dard British Pharmacopoeia (1993)/USP (1990) apparatus II method, except that the
paddle blades were positioned at the surface of the dissolution medium. The studies
were carried out using enteric-coated HALOTM propranolol capsules containing bipha-
sic rapid and sustained-release propranolol base dissolved in oleic acid. The modified
paddle method with its blades set to the surface of the dissolution medium yielded repro-
ducible biphasic-release dissolution profiles and demonstrated the effectiveness of this
modified method in characterizing HALOTM capsules. Despite the reproducible drug-re-
lease profiles using this modified method, a drawback was the adherence of the dosage
form to the paddles.
Burns et al.197 continued this work and modified the standard dissolution apparatus
to assess the performance of the HALOTM floating dosage forms more reliably. The
goals were to eliminate the need for the positioning of the paddle blades at the surface
of the dissolution medium and to prevent adhesion of the dosage forms to the paddle
blades. The floating dosage form was contained under a supported stainless steel mesh
situated 72 mm from the base of the vessel, which divided the vessel into lower portion
representing approximately one-third of the vessel volume and an upper portion. The
dissolution test was carried out with the paddles set 10 mm above the mesh. The dosage
form was retained in the lower portion of the vessel and was prevented from floating
freely to the surface for the duration of the test. The dissolution characteristics of the
enteric-coated HALOTM propranolol capsules using a modified dissolution vessel were
compared with the dissolution method previously developed, in which paddles were set
to the surface of the medium. The results showed that the modified dissolution vessel
provided identical dissolution profiles but eliminated the risk of floating dosage forms
adherence to the paddles.
Durig and Fassihi196 also investigated the effect of hydrodynamic conditions on the
performance of verapamil HCl floating matrix tablets. They suggested the use of alterna-
tive methods to the existing compendial dissolution test apparatus that can better simulate
in vivo conditions and help to attain good in vitro and in vivo correlation. The swellable
guar gum–based matrix tablets of verapamil HCl were prepared and tested for drug re-
lease using the standard USP dissolution apparatus type I and II. They were also tested
using additional configurations to the type II dissolution apparatus that incorporated a
single ring and a mesh device or a double-mesh device placed below the paddle in the
dissolution vessel. Tablets were placed on top of the single-mesh device or in the com-
partment formed by the two mesh surfaces of the double-mesh device. Using the standard
USP type I apparatus, the drug did not show linear release due to the inhibition to the
swelling offered by the basket. Using the standard USP type II apparatus, the majority

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86 Kotreka & Adeyeye

of tablets stuck to the bottom of the vessel, resulting in limited hydration of one of the
tablet faces and causing variability in drug-release profiles. To overcome this problem, a
single-mesh device was placed below the USP type II apparatus and the tablet was placed
above the mesh device and studied for drug release. The flotation and random adhesion
of the tablet to the paddle or sampling aids with the single-mesh configuration resulted in
a large variability (standard deviation ≤ 11%) in the release profiles. This necessitated the
use of two mesh configurations that not only held the tablet in place in the compartment
between the two meshes, but also prevented sticking to the paddle. This method allowed
for the reliable estimation of the true release kinetics of the FDDS with almost superim-
posable release profiles and small standard deviations (≤ 3%).
Karande et al.198 studied the effect of positioning of the cefuroxime axetil FDDS
within the dissolution apparatus on drug release by making some modifications to the
compendial dissolution apparatus (USP type II). The drug release from FDDS was eval-
uated by placing the drug-delivery system in different dissolution apparatuses, as shown
in Figure 7: a USP type II (paddle) apparatus (Figure 7a), a USP type II (mesh designed)
apparatus (Figure 7b), a USP type II (wire helix) apparatus (Figure 7c), and the modi-
fied dissolution apparatus (Figure 7d). The dissolution study was carried out according
to the USP monograph using 900 mL of 0.07N HCl as dissolution medium at 37 ± 0.5°C
and a stirring speed of 55 rpm. The modified dissolution apparatus was subjected to
conditions similar to those experienced in the GIT, with a gastric volume of 70 mL and
gastric-emptying rates of 2 mL/min. This modified device was created by attaching an
S-shaped side arm capable of holding 70 mL of dissolution medium to a 100-mL glass
beaker. The medium was stirred using a magnetic stirrer at the same speed (55 rpm) used
with the USP type II apparatus. From a burette mounted above the beaker to deliver the
dissolution medium, 0.07N HCl was added at a flow rate of 2 mL/min. The dissolution
samples were collected at regular intervals and analyzed upon being filtered through
0.5-mm filter paper. The statistical evaluation of dissolution similarity of the floating

FIGURE 7. Schematic presentation of different types of dissolution apparatuses.198

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Gastroretentive Floating Drug-Delivery Systems 87

tablet under different hydrodynamic conditions was evaluated by mathematical treat-

ment of the data to compute the similarity factor (f2) and t80%. The f2 values were scaled
between 0 and 100, and any value greater than 50 reflected a 10% or less overall differ-
ence between the dissolution curves of test and reference products. t80% is a measure of
the drug-release rate from the floating tablet and estimates the time taken for 80% of the
drug to be released. In this study, floating tablets were evaluated considering the product
being tested using the standard USP type II as a reference, and using the USP type II
(wire helix), USP type II (mesh designed), and modified dissolution apparatus as the test
products. The mathematical equation used to compute f2 is as follows:

(6)

where n is the number of time points, Rt is the dissolution value of the reference batch at
time t, and Tt is the dissolution value of the test batch.
The similarity factor values (f2 > 50) obtained in all three cases indicated identical
drug-release profiles.202 The t80% in the floating tablets tested in the modified dissolution
apparatus was found to be the lowest (9.0 ± 0.20) as a result of greater erosion of the
delivery system due to complete exposure to the medium and maintenance of sink con-
ditions by continuous fluid flow through the setup. The statistical analysis of t80% values
by analysis of variance indicated significant differences only between the USP type II
apparatus and the wire helix (t80% = 10.6 ± 0.30; P < 0.001 at α = 0.05). In the wire helix,
the drug release was suppressed from the dosage form due to inhibition of the three-di-
mensional swelling by the wire helix. The results demonstrated that drug release from
the FDDS was sensitive to its position in the apparatus and also to the hydrodynamic
conditions generated by using a different apparatus. The use of the modified dissolution
apparatus did not affect drug release significantly, but provided a setup that simulates in
vivo–like (i.e., physiologically relevant) conditions by providing full surface exposure,
maintenance of sink conditions, minimization of the dissolution fluid volume, and elimi-
nation of the risk of tablet adherence in the apparatus.
Further characterization of the drug-release kinetics to identify any change in the
drug-release mechanism with time using a different apparatus rate rather than just look-
ing at the overall similarity of the drug-release profiles would offer more insight into
drug release and the influence of the positioning of the dosage form and hydrodynamic
conditions. Such a characterization would also provide an opportunity to test the repro-
ducibility in the drug-release profile of dosage forms for any given testing conditions.

3. In Vitro Imaging Techniques

In recent times, there has been much progress in the area of diagnostic tools to monitor
the in vivo gastric transit of FDDS with the goal of elucidating the exact mechanisms by
which FDDS prolong gastric retention. Additionally, monitoring with the in vivo imag-

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88 Kotreka & Adeyeye

ing technique helps to establish correlation between GIT transit and pharmacokinetic
data, and also identifies any possible safety issues. It also allows for evaluation of effect
of food on gastric retention, mechanical integrity and biodegradation of dosage forms,
and any other physiological and anatomical constraints that restrict drug delivery to a
particular site. There are techniques, both invasive and noninvasive, reported in the liter-
ature that are used to characterize the performance of gastroretentive formulations. Ide-
ally, a noninvasive approach that does not affect the physical properties of the GRDF is
preferred. The most commonly used techniques are gamma scintigraphy,37,188,189,203 mag-
netic resonance imaging,204,205 radiology, gastroscopy,153,206,207 and ultrasonography.53
V. FUTURE DIRECTIONS OF RESEARCH

Despite extensive research in the area of GRDDS for the past four decades, success has
been very limited, with only a few drug products reaching the market. A large number of
formulations have shown successful in vitro performance, but have failed to perform in
vivo to provide any clinical benefits. The scope for future research can be rationalized in
two ways. First, the drawbacks associated with existing formulation technologies, such
as complexity in design, lack of reproducibility, poor scalability, performance dependent
on the state of the stomach, and premature gastric emptying, all of which are pitfalls in
achieving the desired characteristics of floating systems, need to be investigated and
new technologies need to be identified to overcome them. Appropriate controls and ra-
tional design of testing methods for characterizing the efficiency of an intra-gastric float-
ing system must also be adopted. The prolonged GIT residence time provided by float-
ing systems may be utilized to extend the rate of absorption. This may be an advantage
not only for drugs with a narrow absorption window, but for other drugs as well. This
brings us to another area where there is scope for future work. Therapeutic agents that
can benefit by GRDDS need to be identified. A rational way to find such drug candidates
would be to screen different classes of drugs that either act locally in the stomach to treat
any pathological conditions or undergo site-specific absorption in the stomach (e.g., the
drug pranlukast, a cysteinyl leukotriene receptor-1 antagonist, which was found to have
site-specific absorption in the stomach). Formulation efforts in the case of pranlukast
have been limited so far to increasing the oral absorption of the drug by improving its
aqueous solubility, and gastroretentive delivery of this drug has not yet been explored as
a suitable approach.208,209
Future research may concentrate on some of the following aspects:
1. Development of single-step and easily scalable production techniques. Because
most of the currently available techniques appear to be complex, necessitating
the use of a large number of excipients and involving multiple-step process using
organic solvents, they have limited applicability for industrial-scale production.
2. Design of multifunctional excipients that allow for the use of low levels of poly-
mers in the dosage form and increase the drug-loading efficiency.
3. Development of new formulation techniques to provide dosage forms that can
sustain floating after a succession of meals and provide meal-independent gas-
tric retention properties suitable for administration to patients with a wide range
of eating habits.

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Gastroretentive Floating Drug-Delivery Systems 89

4. Development of more rational in vitro tests that can simulate physiological and
hydrodynamic conditions that prevail in the presence of food. Such conditions
include changes in viscosity, density of the gastric contents, and variations in
the amplitude of the contractions in the presence of food.
5. Establishment of a correlation between prolonged gastric retention and phar-
macokinetic characteristics of a dosage form using more sophisticated in vivo
imaging techniques.
6. Investigation of the effects of posture on the performance of single- compared
with multi-unit floating dosage forms when taken before or after a meal.
7. Applicability of a combination of two or more mechanisms of gastric retention
(e.g., floating and mucoadhesion) to provide site-specific delivery and repro-
ducible GRTs.

VI. CONCLUSIONS

GRDDS developed using the mechanism of mucoadhesion, swelling/size expansion,

and high-density/low-density floating provide an efficient means to prolong the GRT
of a dosage form and offer continuous drug supply to the absorption sites located in the
upper small intestine. GRDDS not only improve the oral bioavailability of drugs char-
acterized by a narrow absorption window in the upper GIT, but also provide multiple
pharmacokinetic-pharmacodynamic advantages over conventional immediate release
and continuous-release dosage forms. However, the development of a GRDDS requires
a thorough understanding of the physicochemical properties of the drug, the physiologi-
cal limitations of GIT, and various formulation strategies. A careful consideration of the
interplay of these parameters can help in designing a successful GRDDS.
FDDS are predominantly used because they do not adversely affect the motility
of the GIT. However, the major drawback of these systems is that their performance is
strongly dependent upon the fed state of the stomach. In many of the cases, the advantage
of buoyancy in prolonging gastric retention is masked by the presence of food. Based on
the literature reviewed, it may be concluded that achieving significant gastric retention
is difficult because the primary determinant factor for gastric emptying of floating dos-
age forms is the presence of food. Whereas results from some of the recent studies are
promising, convincing results of prolonged retention of the floating dosage forms in the
fasted state in humans have yet to be presented. Despite these limitations, FDDS still
remains a promising approach, and newer technologies such as pulsatile FDDS could
provide improved clinical benefits in chronotherapy (e.g., hypertension, asthma, and
arthritis) for which synchronization of the medication levels with the disease state is the
most beneficial.

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Volume 28, Number 1, 2011