International Journal of Trend in Scientific Research and Development (IJTSRD)

Volume 6 Issue 7, November-December 2022 Available Online: www.ijtsrd.com e-ISSN: 2456 – 6470

Gastroretentive Drug Delivery System: A Review

Chetan Varade*1, Smita Aher2, Rushikesh Bachhav3
1
Department of Quality Assurance Techniques,
2
Department of Pharmaceutical Chemistry,
3
Department of Pharmacology,
1, 2, 3
R. G. Sapkal College of Pharmacy, Anjaneri, Nashik, Maharashtra, India

ABSTRACT How to cite this paper: Chetan Varade |

The purpose of writing this review on gastroretentive drug delivery Smita Aher | Rushikesh Bachhav
systems was to compile the recent literature with special focus on "Gastroretentive Drug Delivery System:
various gastroretentive approaches that have recently become leading A Review" Published in International
methodologies in the field of site-specific orally administered Journal of Trend in
Scientific Research
controlled release drug delivery. In order to understand various
and Development
physiological difficulties to achieve gastric retention, we have (ijtsrd), ISSN:
summarized important factors controlling gastric retention. 2456-6470,
Afterwards, we have reviewed various gastroretentive approaches Volume-6 | Issue-7,
designed and developed until now, i.e. high density (sinking), December 2022, IJTSRD52341
floating, bio- or mucoadhesive, expandable, unfoldable, super porous pp.578-587, URL:
hydrogel and magnetic systems. Finally, advantages of www.ijtsrd.com/papers/ijtsrd52341.pdf
gastroretentive drug delivery systems were covered in detail.
Copyright © 2022 by author (s) and
KEYWORDS: Gastric retention, Oral controlled release, Floating International Journal of Trend in
dosage form, Drug delivery system Scientific Research and Development
Journal. This is an
Open Access article
distributed under the
terms of the Creative Commons
Attribution License (CC BY 4.0)
(http://creativecommons.org/licenses/by/4.0)

INTRODUCTION
Oral administration is the most convenient and adversities: the short gastric retention time (GRT) and
preferred means of any drug delivery to the unpredictable short gastric emptying time (GET),
systematic circulation. Oral controlled release drug which can result in incomplete drug release from the
delivery have recently been of increasing interest in dosage form in the absorption zone (stomach or upper
pharmaceutical field to achieve improved therapeutic part of small intestine) leading to diminished efficacy
advantages, such as ease of dosing administration, of administered dose [2]. To formulate a site-specific
patient compliance and flexibility in formulation. orally administered controlled release dosage form, it
Drugs that are easily absorbed from gastrointestinal is desirable to achieve a prolong gastric residence
tract (GIT) and have short half-lives are eliminated time by the drug delivery. Prolonged gastric retention
quickly from the systemic circulation. Frequent improves bioavailability, increases the duration of
dosing of these drugs is required to achieve suitable drug release, reduces drug waste, and improves the
therapeutic activity. To avoid this limitation, the drug solubility that are less soluble in a high pH
development of oral sustained-controlled release environment [3]. Also prolonged gastric retention
formulations is an attempt to release the drug slowly time (GRT) in the stomach could be advantageous for
into the gastrointestinal tract (GIT) and maintain an local action in the upper part of the small intestine
effective drug concentration in the systemic e.g. treatment of peptic ulcer, etc. Gastroretentive
circulation for a long time. After oral administration, drug delivery is an approach to prolong gastric
such a drug delivery would be retained in the stomach residence time, thereby targeting site-specific drug
and release the drug in a controlled manner, so that release in the upper gastrointestinal tract (GIT) for
the drug could be supplied continuously to its local or systemic effects. Gastroretentive dosage
absorption sites in the gastrointestinal tract (GIT) [1]. forms can remain in the gastric region for long
These drug delivery systems suffer from mainly two periods and hence significantly prolong the gastric

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retention time (GRT) of drugs. Over the last few form the greater will be the gastric retention time
decades, several gastroretentive drug delivery (GRT) due to the larger size of the dosage form
approaches being designed and developed, including: would not allow this to quickly pass through the
high density (sinking) systems that is retained in the pyloric antrum into the intestine [18]. Dosage forms
bottom of the stomach [4], low density (floating) having a diameter of more than 7.5 mm show a better
systems that causes buoyancy in gastric fluid [5, 6, 7], gastric residence time compared with one having 9.9
mucoadhesive systems that causes bioadhesion to mm [17]. Ring-shaped and tetrahedron-shaped
stomach mucosa [8], unfoldable, extendible, or devices have a better gastric residence time as
swellable systems which limits emptying of the compared with other shapes [19].
dosage forms through the pyloric sphincter of
Food intake and its nature
stomach [9, 10], superporous hydrogel systems[11], Food intake, viscosity and volume of food, caloric
magnetic systems [12] etc. The current review deals value and frequency of feeding have a profound effect
with various gastroretentive approaches that have on the gastric retention of dosage forms. The presence
recently become leading RESEARCH ARTICLE or absence of food in the gastrointestinal tract (GIT)
REVIEW ARTICLE 7methodologies in the field of influences the gastric retention time (GRT) of the
site-specific orally administered controlled release dosage form. Usually the presence of food in the
drug delivery systems. gastrointestinal tract (GIT) improves the gastric
FACTORS CONTROLLING GASTRIC retention time (GRT) of the dosage form and thus, the
RETENTION OF DOSAGE FORMS drugs absorption increases by allowing its stay at the
The stomach anatomy and physiology contain absorption site for a longer period. Again, increase in
parameters to be considered in the development of acidity and caloric value shows down gastric
gastroretentive dosage forms. To pass through the emptying time (GET), which can improve the gastric
pyloric valve in to the small intestine the particle size retention of dosage forms [20].
should be in the range of 1 to 2 mm [13]. The most
Effect of gender, posture and age
important parameters controlling the gastric retention Generally females have slower gastric emptying rates
time (GRT) of oral dosage forms include : density, than male. The effect of posture does not have any
size and shape of the dosage form, food intake and its significant difference in the mean gastric retention
nature, caloric content and frequency of intake, time (GRT) for individuals in upright, ambulatory and
posture, gender, age, sex, sleep, body mass index, supine state. In case of elderly persons, gastric
physical activity and diseased states of the individual emptying is slowed down [21].
(e.g. chronic disease, diabetes etc.) and administration
of drugs with impact on gastrointestinal transit time POTENTIAL DRUG CANDIDATES FOR
for example drugs acting as anticholinergic agents GASTRORETENTIVE DRUG DELIVERY
(e.g. atropine, propantheline), Opiates (e.g. codeine) SYSTEMS
and prokinetic agents (e.g. metclopramide, cisapride.) 1. Drugs those are locally active in the stomach e.g.
[14]. The molecular weight and lipophilicity of the misroprostol, antacids etc.
drug depending on its ionization state are also 2. Drugs that have narrow absorption window in
important parameters [15]. gastrointestinal tract (GIT) e.g. L-DOPA, para
aminobenzoic acid, furosemide, riboflavin etc.
Density of dosage forms 3. Drugs those are unstable in the intestinal or
The density of a dosage form also affects the gastric colonic environment e.g. captopril, ranitidine
emptying rate and determines the location of the HCl, metronidazole.
system in the stomach. Dosage forms having a 4. Drugs that disturb normal colonic microbes e.g.
density lower than the gastric contents can float to the antibiotics against Helicobacter pylori.
surface, while high density systems sink to bottom of 5. Drugs that exhibit low solubility at high pH
the stomach[16]. Both positions may isolate the values e.g. diazepam, chlordiazepoxide,
dosage system from the pylorus. A density of < 1.0 verapamil HCl.
gm/ cm3 is required to exhibit floating property [17].
DRUGS THOSE ARE UNSUITABLE FOR
Shape and size of the dosage form GASTRORETENTIVE DRUG DELIVERY
Shape and size of the dosage forms are important in
SYSTEMS
designing indigestible single unit solid dosage forms. 1. Drugs that have very limited acid solubility e.g.
The mean gastric residence times of nonfloating phenytoin etc.
dosage forms are highly variable and greatly 2. Drugs that suffer instability in the gastric
dependent on their size, which may be large, medium environment e.g. erythromycin etc.
and small units. In most cases, the larger the dosage

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3. Drugs intended for selective release in the colon tract (GIT) which may produce irritation. On the
e.g. 5- amino salicylic acid and corticosteroids other hand multiple-unit floating systems may be an
etc. attractive alternative since they have been shown to
reduce the inter- and intra-subject availabilities in
APPROACHES TO ACHIEVE GASTRIC
drug absorption as well as to lower the possibility of
RETENTION
dose dumping[26]. Various multiple-unit floating
High density (sinking) system or non- floating
system like air compartment multiple-unit system [2],
drug delivery system
hollow microspheres (microballoons) prepared by the
This approach involves formulation of dosage forms
with the density that must exceed density of normal emulsion solvent diffusion method [31],
stomach content (~1.004 gm/cm3). These microparticles based on low density foam powder [5],
formulations are prepared by coating drug on a heavy beads prepared by emulsion gelatin method [32] etc.
can be distributed widely throughout the GIT,
core or mixed with inert materials such as iron
powder, barium sulphate, zinc oxide and titanium providing the possibility of achieving a longer lasting
oxide etc [22]. The materials increase density by up to and more reliable release of drugs. Based on the
1.5-2.4 gm/cm3. A density close to 2.5 gm/cm3 mechanism of buoyancy two distinctly different
technologies, i.e. non-effervescent and effervescent
seems necessary for significant prolongation of
gastric residence time [23]. But, effectiveness of this systems have been utilized in the development of
system in human beings was not observed [24] and no floating drug delivery system.
system has been marketed. Non-effervescent Systems
Non-effervescent floating drug delivery systems are
Floating drug delivery systems
Floating drug delivery systems is one of the important normally prepared from gel-forming or highly
approaches to achieve gastric retention to obtain swellable cellulose type hydrocolloids,
sufficient drug bioavailability [25]. This delivery polysaccharides or matrix forming polymers like
systems is desirable for drugs with an absorption polyacrylate, polycarbonate, polystyrene and
window in the stomach or in the upper small intestine polymethacrylate. In one approach, intimate mixing
[26]. This have a bulk density less then gastric fluids of drug with a gel forming hydrocolloid which results
and so remain buoyant in the stomach without in contact with gastric fluid after oral administration
affecting gastric emptying rate for a prolonged period and maintain a relative integrity of shape and a bulk
and the drug is released slowly as a desired rate from density less than unity within the gastric environment
the system. After release of drug, the residual system [33]. The air trapped by the swollen polymer confers
is emptied from the stomach. This result in an buoyancy to these dosage forms. Excipients used
increased gastric retention time (GRT) and a better most commonly in these systems include
control of the fluctuation in plasma drug hydroxypropyl methylcellulose (HPMC)
concentration. The major requirements for floating polyacrylates, polyvinyl acetate, carbopol, agar,
sodium alginate, calcium chloride, polyethylene oxide
drug delivery system are [22]:
It should release contents slowly to serve as a and polycarbonates [3]. This system can be further
reservoir. divided into the sub-types:
It must maintain specific gravity lower than Hydrodynamically balanced systems:
gastric contents (1.004 – 1.01 gm/cm3). Sheth and Tossounian [34] first designated these
It must form a cohesive gel barrier. ‘hydrodynamically balanced systems’. These systems
The inherent low density can be provided by the contains drug with gel-forming hydrocolloids meant
entrapment of air (e.g. hollow chambers) [27] or by to remain buoyant on the stomach content. These are
the incorporation of low density materials (e.g. fatty single-unit dosage form, containing one or more gel-
materials or oils, or foam powder) [5, 28, 29]. These forming hydrophilic polymers. Hydroxypropyl
following approaches have been used for the design methylcellulose (HPMC), hydroxethyl cellulose
of floating dosage forms of single and multiple-unit (HEC), hydroxypropyl cellulose (HPC), sodium
systems. Recently a single-unit floating system was carboxymethyl cellulose (NaCMC), polycarbophil,
proposed consisting of polypropylene foam powder, polyacrylate, polystyrene, agar, carrageenans or
matrix forming polymers, drug and filler [30] The alginic acid are commonly used excipients to develop
good floating behavior of these systems could be these systems [35, 36]. The polymer is mixed with
successfully combined with accurate control of the drugs and usually administered in hydrodynamically
resulting drug release patterns. Single-unit dosage balanced system capsule. The capsule shell dissolves
forms are associated with problems such as sticking in contact with water and mixture swells to form a
together or being obstructed in the gastrointestinal gelatinous barrier, which imparts buoyancy to dosage

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form in gastric juice for a long period. Because, based on the system was marketed during the 1980’s
continuous erosion of the surface allows water [37]. Effective drug deliveries depend on the balance
penetration to the inner layers maintaining surface of drug loading and the effect of polymer on its
hydration and buoyancy to dosage form [36]. release profile. Several strategies have been tried and
Incorporation of fatty excipients gives low-density investigated to improve efficiencies of the floating
formulations reducing the erosion. Madopar LP®, hydrodynamically balanced systems [36, 37].
Microballoons / Hollow microspheres:
Microballoons / hollow microspheres loaded with drugs in their other polymer shelf were prepared by simple
solvent evaporation or solvent diffusion / evaporation methods [38] (Figure 1) to prolong the gastric retention
time (GRT) of the dosage form. Commonly used polymers to develop these systems are polycarbonate, cellulose
acetate, calcium alginate, Eudragit S, agar and low methoxylated pectin etc. Buoyancy and drug release from
dosage form are dependent on quantity of polymers, the plasticizer polymer ratio and the solvent used for
formulation. The microballoons floated continuously over the surface of an acidic dissolution media containing
surfactant for >12 hours [3]. At present hollow microspheres are considered to be one of the most promising
buoyant systems because they combine the advantages of multiple-unit system and good floating.

Figure 1. Formulation of floating hollow microsphere or microballoon

Alginate beads: Talukdar and Fassihi [32] recently developed a multiple-unit floating system based on cross-
linked beads. They were made by using Ca2+ and low methoxylated pectin (anionic polysaccharide) or Ca2+
low methoxylated pectin and sodium alginate. In this approach, generally sodium alginate solution is dropped
into aqueous solution of calcium chloride and causes the precipitation of calcium alginate. These beads +are then
separated and dried by air convection and freeze drying, leading to the formulation of a porous system, which
can maintain a floating force for over 12 hrs. These beads improve gastric retention time (GRT) more than 5.5
hrs [3, 39].
Microporous compartment system: This approach is based on the principle of the encapsulation of a drug
reservoir inside a microporous compartment with pores along its top and bottom walls [40]. The peripheral walls
of the device were completely sealed to present any direct contact of the gastric surface with the undissolved
drug. In the stomach the floatation chamber containing entrapped air causes the delivery system to float in the
gastric fluid [22]. Gastric fluid enters through the aperture, dissolves the drug and causes the dissolved drug for
continuous transport across the intestine for drug absorption.
Effervescent (gas generating) systems
Floatability can be achieved by generation of gas bubbles. These buoyant systems utilize matrices prepared with
swellable polymers such as polysaccharides (e.g. chitosan), effervescent components (e.g. sodium bicarbonate,
citric acid or tartaric acid) [40]. The optimal stoicheometric ratio of citric acid and sodium bicarbonate for gas
generation is reported to be 0.76: 1 [19]. In this system carbon dioxide is released and causes the formulation to
float in the stomach (Figure 2 and Figure 3). Other approaches and materials that have been reported are a
mixture of sodium alginate and sodium bicarbonate, multiple unit floating dosage forms that generate gas
(carbon dioxide) when ingested, floating mini capsules with a core of sodium bicarbonate, lactose and polyvinyl
pyrrolidone (PVP) coated with hydroxypropyl methylcellulose (HPMC), and floating system based on ion
exchange resin technology etc [3]. Bilayer or multilayer system has also been designed [41, 42]. Drugs and
excipients can be formulated independently and the gas generating material can be incorporated in to any of the
layers. Further modifications involve coating of the matrix with a polymer which is permeable to water, but not
to carbon dioxide. The main difficulty of these formulations is finding a good compromise between elasticity,
plasticity and permeability of the polymers.

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Bioadhesive or Mucoadhesive drug delivery systems

Figure 2. Effervescent (gas generating) systems

Figure 3. Drug release from effervescent (gas generating) systems

Bioadhesive drug delivery systems are used as a delivery device within the human to enhance drug absorption in
a site-specific manner. In this approach, bio adhesive polymers are used and they can adhere to the epithelial
surface in the stomach [43]. Thus, they improve the prolongation of gastric retention. The basis of adhesion in
that a dosage form can stick to the mucosal surface by different mechanism. These mechanisms [44, 45] are:
1. The wetting theory, which is based on the ability of bioadhesive polymers to spread and develop intimate
contact with the mucous layers.
2. The diffusion theory, which proposes physical entanglement of mucin strands the flexible polymer chains, or
an interpenetration of mucin strands into the porous structure of the polymer substrate.
3. The absorption theory, suggests that bioadhesion is due to secondary forces such as Vander Waal forces and
hydrogen bonding.
4. The electron theory, which proposes attractive electrostatic forces between the glycoprotein mucin network
and the bio adhesive material.
Materials commonly used for bioadhesion are poly acrylic acid, chitosan, cholestyramine, sodium alginate,
hydroxypropyl methylcellulose (HPMC), sucralfate, tragacanth, dextrin, polyethylene glycol (PEG) and
polylactic acids etc. Even though some of these polymers are effective at producing bioadhesive, it is very
difficult to maintain it effectively because of the rapid turnover of mucus in the gastrointestinal tract (GIT).
Expandable, unfoldable and swellable systems
A dosage form in the stomach will withstand gastric transit if it bigger than pyloric sphincter. However, the
dosage form must be small enough to be swallowed, and must not cause gastric obstruction either singly or by
accumulation. Thus, their configurations [46, 47] are required to develop an expandable system to prolong
gastric retention time (GRT):
1. a small configuration for oral intake,
2. an expanded gastroretentive form, and
3. a final small form enabling evacuation following drug release from the device.

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Thus, gastroretentivity is improved by the combination of substantial dimension with high rigidity of dosage
form to withstand peristalsis and mechanical contractility of the stomach. Unfoldable and swellable systems
have been investigated and recently tried to develop an effective gastroretentive drug delivery. Unfoldable
systems are made of biodegradable polymers. They are available in different geometric forms like tetrahedron,
ring or planner membrane (4 - label disc or 4 - limbed cross form) of bioerodible polymer compressed within a
capsule which extends in the stomach [48, 49]. Swellable systems are also retained in the gastro intestinal tract
(GIT) due to their mechanical properties. The swelling is usually results from osmotic absorption of water and
the dosage form is small enough to be swallowed by the gastric fluid (Figure 4). Expandable systems have some
drawbacks like problematical storage of much easily hydrolysable, biodegradable polymers relatively short-lived
mechanical shape memory for the unfolding system most difficult to industrialize and not cost effective.50
Again, permanent retention of rigid, large single-unit expandable drug delivery dosage forms may cause brief
obstruction, intestinal adhesion and gastropathy [19].

Figure 4. Drug release from swellable systems

Super porous hydrogel systems
These swell able systems differ sufficiently from the conventional types to warrant separate classification. In this
approach to improve gastric retention time (GRT) super porous hydrogels of average pore size >100 micro miter,
swell to equilibrium size within a minute due to rapid water uptake by capillary wetting through numerous
interconnected open pores [51]. They swell to a large size (swelling ratio: 100 or more) and are intended to have
sufficient mechanical strength to withstand pressure by gastric contraction. This is advised by co-formulation of
hydrophilic particulate material [52].
Magnetic Systems
This approach to enhance the gastric retention time (GRT) is based on the simple principle that the dosage form
contains a small internal magnet, and a magnet placed on the abdomen over the position of the stomach.
Although magnetic system seems to wok, the external magnet must be positioned with a degree of precision that
might compromise patient compliance [45]. Commonly used drugs in formulation of gastroretentive dosage
forms and some gastroretentive products available in the market are listed in Table 1 and Table 2 respectively.
ADVANTAGES OF GASTRORETENTIVE DRUG DELIVERY SYSTEMS
Table 1. Commonly used drug in formulation of gastro retentive dosages forms [17, 22]
Dosage form Drugs
Acetaminophen, Acetylsalicylic acid, Ampicillin, Amoxicillin trihydrate, Atenolol,
Captopril, Cinnerzine, Chlorpheniramine maleate, Ciprofloxacin, Diltiazem,
Floating Tablets
Fluorouracil, Isosorbide dinitrate, Isosorbid mononitrate, pAminobenzoic
acid(PABA), Prednisolone, Nimodipine, Sotalol, Theophylline, Verapamil
Chlordiazepoxide HCl, Diazepam, Furosemide, L-DOPA and Benserazide,
Floating Capsules
Nicardipine, Misoprostol, Propranolol, Pepstatin
Floating
Aspirin, Griseofulvin, p-nitro aniline, Ibuprofen, Terfenadine, Tranilast
Microspheres
Floating Granules Diclofenac sodium, Indomethacin, Prednisolone
Powders Several basic drugs
Films Cinnerzine

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Table 2. Gastroretentive products available in the market [22, 53]
Brand name Active Ingradient
Cifran OD Ciprofloxacin
Madopar L-DOPA and Benserazide
Valrelease Diazepam
Topalkan Aluminum-magnesium antacid
Almagate FlatCoat Aluminum-magnesium antacid
Liquid Gavison Aluminium hydroxide,
Conviron Ferrous sulphate
Cytotec® Misoprostal

1. The bioavailability of therapeutic agents can be 7. Gastroretentive drug delivery can minimize the
significantly enhanced especially for those which counter activity of the body leading to higher drug
get metabolized in the upper GIT by this efficiency.
gastroretentive drug delivery approach in 8. Reduction of fluctuation in drug concentration
comparison to the administration of
makes it possible to obtain improved selectivity in
nongastroretentive drug delivery. There are
receptor activation.
several different factors related to absorption and
transit of the drug in the gastrointestinal tract 9. The sustained mode of drug release from
(GIT) that act concomitantly to influence the Gastroretentive doses form enables extension of
magnitude of drug absorption [54]. the time over a critical concentration and thus
enhances the pharmacological effects and
2. For drugs with relatively short half life, sustained improves the chemical outcomes.
release may result in a flip- flop pharmacokinetics
and also enable reduced frequency of dosing with CONCLUSION
improved patient compliance. Based on the literature surveyed, it may be concluded
that gastroretentive drug delivery offers various
3. They also have an advantage over their potential advantages for drug with poor
conventional system as it can be used to bioavailability due their absorption is restricted to the
overcome the adversities of the gastric retention upper gastrointestinal tract (GIT) and they can be
time (GRT) as well as the gastric emptying time delivered efficiently thereby maximizing their
(GET). As these systems are expected to remain absorption and enhancing absolute bioavailability.
buoyant on the gastric fluid without affecting the Due to complexity of pharmacokinetics and
intrinsic rate of employing because their bulk pharmacodynamics parameters, in vivo studies are
density is lower than that of the gastric fluids. required to establish the optional dosage form for a
4. Gastroretentive drug delivery can produce specific drug. Another promising area of research for
prolong and sustain release of drugs from dosage gastroretentive drug delivery system is eradication of
forms which avail local therapy in the stomach Helicobacter pylori, which is now believed to be
and small intestine. Hence they are useful in the causative bacterium of chronic gastritis and peptic
treatment of disorders related to stomach and ulcers. Although, this micro organism is highly
small intestine. sensitive to many antibiotics, its complete eradication
requires high concentration of antibiotics be
5. The controlled, slow delivery of drug form
maintained within gastric mucosa for prolonged time
gastroretentive dosage form provides sufficient
period. An important feature to take into account is
local action at the diseased site, thus minimizing
the stomach physiology. The time when the drug is
or eliminating systemic exposure of drugs. This
taken (during or apart from the meal) is an important
site-specific drug delivery reduces undesirable
parameter. To develop an efficient gastroretentive
effects of side effects.
dosage form is a real challenge to pharmaceutical
6. Gastroretentive dosage forms minimize the technology. Indeed, the drug delivery system must
fluctuation of drug concentrations and effects. remain for a sufficient time in the stomach, which is
Therefore, concentration dependent adverse not compatible with its normal physiology. All these
effects that are associated with peak gastroretentive drug delivery systems (high density,
concentrations can be presented. This feature is of floating, expandable or unfoldable or swelling,
special importance for drug with a narrow superporous, bioadhesive, magnetic systems etc.) are
therapeutic index [55]. interesting and present their own advantages and
disadvantages. Now, a lot of work is running to

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develop different types of gastroretentive delivery [11] Park K. Enzyme-digestible swelling as
systems of various drugs. In the future, it is expected platforms for longterm oral drug delivery:
that they will become of increasing importance, synthesis and characterization. Biomaterials
ultimately leading to improved efficiencies of various 1988; 9: 435.
types of pharmacotherapies. [12] Fujimori J, Machida Y, Nagai T. Preparation of
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