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37 International Journal of Pharmacy and Pharmaceutical Science Research 2014; 4(2): 37-48

ISSN: 2249-0337

Review Article

Advances in Gastroretentive Drug Delivery System: An Review

Namdeo GS*, Nagesh HA, Ajit SK, Bhagyashree SS, Savita HB, Sharad ND

Department of Pharmaceutics, Satara College of Pharmacy, Degaon, Satara. Shivaji University (MH) India-415 004.

Email: [email protected], Mobile: +91-94239 57518.

Received 11April 2014; accepted 30 April 2014

Abstract

Gastroretention along with controlled drug delivery is advantageous to many drugs having low absorption window and

hence poor bioavailability. For the gastroretention, various approaches are available from that floating DDS gaining more

importance especially floating film DDS. In this system, formulation of multilayer film has more importance in associated

diseases like diabetes and hypertension. The purpose of this review is to compile the data from recent literature with

special focus on varies gastroretentive drug delivery system. Present article gives more emphasize on various approaches

used to produce gastroretention with recent development in stomach specific floating drug delivery system.

© 2014 Universal Research Publications. All rights reserved

Keywords: Floating film drug delivery, multilayer films, Gastroretentive drug delivery system.

INTRODUCTIOIN

The goal of any drug delivery system is to provide a

therapeutic amount of drug to proper site in the body to

achieve and maintain therapeutic concentration within

range and to show pharmacological action with minimum

incidence of adverse effects. To achieve this goal one

should maintain dosing frequency and suitable route of

administration [Bhoyar, 2012]. Various routes that are used

these days include oral, parenteral, topical, nasal, rectal,

vaginal, ocular etc. Out of these routes, oral route of drug

delivery is considered as the most favored route of drug

delivery, because of ease of administration, more flexibility

in designing, ease of production and low cost [Gupta,

2012]. Control of location of a drug delivery system,

especially for drugs exhibiting an absorption window in the

GI tract or drugs with a stability problem, in a specific

region of the GI tract offers several advantages. These

considerations have led to the development of oral

controlled-release (CR) dosage forms possessing gastric

retention capabilities [Kaur, 2013]. Development of oral

controlled release systems has been a challenge to

formulation scientists because of their inability to restrain

and localize the system in the targeted area of the

gastrointestinal tract. Controlled release preparations using

alternative routes have been formulated but the oral route

still remains preferable for any drug delivery because of

ease of administration, patient compliance and flexibility in

formulation [Ratnaparkhi, 2012]. However, this approach is

also having several physiological difficulties such as

inability to restrain and locate the controlled drug delivery

system within the desired region of the gastrointestinal tract

due to variable gastric emptying and motility. Furthermore,

the relatively brief gastric emptying time in humans which

normally averages 2-3 h through the major absorption zone,

i.e., stomach and upper part of the intestine can result in

incomplete drug release from the drug delivery system

leading to reduced efficacy of the administered dose.

Therefore, control of placement of a drug delivery system

in a specific region of the GI tract offers advantages for a

variety of important drugs characterized by a narrow

absorption window in the GIT or drugs with a stability

problem [Singh, 2013].

In conventional dosage forms, there is no precise

control over the release of drug as the administered dose of

drug enters the systemic circulation. The minimum

effective concentration of drug in the blood plasma is not

achieved with frequent administration of a single dose of a

drug because of fluctuations in the plasma drug

concentration (Fig.1).

Figure 1: Drug concentration profiles of multiple doses of an

immediate release drug delivery system.

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Conventional oral controlled dosage forms suffer

from mainly two adversities (Klausner, 2003). The short

gastric retention time (GRT) and unpredictable gastric

emptying time (GET). A relatively brief GI transit time of

most drug products impedes the formulation of single daily

dosage forms. These problems can be overwhelmed by

altering the gastric emptying. Therefore it is desirable, to

formulate a controlled release dosage form that gives an

extended GI residence time.

Extended release dosage form with prolonged

residence time in stomach is highly desirable for drugs that

are locally active in stomach, have an absorption window

in the stomach or in the upper small intestine, which are

unstable in the intestinal or colonic environment, which

have low solubility at high pH values [Singh, 2000;

Timmermans, 1994]. The controlled release dosage forms

have the following advantages [Sampath Kumar, 2012]

1. Avoid patient compliance problems.

2. Employs less total drug

Minimize or eliminate local side effects

Minimize or eliminate systemic side effects

Obtain less potentiating or reduction in drug activity

with chronic use.

Minimize drug accumulation with chronic dosing.

3. Improve efficiency in treatment

Cures or controls condition more promptly.

Improves control of condition i.e., reduced fluctuation

in drug level.

Improves bioavailability of some drugs.

Make use of special effects, e.g. sustained-release

aspirin for morning relief of arthritis by dosing before

bedtime.

4. Economical i.e. reduction in health care costs. The

average cost of treatment over an extended period may

be less, with less frequency of dosing, enhanced

therapeutic benefits and reduced side effects. The time

required for health care personnel to dispense and

administer is also reduced.

In addition to these advantages, there are

following disadvantages of controlled release drug delivery

systems [David, 1986]

1. Decreased systemic availability in comparison to

immediate release conventional dosage forms, which

may be due to incomplete release, increased first-pass

metabolism, increased instability, insufficient

residence time for complete release, site specific

absorption, pH dependent stability etc.

2. Poor in vitro- in vivo correlation.

3. Possibility of dose dumping due to food, physiologic

or formulation variables or chewing or grinding of oral

formulations by the patient and thus, increased risk of

toxicity.

4. Retrieval of drug is difficult in case of toxicity,

poisoning or hypersensitivity reactions.

5. Reduced potential for dosage adjustment of drugs

normally administered in varying strengths.

Sustained release: During the last two decades, there has

been remarkable increase in interest in sustained release

drug delivery system. This has been due to various factor

viz. the prohibitive cost of developing new drug entities,

expiration of existing international patents, discovery of

new polymeric materials suitable for prolonging the drug

release, and the improvement in therapeutic efficiency and

safety achieved by these delivery systems. Now-a-days the

technology of sustained release is also being applied to

veterinary products. These systems also provide a slow

release of drug over an extended period of time and also

can provide some control, whether this be of a temporal or

spatial nature, or both, of drug release in the body, or in

other words, the system is successful in maintaining

constant drug levels in the target tissue or cells.

Most of oral controlled drug delivery systems release

the drug by diffusion, dissolution or combination

mechanism in gastrointestinal tract. The real challenge in

development of oral controlled release drug delivery

system is to sustain the release as well as prolong the

presence of dosage form in stomach or upper small

intestine until drug is completely released in desired period

of time from suitable formulation. Gastroretentive system

can remain in the gastric region for several hours and hence

significantly prolongs gastric residence time of drug which

improves bioavailability, solubility and reduces wastage of

drug. Most of the drugs given via oral route are subjected to

absorption throughout the gastrointestinal tract, with major

absorption from stomach and intestine. Various processes

occur after the drug release from the dosage form, which

affect the absorption of drugs, e.g. degradation of drug by

enzymatic or microbial action, precipitation etc. Drugs,

which get absorb from stomach or show local effect, should

spend maximum time in stomach. This however, is found

very difficult to occur, in case of conventional dosage

forms like tablets and capsules, because of the gastric

emptying. Gastric emptying of a particular dosage form

depends on various factors like volume and composition of

the meal, temperature and viscosity of the meal, pH of

stomach, body posture, emotional state of the individual,

diseased state, gastric motility altering drugs etc.

Parameters that affect the process of gastric emptying can

be studied by various techniques viz. scintigraphy,

ultrasonology, endoscopy, radiotelemetry, radiology etc.

[Gupta, 2012]. Hence, gastroretentive drug delivery

provides better availability of new products with new

therapeutic possibilities and more benefits for patients. The

need for gastroretentive dosage forms has led to extensive

efforts in both academia and industry towards the

development of such drug delivery systems. These efforts

resulted in gastroretentive dosage forms that were designed,

in large part, based on the following approaches [Jaimini,

2013],

Low density form of the dosage form that causes

buoyancy in gastric fluid

High density dosage form that is retained in the

bottom of the stomach

Bioadhesion to stomach mucosa

Slowed motility of the gastrointestinal tract by

concomitant administration of drugs or pharmaceutical

excipients

Expansion by swelling or unfolding to a large size

which limits emptying of the dosage form through the

pyloric sphincter.


Table 1: Features of stomach

Length

(m) pH Microbial count

Absorbing surface area

(m2)

Transit time

(h)

Absorption

mechanism

0.2 Fasting: 1.1 ± 0.15

Fed: 3.6 ± 0.4 ≤103 0.1 Variable P, A, C

[P: Passive diffusion A: Active transport C: Aqueous channel transport

The residence of drug delivery system in upper part of

gastrointestinal tract can be accomplished by intragastric

floating system, swelling and expandable system, delayed

gastric emptying system, low density superporous system

and bioadhesive system. To provide good floating

behaviour in the stomach the density of system should be

less than density of gastric contents (~ 1.004 g/cm3).

Drugs that act locally in the stomach, primarily absorbed in

stomach region, poorly suitable at alkaline pH, having

narrow absorption window and which degrade in colon

region are the good candidates for gastroretentive drug

delivery system. Floating drug delivery system has density

less than density of gastric fluid and hence it remains in the

stomach for prolonged time without affecting gastric

emptying rate. When the system floats on gastric contents,

the drug gets released slowly at desired rate from the

system. After the complete release of drug, the residual

system is emptied from the stomach. This system increases

the gastric retention time and thus ensures better control of

fluctuations in plasma drug concentration. Many buoyant

systems have been developed based on granules, powders,

capsules, tablets, hollow microspheres and films. Hence,

for drugs possessing a narrow absorption window, design

of sustained release properties require both prolongation of

transit time of dosage form and controlled drug release.

Based on the buoyancy, effervescent and non-effervescent

system approaches are applied in development of floating

drug delivery system [Shinde, 2014].

Stomach physiology: It is well recognized that the

stomach may be used as a „depot‟ for sustained-release

(SR) dosage forms, both in human and veterinary

applications. The stomach is anatomically divided into

three parts: fundus, body, and antrum (or pylorus). The

proximal stomach, made up of the fundus and body

regions, serves as a reservoir for ingested materials while

the distal region (antrum) is the major site of mixing

motions, acting as a pump to accomplish gastric emptying

[Sunilkumar, 2012]. There are four major types of secretary

epithelial cells that cover the surface of the stomach and

extend down into gastric pits and glands:

Mucous cells: Secrete alkaline mucus that protects the

epithelium against shear stress and acid.

Parietal cells: Secrete hydrochloric acid.

Chief cells: Secrete pepsin, a proteolytic enzyme.

G cells: Secrete the hormone gastrin.

The contraction of gastric smooth muscle serves two basic

functions,

1. Ingested food is crushed, ground and mixed with

gastric secretion to form Chyme.

2. Chyme is forced through the pyloric canal into the

small intestine, a process called gastric emptying.

Gastric motility: Gastric motility is controlled by a

complex set of neural and hormonal signals. Nervous

control originates from the enteric nervous system as well

as parasympathetic (predominantly vagus nerve) and

sympathetic systems. A large battery of hormones has been

shown to influence gastric motility- for e.g. both gastrin

and cholecystokinin act to relax the proximal stomach and

enhance contractions in the distal stomach. The bottom line

is that the patterns of gastric motility likely are a result

Figure 2: Physiology of stomach

from smooth muscle cells integrating a large number of

inhibitory and stimulatory signals. Liquids readily pass

through the pylorus in spurts, but solids must be reduced to

a diameter of less than 1-2 mm before passing pyloric

gatekeeper. The gastric volume is important for dissolution

of the dosage form in vivo. The resting volume of the

stomach is 25-50 ml. There is a large difference in gastric

secretion of normal and achlorhydric individuals. Gastric

pH also has pronounced effect on absorption of drug from

delivery system. The pH of fasting stomach is 1.2-.2.0 and

in fed conditions 2.0-6.0.

Figure 3: Motility pattern in GIT

Gastric emptying rate: Gastric emptying occurs during

fasting as well as fed states. The pattern of motility is

however distinct in the two states. During the fasting state

an interdigestive series of electrical events take place in

stomach and intestine every 2 to 3 hours. This is called the

interdigestive myoelectric cycle or migrating myoelectric

cycle (MMC), which is further divided into following 4

phases as described by Wilson and Washington [Sharma,

2011],


Table 2: Phases of migrating myoelectric cycle

Phase I (Basal phase) Phase lasts for 40-60 min. with rare contractions.

Phase II

(Pre-burst phase)

Phase lasts for 40-60 min. with intermittent action potential and contractions. As the phase

progresses the intensity and frequency also increases gradually.

Phase III

(burst phase)

Phase lasts for 4-6 min. It includes intense and regular contractions for short period. It is

also known as the housekeeper wave.

Phase IV Phase lasts for 0-5 min and occurs between phases III and I of two consecutive cycles

After the ingestion of a mixed meal, the pattern of

contractions changes from fasted to that of fed state. This is

also known as digestive motility pattern and comprises

continuous contractions as in phase II of fasted state. These

contractions result in reducing the size of food particles (to

less than 1mm), which are propelled toward the pylorus in

a suspension form. During the fed state onset of MMC is

delayed resulting in slowdown of gastric emptying rate.

Factors affecting gastric retention [Jaimini, 2013,

Sharma, 2011]

The gastric retention time (GRT) of dosage forms is

controlled by several factors such as density and size of the

dosage form, food intake, nature of the food, posture, age,

sex, sleep and disease state of the individual (e.g.,

gastrointestinal diseases and diabetes) and administration of

drugs such as prokinetic agents (cisapride and

metoclopramide).

Density: Dosage forms having a density lower than that of

gastric fluid experience floating behavior and hence gastric

retention. A density of <1.0 gm/cm3 is required to exhibit

floating property. However, the floating tendency of the

dosage form usually decreases as a function of time, as the

dosage form gets immersed into the fluid, as a result of the

development of hydrodynamic equilibrium.

Size: In fed conditions, the smaller units get emptied from

the stomach during the digestive phase and the larger units

during the housekeeping waves. In most cases, the larger

the size of the dosage form, the greater will be the gastric

retention time because the larger size would not allow the

dosage form to pass quickly through the pyloric antrum

into the intestine. Thus, the size of the dosage form appears

to be an important factor affecting gastric retention. Dosage

form units with a diameter of more than 9.5 mm are

reported to have an increased GRT.

Shape of dosage form: Tetrahedron and ring-shaped

devices with a flexural modulus of 48 and 22.5 kilopounds

per square inch (KSI) are reported to have better GRT and

exhibit 90-100 % retention at 24 h compared with other

shapes.

Fed or unfed state: Usually, the presence of food increases

the GRT of the dosage form and increases drug absorption

by allowing it to stay at the absorption site for a longer

time. Under fasting conditions, the GI motility is

characterized by periods of strong motor activity or the

migrating myoelectric complex (MMC) that occurs every

1.5-2 h. The MMC sweeps undigested material from the

stomach and, if the timing of administration of the

formulation coincides with that of the MMC, the GRT of

the unit can be expected to be very short. However, in the

fed state, MMC is delayed and GRT is considerably longer.

Nature of meal: Feeding of indigestible polymers or fatty

acid salts can change the motility pattern of the stomach ina

fed state, thus decreasing the gastric emptying rate and

prolonging drug release.

Caloric content: GRT can be increased by 4-10 h with a

meal that is high in proteins and fats.

Frequency of feed: The GRT can be increased by over 400

min when successive meals are given compared with a

single meal due to the low frequency of MMC.

Gender: Generally, females have slower gastric emptying

rates than male, regardless of the weight, height and body

surface.

Age: In case of elderly persons, gastric emptying is slowed

down.

Posture: The effect of posture does not have any

significant difference in the mean gastric retention time

(GRT) for individuals in upright, ambulatory and supine

state. However, in supine position, the floating units are

emptied faster than non-floating units of similar size.

Concomitant drug administration: Anticholinergics like

atropine and propantheline; opiates like codeine and

prokinetic agents like metoclopramide and cisapride

prolong GRT.

Biological factors: Diabetes and crohns disease.

It must be noted that, to achieve gastric retention,

the dosage form must satisfy certain requirements. One of

the key issues is that the dosage form must be able to

withstand the forces caused by peristaltic waves in the

stomach and the constant contractions and grinding and

churning mechanisms. To function as a gastric retention

device, it must resist premature gastric emptying.

Furthermore, once its purpose has been served, the device

should be removed from the stomach with ease

[Ankithkumar, 2013].

Advantages

1. Improved drug absorption: Improvement of

bioavailability and therapeutic efficacy of the drugs

and possible reduction of dose. e.g. furosemide

2. Controlled delivery of drugs: The controlled and slow

delivery of drug from gastroretentive dosage form

provides sufficient local action at the diseased site,

thus minimizing or eliminating systemic exposure of

drugs. This site-specific drug delivery reduces

undesirable effects or side effects. Maintenance of

constant therapeutic level over a prolonged period

causes reduction in fluctuation of therapeutic levels,

minimizing the risk of resistance especially in case of

antibiotics such as β-lactam antibiotics (penicillin and

cephalosporins) is possible.

3. Minimizing the mucosal irritation: A Gastroretentive


Table 3: Comparison between conventional and gastroretentive drug delivery system [Ware, 2013]

Figure 4: Various approaches for gastroretentive drug delivery system

dosage form minimizes the fluctuations of drug

concentration. Therefore, concentration dependent adverse

effects that are associated with peak concentrations can be

prevented. This feature is of special importance for a drug

with a narrow therapeutic index.

4. Treatment of gastrointestinal disorders: Gastroretentive drug delivery can produce prolongs or

sustains release of drugs from dosage forms meant for

local therapy in the stomach and small intestine. Hence

they are useful in the treatment of disorders related to

stomach and small intestine.

5. Site-specific drug delivery: Reduction of fluctuation in

drug concentration makes it possible to obtain

improved selectivity in receptor activation.

6. Ease of administration and better patient

compliance: For drugs with relatively short half-life,

sustained release may result in a flip- flop

pharmacokinetics also; enable to reduce frequency of

dosing with improved patient compliance.

7. They also have an advantage over their conventional

systems as it can be used to overcome the adversities

of the gastric retention time (GRT) as well as the

gastric emptying time (GET). As these systems are

expected to remain buoyant on the gastric fluid without

affecting the intrinsic rate of employing because their

bulk density is lower than that of the gastric fluid.

8. Gastro retentive drug delivery can minimize the

counter activity of the body leading to higher drug

efficiency.

9. Simple and conventional equipments are required for

manufacturing

Disadvantages 1. They are not suitable candidates for drugs with

stability or solubility problem in stomach.

2. FDDS require sufficiently high level of fluid in the

stomach so that the system can float and thus,

sufficient amount of water (200–250 ml) should be

taken together with floating formulation.

3. Drugs having irritant effect on gastric mucosa are not

suitable candidates for FDDS.

4. Drugs which are absorbed along the entire GIT and

which undergo first pass metabolism may not be

desirable e.g. nifedipine.

5. Retention of high-density systems in the antrum part

under the migrating waves of the stomach is

questionable.

Need of gastroretention 1. Drugs that are absorbed from the proximal part of

the gastrointestinal tract (GIT).

2. Drugs that are less soluble or are degraded by the

alkaline pH they encounter at the lower part of GIT.

3. Drugs that are absorbed due to variable gastric

emptying time.

4. Local or sustained drug delivery to the stomach,

proximal part of small intestine to treat certain

conditions.

5. Particularly useful for the treatment of peptic ulcers

caused by H. Pylori Infection.

Strategies for gastroretention

It mainly includes physiological, pharmacological and

pharmaceutical approach as described follows

[Ankithkumar, 2013],

Physiological approach: Use of natural materials or fat

derivatives such as triethanolamine myristate which

stimulate the duodenal receptors to slow gastric emptying.

Use of large amounts of volume filling polymer such as


polycarbophil can also slows gastric emptying.

Pharmacological approach: It involves coadministration

or incorporation of a drug for delaying gastric emptying

e.g. loperamide.

Pharmaceutical approach: the first two approaches are not

used because of toxicity problems. The various

pharmaceutical approaches or systems used for gastro

retention can be classified as:

I. Low density systems/Floating dosage forms

a. Effervescent systems/gas generating systems

b. Non-effervescent systems

i. Swelling or expanding systems

ii. Inherently low-density systems

II. High density systems

III. Modified shape systems

IV. Mucoadhesive systems

V. Superporous hydrogels

VI. Expandable systems

VII. Magnetic systems

Floating Drug Delivery System:

Floating drug delivery systems (FDDS) have a bulk

density less than gastric fluids and so remain buoyant in the

stomach without affecting gastric emptying rate for a

prolonged period of time. While the system is floating on

the gastric contents, the drug is released slowly at the

desired rate from the system [Mushiroda, 2000]. After

release of drug, the residual system is emptied from the

stomach. This results in an increased GRT and a better

control of the fluctuations in plasma drug concentration.

FDDS can be divided into non-effervescent and

effervescent system.

Non-effervescent systems: This type of system, after swallowing, swells unrestrained

via imbibition of gastric fluid to an extent that it prevents

their exit from the stomach. One of the formulation

methods of such dosage forms involves the mixing of the

drug with a gel, which swells in contact with gastric fluid

after oral administration and maintains a relative integrity

of shape and a bulk density of less than one within the outer

gelatinous barrier [Hilton, 1992]. The air trapped by the

swollen polymer confers buoyancy to these dosage forms.

Excipients used most commonly in these systems include

hydroxypropyl methyl cellulose (HPMC), polyacrylate

polymers, polyvinyl acetate, Carbopol, agar, sodium

alginate, calcium chloride, polyethylene oxide and

polycarbonates.

Hydrodynamically balanced intragastric delivery system:

The hydrodynamically balanced gastrointestinal drug

delivery system, in either capsule or tablet form, is

designed to prolong GI residence time in an area of the GI

tract to maximize drug reaching its absorption site in the

solution state and, hence, ready for absorption. It is

prepared by incorporating a high level (20-75 % W/W)

of one or more gel forming hydrocolloids, e.g.

hydroxyethyl cellulose, hydroxypropyl cellulose,

hydroxypropyl methylcellulose and sodium

carboxymethycellulose, into the formulation and then

compressing these granules into a tablet (or encapsulating

into capsules). Formulation of this device must comply

with the criteria that it must have sufficient structure to

form a cohesive gel barrier, maintain an overall specific

gravity lower than that of the gastric contents (1.004-1.010)

and should dissolve slowly enough to serve as a drug

reservoir. On contact with gastric fluid the hydrocolloid in

this intragastric floating device starts to become hydrated

and forms a colloid gel barrier around its surface with

thickness growing with time. This gel barrier controls the

rate of solvent penetration into the device and the rate of

drug release from the device. It maintains a bulk density of

less than 1 and thus remains buoyant in the gastric fluid

inside the stomach for up to 6 h.

Alginate beads: Multi-unit floating dosage forms have

been developed from freeze-dried calcium alginate.

Spherical beads of approximately 2.5 mm in diameter can

be prepared by dropping sodium alginate solution into

aqueous solution of calcium chloride, causing the

precipitation of calcium alginate. The beads are then

separated, snap-frozen in liquid nitrogen, and freeze-dried

at -400C for 24 h, leading to the formation of a porous

system, which can maintain a floating force for over 12 h.

These floating beads gave a prolonged residence time of

more than 5.5 h.

Hollow microspheres / Microballoons: Hollow

microspheres loaded with drug in their outer polymer shelf

can be prepared by an emulsion solvent diffusion method.

The ethanol/dichloromethane solution of the drug and an

enteric acrylic polymer should poured into an agitated

solution of polyvinyl alcohol (PVA) that is thermally

controlled at 40º C. The gas phase is generated in the

dispersed polymer droplet by the evaporation of

dichloromethane formed and internal cavity in the

microsphere of the polymer with drug. The microballoon

floats continuously over the surface of an acidic dissolution

medium containing surfactant for more than 12 h [Jaimini,

2013].

Intragastric FDDS: A gastrointestinal drug delivery

system (GIDS) can be made to float in the stomach by

incorporating a floatation chamber, which may be a

vaccum or filled with air or harmless gas. A drug reservoir

is encapsulated inside a microporous compartment with

apertures along its top and bottom walls. The peripheral

walls of the drug reservoir compartment are completely

sealed to prevent any direct contact of the stomach

mucosal surface with the undissolved drug. In the stomach,

the floatation chamber causes the GIDS to float in the

gastric fluid. Fluids enter through the apertures, dissolve

the drug, and carry the drug solutes out from the delivery

system for continuous transport to the intestine for

absorption.

Figure 5: Intragastric floating drug delivery system


Effervescent Systems:

A drug delivery system can be made to float in the stomach

by incorporating a floatation chamber, which may be filled

with vaccum, air or inert gas. The gas in the floatation

chamber can be introduced either by the volatilization of an

organic solvent or by the effervescent reaction between

organic acids and bicarbonate salts.

Volatile liquid containing systems: The residence time of

the drug delivery device in the stomach can also be

sustained by incorporation of an inflatable chamber, which

contains a liquid e.g. ether that gasifies at body temperature

to cause the chamber to inflate in the stomach. The

inflatable gastrointestinal drug delivery system is fabricated

by loading the inflatable chamber with a drug reservoir,

which can be a drug-impregnated polymeric matrix, and

then encapsulating the unit in a gelatin capsule. After oral

ingestion, the capsule dissolves to release the drug reservoir

compartment together with the inflatable chamber. The

inflatable chamber automatically inflates and retains the

drug reservoir compartment in the stomach. The drug

solutes are continuously released from the reservoir into the

gastric fluid. The inflatable chamber also contains a

bioerodable polymer filament, e.g. a copolymer of PVA

and polyethylene, that gradually dissolves in the gastric

fluid and finally causes the inflatable chamber to release

the gas and become collapsed after a predetermined time

period to permit the spontaneous ejection of the inflatable

GIDS from the stomach.

Gas generating systems: These buoyant delivery systems

utilize effervescent reaction between carbonate/bicarbonate

salts and citric/tartaric acid to liberate CO2, which gets

entrapped in the gellified hydrocolloid layer of the system

thus decreasing its specific gravity and making it float over

chyme. These tablets may be either single layered wherein

the CO2 generating components are intimately mixed within

the tablet matrix, or they may be bilayered in which the gas

generating components are compressed in one hydrocolloid

containing layer, and the drug in other layer formulated for

a SR effect. Multiunit types of floating pills, which

generate CO2, have also been developed. The system

consists of a SR pill as seed, surrounded by double layers.

The inner layer is an effervescent layer containing sodium

bicarbonate and tartaric acid. The outer layer is of a

swellable membrane layer containing PVA, shellac, etc.

Effervescent layer is divided into two sublayers to avoid

direct contact between sodium bicarbonate and tartaric

acid. When the system is immersed in buffer solution at 370

C, swollen pills, like balloons are formed having density

less than 1 mg/ml. This occurs due to the neutralization of

the inner effervescent layer with the diffusion of water

through the outer swellable membrane layer. These kinds

of systems float completely within 10 min, and remain

floating over extended periods of 5-6 h.

Figure 6: Gas generating system

Floating film delivery system: Floating film drug delivery

system has emerged as an advanced alternative to

traditional dosage forms like tablets, capsules and liquids.

A drug loaded thin film strip filled into capsule is typically

designed for oral drug delivery. Floating film offers

advantages as, preparation of film is very simple, time

saving, economically beneficial and chances of cross

contamination are very less, also handling of film is very

easy as compared with microspheres. Floating film is drug

loaded polymeric film consisting of an active

pharmaceutical ingredient, polymers, film forming agent,

plasticizer and suitable solvent. Films can be prepared by

solvent evaporation method in which drug and polymer are

mixed with sufficient quantity of solvent. Other ingredients

are added accordingly, poured in petriplate and allowed to

dry to give thin layered smooth film. Drug release profile

can be modified by using different polymers. Layer-by-

layer film formulation technique in which one layer is of

controlled release polymer and another layer is of sustained

release polymer can be prepared. Hence, by this way one

can go for multilayer approach so that this drug delivery

will play an important role in associated diseases such as

diabetes, hypertension etc. In this type of diseases

multilayer film can be prepared having different release

profile of drug through different layers of film made from

different polymers. Solvent plays important role in

preparation of gastroretentive films. Water can be used as

solvent for drugs which are water insoluble or sparingly

soluble so that film gets dried in short period of time after

its preparation.

Figure 7: Gastroretentive floating film enclosed in hard

gelatin capsule.

Figure 8: Folding pattern of bilayer films in capsule

Although, this type of dosage form has various

advantages such as convenience of hard gelatin capsule and

ability to modify drug release using multilayer design, there

remains number of issues. This includes difficulties in

formulation of drug loaded polymeric films, achieving

required drug release from multilayer films and selection of


polymer with desired ability to unfold and expand in

stomach [Shinde, 2014].

High Density Systems: High density system is another modification of GRDDS.

These systems with density of about 3 g/cc are retained in

the rugae of the stomach and are capable of withstanding its

peristaltic movements. 2.6- 2.8 g/cc acts as a threshold

density after which such systems can be retained in the

lower part of the stomach. Such phenomenon needs to be

confirmed by clinical studies after which the heavy pellet

formulations can hit the market in near future. The only

major drawback with such systems is that it is technically

difficult to manufacture such formulations with high

amount of drug and to achieve a density of 2.8 g/cc. It is

necessary to use diluents like barium sulphate (δ= 4.9), zinc

oxide, titanium dioxide and iron powder, etc. These

materials increase density by up to 1.5–2.4 g/cc.

Bioadhesion system:

Bioadhesive drug delivery systems (BDDS) are used as a

delivery device within the lumen to enhance drug

absorption in a site specific manner. A potential approach

to extend the gastrointestinal residence time is the

development of a bioadhesive polymer based drug delivery

system, which has been conceptualized on the basis of a GI

self protective mechanism. It is known that the surface

epithelium of the stomach and the intestine retains its

integrity throughout the course of its lifetime, even though

it is constantly exposed to a high concentration of

hydrochloric acid and powerful protein splitting enzymes,

like pepsin. This self protective mechanism is due to the

fact that the specialized goblet cells secrete mucus that

remain closely applied to the surface epithelium. The

mucus contains mucin, an oligosaccharide chain with

terminal sialic acid (pKa =2.6), which is capable of

neutralizing the hydrochloric acid and withstanding the

action of pepsin and thus preserving the epithelial cell

membrane. The surface epithelium adhesive properties of

mucin have been and recently applied to the development

of gastrointestinal drug delivery devices based on

bioadhesive polymers. The drug delivery system coated

with mucoadhesive polymer binds to mucin molecules in

the mucus lining and is therefore retained on the surface

epithelium for extended periods of time. The drug

molecules contained in the drug delivery device coated

with mucoadhesive polymer are constantly released for

absorption. A bioadhesive polymer is a natural or a

synthetic polymer capable of producing an adhesive

interaction with a biological membrane. A bioadhesive

polymer is known to have the following molecular

characteristics:

1. It has molecular flexibility and contains hydrophilic

functional groups.

2. It should possess specific molecular weight, chain

length, and conformation and should be non-toxic

and non-absorbable from GI tract.

3. It should form non covalent bond with mucin

epithelial surfaces and have quick adherence to the

moist surfaces.

4. It should offer no hindrance to drug release, have

specific site of attachment and be economical.

Among a number of polymers tested, polyanions with

a high charge density are highly active. The polymers

containing carboxylic groups, such as polyacrylic polymer

show high level of bioadhesion.

Expandable system:

Expandable gastroretentive dosage forms

(GRDFs) have been designed over the past 3 decades.

These are those dosage forms, which after swallowing;

swell to an extent that prevents their exit from the pylorus.

As a result the dosage form is retained in the stomach for a

long period of time. These systems may be named as

“plugs type system”, since they exhibit the tendency to

remain logged at the pyloric sphincter if that exceed a

diameter of approximately 12-18 mm in their expanded

state. The formulation is design for the gastric retention and

controlled delivery of the drug into the gastric cavity. The

balance between the extent and duration of swelling is

maintained by the degree of cross linking between the

polymeric chains. A high degree of crosslinking retards

the swelling ability of the system maintaining its physical

integrity for prolonged period.

Figure 9: Swelling system

Superporous Hydrogels: Superporous hydrogels (SPHs) can be prepared by phase

separation technique, cross-linking technique, gas-blowing

technique. Based upon GI physiology, superporous

hydrogels must possess following properties in order to act

as gastric retention device.

a. Initial size should be small enough for easy

swallowing.

b. Swelling should be fast enough to overcome gastric

emptying by IMMC.

c. Size of swollen hydrogel should be large enough to

be retained in the stomach.

d.Swollen hydrogel should be strong enough to

withstand contraction pressure, abrasion and shear

forces in stomach.

Gas blowing technique is the most widely used

method for the preparation of superporous hydrogels,

where, superporous hydrogels are prepared by crosslinking

polymerization of monomers in the presence of gas

bubbles. Different ingredients like monomer, crosslinker,

foam stabilizer, polymerization initiator, initiation catalyst

(if any) and foaming agent are added sequentially in a test

tube of specific dimensions. Initially and before addition of

foaming agent, the pH of monomer solution is maintained

at 5 to 6, because low pH favors foaming process. The

addition of foaming agent leads to formation of bubbles


Table 4: Drawbacks associated with GRDDS [Pawar, 2012]

Technology Drawbacks

High density

systems

Cannot be manufactured with large amount of drug due to technical problems.

Till date no such system is available in the market.

Floating systems Highly depends on the fed state of stomach; higher level of fluid is required in gastric region.

Expandable

systems

Storage troubles due to hydrolysable, biodegradable polymers.

Difficult to manufacture and not economical.

Mucoadhesive

systems

Efficiency can be reduced in rapid turnover of mucus.

Might bind to other mucosal lining like esophagus.

Magnetic systems Might compromise with patient compliance.

Table 5: Formulations of floating drug delivery system

Microspheres Tablets /Pills Chlorpheniramine maleate, Aspirin, Griseofulvin, Acetaminophen, p-nitroaniline,

Acetylsalicylic acid, Ibuprofen, Ampicillin, Atenolol, Theophylline, Captopril Sotalolol

Granules Cinnarizine, Diclofenac sodium, Diltiazem, Indomethacin, Fluorouracil, Prednisolone

Films P-Aminobenzoic acid, Cinnarizine, Piretanide, Prednisolone, Quinidine gluconate,

Propranolol hydrochloride, Rosuvastatin

Powders Riboflavin phosphate, Sotalol, Theophylline

Capsules Verapamil HCl, Chlordiazepoxide HCl, Diazepam, Furosemide, Propranolol HCl,

Nicardipine

Foams/ Hollow Bodies Ibuprofen

Effervescent floating liquid

alginate preparation Aluminium hydroxide, Magnesium carbonate

followed by increase in pH of solution. The increased pH

accelerates the polymerization process. Thus, simultaneous

foaming and gelation lead to the formation of homogenous

porous hydrogels i.e. superporous hydrogels. After

synthesis, SPHs are subjected to washing, drying using

different methods which influence the swelling and

mechanical behavior of resulting hydrogels.

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 is placed on

the abdomen over the position of the stomach. Although

magnetic system seems to work, the external magnet must

be positioned with a degree of precision that might

compromise patient compliance.

Evaluation of gastroretentive drug delivery system: Each drug product should be evaluated to ensure its

performance characteristics and to control batch-to-batch

quality. Various parameters need to be evaluated to

increase floating duration, specific gravity, resultant

weight, bioadhesive strength, swelling index (weight gain),

and gastroretention and drug release.

Floating lag time and Floating time: The test for

buoyancy is determined in 900 ml of simulated gastric fluid

(0.1N HCl) or intestinal fluid (phosphate buffer)

maintained at 37±0.50C using USP dissolution apparatus

type 2 (Paddle type) [Blumenthal, 2010]. The time required

for the tablet to float on the gastric fluid (Floating time), the

time interval between the introduction of the tablet and its

buoyancy (Floating lag time) are measured. The floating

process depends on the balance between the weight and

volume of dosage forms.

Specific gravity: The specific gravity of floating system is

determined by the displacement method, using benzene as a

displacing medium.

Resultant weight: To determine the floating ability of

buoyant dosage forms, in vitro apparatus is conceived that

measures the total force acting on the immersed object

[Kearney, 2005]. This force determines the resultant

weight. The object floats better if resultant weight is more

positive. It helps in optimizing floating drug delivery

system with respect to stability and durability of floating

forces produced in order to buoyancy capability variations.

It is given by the following equation

Whereas,

F = the resultant weight of object

d(f) = the fluid density

d(s) = the density of solid object

F(b) = sum of the vertical sum of buoyancy of the test

object.

F(g) = force due to gravitational force

g = acceleration due to gravity

M = weight of the test object

V = volume of the test object.

Bioadhesive strength: The bioadhesive strength of

polymers can be determined by measuring the force

required to separate the polymer specimen sandwiched

between the layers of either an artificial (e.g. cellophane) or

biological membrane (rabbit stomach intestine) [Vasan,

2002]. This force can be measured by using a modified


precision balance or an automated texture analyzer.

Swelling systems: The swelling behaviour of dosage forms

can be measured by studying its weight gain [Blumenthal,

2010]. It is performed by immersing the dosage forms in a

stimulated gastric fluid at 37±0.50C using USP dissolution

apparatus type 1 (Basket type). At predetermined time

intervals dosage form is removed from the basket, blotted

and weighed. The dimensional changes are measured in

terms of increase in diameter / thickness over time t. WU is

measured in terms of percentage weight gain and is given

by:

WU = (Wt - W0)/ W0 x 100----------------- (1)

Where, Wt and W0 are the weight of dosage forms at T= t

and at T = 0 respectively.

Gastroretention: In vivo visualization is a crucial

parameter for evaluating the gastrointestinal retention

characteristics of the dosage form. It can be studied by

incorporating a radio- opaque material into a solid dosage

form [Rowe, 2009]. With the help of X rays and gamma

scintigraphy, the gastric retention can be visualized. The

use of X rays involves exposing the patient to X ray beam

thus permitting the visualization of gastrointestinal transit

of dosage forms. In case of scintigraphy gamma (γ) rays are

emitted by the radionuclide and are seen through a camera

to monitor the location of dosage form in the

gastrointestinal tract.

Dissolution / Drug release: Dissolution tests are performed

using USP dissolution apparatus type 2 (Paddle type)

[Burns, 1995]. The dosage form is exposed to the simulated

gastric fluid at 37±0.50C. At predetermined time intervals,

a specified volume of the sample is withdrawn and

analyzed spectrophotometrically.

Stability studies: Stability studies are carried out to

determine the effect of temperature and humidity on

stability of drug in film during storage. The films in capsule

are packed in aluminium foil and stored in ICH certified

stability chamber maintained at 40±2OC (75% ±5 % RH)

for three months. The capsule should be withdrawn

periodically for evaluating drug content and release

kinetics.

CONCLUSION

Recently many drugs have been formulated as floating drug

delivery systems with an objective of sustained release and

restricting the region of drug release to stomach. Gastro-

retentive floating drug delivery systems have emerged as an

efficient means of enhancing the bioavailability and

controlled delivery of many drugs. Floating film drug

delivery system have come forward as an efficient means

of enhancing the bioavailability and controlled delivery of

drugs. The advancement in delivery technology will lead to

the development of large number of floating delivery

system to optimize the delivery of molecules that exhibit

absorption window, low bioavailability and extensive first

pass metabolism.

ACKNOWLEDGEMENT

The author express their sense of gratitude towards

management of Satara College of Pharmacy, Degaon,

Satara for providing all obligatory facilities necessary to

carry out present work.

REFERENCES

1. Pravin K Bhoyar, Jagdish R Baheti, Vishal V Burde.

An overview of a gastro retentive floating drug

delivery system. World Journal of Pharmaceutical

research, 1(2) 2012: 22-40.

2. Garima Gupta, Amit Singh. A Short Review on

Stomach Specific Drug Delivery System. International

Journal of PharmTech Research, 4 (4) 2012: 1527-

1545.

3. Bhavjit Kaur, Shivani Sharma, Geetika Sharma,

Rupinder Saini, Sukhdev Singh, Meenu Nagpal,

Upendra K Jain et al. A Review of Floating Drug

Delivery System. Asian Journal of Biomedical and

Pharmaceutical Sciences, 3 (24) 2013, 1-6.

4. Mukesh P Ratnaparkhi, Shilpa P Chaudhari, Suresh B

Dhiwar, Rahul R Gurav. gastroretentive drug delivery

system and its recent approach. International Journal of

Drug Formulation and Research, 3 (3) 2012: 39-56.

5. Sushma Singh, Kisan Jadhav, Pushpendra Tripathi.

Various Approaches in Floating Drug Delivery. Int Jou

Pharm Phytopharmacol Res, 2 (5) 2013: 360-371.

6. Jaimini Manish, Hardik Patel. Gastro retentive floating

drug delivery system: a review. IJPRBS, 2 (2) 2013:

358-377.

7. Sunil Kumar, Faraz Jamil, Meenu Rajput and Saurabh

Sharma. Gastro Retentive Drug Delivery System:

Features and Facts. International Journal of Research

in Pharmaceutical and Biomedical Sciences, 3 (1)

2012: 125-136.

8. Natasha Sharma, Dilip Agarwal, MK Gupta. A

Comprehensive Review on Floating Drug Delivery

System. International Journal of Research in

Pharmaceutical and Biomedical Sciences, 2 (2) 2011:

428-441.

9. Amit Kumar Nayak, Ruma Maji, Biswarup Das.

Gastroretentive drug delivery systems: a review. Asian

Journal of Pharmaceutical and Clinical Research, 3 (1)

2010: 2-10.

10. Ankith Kumar Reddy B, Hema Faith V, Gayathri V

Subhashis Debnath, M Niranjan Babu. Gastroretentive

Drug Delivery System: A Review. IJPI‟s Journal of

Pharmaceutics and Cosmetology, 3 (13) 2013: 1-17.

11. Vivek K. Pawar, Shaswat Kansal, Shalini Asthana,

Manish K. Chourasia. Industrial Perspective of

Gastroretentive Drug Delivery Systems:

Physiochemical, Biopharmaceutical, Technological

and Regulatory Consideration. Expert opinion on drug

delivery, 9 (5)2012: 551-565.

12. Namdeo G. Shinde, Nagesh H. Aloorkar, Bhaskar N.

Bangar, Sunil M. Deshmukh, Dhanshri U. Gadhave.

Floating Film Drug Delivery System: An Effective

Approach of Gastroretention. Int Jou Phar Integr

Lifesci 2(I3) 2014: 14-23.

13. Ami M, Krunal SA, Hejal P, Yogi P. Advancement in

controlled release gastroretentive drug delivery system:

a review. J Drug Del and Therap, 2(3); 2012: 12-21.

14. Bhosale UV, Kusum Devi V, Jain N, Swamy PV.

Effect of polymer concentration and viscosity grade on

alenolol release from gastric floating drug delivery

systems. Ind J Pharm Edu Res, 44(3); 2010: 267-273.


15. Chawla G, Gupta P, Koradia V, Bansal AK.

Gastroretention a means to address regional variability

in intestinal drug absorption. Pharm Tech, 2006: 50-

60.

16. David SS. The effect of density on the gastric

emptying on single and multiple unit dosage forms.

Pharm Res, 3; 1986: 208-213.

17. Dixit RP, Puthli SP. Oral strip technology: overview

and future potential. J Contrl Rel, 139 (2); 2009: 94-

107.

18. Hwang SJ, Park H, Park K. Gastric retentive drug

delivery systems. Crit Rev Ther Drug Carr Sys, 15;

1998: 243-284.

19. John C, Mortan C. The science of dosage form design,

modified release per oral dosage forms, 2nd

edition,

Churchill Livingstone, 2002: 290-300.

20. Joshi P, Patel P, Modi H, Patel MR, Patel KR, Patel

NM. A review on gastroretentive drug delivery system.

JPSBR, 2 (3); 2012: 123-128.

21. Khosla R, Feely LC, Devis SS. Gastrointestinal transit

of non disintegrating tablet in fed subject. Int J Pharm,

53; 1989: 107-117.

22. Klausner EA, Lavy E, Friedman M, Hiffman A.

Expandable gastroretentive dosage form. J Contrl Rel,

90; 2003: 143-162.

23. Kumar PM, Dachinamoorthi D, Devanna

Chandrashekhar KB, Ramanjireddy T. Gastroretentive

delivery of mucoadhesive films containing

pioglitazone. Int J Adv Pharm Sci, 1 (1); 2010: 88-94.

24. Lee VHL. Controlled drug delivery fundamentals and

applications: Introduction. 2nd

edition, INC, New York,

Marcel Dekker, 1987: 16-29.

25. Moussu NM, Atiti NN, Ghorals DM, El-Saharty Y.

Formulation and evaluation of sustained release

floating capsules of nicardipine hydrochloride.

Pharmszine, 58; 2003: 38-43.

26. Patil MS, Shinde AJ, More HN. Formulation and

evaluation of an oral floating tablet of cephalexin.

Indian J Pharm Edu Res, 44 (3); 2010: 41-50.

27. Sampath Kumar KP, Bhowmik D, Dutta AS, Paswan

S, Deb L. Trends in scope and opportunities of control

release oral drug delivery systems. Critical Review in

Pharmaceutical Science. Earth J Org, 1; 2013: 20-33.

28. Saarojini S, Manavalan R. An overview on various

approaches to gastroretentive dosage forms. Int J Drug

Dev and Res, 4 (1); 2012: 01-13.

29. Semalty M, Semalty A, Kumar G. Formulation and

characterization of mucoadhesive buccal films of

glipizide. Ind J Pharm Sci, 70 (1); 2008: 43-48.

30. Sharma S, Pawar A. Low density multiparticulate

system for pulsatile release of meloxicam. Int J Pharm,

313; 2006: 150-158.

31. Singh BN, Kim HK. Floating drug delivery system: an

approach to oral controlled drug delivery via gastric

retention. J Contr Rel, 63; 2000: 235-259.

32. Timmermans J, Moes AJ. Factors controlling the

buoyancy and gastric retention capabilities of floating

matrix capsule: New data for reconsidering the

controversy. J Pharm Sci, 83; 1994: 18-24.

33. Hassan Bassam Abdul Rasool. J Chromat Separation

Techniq 2013, 4(3): 1.

34. Amit Gupta. Hyperlipidemia: An Updated Review.

IJBTR 2011;1(1): 81-89.

35. Manisha Ware, Sandip Prasad Tiwari, Amit Roy,

Trilochan Satapathy. New insights into gastro-retentive

floating drug delivery systems. World Jou Phar

Pharmceu Sci. 3(1); 2013: 252-270.

36. Hilton AK, Deasy PB. In vitro and in vivo evaluation

of an oral sustained release floating dosage form of

amoxicillin trihydrate. Int J Pham.86; 1986:79-88.

37. Bramhankar DM, Jaiswal SB. Biopharmaceutics and

Pharmacokinetics a treatise. 2nd

Ed. 2009 (pp. 399-

401). Delhi, Vallabh Prakashan.

38. Burns S J. Development and validation of an in vitro

dissolution method for a floating dosage form with

biphasic release characteristics. Int J Pharm, 121

(1);n1995: 37-44.

39. Chein YW. Novel Drug Delivery Systems. 2nd

Ed.

1992 (pp. 01-139). New York, Marcel Dekker.

40. Chen J, Blevins WE, Park H, Park K.. Gastric retention

of superporous hydrogel composites. J Control

Release, 64; 2000: 39-51.

41. Darandale SS, Vavia PR. Design of a gastroretentive

mucoadhesive dosage form of Furosemide for

controlled release. Acta Pharm Sinica B, 2010: 1-9.

http://dx.doi.org/10.1016/j.apsb.2012.05.004.

42. David SS. The effect of density on the gastric

emptying on single and multiple unit dosage forms.

Pharm Res, 3; 1986: 208-213.

43. Davis SS. Formulation strategies for absorption

windows. DDT, 10; 2005: 249-257.

44. http://www.sciencedirect.com/science/article/pii/ S016

8365999002047.

45. http://www.who.int/topics/cardiovascular_diseases/eu/

copy

46. http://www.zuni v.net/physiology/book/chapter22.html

47. Hwang SJ, Park H, Park K. Gastric retentive drug

delivery systems. Crit Rev Ther Drug Carr Syst, 15;

1998: 243-284.

48. India cardiovascular diseases and its risk profile world

health organization, The world health report 2002.

Geneva, Switzerland: WHO; 2009: 1-89.

49. Indian Pharmacopoeia. Controller of Publications,

Govt. of India, New Delhi; Vol. I; 2007: 175-183.

50. Jain NK.. Controlled and novel drug delivery. 1st Ed.

1997 (pp. 1-8). New Delhi, CBS publishers and

distributors.

51. Klausner EA, Lavy, E Friedman, M Hoffman A.

Expandable gastroretentive dosage form. J Control

Rel. 90; 2003: 143-162.

52. Kumar PM, Dachinamoorthi D, Devanna

Chandrasekhar KB, Ramanjireddy T. Gastroretentive

delivery of mucoadhesive films containing

Pioglitazone. Int J Adv Pharm Sci. 1 (1); 2010: 88-94.

53. Sampath Kumar KP, Bhowmik D, Dutta AS, Paswan

S, Deb L. Trends in scope and opportunities of control

release oral drug delivery systems. Critical review in

pharmaceutical sciences. Earth J Org. 1; 2012: 20-33.

54. Sampath Kumar KP, Bhowmik D, Dutta AS,

Srivastava S, Paswan S. Sustained Release Drug

http://dx.doi.org/10.1016/j.apsb.2012.05.004

http://www.who.int/topics/cardiovascular_diseases/eu/copy

http://www.who.int/topics/cardiovascular_diseases/eu/copy


Delivery System Potential. The Pharma J. 1(2); 2012:

48-60.

55. Semalty M, Semalty A, Kumar G. Formulation and

characterization of mucoadhesivebuccal films of

glipizide. Indian J Pharm Sci. 70(1); 2008: 43-48.

56. Sharma S, Pawar A. Low-density multiparticulate

system for pulsatile release of meloxicam. Int J Pharm,

313; 2006: 150-158.

57. Singh BN, Kim HK. Floating drug delivery systems:

an approach to oral controlled drug delivery via gastric

retention. J Control Rel. 63; 2010: 235- 259.

58. Timmermans J, Moes AJ. How Well Do Floating

Dosage Forms Float? Int J Pharm, 62; 1990: 207- 216.

59. Timmermans J, Moes AJ. Factors controlling the

buoyancy and gastric retention capabilities of floating

matrix capsules: New data for reconsidering the

controversy. J Pharm Sci. 83; 1994: 18-24.

60. Tripathi KD. Essentials of pharmacology. 5th ed. (pp.

503-504). New Delhi, Jaypee Bros. Med. Publi. Ltd.

2003.

Source of support: Nil; Conflict of interest: None declared

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