Figure 2: Motility pattern in GIT

1. Phase I (basal phase) lasts from 40 to 60 minutes with rare contractions.

2. Phase II (preburst phase) lasts for 40 to 60 minutes with intermittent action potential and contractions. As the phase progresses the intensity and frequency also increases gradually.

3. Phase III (burst phase) lasts for 4 to 6 minutes. It includes intense and regular contractions for short period. It is due to this wave that all the undigested material is swept out of the stomach down to the small intestine. It is also known as the housekeeper wave.

4. Phase IV lasts for 0 to 5 minutes and occurs between phases III and I of 2 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 1 mm), 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. Scintigraphic studies determining gastric emptying rates revealed that orally administered controlled release dosage forms are subjected to basically 2 complications, that of short gastric residence time and unpredictable gastric emptying rate.^[3]

Different Features of Stomach:

Gastric pH: Fasted healthy subject 1.1 ± 0.15. Fed healthy subject 3.6 ± 0.4 Volume: Resting volume is about 25-50 ml Gastric secretion: Acid, pepsin, gastrin, mucus and some enzymes about 60ml with approximately 4mole of hydrogen ions per hour. Effect of food on Gastric secretion: About 3 litres of secretions are added to the food. Gastro intestinal transit time.^[6]

Floating drug delivery:

FDDS have a bulk density less than gastric fluids and so remain buoyant in the stomach without affecting the 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. After release of drug, the system is eliminated from the stomach. This results in an increased GRT and a better control of fluctuations in plasma drug concentrations. The floating sustained release dosage forms exhibit most of the characteristics of hydrophilic matrices and are known ‘hydrodynamically balanced systems’ (HBS) since they are able to maintain their low apparent density, while the polymer hydrates and builds a gel like barrier at the outer surface. The drug is released progressively from the swollen matrix, as in the case of conventional hydrophilic matrices. These forms are expected to remain buoyant (3–4 h) in the gastric contents without affecting the intrinsic rate of emptying because their bulk density is lower than that of the gastric contents. Many studies have demonstrated the validity of the concept of buoyancy in terms of prolonged GRT of the floating forms, improved bioavailability of drugs and improved effects in clinical situations. The results obtained have also demonstrated that the presence of gastric contents is needed to allow the proper achievement of the buoyancy retention effect. Among the different hydrocolloids recommended for floating form formulations, cellulose ether polymers are the most popular, especially hydroxypropylmethylcellulose (HPMC). Fatty material with a bulk density lower than one may be added to the formulation to decrease the water intake rate and increase buoyancy.^[4]

Factors affecting gastric retention:

Gastric residence time of an oral dosage form is affected by several factors. To pass through the pyloric valve into the small intestine the particle size should be in the range of 1 to 2 mm. The pH of the stomach in fasting state is ~1.5 to 2.0 and in fed state is 2.0 to 6.0. A large volume of water administered with an oral dosage form raises the pH of stomach contents to 6.0 to 9.0. Stomach does not get time to produce sufficient acid when the liquid empties the stomach, hence generally basic drugs have a better chance of dissolving in fed state than in a fasting state. The rate of gastric emptying depends mainly on viscosity, volume, and caloric content of meals. Nutritive density of meals helps determine gastric emptying time. It does not make any difference whether the meal has high protein, fat, or carbohydrate content as long as the caloric content is the same. However, increase in acidity and caloric value slows down gastric emptying time. Biological factors such as age, body mass index (BMI), gender, posture, and diseased states (diabetes, Chrons disease) influence gastric emptying. In the case of elderly persons, gastric emptying is slowed down. Generally females have slower gastric emptying rates than males. Stress increases gastric emptying rates while depression slows it down. The resting volume of the stomach is 25 to 50 ml. Size and shape of dosage unit also affect the gastric emptying. Tetrahedron and rings hoped devices have a better gastric residence time as compared with other shapes. The diameter of the dosage unit is also equally important as a formulation parameter. Dosage forms having a diameter of more than 7.5 mm show a better gastric residence time compared with one having 9.9 mm. The density of a dosage formals affects the gastric emptying rate. A buoyant dosage form having a density of less than that of the gastric fluids floats.^[5]

Advantages of gastroretentive drug delivery system:

Gastro retentive drug delivery systems have numerous advantages listed below:

1. The HBS formulations are not restricted to medicaments, which are principally absorbed from the stomach. Since it has been found that these are equally efficacious with medicaments which are absorbed from the intestine e.g. Chlorpheniramine maleate.

2. The HBS are advantageous for drugs absorbed through the stomach e.g. ferrous salts and for drugs meant for local action in the stomach and treatment of peptic ulcer disease e.g. antacids.

3. The principle of HBS can be used for any particular medicament or class of medicament.

4. The efficacy of the medicaments administered utilizing the sustained release principle of HBS has been found to be independent of the site of absorption of the particular medicaments.

5. Administration of a prolonged release floating dosage form tablet or capsule will result in dissolution of the drug in gastric fluid. After emptying of the stomach contents, the dissolve drug available for absorption in the small intestine. It is therefore expected that a drug will be fully absorbed from the floating dosage form if it remains in solution form even at alkaline pH of the intestine.

6. When there is vigorous intestinal movement and a short transit time as might occur in certain type of diarrhoea, poor absorption is expected under such circumstances it may be advantageous to keep the drug in floating condition in stomach to get a relatively better response.

7. Gastric retention will provide advantages such as the delivery of drugs with narrow absorption windows in the small intestinal region.

8. Many drugs categorized as once-a-day delivery have been demonstrated to have suboptimal absorption due to dependence on the transit time of the dosage form, making traditional extended release development challenging. Therefore, a system designed for longer gastric retention will extend the time within which drug absorption can occur in the small intestine.^[6]

Drug candidates suitable for fdds:

· Drugs that have narrow absorption window in GIT (e.g. L-DOPA, paminobenzoic acid, furosemide, riboflavin)

· Drugs those are locally active in the stomach (e.g. misroprostol, antacids)

· Drugs those are unstable in the intestinal or colonic environment (e.g. captopril, ranitidine HCl, metronidazole)

· Drugs that disturb normal colonic microbes (e.g. antibiotics used for the eradication of Helicobacter pylori, such as tetracycline, clarithromycin, amoxicillin)

· Drugs that exhibit low solubility at high pH values (e.g. diazepam, chlordiazepoxide, verapamil)^[7]

Mechanism of floating systems:

Various attempts have been made to retain the dosage form in the stomach as a way of increasing the retention time. These attempts include introducing floating dosage forms (gas-generating systems and swelling or expanding systems), mucoadhesive systems, high-density systems, modified shape systems, gastric-emptying delaying devices and co-administration of gastric-emptying delaying drugs. Among these, the floating dosage forms have been most commonly used. Floating drug delivery systems (FDDS) have a bulk density less than gastric fluids and so remain buoyant in the stomach without Affecting the 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. 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. However, besides a minimal gastric content needed to allow the proper achievement of the buoyancy retention principle, a minimal level of floating force (F) is also required to keep the dosage form reliably buoyant on the surface of the meal. To measure the floating force kinetics, a novel apparatus for determination of resultant weight has been reported in the literature. The apparatus operates by measuring continuously the force equivalent to F (as a function of time) that is required to maintain the submerged object. The object floats better if F is on the higher positive side, This apparatus helps in optimizing FDDS with respect to stability and durability of floating forces produced in order to prevent the drawbacks of unforeseeable intragastric buoyancy capability variations.

F = F buoyancy - F gravity

= (Df - Ds) gv--- (1)

Where, F= total vertical force, Df = fluid density,

Ds = object density, v = volume and

g = acceleration due to gravity.^[8]

Figure 3: Mechanism of floating systems, GF= Gastric fluid

Classification: based on the mechanism of buoyancy FDDS

A. Single Unit Floating Dosage Systems

a) Non-effervescent Systems

1. Hydrodynamic balanced system (HBS)

2. Floating chamber

3. Multilayer flexible film

b) Effervescent Systems (Gas-generating Systems)

1. Floating systems containing effervescent components

2. Floating system based on ion exchange resin

3. Floating system with inflatable chamber

4. Programmable drug delivery

B. Multiple Unit Floating Dosage Systems

a) Non-effervescent Systems

Alginate beads

b) Effervescent Systems (Gas-generating Systems)

c) Hollow Microspheres

C. Raft Forming Systems

A. Single Unit Floating Dosage Systems

a) Non-effervescent Systems

The Non effervescent FDDS based on the mechanism of swelling of polymer or bioadhesion to mucosal layer in GI tract. The most commonly used excipients in non-effervescent FDDS are gel forming or highly swellable cellulose type hydrocolloids, polysaccharides and matrix forming material such as polycarbonate, polyacrylate, polymethaceylate, polystyrene as well as bioadhesive polymer such as chitosan and carbopol.^[9]

1. Hydrodynamic balanced system (HBS)

These are single-unit dosage forms, containing one or more gel-forming hydrophili polymers. Hydroxypropylmethylcellulose (HPMC) is the most common used excipient, although hydroxylethylcellulose (HEC), hydroxylpropylcellulose (HPC), sodiumcarboxy methyl cellulose (NaCMC), agar, carrageenans or alginic acid are also used .The polymer is mixed with drug and usually administered in a gelatin capsule.

Figure 4: Hydrodynamic balanced system (HBS)

The capsule rapidly dissolves in the gastric fluid, and hydration and swelling of the surface polymers produces a floating mass. Drug release is controlled by the formation of a hydrated boundary at the surface. Continuous erosion of the surface allows water penetration to the inner layers, maintaining surface hydration and buoyancy. The main drawback is the passivity of the operation. It depends on the air sealed in the dry mass centre following hydration of the gelatinous surface layer and hence the characteristics and amount of polymer. Effective drug delivery depends on the balance of drug loading and the effect of polymer on its release profile. A variety of strategies has been employed to improve efficacies of the floating HBS^[10]

1. Floating chamber

Fluid –filled floating chamber which includes incorporation of a gas- filled flotation chamber into a micro porous component that houses a drug reservoir. Apertures or openings are present along the top and bottom walls through which the gastrointestinal tract fluid enters to dissolve the drug. The other two walls in contacts with the fluid are sealed so that the undissolved drug remains therein. The fluid present could be air, under partial vacuum or any other suitable gas, liquid, or solid having an appropriate specific gravity and an inert behaviour. The device is of swallow able size, remains a float within the stomach for a prolonged time and after the complete release the shell disintegrates and passes off to the intestine, and is eliminated.

2. Multilayer flexible film

This device is multilayered, flexible sheet like medicament device that was buoyant in the gastric juice of the stomach and had sustained released characteristics. The device consisted of self supporting carrier films made up water insoluble polymer matrix with the drug dispersed there in, and a barrier film overlaying the carrier film. The barrier film consisted of the water insoluble and water and a drug permeable polymer or copolymer. Both films were sealed together along their periphery, in such a way as to entrap a plurality of small air pockets, which imparted the laminated films their buoyancy and the rate of drug release can be modulated by the appropriated selection of the polymer matrix.

b) Effervescent Systems (Gas-generating Systems)

Effervescent system include used of gas generating agents, carbonates (e.g.Sodium bicarbonates) and other organic acid (e.g. Citric acid and tartaric acid) present in the formulation to produce carbon dioxide (CO2) gas, thus reducing the density of the system and making it float on the gastric fluid.

1. Floating systems containing effervescent components

These are the matrix type of systems prepared with the help of swell able polymers such as methylcellulose and chitosan and various effervescent compounds, e.g. Sodium bicarbonate, tartaric acid, and citric acid. They are formulated in such a way that when in contact with the acidic gastric contents, CO₂ is liberated and gets entrapped in swollen hydrocolloids, which provide buoyancy to the dosage forms. The lag time before the unit floats is <1 minute and the buoyancy is prolonged for 8 to 10 hrs, while the GRT was increased to 4hours.The bilayered tablets were formulated in two layers, one layer consisting of gas generating components in hydrocolloids, while the other layer consist of drug for a sustained released effect.

Figure 5: Gas generating system: schematic monolayer drug delivery system

2. Floating system based on ion exchange resin

The resin beads were loaded with bicarbonate and theophylline which were bound to the resin. The loaded resin beads were coated with a semi permeable membrane to overcome rapid loss of CO₂. After exposure to gastric media, exchange of bicarbonate and chloride ions took place and leads to the formation of CO₂, which was trapped within the membrane, causing the particles to float. GRT was substantially prolonged, compared with a control, when the system was given after a light, mainly liquid meal. Furthermore, the system was capable of sustaining the drug release.

3. Floating system with inflatable chamber

An alternative mechanism of the gas generation can be developed as an osmotically controlled floating device, where gases with a boiling point < 37oC (e.g. cyclopentane, diethyl ether) can be incorporated in solidified or liquefied form into the systems. At physiological temperatures, the gases evaporate enabling the drug containing device to float. To enable the unit to exit from the stomach, the device contained a bioerodible plug that allowed the vapor to escape.

4. Programmable drug delivery

Programmable, controlled released drug delivery system was developed in the form of a non-digestible oral capsule (containing drug in slowly eroding matrix for controlled release). These systems were designated to utilize an automatically operated geometric obstruction that keeps the device floating in the stomach and prevents it from passing through the reminder of the GIT.

Figure 6: A multi-unit oral floating dosage system. Stages of floating mechanism

Marketed products of FDDS:^[7]

Table 1 : Marketed products of FDDS

Dosage Form	Drugs	Brand Name	Company, Country
Floating Controlled Release Capsule	Levodopa, Benserazide	MODAPAR	Roche Products, USA
Floating Capsule	Diazepam	VALRELEASE	Hoffmann-LaRoche, USA
Effervescent Floating Liquid alginate Preparation	Aluminium hydroxide, Magnesium carbonate	LIQUID GAVISON	Glaxo Smith Kline, INDIA
Floating Liquid alginate Preparation	Aluminium - Magnesium antacid	TOPALKAN	Pierre Fabre Drug, FRANCE
Colloidal gel forming FDDS	Ferrous sulphate	CONVIRON	Ranbaxy, INDIA
Gas-generating floating Tablets	Ciprofloxacin	CIFRAN OD	Ranbaxy, INDIA
Bilayer floating Capsule	Misoprostal	CYTOTEC	Pharmacia, USA

Drugs formulated as FDDS:

Table 2: List of drugs formulated as single and multiple unit forms of floating drug delivery systems^[11]

Sr. No.	Dosage Forms	Drugs
1.	Floating tablets	Acetaminophen, Acetylsalicylic acid, Ampicillin, Amoxicillin trihydrate, Atenolol, Captopril, Cinnerzine, Diltiazem, Fluorouracil, Isosorbide dinitrate, Isosorbid mononitrate, p- Aminobenzoic acid
2.	Floating capsules	Furosemide, L-DOPA, Benserazide, Nicardipine, Misoprostol, Propranolol, Pepstatin
3.	Floating microspheres	Aspirin, Griseofulvin, p-nitro aniline, Ibuprofen, Terfenadine, Tranilast
4.	Floating granules	Cinnarizine,Diclofenacsodium,Diltiazem,Indomethacin,Fluorouracil,Prednisolone, Isosorbide mononitrate, Isosorbide dinitrate
5	Powders	Several basic drugs-Riboflavin, phosphate, Sotalol, Theophylline.
6.	Films	Cinnerzine, P-Aminobenzoic acid, Piretanide, Prednisolone, Quinidine gluconate.
7.	Multiple unit floating Dosage form	Clarithromycin, p-aminobenzoic acid
8.	Bilayer tablet	Misoprostal
9.	Foams/hollow bodies	Ibuprofen
10.	Floating controlled release capsule	Levodopa, Benserazide
11.	Effervescent floating liquid alginate preparation	Aluminium hydroxide, Magnesium carbonate
12.	Floating liquid alginate preparation	Aluminium-Magnesium antacid
13.	Colloidal gel forming FDDS	Ferrous sulphate

Polymers and other ingredients:

Following types of ingredients can be incorporated into HBS dosage form in addition to the drugs

· Hydrocolloids (20%-75%): They can be synthetics, anionic or non-ionic like hydrophilic gums, modified cellulose derivatives. Eg. Acacia, pectin, Chitosan,agar, casein, bentonite, veegum, HPMC(K4M, K100M and K15M), Gellan gum (Gelrite®), Sodium CMC, MC, HPC

· Inert fatty materials(5%-75%): Edible, inert fatty materials having a specific gravity of less than one can be used to decrease the hydrophilic property of formulation and hence increase buoyancy. Eg. Beeswax, fatty acids, long chain fatty alcohols, Gelucires® 39/01 and 43/01.

· Effervescent agents: Sodium bicarbonate, citric acid, tartaric acid, Di-SGC (Di-Sodium Glycine Carbonate, CG (Citroglycine).

· Release rate accelerants (5%-60%): eg lactose, mannitol

· Release rate retardants (5%-60%): eg Dicalcium phosphate, talc, magnesium stearate

· Buoyancy increasing agents(upto80%): eg. Ethyl cellulose

· Low density material: Polypropylene foam powder (Accurel MP 1000®).

Evaluation parameters of stomach specific fdds:^[1]

Different studies reported in the literature indicate that pharmaceutical dosage forms exhibiting gastric residence in vitro floating behaviour show prolonged gastric residence in vivo. Although, in vitro floating behaviour alone is not sufficient proof for efficient gastric retention so in vivo studies can provide definite proof that prolonged gastric residence is obtained

1. Hardness, friability, assay, content uniformity (Tablets):

These tests are performed as per described in specified monographs.

2. Floating lag time and total floating time determination

The time between the introduction of the tablet into the medium and its rise to upper one third of the dissolution vessel is termed as floating lag time and the time for which the dosage form floats is termed as the floating or flotation time. These tests are usually performed in simulated gastric fluid or 0.1 mole.lit‐1 HCl maintained at 37^oC, by using USP dissolution apparatus containing 900 ml of 0.1 molar HCl as the dissolution medium

3. Drug release

The test for in vitro drug release studies are usually carried out in simulated gastric and intestinal fluids maintained at 37⁰C.Dissolution tests are performed using the USP dissolution apparatus. Samples are withdrawn periodically from the dissolution medium, replaced with the same volume of fresh medium each time, and then analyzed for their drug contents after an appropriate dilution. Recent methodology as described in USP XXIII states that the dosage unit is allowed to sink to the bottom of the vessel before rotation of blade is started. A small, loose piece of non reactive material such as not more than a few turns of wire helix may be attached to the dosage units that would otherwise float. However, standard Dissolution methods based on the USP or British Pharmacopoeia (BP) have been shown to be poor predictors of in vitro performance for floating dosage forms.

4. Drug loading, drug entrapment efficiency, particle size analysis, surface characterization, micromeritics studies and percentage yield (for floating microspheres and beads)

Drug loading is assessed by crushing accurately weighed sample of beads or microspheres in a mortar and added to the appropriate dissolution medium which is then centrifuged, filtered and analyzed by various analytical methods like spectrophotometry. The percentage drug loading is calculated by dividing the amount of drug in the sample by the weight of total beads or microspheres. The particle size and the size distribution of beads or microspheres are determined in the dry state using the optical microscopy method. The external and cross‐sectional morphology (surface characterization) is done by scanning electron microscope (SEM). The measured weight of prepared microspheres was divided by total amount of all non‐volatile components used for the preparation of microspheres, which will give the total percentage yield of floating microspheres

5. Resultant weight determination

Bulk density and floating duration have been the main parameters to describe the adequacy of a dosage form’s buoyancy Although single density determination does not predict the floating force evolution of the dosage form because the dry material of it is made progressively reacts or interacts with in the gastric fluid to release its drug contents So to calculate real floating capabilities of dosage form as a function of time a novel method has been conceived. It operates by force equivalent to the force F required to keep the object totally submerged in the fluid. This force determines the resultant weight of the object when immersed and may be used to quantify its floating or non floating capabilities. The magnitude and direction of the force and the resultant weight corresponds to the Victoria sum of buoyancy (Fbuoy) and gravity (Fgrav) forces acting on the objects as shown in the equal

F = Fbuoy – Fgrav

F = dfgV – dsgV = (df‐ds) gV

F = (df – M/V) gV

In which the F is total vertical force (resultant weight of the object), g is the acceleration due to gravity, df is the fluid density, ds is the object density is the object mass and V is the volume of the object.^[11]

6. Weight gain and water uptake (WU)

Weight gain or water uptake can be studied by considering the swelling behavior of Floating dosage form. The study is done by immersing the dosage form in simulated gastric fluid at 37^oC and determining the dimensional changes like tablet diameter and/ or thickness at regular 1‐h time intervals until 24 h, the tablets were removed from beaker, and the excess surface liquid was removed carefully using the paper. The swollen tablets were then reweighed and WU is measured in the terms of percent weight gain, as given by equation

WU = (Wt – Wo) X 100 / Wo

In which Wt and Wo are the weights of the dosage form at time t and initially, respectively.

7. X-Ray/Gamma scintigraphy

For in vivo studies, X‐Ray/Gamma Scintigraphy is the main evaluation parameter for floating dosage form. In each experiment, the animals are allowed to fast overnight with free access to water, and a radiograph is made just before the administration of the floating tablet to ensure the absence of radio‐opaque material. Visualization of dosage form by X‐ray is due to the inclusion of a radio‐opaque material. The formulation is administered by natural swallowing followed by 50 mL of water. The radiographic imaging is taken from each animal in a standing position, and the distance between the source of X‐rays and the animal should kept constant for all imaging, so that the tablet movement could be easily noticed. Gastric radiography was done at 30‐min time intervals for a period of 5 h using an X‐ray machine. Gamma scintigraphy is a technique whereby the transit of a dosage form through its intended site of delivery can be non‐invasively imaged in vivo via the judicious introduction of an appropriate short lived gamma emitting radioisotope. The inclusion of a γ‐emitting radionucleide in a formulation allows indirect external observation using a γ‐camera or scintiscanner. But the main drawback of γ‐ scintigraphy are the associated ionizing radiation for the patient, the limited topographic information, low resolution inherent to the technique and the complicated and expensive preparation of radiopharmaceutical.

8. Pharmacokinetic studies

Pharmacokinetic studies include AUC (Area under Curve), C_max, and time to reach maximum plasma concentration (Tmax) were estimated using a computer. Statistical analyses were performed using a Student t test with p, 0.05 as the minimal level of significance

9. Specific Gravity

Displacement method is used to determine the specific gravity of floating system using benzene as a displacing medium

CONCLUSION:

The currently available polymer-mediated Non-effervescent and effervescent FDDS, designed on the basis of delayed gastric emptying and buoyancy principles, appear to be a very much effective approach to the modulation of controlled oral drug delivery. Number of commercial products and patents issued in this field are the evidence of it. The FDDS become an additional advantage for drugs that are absorbed primarily in the upper part of GI tract, i.e., the stomach, duodenum, and jejunum. Some of the unresolved, critical issues like the quantitative efficiency of floating delivery systems in the fasted and fed states, role of buoyancy in enhancing GRT of FDDS and more than that formulation of an ideal dosage form to be given locally to eradicate H.Pylori, responsible for gastric ulcers worldwide. With an increasing understanding of polymer behaviour and the role of the biological factors mentioned above, it is suggested that future research work in the FDDS should be aimed at discovering means to control accurately the drug input rate into the GI tract for the optimization of the pharmacokinetic and toxicological profiles of medicinal agents. It seems that to formulate an efficient FDDS is sort of a challenge and the work will go on and on until an ideal approach with industrial applicability and feasibility arrives.

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9. Gurnany E, Singhai P, Soni A, Jain R, Jain SK, Jain A. Gastro Retentive Drug Delivery System- A Review. Journal of Pharmacy Research. 4 (6); 2011: 1899-1906.

10. Bardonnet PL, Faivre V, Pugh WJ, Piffaretti JC, Falson F. Gastroretentive dosage forms: Overview and special case of Helicobacter pylori. Journal of Controlled Release. 111; 2006: 1-18.

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Received on 11.03.2014 Modified on 14.05.2014

Res. J. Pharm. Dosage Form. and Tech. 6(3):July- Sept. 2014; Page 174-182