INTRODUCTION:

Oral delivery of drugs is by far the most preferable route of drug delivery due to the ease of administration, low cost of therapy, patient compliance and flexibility in formulation etc. Oral sustained drug delivery formulations show some limitations connected with the gastric emptying time [1,7,8]. Variable and too rapid gastrointestinal transit could result in incomplete drug release from the device into the absorption window leading to diminished efficacy of the administered dose. It is evident from the recent research and patent literature that an increased interest in novel dosage forms that are retained in the stomach for a prolonged and predictable period of time exists today [1,2,5].

Gastric emptying of dosage forms is an extremely variable process and ability to prolong and control emptying time is a valuable asset for dosage forms, which reside in the stomach for a longer period of time than conventional dosage forms.

One difficulty of these systems is the ability to confine the dosage form in the desired area of the gastrointestinal tract. To overcome this physiological problem, several drug delivery systems with prolonged gastric retention time have been investigated [5,15]. Attempts are being made to develop a controlled drug delivery system that can provide therapeutically effective plasma drug concentration levels for longer durations, thereby reducing the dosing frequency and minimizing fluctuations in plasma drug concentration at steady state by delivering drug in a controlled and reproducible manner [3,6]. The controlled gastric retention of solid dosage forms may be achieved by the mechanism of mucoadhesion, floatation, sedimentation expansion modified shape systems or by the administration of pharmacological agents that delay gastric emptying. Based on these approaches, floating drug delivery systems seems to be the promising delivery systems for controlled release of drugs [6].

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 (5,7). The bottom line is that the patterns of gastric motility likely are a result from smooth muscle cells integrating a large number of inhibitory and stimulatory signals. Liquid 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 of absorption of drug from delivery system. The pH of fasting stomach is 1.2-.2.0 and in fed condition the pH is 2.0-6.0 (7,9,11).

Factors affecting gastric retention time of the dosage form: (3,7,8,12)

1. Density: GRT is a function of dosage form buoyancy that is dependent on the density. The density of a dosage form also affects the gastric emptying rate and determines the location of the system in the stomach. Dosage forms having a density lower than the gastric contents can float to the surface, while high density systems sink to bottom of the stomach. Both positions may isolate the dosage system from the pylorus. A density of < 1.0 gm/ cm³is required to exhibit floating property.

2. Size and Shape of dosage form:

Shape and size of the dosage forms are important in designing indigestible single unit solid dosage forms. The mean gastric residence times of non floating dosage forms are highly variable and greatly dependent on their size, which may be large, medium and small units. In most cases, the larger the dosage form the greater will be the gastric.

3. Single or multiple unit formulation:

Multiple unit formulations show a more Predictable release profile and insignificant impairing of performance due to failure of units allow co- administration of units with different release profiles or containing incompatible substances and permit a larger margin of safety against dosage form failure compared with single unit dosage forms.

4. Fed or unfed state:

Under fasting conditions: GI motility is characterized by periods of strong motor activity or the migrating myoelectric complex (MMC) that occurs every 1.5 to 2 hours. 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.

5. Nature of meal:

Feeding of indigestible polymers or fatty acid salts can change the motility pattern of the stomach to a fed state, thus decreasing the gastric emptying rate and prolonging drug release.

6. Caloric content:

GRT can be increased by 4 to 10 hours with a meal that is high in proteins and fats.

7. Frequency of feed:

The GRT can increase by over 400 minutes, when successive meals are given compared with a single meal due to the low frequency of MMC.

8. Age:

Elderly people, especially those over 70, have a significantly longer GRT.

9. Posture:

GRT can vary between supine and upright ambulatory states of the patient.

10. Concomitant drug administration:

Anticholinergic like atropine, propentheline-increase GRT.

Metoclopramide and cisapride-decrease GRT.

11. Disease state:

Gastric ulcer, diabetes, hypothyroidism increase GRT.

Hyperthyroidism, duodenal ulcers decrease GRT.

Floating drug delivery system:

The concept of FDDS was first described in the literature as early as 1968, when Davis (1968) disclosed a method to overcome the difficulty experienced by some persons of gagging or choking after swallowing medicinal pills. The author suggested that such difficulty could be overcome by providing pill having a density of less than 1.0g/cm³, so that pill will float on water surface. Since then several approaches have been used to develop an ideal floating drug delivery system (4,8,14). Floating Drug Delivery Systems (FDDS) have a bulk density lower than gastric fluids and thus remain buoyant in stomach for a prolonged period of time, without affecting the gastric emptying rate (11,13). While the system floats on gastric contents, the drug is released slowly at a desired rate from the system. After the release of drug, the residual system is emptied from the stomach. This results in an increase in gastric retention time and a better control of fluctuations in plasma drug concentrations.

Floating systems can be classified into two systems: (1, 2,14)

A. Effervescent systems

1. Volatile liquid containing systems

2. Gas-generating Systems

B. Non-Effervescent Systems

1. Colloidal gel barrier systems

2. Microporous Compartment System

3. Alginate beads

4. Hollow microspheres

Hollow microspheres or microballoons:

Floating microspheres are gastro-retentive drug delivery systems based on non-effervescent approach. Hollow microspheres (microballoons) are in strict sense, spherical empty particles without core. These microspheres are characteristically free flowing powders consisting of proteins or synthetic polymers, ideally having a size less than 200µm (15,16,19). Solid biodegradable microspheres incorporating a drug dispersed or dissolved throughout particle matrix have the potential for controlled release of drugs. Gastro-retentive floating microspheres are low density systems that have sufficient buoyancy to float over gastric contents and remain in stomach for prolonged period (13,16). As the system floats over gastric contents, the drug is released slowly at desired rate resulting in increased gastric retention with reduced fluctuations in plasma drug concentration (16). Hollow microspheres are considered as one of the most promising buoyant systems, as they possess the unique advantages of multiple unit systems as well as better floating properties, because of central hollow space inside the microsphere. The general techniques involved in their preparation include simple solvent evaporation, and solvent diffusion and evaporation (12,15,20). The drug release and better floating properties mainly depend on the type of polymer, plasticizer and the solvents employed for the preparation. Polymers such as polycarbonate, eudragit S and cellulose acetate were used in the preparation of hollow microspheres, and the drug release can be modulated by optimizing the polymer quantity and the polymer-plasticizer ratio (18, 22). 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.

Mechanism:

When microspheres come in contact with gastric fluid the gel formers, polysaccharides, and polymers hydrate to form a colloidal gel barrier that controls the rate of fluid penetration into the device and consequent drug release. As the exterior surface of the dosage form dissolves, the gel layer is maintained by the hydration of the adjacent hydrocolloid layer. The air trapped by the swollen polymer lowers the density and confers buoyancy to the microspheres. However a minimal gastric content needed to allow proper achievement of buoyancy. Hollow microspheres of acrylic resins, eudragit, polyethylene oxide, and cellulose acetate; polystyrene floatable shells; polycarbonate floating balloons and gelucire floating granules are the recent developments. (16,17,22).

Advantages: (15,16,18)

1. Reduces the dosing frequency and there by improve the patient compliance.

2. Better drug utilization will improve the bioavailability and reduce the incidence or intensity of adverse effects and despite first pass effect because fluctuations in plasma drug concentration is avoided, a desirable plasma drug concentration is maintained by continuous drug release.

3. Hollow microspheres are used to decrease material density and Gastric retention time is increased because of buoyancy.

4. Enhanced absorption of drugs which solubilise only in stomach.

5. Drug releases in controlled manner for prolonged period.

6. Site-specific drug delivery to stomach can be achieved.

7. Superior to single unit floating dosage forms as such microspheres releases drug uniformly and there is no risk of dose dumping.

8. Avoidance of gastric irritation, because of sustained release effect.

9. Better therapeutic effect of short half-life drugs can be achieved (21,22).

Limitation: (15,16,18)

1. The modified release from the formulations.

2. The release rate of the controlled release dosage form may vary from a variety of factors like food and the rate of transit though gut.

3. Differences in the release rate from one dose to another.

4. Controlled release formulations generally contain a higher drug load and thus any loss of integrity of the release characteristics of the dosage form may lead to potential toxicity.

5. Dosage forms of this kind should not be crushed or chewed (23).

Applications: (8,15,16,18,25,29)

Hollow microspheres are widely used for different applications-

1. Hollow microspheres are typically used as additives to lower the density of a material. Solid microspheres have numerous applications depending on what material they are constructed of and what size they are?

2. Hollow microspheres can greatly improve the pharmacotherapy of the stomach through local drug release, leading to high drug concentrations at the gastric mucosa, thus eradicating helicobacter pylori from the submucosal tissue of the stomach and making it possible to treat stomach and duodenal ulcers, gastritis and oesophagitis.These microspheres systems provide sustained drug release behavior and release the drug over a prolonged period of time

3. The drugs recently reported to be entrapped in hollow microspheres include Prednisolone, Lansoprazole, Celecoxib, Piroxicam, Theophylline, Diltiazem hydrochloride, Verapamil hydrochloride, Riboflavin, Aspirin, Griseofulvin, Ibuprofen, and Terfenadine.

4. Floating microspheres can greatly improve the pharmacotherapy of stomach through local drug release. Thus, eradicating Helicobacter pylori from sub-mucosal tissue of the stomach are useful in the treatment of peptic ulcers, chronic gastritis, gastroesophageal reflux diseases etc. Hollow microspheres of ranitidine HCl are also developed for the treatment of gastric ulcer.

5. Floating microspheres are especially effective in delivery of sparingly soluble and insoluble drugs. It is known that as the solubility of a drug decreases, the time available for drug dissolution becomes less adequate and thus the transit time becomes a significant factor affecting drug absorption. For weakly basic drugs that are poorly soluble at an alkaline pH, hollow microspheres may avoid chance for solubility to become the rate-limiting step in release by restricting such drugs to the stomach. The gastro-retentive floating microspheres will alter beneficially the absorption profile of the active agent, thus enhancing its bioavailability.

6. The floating microspheres can be used as carriers for drugs with so-called absorption windows, these substances, for example antiviral, antifungal and antibiotic agents (Sulphonamides, Quinolones, Penicillins, Cephalosporins, Aminoglycosides and Tetracyclines) are taken up only from very specific sites of the GI mucosa.

7. Hollow microspheres of non-steroidal anti-inflammatory drugs are very effective for controlled release as well as it reduces the major side effect of gastric irritation; for example floating microspheres of Indomethacin are quiet beneficial for rheumatic patients (24,25).

8. Polymer granules having internal cavities prepared by de acidification when added to acidic and neutral media are found buoyant and provided a controlled release of the drug prednisolone. Floating hollow microcapsules of melatonin showed gastroretentive controlled-release delivery system. Release of the drug from these microcapsules is greatly retarded with release lasting for 1.75 to 6.7 hours in simulated gastric fluid.

9. Most of the mucoadhesive microcapsules are retained in the stomach for more than 10 hours e.g., Metoclopramide and glipizide loaded chitosan microspheres.(10)

Methods of Preparation:

A) Solvent Evaporation Method:

Floating multiparticulate dosage form can be prepared by solvent diffusion and evaporation methods to create the hollowinner core. The polymer is dissolved in an organic solvent and the drug is either dissolved or dispersed in the polymer solution. The solution containing the drug is then emulsified into an aqueous phase containing suitable additive (surfactants /polymer) to form oil in water emulsion. After the formation of a stable emulsion, the organic solvent is evaporated either by increasing the temperature under pressure or by continuous stirring. The solvent removal leads to polymer precipitation at the oil/water interface of droplets, forming cavity and thus making them hollow to impart the floating properties. The polymers studied for the development of such systems include cellulose acetate, chitosan, Eudragit, Acrycoat, Methocil, polyacrylates, polyvinylacetate, carbopol, agar, polyethylene oxide and polycarbonate (20,22).

B) Emulsion Solvent Diffusion Method-

In the emulsion solvent diffusion method the affinity between the drug and organic solvent is stronger than that of organic solvent and aqueous solvent. The drug is dissolved in the organic solvent and the solution is dispersed in the aqueous solvent producing the emulsion droplets even though the organic solvent is miscible. The organic solvent diffuse gradually out of the emulsion droplets in tothe surrounding aqueous phase and the aqueous phase diffuse in to the droplets by which drug crystallizes (19,20,22).

Characterization of microballoons:

1. Micromeritic properties-

Hollow microspheres are characterized by their micromeritic properties such as particle size, tapped density, compressibility index, true density and flow properties. True density is determined by liquid displacement method; tapped density and compressibility index are calculated by measuring the change in volume using a bulk density apparatus; angle of repose is determined by fixed funnel method (16,17).

The compressibility index was calculated using following formula:

I = Vb –Vt / Vb x 100

Where, Vb is the bulk volume and

Vt is the tapped volume.

The value given below 15% indicates a powder with usually give rise to good flow characteristics, whereas above 25% indicate poor flowability.

Porosity (e) was calculated using the following equation:

e = {1- (tapped density/true density)} ×100

2. Particle size analysis-

Particle size analysis can be carried out using the optical microscopic method with the help of a calibrated eye piece micrometer. The size of around 100 particles is measured and median diameter is calculated (18).

3. Percentage yield-

The percentage yield of the floating microspheres was determined for drug and was calculated using the following equation. (21, 22, 23)

Percentage yield ₌	Total weight of microballoons	× 100
	Total weight of non-volatile components

4. Entrapment Efficiency or incorporation efficiency-

Entrapment efficiency was determined by taking 20 mg of hollow microballoons which were thoroughly triturated and dissolved with 10 ml ethanol in 100ml volumetric flask and volume was made up with 0.1 N HCl. The resulting solution is then filtered (Whatmann filter paper No. 44), suitably diluted and the absorbance was measured. The percentage drug entrapment was calculated as follows (28,29)

Percentage Entrapment₌	Calculated drug concentration	× 100
	Theoretical drug concentration

5. Buoyancy percentage-

Appropriate amount of Microspheres were placed in 900 ml of 0.1 N hydrochloric acid. The mixture was stirred at 100 rpm in a dissolution apparatus for 8 hrs. After 8 hrs, the layer of buoyant microspheres were pipetted and separated by filtration. Particles in the sinking particulate layer were separated by filtration. Particles of both types were dried in a dessicator until constant weight. Both the fractions of microspheres were weighed and buoyancy was determined by the weight ratio of floating particles to the sum of floating and sinking particles (25, 27).

Buoyancy (%) ₌	Wf	× 100
	Wf + Ws

Where Wf and Ws are the weights of the floating and settled microspheres.

6. Scanning Electron Microscopy (SEM)-

SEM was performed for morphological characterization of microspheres. The hollow nature of microspheres is confirmed by scanning electron microscopy. They were mounted directly onto the SEM sample stub using double-sided sticking tape and coated with gold film (thickness,200nm)under reduced pressure (0.001mmHg) (26,28,29).

7. In-vivo Studies-

The in-vivo floating behavior can be investigated by X-ray photography of hollow microspheres loaded with barium sulphate in the stomach of beagle dogs. The in-vitro drug release studies are performed in a dissolution test apparatus using 0.1N hydrochloric acid as dissolution media. The in-vivo plasma profile can be obtained by performing the study in suitable animal models (e.g. beagle dogs). (25,26)

8. In- vitro drug release study-

The release rate of floating microspheres was determined in a United States Pharmacopoeia (USP) XXIII basket type dissolution apparatus. A weighed amount of floating microspheres equivalent to required amount of drug was filled into a hard gelatin capsule and placed in the basket of dissolution rate apparatus containing dissolution medium. The dissolution fluid was maintained at 37 ± 1°C and rotation speed at a specific rpm. Perfect sink conditions prevailed during the drug release study. 5ml samples were withdrawn at each time interval, passed through a 0.25µm membrane filter (millipore), and analyzed using LC/MS/MS method to determine the concentration present in the dissolution medium. The initial volume of the dissolution fluid was maintained by adding 5 ml of fresh dissolution fluid after each withdrawal. All experiments were run in triplicate.(28,29)

9. Stability Studies-

During the storage if one performs studies at normal temp it will take a longer time and hence it would be convenient to carry out the accelerated stability studies where the product is stored under extreme conditions of temperature. The selected optimized formulation was placed in borosilicate screw capped glass containers and stored at different temperatures (27±2°C), oven temperature (40±2°C) and in the refrigerator (5-8°C) for a period of 90 days. The samples were assayed for drug content, drug entrapment and drug release at regular intervals (25,27).

10. Release kinetics- (3,22,26,27)

Data obtained from in-vitro release studies can be fitted to various kinetic equations to find out the mechanism of drug release from the microballoons. The kinetic models used were:

Qt = K₀ t (zero-order equation)

ln Q_t = In Q₀ - K₁ t ( first-order equation)

Q_t= Kh t_1/2 (Higuchi equation)

Where, Qt is the amount of drug release in time t,

Q₀ is the initial amount of drug in the microsphere, and

K₀, K₁and Kh are rate constants of zero order, first order and Higuchi equations, respectively.

Further to confirm the mechanism of drug release, the first 60% of drug release was fitted in Korsemeyer-Peppas model (power law).

Mt / M∞= k tn

Where, Mt is the amount of drug release at time t and

M∞ is the amount release at time t = ∞,

Thus Mt / M∞ is the fraction of drug released at time t, k is the kinetic constant, and n is the diffusion exponent which can be used to characterize both mechanism for both solvent penetration and drug release (19,20).

Future potential:

The control of drug release profiles has been a major aim of pharmaceutical research and development in the past two decades and might result in the availability of new products with new therapeutic possibilities and substantial benefits for patients. It is anticipated that various novel products using gastroretentive drug delivery technologies may enhance this possibility. Further investigations may concentrate on the microballoons concepts: (17,19,22,30)

1. Design of an array of gastro retentive drug delivery systems, each having narrow GRT for use according to the clinical need, e.g., dosage and state of diseases.

2. Determination of minimal cut-off size above that dosage forms retained in the GIT for prolonged period of time.

3. Design and development of gastroretentive drug delivery systems as a beneficial strategy for the treatment of gastric, duodenal cancers and treat Parkinson’s disease.

4. Development of various anti-reflux formulation utilizing gastroretentive technologies.

5. Exploring the eradication of Helicobacter pylori by using various antibiotics.

6. Design and synthesis of novel polymers according to their clinical and pharmaceutical need.

7. Design and synthesis of novel mucoadhesive agents to develop bioadhesive drug delivery systems for improved gastroretention.

8. Design of novel mucoadhesive delivery using various natural mucoadhesive agents according to their clinical and pharmaceutical need.

CONCLUSION:

Floating drug delivery system (FDDS) provides an additional advantage to release drug at the desirable rate for prolonged time by increasing the gastric retention time of drugs. Among various approaches of FDDS, microballoons as delivery system is emerging as the innovative, most reliable dug delivery for specially those drugs that can’t withstand the acidic pH of the stomach. Besides many advantages of microballoons drug delivery, there are few disadvantages too on which work is still going to eradicate or overcome them. Although there are number of difficulties to be worked out to achieve prolonged gastric retention, a large number of companies are focusing toward commercializing this technique.

REFERENCES:

1. Mayavanshi A and Gajjar S. Floating Drug Delivery Systems to increase gastric retention of drugs: A Review. Research Journal of Pharmacy and Technology. 1(4); 2008: 345-348.

2. Chowdary K and Chaitanya L. Recent research on Floating Drug Delivery Systems-A Review. Journal of Global Trends in Pharmaceutical Sciences. 5(1); 2014: 1361-1373.

3. Pandey A, Kumar G, Kothiyal P and Barshiliya Y. A Review on current approaches in Gastro Retentive Drug Delivery System. Asian Journal of Pharmacy and Medical Science. 2(4); 2012: 60-77.

4. Sharma A and Khan A. Gastroretentive Drug Delivery System: An approach to enhance gastric retention for prolonged drug release. International Journal of Pharmaceutical Sciences and Research. 5(4); 2014: 1095-1106.

5. Nayak A, Maji R and Das B. Gastroretentive drug delivery systems: A Review. Asian Journal of Pharmacy and Clinical Research. 3(1); 2010: 01-09.

6. Pal P, Sharma V and Singh L. A review on floating type gastroretentive drug delivery system, International Research Journal of Pharmacy. 3(4); 2012: 37- 39.

7. Arora S, Ali J, Ahuja A, Khar R and Baboota S. Floating Drug Delivery Systems: A Review. American Association of Pharmaceutical Scientists PharmSciTech. 6(3); 2005: 372-387.

8. Pujara N, Patel N, Thacker A, Raval B, Doshi S and Parmar R. Floating microspheres: a novel approach for gastro retention. World Journal of Pharmacy and Pharmaceutical Sciences.1(3); 2012: 872-895.

9. Garg R and Gupta G. Progress in controlled gastroretentive delivery systems. Tropical Journal of Pharmaceutical Research. 7(3); 2008: 1055- 1066.

10. Dhole A, Gaikwad P, Bankar V and Pawar SP. A Review on floating multiparticulate drug delivery system- A novel approach to gastric retention, International Journal of Pharmaceutical Sciences Review and Research. 6(2); 2011: 205-211.

11. Somwanshi S, Dolas R, Nikam V, Gaware V, Kotade K, Dhamak K and Khadse A. Floating multiparticulate oral sustained release drug delivery system. Journal of Chemical and Pharmaceutical Research. 3(1); 2011: 536-547.

12. Patel D, Patel M and Patel C. Multi Particulate System: A Novel Approach in Gastro-Retemtive Drug Delivery. International Journal of Advances in Pharmaceutical Research. 2(4); 2011: 96-106.

13. Kawatra M, Jain U and Ramana J. Recent advances in floating microspheres as gastroretentive drug delivery system: A Review. International Journal of Recent Advances in Pharmaceutical Research. 2(3); 2012: 5-23.

14. Patel N, Jani D, Nagesh C, Chandrashekhar S and Patel J. Floating drug delivery system: An innovative acceptable approach in gastro retentive drug delivery. Asian Journal of Pharmaceutical Research. 2(1); 2012: 7-18.

15. Negia R, Goswamia L and Kothiyal P. Microballoons: A better approach for gastro retention. Indian Journal of Pharmaceutical and Biological Research. 2(2); 2014: 100-107.

16. Joshi K and Jaimini M. Microballoons for drug delivery: A Review. Asian Journal of Pharmaceutical Research and Development. 1(1); 2013: 7-17.

17. Dixit N. Floating Drug Delivery System. Journal of Current Pharmaceutical Research. 7(1); 2011: 6-20.

18. Gholap S, Banarjee S, Gaikwad D, Jadhav S and Thorat R. Hollow Microsphere: A Review. International Journal of Pharmaceutical Sciences Review And Research. 1(1); 2010: 74-79.

19. Bharath P, Sruthi K, Krishna K and Kesava R. Microballoons for drug delivery: A review. World Journal of Pharmacy and Pharmaceutical Sciences. 2(5); 2013: 3303-3312.

20. Kawashima Y, Niwa T, Takenchi H, Hino T and Itoh Y. Hollow microspheres for use as a floating controlled drug delivery system in the stomach. Journal of Pharmaceutical Sciences. 8(1); 1992: 135-140.

21. Vyas S and Khar R. Targeted and Controlled Drug Delivery Novel Carrier System. CBS Publishers and Distributors. New Delhi. 2002: 417-54.

22. Kunchu K and Ashwani RV. Albumin Microspheres: A Unique system as drug delivery carriers for non steroidal anti-inflammatory drugs. Pelagia Research Library. 5(2); 2010: 12-20.

23. Kalyan S and Sharma P. Recent advancement in Chitosan based formulation and its pharmaceutical application. Pelagia Research Library. 1(3); 2010: 195-210.

24. Sharma N, Agarwal D, Gupta M and Khinchi M. A Comprehensive Review on Floating Drug Delivery system. International Journal of Research in Pharmaceutical and Biological Sciences. 2(2); 2011: 428-441.

25. Srivastava A. Floating microspheres of Cimetidine: Formulation, characterization and in vitro evaluation. Acta Pharmaceutica. 55; 2005: 277–285.

26. Reddy L and Murthy R. Floating dosage system in drug delivery. Critical Reviews in Therapeutic Drug Carrier Systems. 19(6); 2002: 553-585.

27. Rajput G, Majmudar D, Patel K, Patel N, Thakor S and Patel R. Floating Drug Delivery System- A Review. Pharm Ext. 1(1); 2010: 43-51.

28. Yadav A and Jain D. Formulation development and characterization of Propranolol hydrochloride microballoons for gastroretentive floating drug delivery. African Journal of Pharmacy and Pharmacology. 5(15); 2011: 1801-1810.

29. Singh B and Kim K. Floating drug delivery systems an approach to oral controlled drug delivery via gastric retention. Journal of Controlled Release. 63; 2000: 235-59.

30. Rao YM and Jithan AV. Advances in drug delivery. Volume 1. PharmaMed Press. Hyderabad. 2011.

Received on 05.08.2015 Modified on 30.09.2015

Res. J. Pharm. Dosage Form. and Tech. 7(4): Oct.-Dec., 2015; Page 266-273

DOI: 10.5958/0975-4377.2015.00038.5