B. Multiple Unit Floating Systems:
In spite of extensive research and development in the area of HBS and other floating tablets, these systems suffer from an important drawback of high variability of gastrointestinal transit time, when orally administered, because of their all-or-nothing gastric emptying nature. In order to overcome the above problem, multiple unit floating systems were developed, which reduce the inter-subject variability in absorption and lower the probability of dose-dumping. Reports have been found on the development of both non-effervescent and effervescent multiple unit systems.61 Much research has been focused and the scientists are still exploring the field of hollow microspheres, capable of floating on the gastric fluid and having improved gastric retention properties.

a) Non-effervescent Systems:
No much report was found in the literature on non-effervescent multiple unit systems, as compared to the effervescent systems. However, few workers have reported the possibility of developing such system containing indomethacin, using chitosan as the polymeric excipient.  A multiple unit HBS containing indomethacin as a model drug prepared by extrusion process is reported.62 A mixture of drug, chitosan and acetic acid is extruded through a needle, and the extrudate is cut and dried. Chitosan hydrates and floats in the acidic media, and the required drug release could be obtained by modifying the drug-polymer ratio.

b) Effervescent Systems (Gas-generating Systems):
Ikura et al 63 reported sustained release floating granules containing tetracycline hydrochloride. The granules are a mixture of drug granulates of two stages A and B, of which A contains 60 parts of HPMC, 40 parts of polyacrylic acid and 20 parts of drug and B contains 70 parts of sodium bicarbonate and 30 parts of tartaric acid. 60 parts by weight of granules of stage A and 30 parts by weight of granules of stage B are mixed along with a lubricant and filled into capsule. In dissolution media, the capsule shell dissolves and liberates the granules, which showed a floating time of more than 8 h and sustained drug release of 80% in about 6.5 h. Floating minicapsules of pepstatin having a diameter of 0.1-0.2 mm has been reported by Umezawa.64

Figure No. 6 Different layers i) Semi-permeable membrane, ii) Effervescent Layer iii) Core pill layer b) Mechanism offloatation via CO2 generation.

These mini capsules contain a central core and a coating. The central core consists of a granule composed of sodium bicarbonate, lactose and a binder, which is coated with HPMC. Pepstatin is coated on the top of the HPMC layer. The system floats because of the CO2 release in gastric fluid and the pepstatin resides in the stomach for prolonged period. Alginates have received much attention in the development of multiple unit systems. Alginates are non-toxic, biodegradable linear copolymers composed of L-glucuronic and L-mannuronic acid residues. A multiple unit system prepared by Iannuccelli et al 65 comprises of calcium alginate core and calcium alginate/PVA membrane, both separated by an air compartment. In presence of water, the PVA leaches out and increases the membrane permeability, maintaining the integrity of the air compartment. Increase in molecular weight and concentration of PVA, resulted in enhancement of the floating properties of the system. Freeze-drying technique is also reported for the preparation of floating calcium alginate beads 66. Sodium alginate solution is added drop wise into the aqueous solution of calcium chloride, causing the instant gelation of the droplet surface, due to the formation of calcium alginate. The obtained beads are freeze-dried resulting in a porous structure, which aid in floating. The authors studied the behaviour of radiolabeled floating beads and compared with non floating beads in human volunteers using gamma scintigraphy. Prolonged gastric residence time of more than 5.5 h was observed for floating beads. The non floating beads had a shorter residence time with a mean onset emptying time of 1 h.

Ichikawa et al 67 developed a new multiple type of floating dosage system having a pill in the core, composed of effervescent layers and swellable membrane layers coated on sustained release pills (shown in figure 3). The inner layer of effervescent agents containing sodium bicarbonate and tartaric acid was divided into 2 sub layers to avoid direct contact between the 2 agents. These sub layers were surrounded by a swellable polymer membrane containing polyvinyl acetate and purified shellac. When this system was immersed in the buffer at 37ºC, it settled down and the solution permeated into the effervescent layer through the outer swellable membrane. CO2 was generated by the neutralization reaction between the 2 effervescent agents, producing swollen pills (like balloons) with a density less than 1.0 g/ml.

c) Hollow Microspheres:
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. 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.

Sustained release floating microspheres using polycarbonate were developed by Thanoo et al,68 employing solvent evaporation technique. Aspirin, griseofulvin and p-nitroaniline were used as model drugs. Dispersed phase containing polycarbonate solution in dichloromethane, and micronized drug, was added to the dispersion medium containing sodium chloride, polyvinyl alcohol and methanol. The dispersion was stirred for 3-4 h to assure the complete solvent evaporation, and the microspheres obtained were filtered, washed with cold water and dried. The spherical and hollow nature of the microspheres was confirmed by Scanning electron microscopic studies. The microspheres showed a drug payload of more than 50%, and the amount of drug incorporated is found to influence the particle size distribution and drug release. The larger proportion of bigger particles was seen at high drug loading, which can be attributed to the increased viscosity of the dispersed phase.

Kawashima et al 69 described hollow microspheres (microballoons) with drug in their outer polymer shells, prepared by a novel emulsion solvent diffusion method. A solution of drug and enteric acrylic polymer (Eudragit®S) in a mixture of ethanol and dichloromethane is added to the aqueous phase containing polyvinyl alcohol (0.75% w/v) and stirred continuously to obtain o/w emulsion. The microspheres obtained are filtered, water washed and dried. The diffusion and evaporation profiles of ethanol and dichloromethane, suggested a rapid diffusion of ethanol from the droplets into the aqueous phase, which might reduce the polymer solubility in the droplet because of insoluble property of Eudragit® S in dichloromethane. Hence, the polymer precipitation occurs instantly at the droplet surface, forming a film-like shell enclosing dichloromethane and drug. The microspheres showed good flow and packing properties, and a floating time of more than 12 h on acidic medium containing surfactant.

Josephet al 55 developed a floating dosage form of piroxicam based on hollow polycarbonate microspheres. The microspheres were prepared by the solvent evaporation technique. Encapsulation efficiency of ~95% was achieved. In vivo studies were performed in healthy male albino rabbits. Pharmacokinetic analysiswas derived from plasma concentration vs time plot and revealed that the bioavailability from the piroxicam microspheres alone was 1.4 times that of the free drug and 4.8 times that of a dosage form consisting of microspheres plus the loading dose and was capable of sustained delivery of the drug over a prolonged period.

C.  Raft Forming Systems:
Raft forming systems  have received much attention for the delivery of antacids and drug delivery for gastrointestinal infections and disorders. The mechanism involved in the raft formation includes the formation of viscous cohesive gel in contact with gastric fluids, wherein each portion of the liquid swells forming a continuous layer called a raft. This raft floats on gastric fluids because of low bulk density created by the formation of CO2.Usually, the system contains a gel forming agent and alkaline bicarbonates or carbonates responsible for the formation of CO2 to make the system less dense and float on the gastric fluids.70 Jorgen et al71,72 described an antacid raft forming floating system. The system contains a gel forming agent (e.g. alginic acid), sodium bicarbonate and acid neutralizer, which forms a foaming sodium alginate gel (raft) when in contact with gastric fluids. The raft thus formed floats on the gastric fluids and prevents the reflux of the gastric contents (i.e. gastric acid) into the esophagus by acting as a barrier between the stomach and esophagus. A patent assigned to Reckitt and Colman Products Ltd., describes a raft forming formulation for the treatment of helicobacter pylori (H. Pylori) infections in the GIT. The composition contained drug, alginic acid, sodium bicarbonate, calcium carbonate, mannitol and a sweetener. These ingredients were granulated, and citric acid was added to the granules. The formulation produces effervescence and aerates the raft formed, making it float.

Drugs Used In the Formulations of Stomach Specific Floating Dosage Forms
* Floating microspheres– Aspirin, Griseofulvin, p-nitroaniline, Ibuprofen, Ketoprofen,73 Piroxicam, Verapamil, Cholestyramine, Theophylline, Nifedipine, Nicardipine, Dipyridamol, Tranilast74 and Terfinadine.75
* Floatinggranules – Diclofenac sodium, Indomethacin and Prednisolone.
* Films – Cinnarizine,76 Albendazole.
* Floating tablets and Pills- Acetaminophen, Acetylsalicylic acid, Ampicillin, Amoxycillin trihydrate, Atenolol, Fluorouracil, Isosorbide mononitrate,77 Para - aminobenzoic acid, Piretanide,78 Theophylline, Verapamil hydrochloride, Chlorpheniramine maleate, Aspirin, Calcium Carbonate, Fluorouracil, Prednisolone, Sotalol,79 pentoxyfilline and Diltiazem HCl.
* Floating Capsules- Chlordiazepoxide hydrogen chloride, Diazepam,80 Furosemide, Misoprostol, L-Dopa, Benserazide Ursodeoxycholic acid81 and Pepstatin, and Propranolol.

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. Examples 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®).



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