Need for gastroretention:¹

· Drugs that are absorbed from the proximal part of the gastrointestinal tract (GIT).

· Drugs that are less soluble or that degrade by the alkaline p^H, they encounters at the lower part of GIT.

· Drugs that are absorbed due to variable gastric emptying time.

· Local or sustained drug delivery to the stomach and proximal Small intestine to treat certain conditions.

· Particularly useful for the treatment of peptic ulcers caused by H.Pylori infections.

Formulation considerations for GRDDS:²

· It must be effective retention in the stomach to suit for the clinical demand.

· It must be convenient for intake to facilitate patient compliance.

· It must have sufficient drug loading capacity and control drug release profile.

· It must have full degradation and evacuation of the system once the drug release is over.

· It should not have effect on gastric motility including emptying pattern.

· It should not have other local adverse effects.

Certain types of drugs can benefit from using gastroretentive devices:³

· Drugs acting locally in the stomach.

· Drugs those are primarily absorbed in the stomach.

· Drugs those are poorly soluble at an alkaline P^H.

· Drugs with a narrow window of absorption.

· Drugs absorbed rapidly from the GI tract.

· Drugs those degrade in the colon.

Drugs those are unsuitable for gastroretentive drug delivery systems:⁴

· Drugs that have very limited acid solubility e.g. Phenytoin etc.

· Drugs that suffer instability in the gastric environment e.g. Erythromycin etc.

· Drugs intended for selective release in the colon e.g. 5- amino salicylic acid and corticosteroids etc.

Gastrointestinal Tract:

Anatomy of the gastrointestinal tract¹:

The gastrointestinal tract is divided into three main regions namely: Stomach, Small intestine (Duodenum, Jejunum and Ileum) and large intestine. The GIT is a muscular tube, from the mouth to the anus, which functions to take in nutrients and eliminate waste by secretion, motility, digestion, absorption and excretion, which are known as physiological processes. The stomach is a J-shaped enlargement of the GIT which is divided into 4 anatomical regions: cardia, fundus, body and antrum. The main function of the stomach is to store and mix food with gastric secretions before emptying its load (chyme) through the pyloric sphincter and into the small intestine at a controlled rate suitable for digestion and absorption. During empty state, the stomach occupies a volume of about 50 ml, but this may increase to as much as 1 liter when full. The walls of the GIT, from stomach to large intestine, have the same basic arrangement of tissues, the different layers, from outside to inside, comprising serosa, intermuscular plane, longitudinal muscle, submucosa, circular muscle, lamina propria, muscularis mucosae, and epithelium. In addition to longitudinal and circular muscle, the stomach has a third muscle layer known as the "oblique muscle layer", which is situated in the proximal stomach, branching over the fundus and higher regions of the gastric body. The different smooth muscle layers are responsible for performing the motor functions of the GIT, i.e. gastric emptying and intestinal transit.

Figure 1: Anatomy of the gastrointestinal tract

Basic gastrointestinal tract physiology¹

The stomach is divided into 3 regions anatomically: fundus, body, and antrum pylorus. The proximal part is the fundus and the body acts as a reservoir for undigested material, where as the antrum is the main site for mixing motions and acts as a pump for gastric emptying by propelling actions. Gastric emptying occurs during fasting as well as fed states but the pattern of motility is distinct in the 2 states. During the fasting state an interdigestive series of electrical events take place, which cycle through both stomach and intestine every 2 to 3 hours. This is called the interdigestive myloelectric cycle or migrating myloelectric cycle (MMC), which is divided into following 4 phases.

Figure 2: Schematic representation of interdigestive motility

Table 1: Good candidates for gastroretentive drug delivery systems⁵

S.NO:	Drug	Category	Half life	Peak time(hrs)	Bioavailability
1	Verapamil	Calcium channel blocker	6	1-2	20-35%
2	Nifedipine	Calcium channel blocker	2	0.5-0.2	45-65%
3	Omeprazole	Proton pump inhibitor	1-2	1	35-60%
4	Atenolol	Antihypertensive	4	3	40-50%
5	Propranolol	Antihypertensive	4-5	4	26%
6	Diltiazem	Calcium channel blocker	3-4.5	50min	40%
7	Lidocaine	Local anaesthetic	1.5-2	4	35%
8	Clarithromycin	Antibiotic	3-4	2-2.5	50%
9	Ramipril	ACE inhibitor	2-4	3-5	28%

Table 2: Marketed formulations available as GRDDS^{3, 6}

S.NO:	Brand Name	Drug(dose)	Company,Country	Remarks
1	Madopar®HBS (Propal® HBS)	Levodopa(100mg) and Benserazide(25mg)	Roche Products, USA	Floating CR capsules
2	Valrelease®	Diazepam (15mg)	Hoffmann-LaRoche, USA	Floating Capsules
3	Topalkan®	Al-Mg antacid	Pierre Fabre Drug, France	Effervescent floating liquid alginate preparation.
4	Conviron®	Ferrous sulphate	Ranbaxy, India	Colloidal gel forming FDDS.
5	Cifran OD®	Ciprofloxacine (1gm)	Ranbaxy,India	Gas generating floating form.
6	Liquid Gavison®	Al hydroxide (95 mg), Mg Carbonate (358 mg)	GlaxoSmithkline, India.	Effervescent floating liquid alginate preparations
7	Almagate Flot coat®	Al-Mg antacid	----------	Floating dosage form.
8	Cytotech®	Misoprostol (100µg/200µg)	Pharmacia, USA	Bilayer floating capsule.
9	Oflin OD®	Ofloxacin (400mg)	Ranbaxy, India	Gas generating floating tablet.

Floating systems:

Floating Drug Delivery Systems (FDDS) have a bulk density lower than gastric fluids and thus remain buoyant in the stomach for a prolonged period of time, without affecting the gastric emptying rate and the drug is released slowly at a desired rate from the system, results in an increase in the gastric residence time and a better control of fluctuations in the plasma drug concentrations and after complete release of the drug, the residual system is emptied from the stomach.

Figure 3: Graphic of the buoyant tablet which is less dense than the stomach fluid and therefore remains in the fundus.

Types of floating drug delivery systems (FDDS):

Based on the mechanism of buoyancy, two different technologies have been used in development of FDDS. These include:

A. Effervescent system.

B. Non- Effervescent system.

A. Effervescent System:

Effervescent systems include use of gas generating agents, carbonates (e.g. Sodium bicarbonate) 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. An alternative is the incorporation of matrix containing portion of liquid, which produce gas that evaporate at body temperature.

These effervescent systems further classified into two types:

I. Gas generating systems.

II. Volatile liquid or Vacuum containing systems.

I. Gas generating systems:

A. Tablets:

1. Intragastric single layer floating tablets or Hydrodynamically Balanced System (HBS):

These formulations have bulk density lower than gastric fluids and thus float in the stomach that increases the gastric emptying rate for a prolonged period. These are formulated by intimately mixing the gas (CO₂) generating agents and the drug within the matrix tablet. The drug is released slowly at a desired rate from the floating system and the residual system is emptied from the stomach after the complete release of the drug. This leads to an increase in the gastric residence time (GRT) and a better control over fluctuations in plasma drug concentration.

Figure 4: Intragastric single layer floating tablet

2. Intragastric bilayer floating tablets:

These are also compressed tablets, containing two layers:

· Immediate release layer and

· Sustained release layer.

Figure 5: Intragastric bilayer floating tablet.

B. Floating capsules:

These floating capsules are formulated by filling with a mixture of sodium alginate and sodium bicarbonate. The systems float as a result of the generation of CO₂ that was trapped in the hydrating gel network on exposure to an acidic environment.

C. Multiple unit type floating pills:

These multiple unit type floating pills are sustained release pills, known as ‘seeds’, which are surrounded by two layers. The outer layer is of swellable membrane layer while the inner layer consists of effervescent agents. This system sinks at once and then it forms swollen pills like balloons which float as they have lower density, when it is immersed in the dissolution medium at body temperature. The lower density is due to generation and entrapment of CO₂ within the system.

Figure 6: (a) A multiple-unit oral floating dosage system. (b) Stages of floating mechanism: (A) penetration of water; (B) generation of CO₂ and floating; (C) dissolution of drug. Key: (a) conventional SR pills; (b) effervescent layer; (c) swellable layer; (d) expanded swellable membrane layer; (e) surface of water in the beaker (37⁰C).

D. Floating system with Ion-Exchange resins:

Floating system using bicarbonate loaded ion exchange resin was made by mixing the beads with 1M sodium bicarbonate solution, and then the semi-permeable membrane is used to surround the loaded beads to avoid sudden loss of CO₂. On contact with gastric contents an exchange of bicarbonate and chloride ions takes place that results in generation of CO₂ that carries beads towards the top of gastric contents and producing a floating layer of resin beads.

II. Volatile liquid or Vacuum containing systems:

A. Intragastric floating gastrointestinal drug delivery system:

This system floats in the stomach because of floatation chamber, which is vacuum or filled with a harmless gas or air, while the drug reservoir is encapsulated by a microporous compartment.

Figure 7: Intragastric floating gastrointestinal drug delivery device

B. Inflatable gastrointestinal delivery systems

These systems are incorporated with an inflatable chamber, which contains liquid ether that gasifies at body temperature to inflate the chamber in the stomach. These systems are fabricated by loading the inflatable chamber with a drug reservoir, which can be a drug, impregnated polymeric matrix, then encapsulated in a gelatin capsule. After oral administration, the capsule dissolves to release the drug reservoir together with the inflatable chamber. The inflatable chamber automatically inflates and retains the drug reservoir compartment in the stomach. The drug is released continuously from the reservoir into gastric fluid.

Figure 8: Inflatable gastrointestinal delivery system

C. Intragastric osmotically controlled drug delivery system

This system is comprised of an osmotic pressure controlled drug delivery device and an inflatable floating support in a biodegradable capsule. On contact with the gastric contents in the stomach, the capsule disintegrates quickly to release the intragastirc osmotically controlled drug delivery device. The inflatable support inside forms a hollow polymeric bag which contains a liquid that gasifies at body temperature to inflate the bag and it is deformable. The osmotic pressure controlled drug delivery device consists of two components, osmotically active compartment and a drug reservoir compartment. The drug reservoir compartment is enclosed by a pressure responsive collapsible bag, which is impermeable to liquid and vapor and has a drug delivery orifice. The osmotically active compartment contains an osmotically active salt and is enclosed within a semi-permeable housing. In the stomach, the osmotically active salt present in the osmotically active compartment is dissolved by absorbing the water continuously present in the GI fluid through the semi-permeable membrane. An osmotic pressure is thus created which acts on the collapsible bag and in turn forces the drug reservoir compartment to reduce its volume and activate the drug reservoir compartment to reduce its volume and activate the drug release of a drug solution formulation through the delivery orifice.The floating support is also made to contain a bioerodible plug that erodes after a predetermined time to deflate the support. The deflated drug delivery system is then emptied from the stomach.

Figure 9: Intragastric osmotically controlled drug delivery system

B. Non-Effervescent systems:

The Non-Effervescent floating drug delivery systems are based on mechanism of swelling of polymer or bioadhesion to mucosal layer in GI tract. The various types of this system are:

1. Single layer floating tablets:

These are formulated by intimate mixing of drug with a gel forming hydrocolloid, that swells on contact with gastric fluid and maintain bulk density of less than unity. The air trapped by the swollen polymer confers buoyancy to these dosage forms.

2. Bilayer floating tablets:

A bilayer tablet contain two layer one immediate release layer which release initial dose from system while the another sustained release layer absorbs gastric fluid, forming an impermeable colloidal gel barrier on its surface, and maintain a bulk density of less than unity and thereby it remains buoyant in the stomach.

3. Alginate beads:

Multi unit floating dosage forms were developed from freeze dried calcium alginate. Spherical beads of approximately 2.5 mm diameter can be prepared by dropping a sodium alginate solution into aqueous solution of cacl₂, causing precipitation of calcium alginate leading to formation of porous system, which can maintain a floating force for over 12 hours. When compared with solid beads, which gave a short residence, time of 1 hour, and these floating beads gave a prolonged residence time of more than 5.5 hours.

4. Hollow microspheres:

Hollow microspheres (microballons), loaded with drug in their outer polymer shells were prepared by a novel emulsion-solvent diffusion method. The ethanol: dichloromethane solution of the drug and an enteric acrylic polymer was poured into an agitated aqueous solution of PVA that was thermally controlled at 40ºC. The gas phase generated in dispersed polymer droplet by evaporation of dichloromethane formed an internal cavity in microsphere of polymer with drug. The microballons floated continuously over the surface of acidic dissolution media containing surfactant for more than 12 hours in vitro.

Figure 10: Formulation of floating hollow microsphere or microballoon

Advantages of floating drug delivery system :³

· The principle of Hydrodynamically Balanced System (HBS) can be used for any particular medicament or class of medicament. 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.

· 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.

· 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.

· 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 dissolved drug is available for absorption in the small intestine, therefore it is expected that a drug will be fully absorbed from the floating dosage form if it remains in solution form even at alkaline p^H of the intestine.

· 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.

· 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.

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

Limitations of floating drug delivery system:⁹

· The floating system requires, sufficiently high level of fluid in the stomach for the system to float, this can be overcome by administering dosage form with a glass full of water (200-250 ml) or coating the dosage form with bioadhesive polymer which adhere to gastric mucosa.

· Aspirin and non steroidal anti-inflammatory drugs are known to cause gastric lesions, and slow release of such drugs in the stomach is unwanted.

· Drugs, such as Isosorbide dinitrate, that are absorbed equally throughout the GI tract, drugs undergoing first pass metabolism will not benefit from incorporation into a gastric retention system.

· Floating dosage form should not be given to the patients just before going to the bed as gastric emptying occurs rapidly when the subject remains in supine posture.

· Drugs that have stability or solubility problem in gastrointestinal fluid or that irritate gastric mucosa are not suitable.

· Drugs that have multiple absorption sites or which undergo first pass metabolism were not desirable.

· The single unit floating dosage form is associated with “all or none concept”. This problem can be overcome by formulating multiple unit system like floating microballons or microspheres.

Applications of floating drug delivery system:⁹

1. Sustained drug delivery:

Hydrodynamically Balanced System (HBS) type dosage forms which have bulk density less than one, relatively large in size and did not easily pass through pylorus, releases the drug over a prolonged period of time by retaining in the stomach for several hours and by increasing the gastric residence time. Madopar HBS formulation has shown to release levodopa for up to 8 hour in vitro, whereas the standard formulation released levodopa in less than 30 min.

2. Site specific drug delivery:

Floating drug delivery systems are particularly useful for drugs having specific absorption from stomach or proximal part of the small intestine e.g. riboflavin, furosemide etc. The absorption of Captopril has been found to be site specific, stomach being the major site followed by duodenum. This property prompts the development of a monolithic floating dosage form of Captopril which prolongs the gastric residence time and thus increases the bioavailability, which has shown AUC, approximately 1.8 times than that of conventional tablets.

3. Absorption enhancement:

Drugs that have poor bioavailability, because of their absorption is restricted to upper GIT are potential candidates to be formulated as floating drug delivery systems, thereby improving their absolute bioavailability.

4. Minimized adverse activity at the colon:

Retention of the drug at the stomach (HBS system), minimizes the amount of drug that reaches the colon, that prevents the undesirable activities of the drug in colon. This Pharmacodynamic aspect provides the rationale for GRDF formulation for betalactam antibiotics that are absorbed only from the small intestine, and whose presence in the colon leads to the development of microorganism’s resistance.

5. There are some cases in where the relative bioavailability of floating dosage form is reduced as compared to conventional dosage form e.g. floating tablets of amoxicillin trihydrate has bioavailability reduced to 80.5% when compared with conventional capsules. In such cases, the reduction in bioavailability is compensated by the advantages offered by FDDS e.g. patients with advanced Parkinson’s disease, experienced pronounced fluctuations in symptoms while treatment with standard L-dopa. A HBS dosage form provided a better control of motor fluctuations although its bioavailability was reduced by 50-60% of the standard formulation.

6. H. Pylori, causative bacterium for peptic ulcers and chronic gastritis. Patients require high concentration of drug, to be maintained at the site of infection that is within the gastric mucosa. The floating dosage form due to its floating ability was retained in stomach and maintained high concentration of drug in the stomach. A sustained liquid preparation of Ampicillin, using sodium alginate was developed that spreads out and adheres to gastric mucosal surfaces and releases the drug continuously.

7. Floating drug delivery systems are particularly useful for drugs which are poorly soluble or unstable in intestinal fluids and acid stable drugs and for those which undergo abrupt changes in their pH-dependent solubility due to pathophysiological conditions of GIT, food and age, e.g. floating system for furosemide lead to potential treatment of Parkinson’s disease. Approximate 30% drug was absorbed after oral administration.

Bio/Muco-adhesive systems:

Bio/muco-adhesive systems bind to the gastric epithelial cell surface or mucin, which extends the GRT of drug delivery system in the stomach. The surface epithelial adhesive properties of mucin have been well recognized and applied to the development of GRDDS based on bio/muco-adhesive polymers. The ability to provide adhesion of a drug delivery system to the gastrointestinal wall provides longer residence time in a particular organ site, thereby producing an improved effect in terms of local action or systemic effect. Binding of polymers to the mucin/epithelial surface can be divided into three categories:

· Hydration-mediated adhesion.

· Bonding-mediated adhesion.

· Receptor-mediated adhesion.

1. Hydration-mediated adhesion:

Certain hydrophilic polymers tend to imbibe large amount of water and become sticky, thereby acquiring bioadhesive properties.

2. Bonding-mediated adhesion:

The adhesion of polymers to a mucus/epithelial cell surface involves various bonding mechanisms, including physical-mechanical bonding and chemical bonding. Physical-mechanical bonds can result from the insertion of the adhesive material into the folds or crevices of the mucosa. Chemical bonds may be either covalent (primary) or ionic (secondary) in nature. Secondary chemical bonds consist of dispersive interactions (i.e., Vander Waals interactions) and stronger specific interactions such as hydrogen bonds. The hydrophilic functional groups responsible for forming hydrogen bonds are the hydroxyl and carboxylic groups.

3. Receptor-mediated adhesion:

Certain polymers bind to specific receptor sites on the cell surfaces, thereby enhancing the gastric retention of dosage forms. Various investigators have proposed different mucin-polymer interactions, such as:

· Wetting and swelling of the polymer to permit intimate contact with the biological tissue.

· Interpenetration of bioadhesive polymer chains and entanglement of polymer and mucin chains.

· Formation of weak chemical bonds.

· Sufficient polymer mobility to allow spreading.

· Water transport followed by mucosal dehydration (Lehr, 1992; Mortazavi, 1993).

The bioadhesive coated system when comes in contact with the mucus layer, various non-specific (Vander Waals, hydrogen bonding and/or hydrophobic interactions) or specific interactions occurs between the complimentary structures and these interactions last only until the turnover process of mucin and the drug delivery system should release its drug contents during this limited adhesion time, in order for a bioadhesive system to be successful.

Raft-forming systems:

These systems contain gel-forming solution (e.g. sodium alginate solution containing carbonates or bicarbonates), which on contact with the gastric contents, swells and forms a viscous cohesive gel containing entrapped CO₂ bubbles, releases drug slowly in stomach by forming the raft layer on the top of gastric fluid. These formulations contain antacids such as calcium carbonate or aluminium hydroxide to reduce gastric acidity.

Figure 11: Barrier formed by a raft-forming system

Low density systems:

Low density systems (<1 g/cm3) which have immediate buoyancy have been developed because, the gas-generating systems have a lag time before floating on the stomach contents, during which the dosage form may undergo premature evacuation through the pyloric sphincter. These are made of low density materials, entrapping air or oil. Most of the low density systems are multiple unit systems, also called as ‘‘microballoons’’ because of the low-density core (Sato and Kawashima, 2004). The preparation of these hollow microspheres involves simple solvent evaporation or solvent diffusion methods. Polycarbonate, cellulose acetate, Eudragit S, calcium alginate, low methoxylated pectin and agar are commonly used as polymers. Drug release and buoyancy are dependent on the plasticizer-polymer ratio, quantity of polymer, and the solvent used.

Figure 12: (a) Micro balloons (b) Foam-particles.

Swelling/Expanding/Unfoldable systems

A dosage form in the stomach will withstand gastric transit if it is bigger than the pyloric sphincter, also the dosage form must be small enough to be swallowed, and must not cause gastric obstruction either singly or by accumulation. Thus, their configurations are required to develop an expandable system in order to prolong the gastric retention time (GRT):

1) A small configuration for oral intake.

2) An expanded gastroretentive form.

3) A final small form enabling evacuation following drug release from the device.

Thus, gastro retentivity is improved by the combination of substantial dimension with high rigidity of dosage form to withstand peristalsis and mechanical contractility of the stomach. Unfoldable and swellable systems have been investigated and recently tried to develop an effective gastroretentive drug delivery.

· Unfoldable systems are made of biodegradable polymers. They are available in different geometric forms like tetrahedron, ring or planner membrane (4 - label disc or 4 - limbed cross form) of bioerodible polymer compressed within a capsule which extends in the stomach.

Figure 13: Different geometric forms of unfoldable systems.

· Swellable systems are also retained in the gastro intestinal tract (GIT) due to their mechanical properties. The swelling is usually results from osmotic absorption of water and the dosage form is small enough to be swallowed by the gastric fluid.

· Expandable systems have some drawbacks like problematical storage of much easily hydrolysable, biodegradable polymers relatively short-lived mechanical shape memory for the unfolding system most difficult to industrialize and not cost effective. Again, permanent retention of rigid, large single-unit expandable drug delivery dosage forms may cause brief obstruction, intestinal adhesion and gastropathy.

Figure 14: Drug release from swellable systems

Superporous Hydrogels:

Conventional hydrogels, with pore size ranging between 10 nm and 10 µm has very slow process of water absorption and require several hours to reach an equilibrium state during which premature evacuation of the dosage form may occur while the superporous hydrogel, having average pore size (>100 µm), swell to equilibrium size within a minute, due to rapid water uptake by capillary wetting through numerous interconnected open pores. Moreover they swell to a large size (swelling ratio 100 or more) and are intended to have sufficient mechanical strength to withstand pressure by gastric contractions. This is achieved by a co- formulation of a hydrophilic particulate material, Ac-Di-Sol (crosscarmellose sodium).

Figure 15: On the left, Superporous Hydrogels in its dry (a) and water-swollen (b) state. On the right, schematic illustration of the transit of Superporous Hydrogel.

Magnetic systems:

This approach is based on the simple principle that the dosage form contains a small internal magnet, and a magnet placed on the abdomen over the position of the stomach to enhance the gastric retention time (GRT). The external magnet must be positioned with a degree of precision that might compromise patient compliance.

Self-unfolding systems:

The self-unfolding systems are capable of mechanically increasing in size relative to the initial dimensions. This increase prevents the system from passing through the pylorus and retains for a prolonged period of time in the stomach. A drug can be either contained in a polymeric composition of the gastroretentive system or included as a separate component. Several methods were suggested to provide for the self-unfolding effect:

1. The use of hydrogels swelling in contact with the gastric juice.

2. Osmotic systems, comprising an osmotic medium in a semi-permeable membrane.

3. Systems based on low-boiling liquids converting into a gas at the body temperature.

d) High density systems:

These systems with a density of about 3 g/cm³ are retained in the rugae of the stomach and are capable of withstanding its peristaltic movements. A density of 2.6-2.8 g/cm³ acts as a threshold value after which such systems can be retained in the lower part of the stomach. High density formulations include coated pellets. Coating is done by heavy inert material such as barium sulphate, zinc oxide, titanium dioxide, iron powder etc. They are retained in the antrum of stomach.

Figure 16: Graphic of heavy tablet which is denser than the stomach fluid and therefore sinks to the antrum

Factors affecting gastricretention:³

Various factors that affect the bioavailability of dosage form and efficacy of the gastro retentive system are:

· Density: Gastricretention time (GRT) is a function of buoyancy of dosage form that is dependent on the density.

· Size: Dosage form units with a diameter of more than 7.5 mm are reported to have an increased GRT compared with those with a diameter of 9.9 mm.

· Shape: Tetrahedron and ring shaped devices with a flexural modulus of 48 and 22.5 kilo pounds per square inch (KSI) are reported to have better GRT 90% to 100% retention at 24 hours compared with other shapes.

· 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.

· Fed or unfed state: 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 to 2hrs. 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 to a fed state, thus decreasing the gastric emptying rate and prolonging drug release.

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

· 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.

· Gender: Mean ambulatory GRT in males (3.4±0.6 hours) is less compared with their age and race matched female counterparts (4.6±1.2 hours), regardless of the weight, height and body surface).

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

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

· Concomitant drug administration: Anticholinergics like atropine, propantheline, opiates like codeine and prokinetic agents like Metoclopramide and Cisapride, can affect floating time.

· Biological factors: Diabetes and Crohn’s disease etc.

REFERENCES:

1. S.U. Zate, P.I. Kothawade, G.H. Mahale, K.P. Kapse, S.P. Anantwar. Gastroretentive Bioadhesive Drug Delivery System: A Review. International Journal of PharmTech Research Res. 2(2); 2010: 1227-1235.

2. Vinod K.R., Santhosh Vasa, Anbuazaghan S, David Banji1, Padmasri A, Sandhya S. Approaches for Gastroretentive Drug Delivery Systems. 1(2); 2010: 589-601.

3. Debjit Bhowmik, Chiranjib.B, Margret Chandira, B. Jayakar, K.P.Sampath Kumar. Floating Drug Delivery System: A Review. Der Pharmacia Lettre. 1(2); 2009: 199-218.

4. Amit Kumar Nayak, Ruma Maji, Biswarup Das. Gastroretentive drug delivery systems: A review. 3(1); 2010: 2-10.

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Received on 24.02.2011

Accepted on 14.04.2011

Research Journal of Pharmaceutical Dosage Forms and Technology. 3(4): July-Aug. 2011,159-168

S. NO:	Dosage Form	Drugs
1.	Floating Tablets/Pills	Acetaminophen, Acetylsalisylic acid, Amoxicillin trihydrate, Ampicillin, Atenolol, Cinnazirine, captopril, Cinnarazine, carbamazepine, Chlorpheniramine maleate, Ciprofolxacin, Diazepam, Diltiazem, Fluorouracil, Furosamide, Isosorbide mononitrate, Isosorbidedinitrate, Nimodipine, p-aminobenzoic acid(PABA), Piretanide, Prednisolone, Pentoxyphylline, Quinidine gluconate, Riboflavin, Sotalol, Theophylline, Verapamil HCl.
2.	Floating Capsules	Benserazide, Chlordiazepoxide HCl, Diazepam, Furosemide, Nicardipine, Misoprostal, L-Dopa, Propranolol HCl, Pepstatin, Ursodeoxycholic acid, Verapamil HCl.
3.	Floating Microspheres/ Floating beads	Amoxicillin, Aspirin, Cholestyramine, Dipyridamol, Griseofulvin, Ibuprofen, Ketoprofen, p-nitroaniline, Piroxicam Nifedipine, Nicardipine, Tranilast, Terfinadin, Theophylline, Verapamil HCl.
4.	Floating Granules	Diclofenac sodium, Indomethacin, Meloxicam, Nicardepine, Prednisolone, Riboflavin.
5.	Powders	Several basic drugs.
6.	Films	Albendazole, Cinnarizine.