This leads to incomplete absorption of drugs having absorption window especially in the upper part of the small intestine, as once the drug passes down the absorption site, the remaining quantity goes unabsorbed. The gastric emptying of dosage forms in humans is also affected by several factors because of which wide inter- and intra-subject variations are observed. Since many drugs are well absorbed in the upper part of the gastrointestinal tract, such high variability may lead to non-uniform absorption and makes the bioavailability unpredictable.

The real challenge in the development of a controlled drug delivery system is not just tosustain the drug release but also to prolong the presence of dosage form in the stomach or upper small intestine until all the drug is completely released from the desired period of time. One of the most feasible approaches for achieving a prolongedand predictable drug delivery profiles in gastrointestinal tract is to control the gastric residence time (GRT) using gastro retentive dosage forms (GRDFs) that offer a new and better option for drug therapy. Dosage forms that can be retained in stomach are called gastro retentive drug delivery systems². GRDDS can improve the controlled delivery of drugs that have an absorption window by continuously releasing the drug for a prolonged period of time before it reaches its absorption site thus ensuring its optimal bioavailability. The controlled gastric retention of solid dosage forms may be achieved by the mechanisms of mucoadhesion,^3,4 flotation,⁵ sedimentation,^6,7 expansion,^8,9 modified shape systems,^10,11 or by the simultaneous administration of pharmacological agents^12,13 that delay gastric emptying.

Gastric emptying:

Gastric emptying occurs during fasting as well as fed states. The pattern of motility is however distinct in the 2 states. During the fasting state an interdigestive series of electrical events take place, which cycle both through stomach and intestine every 2 to 3 hours.¹⁴ This is called the interdigestive myloelectric cycle or migrating myloelectric cycle (MMC), which is further divided into following 4 phases as described by Wilson and Washington.¹⁵

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

· 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.

· 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.

· Phase IV lasts for 0 to 5 minutes and occurs between phases III and I of 2 consecutive cycles.

Under fasting conditions, the stomach is a collapsed bag with a residual volume of approximately 50 ml and contains a small amount of gastric fluid (pH 1–3) and air. The mucus spreads and covers the mucosal surface of the stomach as well as the rest of the GI tract. The GI tract is in a state of continuous motility consisting of two modes, interdigestive motility pattern and digestive motility pattern. The former is dominant in the fasted state with a primary function of cleaning up the residual content of the upper GI tract. The interdigestive motility pattern is commonly called the ‘migrating motor complex’ (‘MMC’) and is organized in cycles of activity and quiescence.¹⁶

Figure 1: Gastro intestinal motility pattern

Each cycle lasts 90–120 minutes and consists of four phases. The concentration of the hormone motilin in the blood controls the duration of the phases. In the interdigestive or fasted state, an MMC wave migrates from the stomach down the GI tract every 90–120 minutes. A full cycle consists of four phases, beginning in the lower esophageal sphincter / gastric pacemaker, propagating over the whole stomach, the duodenum and jejunum, and finishing at the ileum. Phase III is termed the ‘housekeeper wave’ as the powerful contractions in this phase tend to empty the stomach of its fasting contents and indigestible debris. The administration and subsequent ingestion of food rapidly interrupts the MMC cycle, and the digestive phase is allowed to take place. The upper part of the stomach stores the ingested food initially, where it is compressed gradually by the phasic contractions.

The digestive or fed state is observed in response to meal ingestion. It resembles the fasting Phase II and is not cyclical, but continuous, provided that the food remains in the stomach. Large objects are retained by the stomach during the fed pattern but are allowed to pass during Phase III of the interdigestive MMC. It is thought that the sieving efficiency (i.e. the ability of the stomach to grind the food into smaller size) of the stomach is enhanced by the fed pattern or by the presence of food.¹⁷

Generally, a meal of ~450 kcal will interrupt the fasted state motility for about three to four hours. It is reported that the antral contractions reduce the size of food particles to ≤1mm and propel the food through the pylorus. However, it has been shown that ingestible solids ≤7mm can empty from the fed stomach in humans.

Need For Gastro Retention¹⁸

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

2. Drugs that are less soluble or are degraded by the alkaline pH they encounters at the lower part of GIT.

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

4. Local or sustained drug delivery to the stomach and proximal small intestine to treat certain conditions.

5. Particularly useful for the treatment of peptic ulcers caused by H. Pylori infection.

Factors Affecting Gastric Retention¹⁹

1. Density: A buoyant dosage form having a density of less than that of the gastric fluids floats. Since it is away from the pyloric sphincter, the dosage unit is retained in the stomach for a prolonged period.

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

3. Shape of dosage form: 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.

4. 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.

5. 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.

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. 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.

9. Concomitant drug administration: Anticholinergics like atropine and propantheline, opiates like codeine and prokinetic agents like metoclopramide and cisapride.

10. Biological factors: Diabetes and Crohn’s disease

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

12. 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.

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

Figure 2: Intragastric residence positions of floating and non-floating units

Approaches to gastric retention:

Several approaches have been attempted in the preparation of gastro-retentive drug delivery systems. These include floating systems, swell able and expandable systems, high density systems, bioadhesive systems, altered shape systems, gel forming solution or suspension systems and sachet systems. Various approaches have been followed to encourage gastric retention of an oral dosage form.

Figure 3: Approaches to gastric retention

Floating Drug Delivery^{20, 21}

The floating sustained release dosage forms present most of the characteristics of hydrophilic matrices and are known as ‘hydrodynamically balanced systems’ (‘HBS’) since they are able to maintain their low apparent density, while the polymer hydrates and builds a gelled 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 hours) on the gastric contents without affecting the intrinsic rate of emptying because their bulk density is lower than that of the gastric contents. Many results have demonstrated the validity of the concept of buoyancy in terms of prolonged GRT of the floating forms, improved bioavailability of drugs and improved clinical situations. These results also demonstrate that the presence of gastric content is needed to allow the proper achievement of the buoyancy retention principle. Among the different hydrocolloids recommended for floating form formulations, cellulose ether polymers are most popular, especially hydroxypropyl methylcellulose. Fatty material with a bulk density lower than one may be added to the formulation to decrease the water intake rate and increase buoyancy.

Mechanism of floating systems:

Floating systems have low bulk density so that they can float on the gastric juice in the stomach. The problem arises when the stomach is completely emptied of gastric fluid. In such a situation, there is nothing to float on. While the system is floating on the gastric contents (see in figure 4 (a)), the drug is released slowly at the desired rate from the system. After release of drug, the residual system is emptied from the stomach. These results in an increased GRT and a better control of fluctuations in plasma drug concentration.²¹However, 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 (RW) has been reported in the literature. The RW 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 RW is on the higher positive side (see in figure 4 (b). 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.²²

RW or F = F buoyancy - F gravity

= (DF - Ds) gV,

Where RW = total vertical force, DF = fluid density, Ds = object density, V = volume and g = acceleration due to gravity.

Figure 4: Mechanism of floating systems, GF= Gastric fluid

Criteria for selection of drugs for FDDS

· Drugs acting locally in the stomach;

· Drugs those are primarily absorbed in the stomach;

· Drugs those are poorly soluble at an alkaline pH;

· Drugs with a narrow window of absorption;

· Drugs absorbed rapidly from the GI tract; and

· Drugs those degrade in the colon.

Advantages:

1. HBS type dosage forms can retain in the stomach for several hours and therefore, significantly prolong the GRT of numerous drugs.

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

3. The HBS formulations are not restricted to medicaments, which are principally absorbed from the stomach or intestine e.g. Chlorpheniramine maleate.

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. FDDS dosage forms are advantageous in case of vigorous intestinal movement and in diarrhoea to keep the drug in floating condition in stomach to get a relatively better response.

6. 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.

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

8. FDDS designed for longer gastric retention will extend the time within which drug absorption can occur in the small intestine.

9. FDDS are advantageous for drugs meant for local action in the stomach eg. antacids

Disadvantages:

1. The major disadvantage of floating system is requirement of a sufficient high level of fluids in the stomach for the drug delivery to float. However this limitation can be overcome by coating the dosage form with the help of bioadhesive polymers that easily adhere to the mucosal lining of the stomach.

2. Floating system is not feasible for those drugs that have solubility or stability problem in gastric fluids.

3. The dosage form should be administered with a minimum of glass full of water (200-250 ml).

4. The drugs, which are absorbed throughout gastro-intestinal tract, which under go first-pass metabolism (nifedipine, propranolol, isosorbide dinitrate etc.), are not desirable candidate.

5. Some drugs present in the floating system causes irritation to gastric mucosa.

6. There are certain situations where gastric retention is not desirable. Aspirin and non-steroidal anti-inflammatory drugs are known to cause gastric lesions, and slow release of such drugs in the stomach is unwanted.

Approaches to Design Floating Dosage Forms:

Floating systems can be based on the following:

I. Hydrodynamically balanced systems (HBS) – incorporated buoyant materials enable the device to float;

II. Effervescent systems – gas-generating materials such as sodium bicarbonates or other carbonate salts are incorporated. These materials react with gastric acid and produce carbon dioxide, which entraps in the colloidal matrix and allows them to float;

III. Low-density systems -- have a density lower than that of the gastric fluid so they are buoyant;

IV. Bioadhesive or mucoadhesive systems – these systems permit a given drug delivery system (DDS) to be incorporated with bio/mucoadhesive agents, enabling the device to adhere to the stomach (or other GI) walls, thus resisting gastric emptying. However, the mucus on the walls of the stomach is in a state of constant renewal, resulting in unpredictable adherence.

V. High-density Systems - High-density formulations include coated pellets, which have a density greater than that of the stomach contents (1.004 g/ cm). Sedimentation has been employed as a retention mechanism for pellets that are small enough to be retained in the rugae or folds of the stomach body near the pyloric region, which is the part of the organ with the lowest position in an upright posture. Dense pellets (approximately 3 g/cm³) trapped in rugae also tend to withstand the peristaltic movements of the stomach wall. With pellets, the GI transit time can be extended from an average of 5.8–25 hours; this is accomplished by coating the drug with a heavy inert material such as barium sulfate, zinc oxide, titanium dioxide, iron powder, etc.

Methods:

1. Using gel forming hydrocolloids such as hydrophilic gums, gelatin, alginates, cellulose derivatives, etc.

2. Using low density enteric materials such as methacrylic polymer, cellulose acetate phthalate.

3. By reducing particle size and filling it in a capsule.

4. By forming carbon dioxide gas and subsequent entrapment of it in the gel network.

5. By preparing hollow micro-balloons of drug using acrylic polymer and filled in capsules.

6. By incorporation of inflatable chamber which contained in a liquid e.g. solvent that gasifies at body temperature to cause the chambers to inflate in the stomach.

Based on the mechanism of buoyancy FDDS can be classified into:

A) Single Unit Floating Dosage Systems:

1) Effervescent Systems (Gas-generating Systems):

These buoyant systems utilized matrices prepared with swellable polymers like HPMC, polysaccharides like chitosan, effervescent components like sodium bicarbonate, citric acid and tartaric acid or chambers containing a liquid that gasifies at body temperature. The optimal stoichiometric ratio of citric acid and sodium bicarbonate for gas generation is reported to be 0.76:1. Involves resin beads loaded with bicarbonate and coated with ethyl cellulose. The coating, which is insoluble but permeable, allows permeation of water. Thus, carbon dioxide is released, causing the beads to float in the stomach.²³

Excipients used most commonly in these systems include HPMC, polyacrylate polymers, polyvinyl acetate Carbopol®, agar, sodium alginate, calcium chloride, polyethylene oxide and polycarbonates.

Penners et al ²⁴ prepared an expandable tablet containing mixture of polyvinyl lactams and polyacrylates that swell rapidly in an aqueous environment and thus stays in stomach over an extended period of time. In addition to this, gas-forming agents were also incorporated so as soon as the gas formed, the density of the system was reduced and thus the system tended to float on the gastric environment.

2) Non-effervescent Systems:

This type of system, after swallowing, swells unrestrained via imbibitions of gastric fluid to an extent that it prevents their exit from the stomach. These systems may be referred to as the ‘plug-type systems’ since they have a tendency to remain lodged near the pyloric sphincter. One of the formulation methods of such dosage forms involves the mixing of drug with a gel, which swells in contact with gastric fluid after oral administration and maintains a relative integrity of shape and a bulk density of less than one within the outer gelatinous barrier. The air trapped by the swollen polymer confers buoyancy to these dosage forms. Examples of this type of FDDS include colloidal gel barrier ²⁵, microporous compartment system ²⁶, alginate beads ²⁷, and hollow microspheres ²⁸.

Another type is a fluid-filled floating chamber ²⁹which includes incorporation of a gas-filled floatation chamber into a microporous 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 contact 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 swallowable size, remains afloat within the stomach for a prolonged time, and after the complete release the shell disintegrates, passes off to the intestine, and is eliminated.

Figure 5: Gas filled floatation chamber

A newer self-correcting floatable asymmetric configuration drug delivery system ³⁰ has a 3-layer matrix to control the drug release. This 3-layer principle has been improved by development of an asymmetric configuration drug delivery system in order to modulate the release extent and achieve zero-order release kinetics by initially maintaining a constant area at the diffusing front with subsequent dissolution/erosion toward the completion of the release process. The system was designed in such a manner that it floated to prolong gastric residence time in vivo, resulting in longer total transit time within the gastrointestinal tract environment with maximum absorptive capacity and consequently greater bioavailability. This particular characteristic would be applicable to drugs that have pH-dependent solubility, a narrow window of absorption, and are absorbed by active transport from either the proximal or distal portion of the small intestine.

Streubel et al ³¹ prepared single-unit floating tablets based on polypropylene foam powder (Accurel MP 1000®) and matrix-forming polymer. Highly porous foam powder in matrix tablets provided density much lower than the density of the release medium. It was concluded that varying the ratios of matrix-forming polymers and the foam powder could alter the drug release patterns effectively.

Wu et al ³² prepared floating sustained release tablets of nimodipine by using HPMC and PEG 6000. Prior to formulation of floating tablets, nimodipine was incorporated into poloxamer-188 solid dispersion after which it was directly compressed into floating tablets. It was observed that by increasing the HPMC and decreasing the PEG 6000 content a decline in in vitro release of nimodipine was observed.

Single-unit formulations are associated with problems such as sticking together or being obstructed in the gastrointestinal tract, which may have a potential danger of producing irritation. The main drawback of such system is “all or none” phenomenon. In such cases there is a danger of passing of the dosage form to intestinal part at the time of house-keeper waves. To overcome this difficulty multiple unit dosage forms are designed.

B) Multiple Unit Floating Dosage Systems:

In order to overcome the above problem, multiple unit floating systems were developed, which reduce the intersubject variability in absorption and lower the probability of dose-dumping.

1) 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 ³³. 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.

The most commonly used excipients in non-effervescent FDDS are gel-forming or highly swellable cellulose type hydrocolloids, polysaccharides, and matrix forming polymers such as polycarbonate, polyacrylate, polymethacrylate and polystyrene. One of the approaches to the formulation of such floating dosage forms involves intimate mixing of drug with a gel-forming hydrocolloid, which swells in contact with gastric fluid after oral administration and maintains a relative integrity of shape and a bulk density of less than unity within the outer gelatinous barrier³⁴. The air trapped by the swollen polymer confers buoyancy to these dosage forms. In addition, the gel structure acts as a reservoir for sustained drug release since the drug is slowly released by a controlled diffusion through the gelatinous barrier. Sheth and Tossounian³⁵postulated that when such dosage forms come in contact with an aqueous medium, the hydrocolloid starts to hydrate by first forming a gel at the surface of the dosage form. The resultant gel structure then controls the rate of diffusion of solvent-in and drug-out of the dosage form. As the exterior surface of the dosage form goes into solution, the gel layer is maintained by the immediate adjacent hydrocolloid layer becoming hydrated. As a result, the drug dissolves in and diffuses out with the diffusing solvent, creating a ‘receding boundary’ within the gel structure ³⁵. The working principle of the HBS is more clearly illustrated in Figure 6.

Sheth and Tossounian³⁶ developed a HBS capsule containing a mixture of a drug and hydrocolloids. Upon contact with gastric fluid, the capsule shell dissolves; the mixture swells and forms a gelatinous barrier thereby remaining buoyant in the gastric juice for an extended period of time. Ushimaru et al.³⁷ developed SR capsules containing a of a drug, a cellulose derivative or starch derivative which forms a gel in water, and a higher acid glyceride or higher alcohol or a mixture thereof which is solid at room temperature capsules were prepared by filling capsules with the as a above mixture, then heating them to a temperature the melting point of the fat / oil component and finally cooling and solidifying the mixture.

Figure 6: Working principle of hydrodynamically balanced system

2) Effervescent Systems (Gas-generating Systems):

Ikura et al ³⁸ 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 Umezawa³⁹.

These minicapsules 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 ⁴⁰comprises 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 ⁴¹. 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 radiolabelled 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.

Figure 7-a) Different layers i) Semi-permeable membrane,

ii) Effervescent Layer iii) Core pill layer

Figure 7: b) Mechanism of floatation via CO₂ generation.

Figure 8: Schematic presentation of working of a triple-layer system. (A) Initial configuration of triple-layer tablet. (B) On contact with the dissolution medium the bismuth layer rapidly dissolves and matrix starts swelling. (C) Tablet swells and erodes. (D) And (E) Tablet erodes completely.

3) 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.

Joseph et al ⁴² 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 analysis was 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 fluids⁴³. Jorgen et al^44,45described 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 reported to be used in the formulation of floating dosage forms are:

· Floating microspheres – Aspirin, Griseofulvin, p-nitroaniline, Ibuprofen, Ketoprofen⁴⁶, Piroxicam, Verapamil, Cholestyramine, Theophylline, Nifedipine, Nicardipine, Dipyridamole, Tranilast⁴⁷ and Terfenadine⁴⁸

· Floating granules - Diclofenac sodium, Indomethacin and Prednisolone

· Films – Cinnarizine⁴⁹, Albendazole

· Floating tablets and Pills - Acetaminophen, Acetylsalicylic acid, Ampicillin, Amoxicillin trihydrate, Atenolol, Fluorouracil, Isosorbide mononitrate⁵⁰, Paraaminobenzoic acid, Piretanide⁵¹, Theophylline, Verapamil hydrochloride, Chlorpheniramine maleate, Aspirin, Calcium Carbonate, Fluorouracil, Prednisolone, Sotalol⁵², Pentoxyfilline and Diltiazem HCl.

· Floating Capsules - Chlordiazepoxide hydrogen chloride, Diazepam⁵³, Furosemide, Misoprostol, L-Dopa, Benserazide, Ursodeoxycholic acid⁵⁴ and Pepstatin, and Propranolol.

Polymers and other ingredients:

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

1. 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

2. 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.

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

4. Release rate accelerants (5%-60%): eg. Lactose, mannitol

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

6. Buoyancy increasing agents (upto 80%): eg. Ethyl cellulose

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

CONCLUSION:

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. 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. 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.

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Received on 15.05.2013

Modified on 18.06.2013

Accepted on 30.06.2013

Research Journal of Pharmaceutical Dosage Forms and Technology. 5(4): July-August, 2013, 191-201