Approaches To Design Floating Dosage Forms:

The following approaches have been used for the design of floating dosage forms of single and multiple unit systems.⁽⁹⁾

v Single-Unit Dosage Forms

v Multiple-Unit Dosage Forms

Single-Unit Dosage Forms:

In low density approaches, the globular shells apparently

having lower density than that of gastric fluid can be used as a carrier for drug for its controlled release. A buoyantdosage form can also be obtained by using a fluid-filled system that floats in the stomach. In coated shells popcorn, poprice, and polystyrol have been exploited as drug carriers. Sugar polymeric materials such as methacrylic polymer and cellulose acetate phthalate have been used to undercoat these shells. These are further coated with a drug-polymer mixture. The polymer of choice can be either ethylcellulose or hydroxypropyl cellulose depending on the type of released desired. Finally the product floats on the gastric fluid while releasing the drug gradually over a prolonged duration.

Multiple-Unit Dosage Forms:

The purpose of designing multiple-unit dosage form is to develop a reliable formulation that has all the advantages of a single-unit form and also is devoid of any of the above mentioned disadvantages of single-unit formulations. In pursuit of this endeavor many multipleunit floatable dosage forms have been designed. Microspheres have high loading capacity and many polymers have been used such as albumin, gelatin, starch, polymethacrylate, polyacrylamine, and poly alkyl cyanoacrylate. Spherical polymeric microsponges also referred to as “microballoons” have been prepared. Microspheres have a characteristic internal hollow structure and show an excellent in vitro floatability. In Carbon dioxide- generating multiple-unit oral formulations several devices with features that extend, unfold, or are inflated by carbon dioxide generated in the devices after administration have been described.

Basic Gastrointestinal Tract Physiology:

Anatomically the stomach is divided into 3 regions: fundus, body, and antrum (pylorus). The proximal part made of fundus and body acts as a reservoir for undigested material, whereas the antrum is the main site for mixing motions and act as a pump for gastric emptying by propelling actions.¹⁰

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. 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.⁽¹¹⁾

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

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

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

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

After the ingestion of a mixed meal, the pattern of contractions changes from fasted to that of fed state. This is also known as digestive motility pattern and comprises continuous contractions as in phase II of fasted state. These contractions result in reducing the size of food particles (to less than 1 mm), which are propelled toward the pylorus in a suspension form. During the fed state onset of MMC is delayed resulting in slowdown of gastric emptying rate.⁽¹²⁾

Scintigraphic studies determining gastric emptying rates revealed that orally administered controlled release dosage forms are subjected to basically 2 complications, that of short gastric residence time and unpredictable gastric emptying rate.⁽¹²⁾

Factors Affecting Gastric Retention:

Gastric residence time of an oral dosage form is affected by several factors. To pass through the pyloric valve into the small intestine the particle size should be in the range of 1 to 2 mm.15 The pH of the stomach in fasting state is ~1.5 to 2.0 and in fed state is 2.0 to 6.0. A large volume of water administered with an oral dosage form raises the pH of stomach contents to 6.0 to 9.0. Stomach doesn’t get time to produce sufficient acid when the liquid empties the stomach, hence generally basic drugs have a better chance of dissolving in fed state than in a fasting state.⁽¹³⁾

Rate of gastric emptying depends mainly on viscosity, volume, and caloric content of meals. Nutritive density of meals helps determine gastric emptying time. It does not make any difference whether the meal has high protein, fat, or carbohydrate content as long as the caloric content is the same. However, increase in acidity and caloric value slows down gastric emptying time. Biological factors such as age, body mass index (BMI), gender, posture, and diseased states (diabetes, Chron’s disease) influence gastric emptying. In the case of elderly persons, gastric emptying is slowed down. Generally females have slower gastric emptying rates than males. Stress increases gastric emptying rates while depression slows it down.⁽¹³⁾

The resting volume of the stomach is 25 to 50 mL. Volume of liquids administered affects the gastric emptying time. When volume is large, the emptying is faster. Fluids taken at body temperature leave the stomach faster than colder or warmer fluids. Studies have revealed that gastric emptying of a dosage form in the fed state can also be influenced by its size. Small-size tablets leave the stomach during the digestive phase while the large-size tablets are emptied during the housekeeping waves.⁽¹⁴⁾

Timmermans and Andre18 studied the effect of size of floating and nonfloating dosage forms on gastric emptying and concluded that the floating units remained buoyant on gastric fluids. These are less likely to be expelled from the stomach compared with the nonfloating units, which lie in the antrum region and are propelled by the peristaltic waves.⁽¹⁴⁾

It has been demonstrated using radiolabeled technique that there is a difference between gastric emptying times of a liquid, digestible solid, and indigestible solid. It was suggested that the emptying of large (>1 mm) indigestible objects from stomach was dependent upon interdigestive migrating myoelectric complex. When liquid and digestible solids are present in the stomach, it contracts ~3 to 4 times per minute leading to the movement of the contents through partially opened pylorus. Indigestible solids larger than the pyloric opening are propelled back and several phases of myoelectric activity take place when the pyloric opening increases in size during the housekeeping wave and allows the sweeping of the indigestible solids. Studies have shown that the gastric residence time (GRT) can be significantly increased under the fed conditions since the MMC is delayed.⁽¹⁵⁾

Several formulation parameters can affect the gastric residence time. More reliable gastric emptying patterns are observed for multiparticulate formulations as compared with single unit formulations, which suffer from “all or none concept.” As the units of multiparticulate systems are distributed freely throughout the gastrointestinal tract, their transport is affected to a lesser extent by the transit time of food compared with single unit formulation.⁽¹⁵⁾

CLASSIFICATION OF FLOATING DRUG DELIVERY SYSTEMS (FDDS):

Floating drug delivery systems are classified depending on the use of 2 formulation variables:

v effervescent and

v non-effervescent systems.

Effervescent Floating Dosage Forms:

These are matrix types of systems prepared with the help of swellable polymers such as methylcellulose and chitosan and various effervescent compounds, e.g., sodium bicarbonate, tartaric acid, and citric acid. They are formulated in such a way that when in contact with the acidic gastric contents, CO2 is liberated and gets entrapped in swollen hydrocolloids, which provides buoyancy to the dosage forms^.(¹⁶⁾

Ichikawa et aldeveloped a new multiple type of floating dosage system composed of effervescent layers and swellable membrane layers coated on sustained release pills. The inner layer of effervescent agents containing sodium bicarbonate and tartaric acid was divided into 2 sublayers to avoid direct contact between the 2 agents. These sublayers 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. It was found that the system had good floating ability independent of pH and viscosity and the drug (Para-amino benzoic acid) released in a sustained manner (Figure 2, A and B).⁽¹⁷⁾

Figure 2. (A) Multiple-unit oral floating drug delivery system. (B) Working principle of effervescent floating drug delivery system.

Yang et al developed a swellable asymmetric triple-layer tablet with floating ability to prolong the gastric residence time of triple drug regimen (tetracycline, metronidazole, and clarithromycin) in Helicobacter pylori–associated peptic ulcers using hydroxy propyl methyl cellulose (HPMC) and poly (ethylene oxide) (PEO) as the rate-controlling polymeric membrane excipients. The design of the delivery system was based on the swellable asymmetric triple-layer tablet approach^.(¹⁸⁾

Hydroxypropylmethylcellulose and poly(ethylene oxide) were the major rate-controlling polymeric excipients. Tetracycline and metronidazole were incorporated into the core layer of the triple-layer matrix for controlled delivery, while bismuth salt was included in one of the outer layers for instant release. The floatation was accomplished by incorporatinga gas-generating layer consisting of sodium bicarbonate: calcium carbonate (1:2 ratios) along with the polymers. The in vitro results revealed that the sustained delivery of tetracycline and metronidazole over 6 to 8 hours could be achieved while the tablet remained afloat. The floating feature aided in prolonging the gastric residence time of this system to maintain high-localized concentration of tetracycline and metronidazole (Figure 3).^.(18)

Figure 3 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

Figure 4. Pictorial presentation of working of effervescent floating drug delivery system based on ion exchange resin.

Atyabi and coworkers42 developed a floating system using ion exchange resin that was loaded with bicarbonate by mixing the beads with 1 M sodium bicarbonate solution. The loaded beads were then surrounded by a semipermeable membrane to avoid sudden loss of CO2. Upon coming in contact with gastric contents an exchange of chloride and bicarbonate ions took place that resulted in CO2 generation thereby carrying beads toward the top of gastric contents and producing a floating layer of resin beads (Figure 4) .The in vivo behavior of the coated and uncoated beads was monitored using a single channel analyzing study in 12 healthy human volunteers by gamma radio scintigraphy. Studies showed that the gastric residence time was prolonged considerably (24 hours) compared with uncoated beads (1 to 3 hours).⁽¹⁹⁾

Non-Effervescent Floating Dosage Forms:

Non-effervescent floating dosage forms use a gel forming or swellable cellulose type of hydrocolloids, polysaccharides, and matrix-forming polymers like polycarbonate, polyacrylate, polymethacrylate, and polystyrene. The formulation method includes a simple approach of thoroughly mixing the drug and the gel-forming hydrocolloid. After oral administration this dosage form swells in contact with gastric fluids and attains a bulk density of < 1. The air entrapped within the swollen matrix imparts buoyancy to the dosage form. The so formed swollen gel-like structure acts as a reservoir and allows sustained release of drug through the gelatinous mass.

Thanoo et a developed polycarbonate microspheres by solvent evaporation technique. Polycarbonate in dichloromethane was found to give hollow microspheres that floated on water and simulated biofluids as evidenced by scanning electron microscopy (SEM). High drug loading was achieved and drug-loaded microspheres were able to float on gastric and intestinal fluids. It was found that increasing the drug-to-polymer ratio increased both their mean particle size and release rate of drug.^.(20)

Fell et a prepared floating alginate beads incorporating amoxycillin. The beads were produced by dropwise addition of alginate into calcium chloride solution, followed by removal of gel beads and freeze-drying. The beads containing the dissolved drug remained buoyant for 20 hours and high drug-loading levels were achieved^.(²¹⁾

Streubel et a prepared single-unit floating tablets based on polypropylene foam powder and matrix-forming polymer. Incorporation of highly porous foam powder in matrix tablets provided density much lower than the density of the release medium. A 17% wt/wt foam powder (based on mass of tablet) was achieved in vitro for at least 8 hours. It was concluded that varying the ratios of matrix-forming polymers and the foam powder could alter the drug release patterns effectively^.(²²⁾

Asmussen et al invented a device for the controlled release of active compounds in the gastrointestinal tract with delayed pyloric passage, which expanded in contact with gastric fluids and the active agent was released from a multiparticulate preparation. It was claimed that the release of the active compound was better controlled when compared with conventional dosage forms with delayed pyloric passage^.(²³⁾

Sheth and Tossounian developed an HBS system containing a homogeneous mixture of drug and the hydrocolloid in a capsule, which upon contact with gastric fluid acquired and maintained a bulk density of less than 1 thereby being buoyant on the gastric contents of stomach until all the drug was released (Figure 5).⁽²⁴⁾

Figure5. Working principle of hydrodynamically balanced system.

Sheth and Tossounian developed hydrodynamically balanced sustained release tablets containing drug and hydrophilic hydrocolloids, which on contact with gastric fluids at body temperature formed a soft gelatinous mass on the surface of the tablet and provided a water-impermeable colloid gel barrier on the surface of the tablets. The drug slowly released from the surface of the gelatinous mass that remained buoyant on gastric fluids (Figure 6, A and B).⁽²⁵⁾

Figure 6. Intragastric floating tablets. (A) United States patent 4

167 558, September 11, 1979. (B) United States patent 4 140 755, February 20, 1979.

Ushomaru et al developed sustained release composition for a capsule containing mixture of cellulose derivative or a starch derivative that formed a gel in water and higher fatty acid glyceride and/or higher alcohol, which was solid at room temperature. The capsules were filled with the above mixture and heated to a temperature above the melting point of the fat components and then cooled and solidified⁽²⁶⁾

The some Marketed Preparations of Floating Drug Delivery Systems is shown in table-1.

Table 1. Marketed Preparations of Floating Drug Delivery Systems

S. no.	Product	Active Ingredient	Reference No.
1	Madopar	Levodopa and benserzide	27
2	Valrelease	Diazepam	28
3	Topalkan	Aluminum magnesium antacid	29
4	Almagate flatcoat	Antacid	30
5	Liquid gavison	Alginic acid and sodium bicarbonate	31

MECHANISM OF FLOATING SYSTEMS:

Various attempts have been made to retain the dosage form in the stomach as a way of increasing the retention time.These attempts include introducing floating dosage forms (gas-generating systems and swelling or expanding systems), mucoadhesive systems, high-density systems,modified shape systems, gastric-emptying delaying devices and co-administration of gastric-emptying delaying drugs. Among these, the floating dosage forms have been most commonly used. Floating drug delivery systems (FDDS) have a bulk density less than gastric fluids and so remain buoyant in the stomach without affecting the gastric emptying rate for a prolonged period of time. While the system is floating on the gastric contents (given in the Figure 7 (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. This results in an increased GRT and a better control of the fluctuations in plasma drug concentration. However, besides a minimal gastric content needed to allow the proper achievement of the buoyancy retention principle, a minimal level of floating force (F) is also required to keep the dosage form reliably buoyant on the surface of the meal. To measure the floating force kinetics, a novel apparatus for determination of resultant weight has been reported in the literature. The apparatus operates by measuring continuously the force equivalent to F (as a function of time) that is required to maintain the submerged object. The object floats better if F is on the higher positive side (Figure 7(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 ⁽³²⁾

F = F buoyancy - F gravity

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

Where, F= total vertical force,

Df = fluid density,

Ds = object density,

v = volume and

g = acceleration due to gravity.

Fig.7 a. Mechanism of floating systems, GF= Gastric fluid

Based on the mechanism of buoyancy FDDS can be

classified into:

A. Single Unit Floating Dosage Systems

a) Effervescent Systems (Gas-generating Systems)

b) Non-effervescent Systems

B. Multiple Unit Floating Dosage Systems

a) Non-effervescent Systems

b) Effervescent Systems (Gas-generating Systems)

c) Hollow Microspheres

C. Raft Forming Systems

A. Single Unit Floating Dosage Systems:

a) Effervescent Systems (Gas-generating Systems):

These buoyant systems utilised 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. The common approach for preparing these systems involves resin beads loaded with bicarbonate and coated with ethylcellulose. The coating, which is insoluble but permeable, allows permeation of water. Thus, carbon dioxide is released, causing the beads to float in the stomach Excipients used most commonly in these systems include HPMC, polyacrylate polymers, polyvinyl acetate, Carbopol®, agar, sodium alginate, calcium chloride, polyethylene oxide and polycarbonates.⁽³³⁾

Ozdemir et al prepared floating bilayer tablets with controlled release for furosemide. The low solubility of the drug could be enhanced by using the kneading method, preparing a solid dispersion with β cyclodextrin mixed in a 1:1 ratio. One layer contained the polymers HPMC 4000, HPMC 100, and CMC (for the control of the drug delivery) and the drug. The second layer contained the effervescent mixture of sodium bicarbonate and citric acid. Radiographic studies on 6 healthy male volunteers showed that floating tablets were retained in stomach for 6 hours and further blood analysis studies showed that bioavailability of these tablets was 1.8 times that of the conventional tablets. On measuring the volume of urine the peak diuretic effect seen in the conventional tablets was decreased and prolonged in the case of floating dosage form^.(³⁴⁾

Penners et al 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^.(³⁵⁾

Talwar et al prepared a once-daily formulation for oral administration of ciprofloxacin. The formulation was composed of 69.9% ciprofloxacin base, 0.34% sodium alginate, 1.03% xanthum gum, 13.7% sodium bicarbonate, and 12.1% cross-linked poly vinyl pyrrolidine. The cross linked PVP initially and the gelforming polymers later formed a hydrated gel matrix that entrapped the gas, causing the tablet to float and be retained in the stomach The hydrated gel matrix created a diffusion path for the drug, resulting in sustained release of the drug^.(36)

b) 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, microporous compartment system^, alginate beads and hollow microspheres^.(³⁷⁾

Another type is a Fluid- filled floating chamber which 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^.(³⁸⁾

Fig.7 b. Gas filled floatation chamber

A newer Self-correcting floatable asymmetric configuration drug delivery system 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^.(39)

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.^.(39)

Yang et al developed a swellable asymmetric triplelayer tablet with floating ability to prolong the gastric residence time of triple drug regimen (tetracycline,metronidazole, and clarithromycin) in Helicobacter pylori–associated peptic ulcers using HPMC and poly (ethylene oxide) (PEO) as the rate-controlling polymeric membrane excipients. The design of the delivery system was based on the swellable asymmetric triple-layer tablet approach. HPMC and poly(ethylene oxide) were the major rate-controlling polymeric excipients. Tetracycline and metronidazole were incorporated into the core layer of the triple-layer matrix for controlled delivery, while bismuth salt was included in one of the outer layers for instant release. The floatation was accomplished by incorporating a gas-generating layer consisting of sodium bicarbonate and calcium carbonate with swelleble polymers. Over 6-8 hours of sustained delivery of tetracycline and metronidazole was achieved with this dosage form which was still floating. ⁽⁴⁰⁾

Streubel et al prepared single-unit floating tablets based on polypropylene foam powder (Accrual 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. ⁽⁴¹⁾

Wu et al 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 invitro release of nimodipine was observed^.(⁴²⁾

Nur and Zhang prepared floating tablets of captopril using HPMC (4000 and 15 000 cps) and carbopol 934P. It was concluded that the buoyancy of the tablet is governed by both the swelling of the hydrocolloid particles on the tablet surface when it contacts the gastric fluids and the presence of internal voids in the centre of the tablet (porosity). A prolonged release from these floating tablets was observed as compared with the conventional tablets and a 24-hour controlled release from the dosage form of captopril was achieved^.(⁴³⁾

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 intersubject 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 ^[30]. Much research has been focussed and the scientists are still exploring the field of hollow microspheres, capable of floating on the gastric fluid and having improved gastric retention properties^.(⁴⁴⁾

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 reporte 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^.(⁴⁵⁾

b) Effervescent Systems (Gas-generating Systems):

Ikura et al 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. 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 ^[28] 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 ^[29]. 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 nonfloating beads in human volunteers using gamma scintigraphy. Prolonged gastric residence time of more than 5.5 h was observed for floating beads. The nonfloating beads had a shorter residence time with a mean onset emptying time of 1 h^.(⁴⁶⁾

Ichikawa et al 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 8). The inner layer of effervescent agents containing sodium bicarbonate and tartaric acid was divided into 2 sublayers to avoid direct contact between the 2 agents. These sublayers 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.⁽⁴⁷⁾

Fig.8 a) Different layers i) Semi-permeable membrane, ii) Effervescent Layer iii) Core pill layer

b) Mechanism of floatation via CO2 generation.

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 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.⁽⁴⁸⁾

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.⁽⁴⁸⁾

Kawashima et al 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^.(⁴⁹⁾

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. Joseph et al ^[28] 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^.(⁵⁰⁾

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^.(⁵¹⁾

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^[7]Jorgen et al ^[8,9] 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 fluid.^.(51)

METHOD OF PREPARATION:

Preparation of Tablet:

Floating matrix tablets containing active drug were prepared by wet granulation technique using varying concentrations of different grades of polymers with sodium bicarbonate. Polymers and active drug were mixed homogeneously using glass mortar and pestle. Isopropyl alcohol was used as granulating agent. Granules were prepared by passing the wet coherent mass through a BSS # 16 sieve. The granules were dried in hot air oven at a temperature of 60OC. Dried granules were sieved through BSS # 20/44 sieves and mixed with sodium bicarbonate used as gas generating agent and lubricated with magnesium stearate and talc just 4-5 min before compression. Lubricated granules were compressed into tablets using Rimek Minipress-I rotary tablet machine to obtain tablets of desired specifications^.(⁵²⁾

Weight variation and hardness:

Weight variation test was done according to USP and hardness was measured with Monsanto hardness tester.^.(52)

Buoyancy / Floating test:

The time between introduction of dosage form and its buoyancy on the simulated gastric fluid and the time during which the dosage form remained buoyant were measured. The time taken for dosage form to emerge on surface of medium called Floating Lag Time (FLT) or Buoyancy Lag Time (BLT) and total duration of floatation i.e. as long the dosage form remains buoyant is called Total Floating Time (TFT).^.(52)

Tablet density:

Tablet density is an important parameter for floating tablets. The tablet will float only if its density is less than that of gastric fluid (1.004). Density (d) was determined using the relationship d = m/v where v = πr2h.^.⁽⁵²⁾

In vitro release study:

The in vitro release study for all the formulations were carried out by USP Dissolution Test Apparatus Type-II. The temperature of the dissolution medium (0.1 M HCl, 900 mL) was maintained at 37OC ± 1OC with a stirring rate of 50 rpm. This study was done for 8 h. The tablet was placed inside the dissolution vessel. At time of 15, 30, 60, 120 and 180 min 6 mL of samples werewithdrawn, at time of 240, 300 and 360 min 3.5 mL whereas after 420 and 480 min 2.5 ml of samples were withdrawn, respectively. The volume of dissolution fluid was adjusted every time to 900 mL. Samples were suitably diluted with 2 mL Folin-Ciocalteuís phenol reagent (diluted to 1:2 with distilled water) and 2 mL of 20% sodium carbonate solution and 0.1 M HCl up to 10 mL and assayed spectrophotometrically at λ=760 nm in a double beam UV and visible spectrophotometer (Shimadzu UV 1700) against reagent blank. The drug concentration was calculated using standard calibration curve ^.(⁵³⁾

Mechanism of release:

The mechanism of release was determined by fitting the release data to the various kinetic equations such as zero-order, first-order, Higuchi, and Korsmeyer-Peppas and finding the R2 values of the release profile corresponding to each model ⁽⁵⁴⁾

Optimization of the final formula:

The final optimized formula was found after analyzing the response variables (f2, CDR1, CDR2, CDR3, CDR5, CDR8 corresponding to the cumulative % drug released at the specified time, DLE, FLT) using Design-Expert software of the D-optimal experimental design. The ANOVA study of each of the response variables yielded the best fitting polynomial model for that variable Only those models were considered which had a high F-value corresponding to p <0.05. Repeating this procedure for all the variables yielded 9 polynomial models which were solved simultaneously by numerical methods keeping the target values as given in. The target for f2 and DLE were set at maximum, CDR values as per the dissolution points obtained for the marketed sustained release product (URCLAR), which is in consonance with the profile desirable for the pharmacokinetics of the drug, and FLT was set at minimum for optimization. ⁽⁵⁴⁾

EVALUATION OF FLOATING DRUG DELIVERY SYSTEMS:

Various parameters that need to be evaluated in gastroretensive formulations include;⁽⁵⁵⁾

v In case of solid dosage forms

· Floating duration,

· Dissolution profiles,

· Specific gravity,

· Content uniformity,

· Hardness, and

· Friability

v In the case of multiparticulate drug delivery systems

· Differential scanning calorimetry (DSC),

· Particle size analysis,

· Flow properties,

· Surface morphology,

· Mechanical properties and X-ray diffraction studies are also performed.

APPLICATION OF FLOATING DRUG DELIVERY SYSTEMS:

Floating drug delivery offers several applications for drugs having poor bioavailability because of the narrow absorption window in the upper part of the gastrointestinal tract. It retains the dosage form at the site of absorption and thus enhances the bioavailability. These are summarized as follows.

1. Sustained Drug Delivery:

HBS systems can remain in the stomach for long periods and hence can release the drug over a prolonged period of time. The problem of short gastric residence time encountered with an oral CR formulation hence can be overcome with these systems. These systems have a bulk density of <1 as a result of which they can float on the gastric contents. These systems are relatively large in size and passing from the pyloric opening is prohibited.

Eg. Sustained release floating capsules of nicardipine hydrochloride were developed and were evaluated in vivo. The formulation compared with commercially available MICARD capsules using rabbits. Plasma concentration time curves showed a longer duration for administration (16 hours) in the sustained release floating capsules as compared with conventional MICARD capsules (8 hours).⁽⁵⁶⁾

2. Site-Specific Drug Delivery:

These systems are particularly advantageous for drugs that are specifically absorbed from stomach or the proximal part of the small intestine, eg, riboflavin and furosemide.

Eg. Furosemide is primarily absorbed from the stomach followed by the duodenum. It has been reported that a monolithic floating dosage form with prolonged gastric residence time was developed and the bioavailability was increased. AUC obtained with the floating tablets was approximately 1.8 times those of conventional furosemide tablets.⁽⁵⁶⁾

3. Absorption Enhancement:

Drugs that have poor bioavailability because of sitespecific absorption from the upper part of the gastrointestinal tract are potential candidates to be formulated as floating drug delivery systems, thereby maximizing their absorption.

Eg. A significantly increase in the bioavailability of floating dosage forms(42.9%) could be achieved as compared with commercially available LASIX tablets (33.4%) and enteric coated LASIX-long product (29.5%)⁽⁵⁷⁾

CONCLUSION:

Gastro-retentive floating drug delivery systems have emerged as an efficient means of enhancing the bioavailability and controlled delivery of many drugs. The increasing sophistication of delivery technology will ensure the development of increase number of gastroretentive drug delivery to optimize the delivery of molecules that exhibit absorption window, low bioavailability and extensive first pass metabolism.

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Received on 30.10.2011

Accepted on 27.11.2011

Research Journal of Pharmaceutical Dosage Forms and Technology. 4(1): Jan. - Feb., 2012, 1-13