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INDEX

1. INTRODUCTION a. Definition b. Classification c. Basic GIT physiology d. Advantages & disadvantages e. Floating Tablet f. Literature review g. Physiochemical characteristics h. List of drugs i. Marketed preparation 2. 3. 4. 5. 6. 7. 8. 9. 10. INGREDIENTS MECHANISM OF FLOATING APPROACH & METHODS FACTORS AFFECTING LIMITATIONS PRODUCTION & DEVELOPMENT EVALUATION APPLICATION CONCLUSION

INTRODUCTION
The oral route is considered as the most promising route of drug delivery. Effective oral drug delivery may depend upon the factors such as gastric emptying process, gastrointestinal transit time of dosage form, drug release from the dosage form and site of absorption of drugs. Most of the oral dosage forms possess several physiological limitations such as variable gastrointestinal transit, because of variable gastric emptying leading to non-uniform absorption profiles, incomplete drug release and shorter residence time of the dosage form in the stomach. 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 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. Hence a beneficial delivery system would be one which possesses the ability to control and prolong the gastric emptying time and can deliver drugs in higher concentrations to the absorption site (i.e. upper part of the small intestine). The identification of new diseases and the resistance shown towards the existing drugs called for the introduction of new therapeutic molecules. In response, a large number of chemical entities have been introduced, of which some have absorption all over the gastrointestinal tract (GIT), some have absorption windows (i.e. absorption sites, especially the upper part of the small intestine) and some drugs have poor solubility in intestinal media. The drugs belonging to the second and third categories, and the drugs which are required for local action in the stomach, require a specialized delivery system. All the above requirements can be met and effective delivery of the drugs to the absorption window, for local action and for the treatment of gastric disorders such as gastro-esophageal reflux, can be achieved by floating drug delivery systems (FDDS). To date, a number of FDDS involving various technologies, carrying their own advantages and limitations were developed such as, single and multiple unit hydro dynamically balanced systems (HBS), single and multiple unit gas generating systems, hollow microspheres and raft forming systems.
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The hydrodynamic balanced system (HBS) also called Floating drug delivery system (FDDS) is an oral dosage form (capsule or tablet) designed to prolong the residence time of the dosage form within the GIT. It is a formulation of a drug with gel forming hydrocolloids meant to remain buoyant in the stomach contents. Drug dissolution and release from the dosage form retained in the stomach fluids occur at the pH of the stomach under fairly controlled conditions. The retentive characteristics of the dosage form are not significant for the drugs that: Are insoluble in intestinal fluids Act locally Exhibit site-specific absorption. The formulation of the dosage form must comply with three major criteria for HBS. It must have sufficient structure to form a cohesive gel barrier. It must maintain an overall specific gravity less than that of gastric content. It should dissolve slowly enough to serve as a Reservoir for the delivery system. Floating systems are one of the important categories of drug delivery systems with gastric retentive behavior. Drugs that could take advantage of gastric retention include: furosemide, cyclosporine, allopurinol ciprofloxacin and metformin. Drugs whose solubility is less in the higher pH of the small intestine than the stomach (e.g. chlordiazepoxide and cinnarizine, the drugs prone for degradation in the intestinal pH (e.g. captopril), and the drugs for local action in the stomach (e.g. misoprostol) can be delivered in the form of dosage forms with gastric retention. Antibiotics, catecholamines, sedative, analgesics, anticonvulsants, muscle relaxants, antihypertensive and vitamins can be administered in HBS dosage form. Drugs reported to be used in the formulation of floating dosage forms are: Floating microspheres (aspirin, griseofulvin, p-nitroaniline, ibuprofen, terfinadine and tranilast), floating granules (diclofenac sodium, indomethacin and prednisolone), films (cinnarizine), floating capsules (chlordiazepoxide hydrogen chloride,diazepam, furosemide, misoprostol, L-Dopa, benserazide, ursodeoxycholic acid and pepstatin) andfloating tablets and pills (acetaminophen, acetylsalicylic acid, ampicillin, amoxycillin
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trihydrate, atenolol, diltiazem, fluorouracil, isosorbide mononitrate, para aminobenzoic acid, piretamide, theophylline and verapimil hydrochloride, etc.). Excipients used most commonly in these systems include HPMC, polyacrylate polymers, polyvinyl acetate, Carbopol, agar, sodium alginate, calcium chloride, polyethylene oxide and polycarbonates.

Floating tablets are the low density systems; contain one or more Hydro-Colloids which swell on contact with water to form a gel layer. This layer presents a low density system that floats on the gastro intestinal contents, thereby prolonging gastric residence time. Or Floating tablet is a solid controlled release, oral, buoyant unit dose pharmaceutical composition, which comprises of one or more therapeutic agent/drug, a gel forming husk powder one or more cross linking enhancer, one or more gas generating component and pharmaceutically accepted excipients. Or Floating tablet is a therapeutic unit dosage form as a non compressed tablet having network of multitudinous air holes and passage therein and a density of less than one and capable of floating on gastric fluid in vivo and providing sustained release of the therapeutic agent over an extended period of time.
DEFINITION

Tablets are solid dosage forms usually prepared with the aid of suitable pharmaceutical excipients. They may vary in size, shape, and weight, hardness, thickness, and disintegration and dissolution characteristic and in other aspects depending upon their intended use and method of manufacturing. Tablet is an essentially tamperproof dosage form.
TYPES OF TABLETS

A. Tablets Ingested Orally (I) Compressed Tablets (C. T.) : - In addition to medicinal agent compressed tablets usually contains a number of pharmaceuticals adjancts including

(a) Diluents or fillers, which add the necessary bulk to formulation to prepare tablets of the desired size. (b) Binders or adhesives which promote the adhesion of the particles of the formulation, enabling a granulation to be prepared and the maintenance of the integrity of the final tablet. (c) Disintegrates which promote the breakup of the tablets after administration to smaller particles for more ready drug availability. (d) Glidants lubricant (e) Colorant & flavorants (II)Multiple compressed tablets(M.C.T.) : - Multiple compressed tablets are prepared by subjecting the fill material to more than a single compression. The result may be a multiple layered tablet or a tablet-within-a-tablet, the inner tablet being the core and the outer being the shell. Each layer may contain different medical agent, separated from one another from for reasons of chemical or physical incompatibility or for unique appearance of multiple layered tablets. (III) Sugar coated tablets(S.C.T.) : - Compressed tablets may be with a colored or an uncolored sugar later . the coating coated is water soluble and

is quickly dissolved after swallowing, it serves the purpose of protecting the enclosed drug from the environment mask the objectionable tasting or smelling drugs. (IV) Film coated tablets : - Film coated tablets are compressed tablets coated with a thin layer film over the tablet. The film is usually ( colored & more durable Jess bulky & less time consuming to apply. (V) Chewable tablets : - Chewable tablets have a smooth rapid disintegration when chewed or allowed to dissolved in the mouth chewable tablets are especially useful for administration of tablets of large size to children and adults who have difficulty swallowing solid dosage forms. (VI) Enteric Coated tablets (ECT) : - E C T have delayed relays features. They are designed to pass unchanged through the stomach with transit to the intestines where the tablets disintegrates and allow drug dissolution and absorption effect.

(VII) Gelatin coated tablets : - The innovator product termed GELCAPS is capsule shaped compressed tablet that allows the coated product to be about one third smaller than a capsule filled with an equivalent amount of powder.

B. Tablet Used In Oral Cavity (I) Buccal and Sublingual Tablets: -Buccal Tablets are intended to be dissolve in the buccal and sublingual tablets, beneath tongue for absorption through the oral mucosa (II) Troches and Eozenges: - These are used in the oral cavity when they are intended to extent a local effect in the mouth or throat. These tablet forms are commonly used to treat throat or to do control coughing in the common cold. They may contain local anaesthetic and antibacterial agent's demulcents, astringents. (iii) Dental cones: - dental cones are design to be placed in the empty socket remaining following a tooth extraction. Their usual purpose is to present multiplication of bacteria in the socket following suck extraction by employing a slow-releasing antibacterial compound or to reduce bleeding by ( containing an astringent or coagulant. (C) Tablets Administerd By Other Routes (I) Implementation Tablets: - Implantation or depot tablets are designed for subcutaneous implantation in animals or man. There purpose is to provide prolonged drug effect from one month to one a year. They are usually designed to provide as constant a drug delivery release rate as possible. (II) Vaginal Tablets:-Vaginal tablets are designed to undergo slave and delay releases in the vaginal cavity tablets are ovoid or pear shape to facilitate retention in the vaginal. Tablet used to release antibacterial; agents antiseptics are astringents to treat vaginal infection are possible to release ( steroids for systematic absorption. (D) Tablets Used To Prepare Solution (I) Effervescent Tablets

Effervescent tablets are prepared by compressing granular effervescent salts that releases gas when in contact with water, These tablets generally content medicinal substances which dissolve rapidly when added to water. (II) Dispensing Tablets
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Materials that have been commonly incorporated in dispensing tablets include mild silver proteinate, bichloride of mercury, quaternary ammonium compounds.The dispensing tablets must typically comprised totally soluble components and the excipients ingredients of the tablet must not produce deleterious effects in the intended application of the solution or undesirable, physical or chemical interactions with the active agent. (III) Hypodermic Tablets Hypodermic tablets are composed of one or more drugs with other readily water-soluble ingredients and are intended to be adding to sterile water for injection. Little used today. (IV) Tablet Triturates Tablet triturates are small usually cylindrical molded are compressed tablets containing small amount of usually patient drugs. Since tablet triturate must be readily and completely soluble in water only a minimal amount of pressure is applied during their manufacture There are few tablet triturates, which remain, are used sublingually as nitroglycerine tablets.

Sustained release dosage form are drug delivery system that are designed to achieve a prolonged therapeutic effect by continuously releasing medication over an extended period of time after administration of a single dose. In recent years scientific and technological advancements have been made in the research and development of rate-controlled oral drug delivery systems by overcoming physiological adversities, such as short gastric residence times (GRT) and unpredictable gastric emptying times (GET). Several approaches are currently utilized in the prolongation of the GRT, including floating drug delivery systems (FDDS), also known as hydrodynamically balanced systems (HBS), swelling and expanding systems, polymeric bio-adhesive systems, modified-shape systems, high-density systems, and other delayed gastric emptying devices. In this review, the current technological developments of FDDS including patented delivery systems and marketed products, and their advantages and future potential for oral controlled drug delivery are discussed.

BASIC

GASTROINTESTINAL

TRACT

PHYSIOLOGY
Anatomically the stomach is divided into three regions: Fundus: proximal part of stomach. Body: it acts as a reservoir for undigested material. Antrum: main sight for mixing motions and act as a pump for gastric emptying by propelling actions. Gastric emptying occurs during fasting as well as fed states. The pattern of motility is however distinct in the two states. During the fasting state an inter-digestive series of electrical events take place ,which cycle both through stomach and intestine every two to three hours. This is called the INTERDIGESTIVE MYLOELECTRIC CYCLE or into MIGRATING MYLOELECTRIC CYCLE (MMC), which is further divided following four phases as described by Wilson and Washington. 1) 2) Phase 1 (basal phase) lasts from 40 to 60 minutes with rare contractions. Phase 2 (pre-burst phase) lasts for 40 to 60 minutes intermittent action potential and contractions. As the phase progresses the intensity and frequency also increases gradually. 3) Phase 3 (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 4 lasts for 0 to 5 minutes and occurs between phase 3 and 1 of two consecutive cycles.

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After the ingestion of 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 contraction as in phase 2 of fasted state. These contractions results in reducing the size of food particles(to less than 1mm), which are propelled toward pylorus in a suspension form. During the fed state onset of MMC is delayed resulting in slowdown of gastric emptying rate. Scintigraphic studies determining gastric emptying rates revealed that orally administered controlled release dosage forms are subjected to basically 2 complications,l)short gastric residence time and 2) unpredictable gastric emptying rate. These above 2 problems are overcome by designing the floating tablets. On comparison of floating and non-floating dosage units, it was concluded that regardless of their size (the floating dosage units remained buoyant on the gastric contents throughout their (. residence in the GIT, while the non floating dosage units sank and remained in the lower part of the stomach. Floating units away from the gastroduodenal junction were protected from the peristaltic waves during digestive phase while the non floating forms stayed close to the pylorus and were subjected to propelling and retropelling waves of the digestive phase.

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CLASSIFICATION OF

FLOATING

DRUG DELIVERY SYSTEMS


Floating drug delivery systems are classified depending on the use of 2 formulation variables: effervescent and non-effervescent systems.

Effervescent Floating Dosage Form


These are matrix type of systems prepared with the help of swell able polymers such as methylcellulose e.g. and chitosan and various effervescent compounds sodium carbonate, tartaric acid, and citric acid. They are formulated in such a

way that when in contact with the acidic gastric contents, carbon dioxide is liberated and gets entrapped in swollen hydrocolloids, which provides buoyancy to the dosage forms. There has been developed a new multiple type of floating dosage system composed of effervescent layers and swell able 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 two 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 37 oC, it settled down and the solution permeated into the effervescent layer through the outer swellable membrane. Carbon dioxide was generated by the neutralization reaction between the effervescent agents, producing swollen pills (like balloons) with a density lees than 1.0 g/ml. it was found that the system has good floating ability independent of pH and viscosity and the drug released in a sustained manner.

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It has also been 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 hydroxyl propyl ( methyl cellulose (HPMC) and poly ethylene oxide (PEO) as the rate controlling polymeric membrane excipients. Tetracycline and metronidazole were incorporated into the core layer of the triple layer on matrix for controlled delivery, while bismuth salt was included in one layer of the outer layers for instant release. The floatation was accomplished by incorporating a gas generating layer consisting of sodium bicarbonate: calcium carbonate (1:2) ratios along with the polymers. The in vitro results revealed that the sustained release of tetracycline and metronidazole over 6 to8 hours could be ( achieved while the tablet remained afloat. The floating feature aided in prolonging the) C gastric residence time of this system to maintain high localized concentration of tetracycline and metronidazole. There has been 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 semi-permeable membrane to avoid sudden loss of carbon dioxide . Upon coming in contact with gastric contents an exchange of chloride and bicarbonate ions took place that resulted in carbon dioxide generation thereby carrying beads towards the top of gastric contents and producing a floating layer of resin beads.

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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. It has been 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 <1 thereby being buoyant on the gastric contents of stomach until all the drug was released. It has also been developed hydrodynamically balanced sustained release tablets containing drug and hydrophilic hydrocolloid, which on contact with gastric fluids at body temperature form 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.

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ADVANTAGES & DISADVANTAGES


Advantages
1. convenient to patients. 2. less loss of drug. 3. toxicity can be reduced. 4. steady state of drug is obtained. 5. reduction in dosing frequency. 6. improve the tolerability 7.higher minimum plasma concentration increases the efficacy.

Disadvantages
1. Administration of sustained release medication dose not permit termination of therapy. 2. Physicians has less flexibility in adjusting dosage regimens. 3. It is designed for the normal population. 4. More costly when compared to normal formulations. 5. The drug is not effectively absorbed in the lower intestine; sustained can not be formulated when *drugs have short half life e.g.-furosemide. *drugs have long biologically half life e.g.-diazepam. * large dose is required e.g.-sulphonamides. release

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FLOATING TABLET
Floating tablet is related to an effervescent pharmaceutical preparation comprising effervescent excipients and a plurality of individual units comprising a pharmaceutically active compound and optional excipients wherein the units (1) are provided with a floating generating system. The floating generating systems comprises at least two coating layers, one of which is a gas generating layer (2) and the other layer is a barrier layer (3) enclosing the generated gas. Furthermore the invention is related to a process for the manufacture of the dosage forms, and their use in medicine.

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LITERATURE REVIEW
Ichikawa et al developed 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 37C, 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(Ichikawa et al) (Figure 1, A and B).

Figure 1. (A) Multiple-unit oral floating drug delivery system. (B) Working principle of effervescent floating drug delivery system.

Ichikawa et al developed floating capsules composed of a plurality of granules that have different residence times in the stomach and consist of an inner foamable layer of gasgenerating agents. This layer was further divided into 2 sublayers, the outer containing sodium bicarbonate and the inner containing tartaric acid. This layer was surrounded by an expansive polymeric film (composed of poly vinyl acetate [PVA] and shellac), which allowed gastric juice to pass through, and was found to swell by foam produced by the action 17

between the gastric juices and the gas-generating agents.29 It was shown that the swellable membrane layer played an important role in maintaining the buoyancy of the pills for an extended period of time. Two parameters were evaluated: the time for the pills to be floating (TPF) and rate of pills floating at 5 hours (FP5h). It was observed that both the TPF and FP5h increased as the percentage of swellable membrane layer coated on pills having a effervescent layer increased. As the percentage of swellable layer was increased from 13% to 25% (wt/wt), the release rate was decreased and the lag time for dissolution also increased. The percentage of swellable layer was fixed at 13% wt/wt and the optimized system showed excellent floating ability in vitro (TPF ~10 minutes and FP5h ~80%) independent of pH and viscosity of the medium(Ichikawa et al ) 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 pyloriassociated 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. 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 (Yang et al)(Figure 2).

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Figure 2.

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.

Ozdemir et al developed 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 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. The in vitro floating studies revealed that the lesser the compression force the shorter is the time of onset of floating, ie, when the tablets were compressed at 15 MPa, these could begin to float at 20 minutes whereas at a force of 32 MPa the time was prolonged to 45 minutes. Radiographic studies on 6 healthy male volunteers revealed 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(Ozdemir et al ). Choi et al prepared floating alginate beads using gas-forming agents (calcium carbonate and sodium bicarbonate) and studied the effect of CO2 generation on the physical properties, morphology, and release rates. The study revealed that the kind and amount of gas-forming 19

agent had a profound effect on the size, floating ability, pore structure, morphology, release rate, and mechanical strength of the floating beads. It was concluded that calcium carbonate formed smaller but stronger beads than sodium bicarbonate. Calcium carbonate was shown to be a less-effective gas-forming agent than sodium bicarbonate but it produced superior floating beads with enhanced control of drug release rates. In vitro floating studies revealed that the beads free of gas-forming agents sank uniformly in the media while the beads containing gas-forming agents in proportions ranging from 5:1 to 1:1 demonstrated excellent floating (100%).( Choi et al) Li et al evaluated the contribution of formulation variables on the floating properties of a gastro floating drug delivery system using a continuous floating monitoring device and statistical experimental design. The formulation was conceived using taguchi design. HPMC was used as a low-density polymer and citric acid was incorporated for gas generation. Analysis of variance (ANOVA) test on the results from these experimental designs demonstrated that the hydrophobic agent magnesium stearate could significantly improve the floating capacity of the delivery system. High-viscosity polymers had good effect on floating properties. The residual floating force values of the different grades of HPMC were in the order K4 M~ E4 M~K100 LV> E5 LV but different polymers with same viscosity, ie, HPMC K4M, HPMC E4M did not show any significant effect on floating property. Better floating was achieved at a higher HPMC/carbopol ratio and this result demonstrated that carbopol has a negative effect on the floating behavior(Li et al). Penners et al developed an expandable tablet containing mixture of polyvinyl lactams and polyacrylates that swell rapidly in an aqueous environment and thus reside in stomach over an extended period of time. In addition to this, gas-forming agents were incorporated. As the gas formed, the density of the system was reduced and thus the system tended to float on the gastric contents(Penners et al). Fassihi and Yang developed a zero-order controlled release multilayer tablet composed of at least 2 barrier layers and 1 drug layer. All the layers were made of swellable, erodible polymers and the tablet was found to swell on contact with aqueous medium. As the tablet dissolved, the barrier layers eroded away to expose more of the drug. Gas-evolving agent was added in either of the barrier layers, which caused the tablet to float and increased the retention of tablet in a patients stomach (Fassihi and Yang).

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Talwar et al developed 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 viscolysing agent initially and the gel-forming polymer later formed a hydrated gel matrix that entrapped the gas, causing the tablet to float and be retained in the stomach or upper part of the small intestine (spatial control). The hydrated gel matrix created a tortuous diffusion path for the drug, resulting in sustained release of the drug (temporal delivery) ( Talwar et al). Two patents granted to Alza Corporation revealed a device having a hollow deformable unit that was convertible from a collapsed to expandable form and vice versa. The deformable unit was supported by a housing that was internally divided into 2 chambers separated by a pressure-sensitive movable bladder. The first chamber contained the therapeutic agent and the second contained a volatile liquid (cyclopentane, ether) that vaporized at body temperature and imparted buoyancy to the system. The system contained a bioerodible plug to aid in exit of the unit from the body. Baumgartner et al developed a matrix-floating tablet incorporating a high dose of freely soluble drug. The formulation containing 54.7% of drug, HPMC K4 M, Avicel PH 101, and a gas-generating agent gave the best results. It took 30 seconds to become buoyant. In vivo experiments with fasted state beagle dogs revealed prolonged gastric residence time. On radiographic images made after 30 minutes of administration, the tablet was observed in animals stomach and the next image taken at 1 hour showed that the tablet had altered its position and turned around. This was the evidence that the tablet did not adhere to the gastric mucosa. The MMC (phase during which large nondisintegrating particles or dosage forms are emptied from stomach to small intestine) of the gastric emptying cycle occurs approximately every 2 hours in humans and every 1 hour in dogs but the results showed that the mean gastric residence time of the tablets was 240 60 minutes (n = 4) in dogs. The comparison of gastric motility and stomach emptying between humans and dogs showed no big difference and therefore it was speculated that the experimentally proven increased gastric residence time in beagle dogs could be compared with known literature for humans, where this time is less than 2 hours(Baumgartner et al). Moursy et al developed sustained release floating capsules of nicardipine HCl. For floating, hydrocolloids of high viscosity grades were used and to aid in buoyancy sodium bicarbonate 21

was added to allow evolution of CO2. In vitro analysis of a commercially available 20-mg capsule of nicardipine HCl (MICARD) was performed for comparison. Results showed an increase in floating with increase in proportion of hydrocolloid. Inclusion of sodium bicarbonate increased buoyancy. The optimized sustained release floating capsule formulation was evaluated in vivo and compared with MICARD capsules using rabbits at a dose equivalent to a human dose of 40 mg. Drug duration after the administration of sustained release capsules significantly exceeded that of the MICARD capsules. In the latter case the drug was traced for 8 hours compared with 16 hours in former case(Moursy et al). Atyabi and coworkers 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 3) .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)( Atyabi and coworkers).

Figure 3. Pictorial presentation of working of effervescent floating drug delivery system based on ion exchange resin.

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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 al 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 (Thanoo et al). Nur and Zhang developed floating tablets of captopril using HPMC (4000 and 15 000 cps) and carbopol 934P. In vitro buoyancy studies revealed that tablets of 2 kg/cm2 hardness after immersion into the floating media floated immediately and tablets with hardness 4 kg/cm2 sank for 3 to 4 minutes and then came to the surface. Tablets in both cases remained floating for 24 hours. The tablet with 8 kg/cm2 hardness showed no floating capability. 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 center 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(Nur and Zhang). Bulgarelli et al studied the effect of matrix composition and process conditions on casein gelatin beads prepared by emulsification extraction method. Casein by virtue of its emulsifying properties causes incorporation of air bubbles and formation of large holes in the beads that act as air reservoirs in floating systems and serve as a simple and inexpensive material used in controlled oral drug delivery systems. It was observed that the percentage of casein in matrix increases the drug loading of both low and high porous matrices, although the loading efficiency of high porous matrices is lower than that of low porous matrices. (Bulgarelli et al) 23

Fell et al 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(Fell et al). Streubel et al 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(Streubel et al ). 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(Asmussen et al). El-Kamel et al prepared floating microparticles of ketoprofen, by emulsion solvent diffusion technique. Four different ratios of Eudragit S 100 with Eudragit RL were used. The formulation containing 1:1 ratio of the 2 above-mentioned polymers exhibited high percentage of floating particles in all the examined media as evidenced by the percentage of particles floated at different time intervals. This can be attributed to the low bulk density, high packing velocity, and high packing factor(El-Kamel et al ). Illum and Ping developed microspheres that released the active agent in the stomach environment over a prolonged period of time. The active agent was encased in the inner core of microspheres along with the rate-controlling membrane of a water-insoluble polymer. The outer layer was composed of bioadhesive (chitosan). The microspheres were prepared by spray drying an oil/water or water/oil emulsion of the active agent, the water-insoluble polymer, and the cationic polymer(Illum and Ping). Streubel et al developed floating microparticles composed of polypropylene foam, Eudragit S, ethyl cellulose (EC), and polymethyl metha acrylate (PMMA) and were prepared by solvent evaporation technique. High encapsulation efficiencies were observed and were 24

independent of the theoretical drug loading. Good floating behavior was observed as more than 83% of microparticles were floating for at least 8 hours. The in vitro drug release was dependent upon the type of polymer used. At similar drug loading the release rates increased in the following order PMMA < EC < Eudragit S. This could be attributed to the different permeabilities of the drug in these polymers and the drug distribution within the system (Streubel et al). 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 (Sheth and Tossounian)(Figure4).

Figure 4. 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 25

temperature formed a soft gelatinous mass on the surface of the tablet and provided a waterimpermeable 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. (Sheth and Tossounian)

Figure 5. 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 (Ushomaru et al). Bolton and Desai developed a noncompressed sustained release tablet that remained afloat on gastric fluids. The tablet formulation comprised 75% of drug and 2% to 6.5% of gelling agent and water. The noncompressed tablet had a density of less than 1 and sufficient mechanical stability for production and handling(Bolton and Desai). Kawashima et al prepared multiple-unit hollow microspheres by emulsion solvent diffusion technique. Drug and acrylic polymer were dissolved in an ethanol-dichloromethane mixture, and poured into an aqueous solution of PVA with stirring to form emulsion droplets. The rate of drug release in micro balloons was controlled by changing the polymer-to-drug ratio. 26

Microballoons were floatable in vitro for 12 hours when immersed in aqueous media. Radiographical studies proved that microballoons orally administered to humans were dispersed in the upper part of stomach and retained there for 3 hours against peristaltic movements.( Kawashima et al) Dennis et al invented a buoyant controlled release pharmaceutical powder formulation filled into capsules. It released a drug of a basic character at a controlled rate regardless of the pH of the environment. PH-dependent polymer is a salt of a polyuronic acid such as alginic acid and a pH-independent hydrocarbon gelling agent, hydroxypropylmethyl cellulose(Dennis et al). Spickett et al invented an antacid preparation having a prolonged gastric residence time. It comprised 2 phases. The internal phase consisted of a solid antacid and the external phase consisted of hydrophobic organic compounds (mono-, di-, and triglycerides) for floating and a non-ionic emulsifier(Spickett et al). Franz and Oth described a sustained release dosage form adapted to release of the drug over an extended period of time. It comprised a bilayer formulation in which one layer consisted of drug misoprostal and the other had a floating layer. The uncompressed bilayer formulation was kept in a capsule and was shown to be buoyant in the stomach for 13 hours. The dosage form was designed in such a way that all the drug was released in the stomach itself(Franz and Oth ). Wu et al developed 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 occurred(Wu et al). Wong et al developed a prolonged release dosage form adapted for gastric retention using swellable polymers. It consisted of a band of insoluble material that prevented the covered portion of the polymer matrix from swelling and provided a segment of a dosage form that was of sufficient rigidity to withstand the contractions of the stomach and delayed the expulsion of the dosage form from the stomach(Wong et al).

27

Mitra developed a sustained release multilayered sheet-like medicament device. It was buoyant on the gastric contents and consisted of at least 1 dry, self-supporting carrier film of water-insoluble polymer. The drug was dispersed or dissolved in this layer and a barrier film overlaid the carrier film. The barrier film was compsosed of 1 water-insoluble layer and another water-soluble and drug-permeable polymer or copolymer layer. The 2 layers were sealed together in such a way that plurality of small air pockets were entrapped that gave buoyancy to the formulation(Mitra). Harrigan developed an intragastric floating drug delivery system that was composed of a drug reservoir encapsulated in a microporous compartment having pores on top and bottom surfaces. However, the peripheral walls were sealed to prevent any physical contact of the drug in the reservoir with the stomach walls(Harrigan). Joseph et al 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(Joseph et al).

28

PHYSICOCHEMICAL CHARACTERISTICS
Physicochemical Characteristics Of Drug Molecules are

l. pKa 2. Solubility and Dissolution Rate Solubility Dissolution Rates Factors Affecting Solubility and Dissolution Rates 3. Chemical Stability 4. Complexation 5. Adsorption

Dosage Form Design Considerations


1. Liquid versus Solid Dosage Forms 2. Modulation of Gastric Emptying 3. Enteric-Coated Products 1. Rationale 2. Definition 3. Henderson-Hassel balch-Equations The majority of drugs are either weak acids or weak bases. Each weak acid/base has a pKa value. The pKa value is the single most important parameter that permeates the entire learning process in pharmaceutics. It will remain to be a necessary part of your professional practice as well. You will meet it again, again, and again.unionized form affects drug's solubility, permeability, binding, and other. Why is it so important? It is because pKa affects the proportion of drug molecules in the ionized and unionized forms. The ratio of ionized over characteristics.

Definition
29

Ka and KB are originally defined as the equilibrium constant of the dissociation process of an acid and a base, respectively. pKa (pKb) is equal to -logKa (-log Kb).
W For Acids:
.

For Bases:

f HA <--> H+ + A' Ka = [H+][A']/[HA]

NaOH <--> OH" + Na+ * Kb = [OH'] [Na+]/[NaOH]

For weak acids, the higher the [FT 1"] or the stronger the acid, the higher the Ka, the higher the logKa, but the lower the -logKa or pKa. For weak bases, the higher the [OH'J or stronger the base, the higher the Kb, the higher the logKb, but the lower the-pKb.

Henderson-Hassel balch Equations


One of the best known set of equations in the pharmaceutics, it will permeate all the classes that deal with dosage forms. pH - pKa = log [A"]/[HA] The world famous Henderson-Hasselbalch equation for acids. pH - pKa = log [B]/[BH+] The world famous Henderson-Hasselbach equation for bases

Solubility and Dissolution Rate 1 Solubility


Solubility is the concentration of drug molecules in a particular dissolution media. Solubility is measured after drug of interest has had sufficient contact time (how ever long it takes) with the dissolution media. They are two types of solubility: one is called intrinsic solubility, the other the apparent solubility. The intrinsic solubility is defined as concentration of drug in pure water. It is often derived from calculation, and is a single numeric number microgram/milliliter) that is independent of the environmental factors
.

The apparent solubility is dependent on the environmental factors such as pH and ionic strength. This number may be obtained with experimental C measurement.
30

C o The relationship: Cs = Cs* (1+Ka/fH*]) for weak acids Cs


.

(l+[FT]/Ka)

for

weak

bases

2 Dissolution Rate
Dissolution rate is the rate at which drug solids dissolve in a dissolution media. For drugs whose absorption rates are faster than the dissolution rates (e.g., steroids), the ratelimiting step in the absorption process is often the dissolution rate. Because of a limited residence time at the absorption site, drugs that are not dissolved before they are removed from intestinal absorption site are considered useless. Therefore, the rate of dissolution has a major impact on the performance of drugs that are poorly soluble. Because of this factor, the dissolution rate of drugs in solid dosage forms is an important, routine, quality control parameter used in the drug manufacturing process. o Dissolution rate = K S (CSC)

31

where K is dissolution rate constant, S is the surface area, Cs is the apparent solubility, and C is the concentration of drug in the dissolution 4. media. For rapid drug absorption, CS-C is approximately equal to Cs T.' f Therefore, Dissolution rate = KS (Cs)

Factors Affecting Dissolution Rates:


Factors affecting apparent solubility of acids and bases.

Cs = [HA] + [A'] + [A'] for weak acids Cs = [B] + [BH+] = C* + [BH+] for weak bases where Cs* is the intrinsic solubility of the unionized form. These equations indicate that pH will affect the solubility of weak acids/bases. Because the ionized form has higher apparent solubility than the unionized form, manipulation of pH is an effective means of changing a drug's apparent solubility. This strategy is commonly used in the development of parenteral drugs, where salt form of the drug molecules are frequently used.

Factors affecting K
Chemical form: Salt forms generally have a higher solubility and dissolution rate than their acidic and basic counterparts. Crystal form: The amorphous form generally has a higher solubility than the rystalline form. Wettability: For poorly soluble drugs that are difficult to wet, wetting agents (e.g., surfactants) may be useed to increase the solubtility.

32

Factors affecting
Particle size: The smallest particle size/unit weight has the largest surface area/unit weight.

Chemical Stability
Chemical stability at the absorption site is seldom a problem for modern p. pharmaceuticals. However, instability in the stomach has prevented many drugs to be developed, including many peptide and nucleotide-like drugs that were very potent. Chemical instability can sometimes be circumvented by using prodrugs to mask the unstable functional group(s).Documented examples of chemical instability in the GI tract are: penicillin G, digoxin, and certain ester analogs of erythromycin.

Complexation
Complexation of a drug in the GI fluid/tract may significantly alter the absorption characteristics of the drugs. Documented examples include: Intestinal mucus, which contains the polysaccharide mucin, can avidly bind streptomycin and dihydrostreptomycin. These binding may contribute to the poor absorption of antibiotics. Bile salts may interact with certain drugs such as tubocurarine, neomycin, and kanamycin to form insoluble, nonabsorble complexes. Tetracycline form insoluble complexes with Ca. been used to form a complex with digoxin for increased solubility, which results in increased absorption rate. Complexes are sometimes used to increase or decrease solubility. Hydroquinone has

33

Adsorption
Adsorption of drug molecules to certain components of dosage forms or to L0 macromolecular resin could be both beneficial and detrimental to achieving 4 desirable outcomes. Charcoal is a strong absorber, and a common antidote in drug intoxication.It is effective in decreasing the absorption of promazine, by forming a strong complex of promazine and charcoal. Absorption of lincomycin has been shown to be less when taken with a ^ commercial kaolin-pectin mixture for diarrhea, because the mixture binds strongly with lincomycin. Cholestyramine and colestipol are resin that binds to bile salts and cholesterol metabolites to make them not available for absorption. Unfortunately, they may' also bind to other drugs. Cholestyramine has been shown to decrease the If absorption of thyroxine, warfarin, phenoprocoumon, and digoxin.

Dosage Form Design Considerations


o o Liquid versus Solid Dosage Forms The absorption of drugs delivered as liquid dosage forms is generally much faster than the absorption of drugs delivered as the solid dosage forms. The faster absorption is the result of faster gastric emptying and/or faster dissolution. The latter is only relevant if the liquid dosage form has co-solvents which enhance drug solubility. In other words, the drug may precipitate into fine particles, which require subsequent dissolution before they are absorbed. o Absorption of solid dosage forms may also be decreased by various factors that decrease the gastric emptying of intact doage forms. These factors include: size of the dosage forms, presence or absence of food, and density of the dosage forms. In general, larger and lighter dosage forms are emptied slower, whereas the presence of food (especially those that are rich in sugar and fat) slows down the emptying of the dosage form. Modulation of Gastric Emptying o Solid dosage forms can be designed to slow the gastric emptying to achieve sustained release of drugs. These dosage forms include:
34

Floating devices o Natural floating tablets: wafer The retention potentials of dosage forms depends on their design, o Balloon device o Swelling device Sandwich Hydrogel: Experimental Hydrogels expand greatly in volume when it gains contact with water. Bioadhesive polymers

This delivery strategy uses ionic attraction between negative charge (biomembrane) and positive charge (polymer) to improve the retention of the dosage forms in the stomach.Other devices Shape of dosage forms have a significant effect on their gastric emptying. It has been shown that dosage forms with rigid bulky structures have higher retention in the stomach than those with more flexible linear structures.

Enteric-Coated Products
Enteric-coated products are not disintegraded in the stomach. It will be emptied intact into the small intestine, where it will disintegrate, dissolve, IP and eventually be absorbed.Enteric-coated products typically have slower onset. Therefore, entericcoated products are mainly used for drugs that are unstable in, or cause irritation to the stomach. Therefore, enteric-coated products cannot be cut or physically altered, because the intactness of the coat is critical to its desirable performance.

35

List of Drugs Formulated as Floating Drug Delivery Systems


Dosage form Example
Tablets Capsules Chlorpheniramine maleate Theophylline Furosemide Ciprofloxacin Captopril Acetylsalisylic acid Amoxycillin tryhydrate Verapamil HCL Isosorbide dinitrate Sotalol Atenolol Ampicillin Diltiazem Florouracil Prednisolone Riboflavin-5' phosphate Nicardipine L-dopa and benserzide Chlordizepoxide Furosemide
Misoprostal Diazepam Propranolol
36

Microspheres Verapamil Aspirin Iboprufen Granules Indomethacin Diclofenac sodium Prednisolone Films Drug delivery device Cinnarizine Powders Several basic drugs

37

Marketed Preparations of Floating Tablets


Product active ingredient
Madopar levodopa and benserzide Valrelease diazepam Topalkan aluminium magnesium antacid Almagate flatcoat antacid Liquid gavison alginic acid and sodium bicarbonate

38

Some of the marketed formulations are listed as follows: Table Marketed Products of GRDDS Brand name Valrelease Delivery system Floating capsule Drug (dose) Diazepam (15mg) Company name Hoffmann-LaRoche, USA Madopar HBS (Prolopa HBS) Floating, CR capsule Benserazide (25mg) and Roche Products, USA L-Dopa (100mg)

Liquid Gaviscon Effervescent Floating liquid alginate preparations

Al hydroxide (95 mg), Mg Carbonate (358 mg)

GlaxoSmithkline, India

Topalkan

Floating liquid alginate Al Mg antacid preparation

Pierre Fabre Drug, France

Almagate Flot coat Conviron

Floating dosage form

Al Mg antacid

-----------

Colloidal gel forming FDDS

Ferrous sulphate

Ranbaxy, India

Cytotech

Bilayer floating capsule Misoprostol (100g/200g)

Pharmacia, USA

Cifran OD

Gas-generating floating Ciprofloxacin (1gm) form

Ranbaxy, India

39

INGREDIENTS OF FLOATING TABLETS


ACTIVE INGREDIENTS:Food supplement, vitamins, minerals, trace elements, active drug substances. HIGHLY SWELLING SUBSTANSES:Water soluble-: alginates, pectins, dextran, chitin, gelatin, hemicellulose, methylcellulose, alcohol, etc. Lipophilic-: steryl alcohol, stearic acid, glycerides, fatty alohol esters, cellulose acetate, acrylic acetate, etc. hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, corboxy methylcellulose, polyacrylic acid polyvinyl

EXCIEPIENTS:Lubricants-: stearates of alluminium, calcium, magnesium, tin, magnesium silicates, etc. Binders-: starch, alginates, corboxymethyl cellulose, polyvinyl pyrolidone, etc. Disintegrates-: starch, starch paste, microcrystalline cellulose, etc. Flow regulators-: talc, colloidal silica, starch, free flowingmicrocrystaline cellulose, etc. Stabilizers-: microcrystaline cellulose, corboxymethyl cellulose, etc. Bulking agents-: alluminium oxide, magnesium oxide, silicon oxide, titanium oxide, calcium carbonate, etc.

40

MECHANISM OF FLOATING TABLETS


After intake of the slow-release dosage form it reaches the stomach, where it is normally transported after 0.5-3 h into the small intestine. The time to pass through the small intestine is usually 3-6 h. The result of this is that absorption of the active ingredient must be complete within about 3-6 h because most active ingredients are absorbed in the colon to only a negligible extent or not at all. It is therefore possible to adjust a longer release-slowing period only with difficulty. The bioavailability of active ingredients which are not completely absorbed in this period decreases because part of the dose is lost. An additional factor is that certain active ingredients have an absorption window, which is very quickly passed through with conventional dosage forms, in the small intestine. A system which remains in the stomach for a longer time and continuously releases active ingredient would avoid these disadvantages, since the active ingredient would continuously pass through the pylorus in dissolved form and could be taken up in the small intestine. It is possible in this way on the one hand to extend the bioavailability but also, on the other hand, to extend the duration of action, for example of a drug product. There have been frequent approaches to extending the residence time by tablets which swell in the stomach and become so large that they are no longer able to pass through the pylorus. All these forms have the disadvantage that they may block the outlet from the stomach and may cause health problems. In addition, the swelling depends greatly on the contents of the stomach and the osmolarity of the medium. These eventually also influence the release-slowing action and the residence time. Another possibility for extending the residence time in the stomach is to produce floating forms. These float on the contents of the stomach and, because the pylorus is located in the lower part of the stomach, are not discharged into the small intestine for a lengthy period.

41

APPROACHES & METHOD


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. 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. Floating systems can be based on the following: 1. Hydrodynamically balanced systems (HBS) incorporated buoyant materials enable the device to float; 2. 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; 3. Low-density systems -- have a density lower than that of the gastric fluid so they are buoyant; 4. 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.
5. High-density Systems - 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 3g/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 5.825 hours, depending more on density than on diameter of the pellets, although many conflicting reports stating otherwise also abound in literature.
42

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.

43

Fig: 1 is showing the floating drug delivery in stomach and fig: 2 demonstrate the mechanism of floating drug delivery systems.

44

FACTORS AFFECTING
1. Density gastric retention time (GRT) is a function of dosage form buoyancy that is dependent on the density; 2. 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; 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, the 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 longe 6. 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; 7. Caloric content GRT can be increased by four to 10 hours with a meal that is high in proteins and fats; 8. 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; 9. Gender mean ambulatory GRT in males (3.40.6 hours) is less compared with their age and race matched female counterparts (4.61.2 hours), regardless of the weight, height and body surface); 10. Age elderly people, especially those over 70, have a significantly longer GRT;

45

11. Posture GRT can vary between supine and upright ambulatory states of the patient; 12. Concomitant drug administration anticholinergics like atropine and propantheline, opiates like codeine and prokinetic agents like metoclopramide and cisapride; can affect floating time. 13. Biological factors diabetes and Crohns disease, etc.

46

LIMITATIONS
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 Floating system is not feasible for those drugs that have solubility or stability problem in gastric fluids. The dosage form should be administered with a minimum of glass full of water (200250 ml). The drugs, which are absorbed throughout gastro-intestinal tract, which under go firstpass metabolism (nifedipine, propranolol etc.), are not desirable candidate. Some drugs present in the floating system causes irritation to gastric mucosa.

47

PRODUCTION OF FLOATING TABLETS


Various processes are known for producing sustained release dosage forms or floating tablets. Thus, it is possible to incorporate substances which have per se a low density, such as, for example, fats, oils or waxes. However, relatively large amounts are necessary for this and increase the volume of the dosage forms and makes them more difficult to swallow and, in addition, these substances have a very disadvantageous effect on the strength of the shaped products. Compression results in tablets with low harnesses, and the tablets frequently adhere to the punch during production. Fat-containing mixtures which are packed into a capsule and must be heated for solidification. This is complicated and entirely unsuitable for temperature-labile active ingredients. Shaped articles are produced by cooling and gelling and drying. This process is even more elaborate. Another method makes use of the evolution of gas from salts of carbonic acid. This entails these salts being incorporated together with gel formers into the dosage forms and, after exposure to gastric acid, produced and inflates the form and leads to the floating. In order to be independent of gastric acid there is frequently incorporation of physiologically tolerated acids such as, for example, citric acid or tartaric acid. These preparations are very sensitive to moisture, so that humidity must be low during \ production and no water-containing excipients can be employed. The packaging material for the dosage forms must be very leakproof so that the forms do not effervesce even during storage. The evolution of gas on contact with acid often also affects the structure of the dosage forms and the release-slowing effect is reduced. Since these preparations are often difficult to compress, and tablets with adequate mechanical stability are not obtained, such preparations are frequently and inconveniently packed in hard or soft if gelatin capsules. Besides the disadvantages already mentioned above, with these tablets there are enormous problems with reproducibility of the release. It is generally known that the gelforming capacity and the gel strength of polysaccharides varies from batch to batch because of the variation in the chain length and the degree of substitution, and this is

exacerbated by the disturbance of the gel structure through evolution of C02 In addition, T the gel formers react very sensitively to differences in the qsmolarity of the release * media, with alterations in the release.

48

Some other methods


The tablets of this invention have a density of less than one and will float on gastric fluid in vivo. They are sustained release dosage units, i.e. they release their medicaments over an extended period of time. The actual rate of release varies with the amount of exposed surface area and, therefore, with size and shape of the tablet. The non-compressed tablets of the present invention may be prepared by the following method: 1.
2. 3.

Prepare a solution of the hydrocolloid gelling agent and excipients, if any, in hot water;
Prepare a mixture of a therapeutic agent and therapeutically acceptable inert oil; Cool the solution of gelling agent, but not to the point where gelation takes place, and combine the solution and the mixture from step (2) with stirring, while maintaining the temperature above the gelation temperature;

4. 5.

Pour the mixture from step (3) into a tablet mold and allow to stand in the mold to form a gel; and Dry the molded gel tablets to reduce the water content. The solution temperature for

the gelling agent is generally about 70 degree.

The specific temperature depends upon the gelling agent used in the formulation. The following examples are given by way of illustration only to have idea about the formulation of floating tablet.

EXAMPLE-1 (www.patentgenius.com/patent/4814179.html)
Theophylline tablets were prepared from the following formulation, using agar as gelling Ingredients grams Theophylline 9.0 Light mineral oil 2.0 Agar 0.2 Water 10. The theophylline and mineral oil were charged into % 42 9. 0.9 a beaker and stirred. Water and

agar were placed in a separate beaker, stirred and heated to boiling to effect solution.
49

The agar solution was cooled to TO.degree. C. and gradually added to the theophylline-oil mixture with vigorous stirring to form an oil-in-water emulsion. The warm emulsion was poured at 50.degree.-55.degree. C. into a tablet mold in which the cylindrical holes had a height of about 0.46 cm and a diameter of about 1.10 cm. The compositions in the holes, were allowed to cool and gelled in about 5 minutes. The tablets were removed from the mold and air dried for 24 hours. The average density of the tablets (average of 10 tablets) was 0.70. The release of theophylline from the tablets was determined using the U.S. Pharmacopeia basket method at 50 rpm and 37.degree. C. The dissolution medium was either at pH 1.2

50

(concentrated HC1 diluted withwater) or pH 7.4 (buffer solution containing sodium hydroxide, potassium phosphate and distilled water, as described in U.S.P. XX).

EXAMPLE -2
Theophylline tablets were prepared as described in Example 1, using iota carrageenan as the gelling agent, in the following formulation: Ingredients grams %

Theophylline 6.0 32.8 Iota carrageenan 0.3 1.6 Mineral oil 2.0 10.9 Water 10.0 54.6 After 24 hours air drying, the l.ll.times.0.48 cm tablet weighed 234 mg, the hardness was 6.2 kg and the density was 0.576.

EXAMPLE-3
Theophylline tablets were prepared as described in Example 1, using kappa carrageenan as the gelling agent, in the following formulation: Ingredients Theophylline Kappa carrageenan Mineral oil Water grams 6.0 0.3 2.0 10.0
:

% 32.8 1.6 10.9 54.6

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After 24 hours air drying, the l.ll.times.0.48 cm tablet weighed 237 mg, the hardness was 5.2 kg and the density was 0.580.

EXAMPLE -4
Theophylline tablets were prepared as described in Example 1, using a mixture of iota carrageenan and locust bean gum as gelling agent in the following formulation: Ingredients Theophylline Iota carrageenan Locust bean gum Mineral oil Water After 24 hours air drying, grams % 6.0 32.8 0.2 1.1 0.1 0.5 2.0 10.9 10.0 54.6 the l.ll.times.0.48 cm tablet weighed 221 mg, the hardness

was 7.9 kg and the density was 0.546.

EXAMPLE - 5
Theophylline tablets were prepared as described in Example 1, using a mixture of alginic T acid and locust bean gum as gelling agent, in the following formulation: Ingredients grams Theophylline Alginic acid Locust gum Mineral oil Water 2.0 10.0 10.9 54.6 %* 6.0 0.2 bean 0.1 32.8 1.1 0.5

After 24 hours air drying, the 1.11=0.48 cm tablet weighed 226 mg and the hardness was 7.4 kg. The density of the tablet was 0.554.

EXAMPLE - 6
Ampicillin floating tablets were prepared using agar as the gelling agent, according to the following formulation: Ingredients grams 52

Ampicillin, anhydrous

90.0

32.5 5.8 1.15 2.9

Light mineral oil 16.0 Agar Sodium citrate Water 3.2 8.0

160.0 57.7

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This formulation was used to make a batch of 300 tablets. The mineral oil was added to the ampicillin previously charged into a 500 ml beaker and mixed thoroughly with a glass rod. In a separate beaker, the water was heated to 90.degree. C. and the sodium citrate was dissolved therein with stirring. The agar was added to the aqueous solution and stirred while heating until the agar dissolved. The ampicillin-oil mixture which was in the form of a powder was added in portions to the agar solution at 70.degree.C. and mixed with an electric whisk until a smooth, creamy suspension was obtained. The suspension was poured into a tablet mold at 48.degree.-50.degree. C. The suspension gelled after cooling for 10 minutes. The excess was scraped off the top of the molds, the tablets were pushed out of the molds and air dried at room temperature for 24 hours.

EXAMPLE - 7
Captopril tablets were prepared in the same manner as described in Example 6, using agar as gelling agent, according to the following recipe: Ingredients grams % Captopril Light mineral Oil Agar Lactose 7.0 1.0 0.3 1.0 35.7 5.1 1.5 5.1 1.5 51.0

Calcium Gluconate 0.3 Water 10.0

The captopril-oil mixture was added to the aqueous solution containing agar, lactose and calcium gluconate at 70.degree. C. and after mixing thoroughly was poured into the tablet mold at 50.degree. C. The molded gel tablets were air dried for 36 hours. The size of the dried tablet was 0.95.times.0.32 cm and the average tablet weight was 134 mg. The hardness was 9.9 kg and the average tablet density was 0.817. A friability test showed a loss of 0.84%.

Development of floating drug dosage form


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Development of a multifunctional matrix drug delivery system surrounded by an impermeable cylinder

A multifunctional drug delivery system based on hydroxypropyl methylcellulose (HPMC)-matrices (tablets) placed within an impermeable polymeric cylinder (open at both ends) was developed. Depending on the configuration of the device, extended release, floating or pulsatile drug delivery systems could be obtained. The release ( behaviour of the different devices was investigated as a function of HPMC viscosity C grade, HPMC content, type of drug (chlorpheniramine maleate or ibuprofen), matrix weight, position of the matrix within the polymeric cylinder, addition of various fillers (lactose, dibasic calcium phosphate or microcrystalline cellulose) and agitation rate of the release medium. The drug release increased with a reduced HPMC viscosity grade, higher aqueous drug solubility, decreased HPMC content and increased surface area of the matrix. The release was fairly independent of the agitation rate, the position of the tablet within the polymeric cylinder and the length of the cylinder. With the pulsatile device, the lag time prior to the drug release could be controlled through the erosion rate of the matrix (matrix weight and composition).

55

OPTIMISATION TABLETS

OF FLOATING

MATRIX

AND EVALUATION OF THEIR

GASTRIC RESIDENCE TIME


Effervescent FDDS investigation concerns the development of the floating matrix tablets, which after oral administration are designed to prolong the gastric residence time, increase the drug bioavailability and diminish the side effects of irritating drugs. The importance of the composition optimization, the technological process development for the preparation of the floating tablets with a high dose of freely soluble drug and characterization of those tablets (crushing force, floating properties in vitro and in vivo, drug release) was examined. Tablets containing hydroxypropyl methylcellulose (HPMC), drug and different additives were compressed. The investigation shows that tablet composition and mechanical strength have the greatest influence on the floating properties and drug release. With the incorporation of a gas-generating agent together with microcrystalline cellulose, besides optimum floating (floating lag time, 30 s; duration of floating, '(8 h), the drug content was also increased. The drug release from those tablets was sufficiently sustained (more than 8 h) and non-Fickian transport of the drug :from tablets was confirmed. Radiological evidence suggests that, that the formulated tablets did not adhere to the stomach mucus and that the mean gastric residence time was prolonged. FDDS buoyant delivery systems utilize matrices prepared with swellable polymers such as hypromellose or polysaccharides, e.g., Chitosan, and effervescent components, e.g., sodium bicarbonate and citric or tartaric acid or matrices containing chambers of liquid that gasify at body temperature. The matrices are fabricated so that upon arrival in the stomach, carbon dioxide is liberated by the acidity of the gastric contents and is entrapped in the gellified hydrocolloid. This produces an upward motion of the dosage form to float on the chyme. The carbonates, in addition to imparting buoyancy to these formulations, provide the initial alkaline microenvironment for polymers to gel. Moreover, the release of CO2 helps to accelerate the hydration of the floating tablets, which is essential for the formation of a bioadhesive hydrogel. This provides an additional mechanism (bioadhesion) for retaining the dosage form in the stomach, apart
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from floatation. Floating dosage forms with an in situ gas generating mechanism are expected to have grater buoyancy and improved drug release characteristics. However, the optimization of the drug release may alter the buoyancy and, therefore, it is sometimes necessary to separate the control of buoyancy from that of drug release kinetics during formulation optimization. From the results of resultant-weight measurements of various excipients, it is concluded that higher molecular weight polymers and slower rates of polymer hydration are usually associated with enhanced floating behavior. Hence, the selection of high molecular weight and less hydrophilic grades of polymers seems to improve floating characteristics.

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EVALUATION OF FLOATING TABLETS


Invitro evaluation of SR formulation are done for two purposes: (1) As a guide to formulation during development stage. (2) To ensure batch to batch uniformity

Invitro evalution:
Assay: To ensure drug content, the SR formulations are assayed by Colorimetric and Spectrophotometric methods. Dissolution : dissolution testing for SR formulations are limited to USP dissolution testing methods, using either the rotating basket method (apparatus 1) and the paddle type (apparatus 2) . Apparatus 1: it is basically a close compartment, beaker type of a cylinder glass vessel with hemispherical bottom of 1 liter capacity partially immersed in water bath to maintain temperature at 37 C. a cylindrical basket made of mesh no 22 to hold the dosage form is located centrally in the vessel at a distance of 2 cm from bottom and rotated by a variable speed motor through a shaft. Apparatus 2: The assembly is same as that of apparatus 1 except that the rotating basket is replaced with a paddle which act as a stirrer. The SR tablets are first kept in 0.1 N HCL for specific time (stimulated gastric fluid) and followed by a media of pH 7.2 (simulated intestinal fluid) for specific time.

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Beside the USP dissolution testing apparatus the rotating bottle, stationary basket and rotating filter, Sartorius absorption and solubility stimulater, and column type flow through apparatus are aso used.
Rotating bottle : The Rotating bottle apparatus consists of a rotating bottle of capacity 90 ml. 60 ml of fluid is kept at 37 C and rotetas at a speed of 40 rpm. The tablet which has to be evaluated is introtruced onto the samples are withdrawal at regular interval and is analysed. Sartorius device : the Sartorius device consists of an artificial lipid membrane which separates the dissolution chamber from a simulated plasma compartment in which drug concentration are measured. The time of testing may vary from 6-12 hours. Sink condition can obtained by recirculating the media and thus the cumulative release can be obtained. In certain case, the drug is exposed to media of pH 4-5, considering the transition between gastric and intestinal pH Stability studies are completed since accelerated stability studies may induce changes in the system. For a sustained release product, the stability testing dependson the dosage -form and its composition.

In vivo evaluation:
In vivo Mesurment of drug availability: In vivo testing for drug is done in human beings or animal models like dogs during the product development stage, animal models are preferred. In vivo drug availability for SR formulation are done either by periodic blood level determination or urinary excretion data. In vivo measurements are done to find out release rate of drug and to notice the drug dumping. If drug level cannot be measured in biological fluids, the pharmacological effect must be observed.

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APPLICATIONS OF FLOATING TABLETS


Floating drug delivery offers several applications for drugs having poor bioavailability dosage form at the site of absorption and thus enhances the bioavailability. These are summarized as follows.

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 this system. These systems have 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. Recently 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 (Shours). Similarly a comparative study between the madopar HBS and Madopar standard formulation was done and it was shown that the drug was released up to 8 hours in vitro in the former case and release was essentially complete in less than 30 minutes in the latter case.

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Site Specific Drug Delivery


These systems are particularly advantageous for drugs that are specially absorbed for stomach or the proximal part of the small intestine, e.g. riboflavin and fiirosemide. 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. A bilayer floating capsule was developed for local delivery of misoprostol, which is a synthetic analog of prostaglandin El used as a protectant of gastric ulcers caused by administration of NSAIDs. By targeting slow delivery of misoprostol to the stomach, desired therapeutic levels could be achieved and drug waste could be reduced.

Absorption enhancement
Drugs that have poor bioavailability because of site specific absorption from the upper part of the GIT are potential candidates to be formulated as floating drug delivery systems, thereby maximizing their absorption. A significant increase in the bioavailability of floating dosage forms (42.95%) could be achieved as compared with commercially available LASIX tablets (33.4%) and enteric coated LASIX long product (29.5%). The absorption of bromocriptine is limited to 30% from the GIT tract, however an HBS of the same can enhance the absorption.

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Floating tablets as a new approach to the treatment of Helicobacter pylori infections


Floating tablets offer a new possibility of treating the stomach infected with Helicobacter pylori. The objective of this study was to select suitable materials for the formulation of floating tablets with sustained drug release properties. In the preformulation studies the differences between cellulose polymer (HEC, HPC, HPMC K4M, Avicel) isotherms were estimated using the DVS method and the disappearance of gas-generating agent at higher relative humidities was observed. The correlation between wettability and the floating lag time proves that the first contact with water is not essential for good floating. Tablets with an incorporated drug stored at high relative humidity have a lower crushing force, the floating lag time increased, but the release profile did not change. Optimally designed tablets with ciprofloxacin hydrochloride monohydrate have good resistance to crushing, a floating lag time of less than 1 minute, float longer than 24 hours. The fact that they enable a more than 8-hour-long controlled drug release from non-disintegrated matrices plays an important role in prolonging gastric residence time.

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CONCLUSION
In recent years scientific and technological advancements have been made in the research and development of controlled release oral drug delivery systems by overcoming physiological adversities like short gastric residence times and unpredictable gastric emptying times. Floating tablets are the systems which are retained in the stomach for a longer period of time and thereby improve the bioavailability of drugs. Floating tablets were prepared using directly compression technique using polymers like HPMC K4M and HPMCK100M for their gel-forming properties.

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