Title of Invention

CONTROLLED RELEASE GASTRO-RETENTIVE BUOYANT MATRIX TABLETS

Abstract

A once a day buoyant gas powered matrix composition in the form of a tablet for oral administration in mammals for controlled release of ciprofloxacin which comprises ciproflaxin, from 5 to 40% by wt of a gas evolving agent and from 0.5 to 10% by wt of a binder, the balance consisting of pharmaceutically acceptable excipients, said composition having been granulated by a wet granulating process and compressed into tablets.

Full Text

FORM 2 THE PATENTS ACT, 1970 COMPLETE SPECIFICATION (See section 10; rule 13) TITLE OF THE INVENTION "Controlled Release Gastro-Retentive Buoyant Matrix Tablets" We, CADILA HEALTHCARE LIMITED, of company incorporated Companies Act, 1956, of Zydus Tower, Satellite Cross Roads, Ahmedabad-380 015, Gujarat, India The following specification describes the nature of the invention and the manner in which it is to be performed: Field of Invention The present invention relates to a gas powered buoyant matrix dosage form, which is intended to be retained in the stomach for controlled release of the active pharmaceutical ingredient. Present invention also relates to use of such pharmaceutical composition prepared by said process in prophylaxis and/or treatment of infections due to microorganisms in mammals. Background of the Invention The present invention relates to a pharmaceutical process for the preparation of unit dosage form in tablet form, which provides a combination of spatial and temporal control of delivery of drugs specifically for the drug ciprofloxacin, to a patient for therapeutic results. In the present invention, a pharmaceutical process for preparation of gas powered buoyant matrix tablet of ciprofloxacin is by means of wet granulation using an aqueous or non-aqueous granulating agent and a binder in addition to other pharmaceutical excipients and is designed to extend the delivery of the drug in the stomach or the upper part of the small intestine. The pharmaceutical process comprises of a binding agent to retain the shape of the dosage form intact and also contains additional pharmaceutical excipients such as a gas evolving agent, supergelling agent, and release retarding polymer, super disintegrant and other pharmaceutically acceptable lubricant. The preferred route for administration of most of the drugs is via gastro-intestinal tract. Considerable efforts have been made in the last few decades to develop new pharmaceutically viable and therapeutically effective controlled drug delivery systems. Great attention has been focused particularly on orally administered controller drug delivery systems because of the ease of administration via the oral route as well as the ease and economy of manufacture of oral dosage forms such as tablets and capsules. An orally administered controlled drug delivery system encounters a wide range of highly variable conditions, such as pH, agitation intensity and composition of the gastrointestinal fluids as it passes down the gastrointestinal tract. Most of the drugs are well absorbed from the entire gastrointestinal tract. But certain drugs which are acidic in nature, are best absorbed from the stomach or upper part of the small intestine i.e., for these drugs stomach/upper part of intestine is "Absorption window", where the maximum absorption of drug occurs. Particularly, in instances where a drug has a clear cut "absorption window" i.e., -2- the drug is absorbed only from specific regions of the stomach or upper parts of the small intestine, it may not be completely absorbed when administered in the form of a typical controlled drug delivery system. It is apparent that for a drug having such an "absorption window" an effective oral controlled drug delivery system should be designed not only to deliver the drug at a controlled rate, but also to retain the drug in the upper parts of the gastrointestinal tract for a long period of time. It is well known to those skilled in the art that for most of the ailments multiple dosage regimen of the drug is required to maintain the drug concentration in the therapeutic window. The drug concentration should be maintained above the minimum effective concentration and below the minimum toxic concentration (therapeutic window) to get better efficacy and to avoid the side effects. Immediate release dosage form leads to high fluctuation in the drug blood level concentration. Controlled release dosage form provides a prolonged delivery of active agent at the site of absorption. Drugs for which stomach acts as an absorption window should be preferably released in the gastrointestinal fluid of the stomach. If the dosage form traverse beyond stomach before the drug gets released completely, the remaining drug in the dosage form will reach the intestine leading to poor absorption and poor therapeutic efficacy. Since it has been found very difficult to alter the gastrointestinal transit time to make the dosage form to stay for a long period in the stomach, rather different techniques have been used. Some of the techniques available for gastroretention of the dosage form are; • Gas generating systems • Hydrodynamically balanced systems • Multiple-unit floating dosage forms • Ion-exchange resins • Alginate beads v The controlled release dosage form is meant ideally to deliver the drug at a constant rate, which is equivalent to the rate of eUmination of the drug from the body at a steady state " concentration. Though the dosage form is releasing the drug at a constant rate at the required site of absorption, it can be rapidly transported from maximum absorptive upper gastric region leading to lesser absorption and lower efficacy of the drug. Therefore, spatial control plays an important role in obtaining better efficacy of the drug. For the class of aforementioned drugs, the dosage form should be designed to deliver the drug in stomach and upper parts of the intestine. Present invention relates to a process for the preparation of gas powered buoyant matrix tablets of ciprofloxacin for once a day administration, wherein the process of the said invention -3-- wet granulation using an aqueous or non-aqueous granulating agent and a binder in addition to other pharmaceutical excipients such as gas evolving agent, super gelling agent, rate retarding polymer, superdisintegrant and pharmaceutically acceptable lubricants. The overall drug in the present invention may vary in an amount from about lmg to 1 lOOmg WO 01/64183 assigned to Ranbaxy Laboratories describes a pharmaceutical composition in the form of tablets or capsules which provides a combination of spatial and temporal control of the drug delivery, specifically for the drug ciprofloxacin. According to the invention, the pharmaceutical composition is prepared by mixing the drug with the gas generating component, the swelling agent, and one or both of the viscolysing agent and the gelling agent, plus other excipients and lubricants. The blend was directly compressed into tablets or may be filled into capsules. Alternatively, the pharmaceutical composition is prepared by mixing the foregoing ingredients with only one-half of the lubricants. The blend is subjected to dry granulation technique by passing it through the roller compactor and then sieved to obtain granules. The granules are then mixed with the remaining lubricants, and filled into capsules or compressed into tablets. WO 00/15198 also assigned to Ranbaxy Laboratories Ltd. discloses a pharmaceutical composition of oral dosage form in the form of tablet/capsule. The formulation was prepared by dry granulation technique to provide temporal and spatial control of the drug delivery. The formulation comprises an active pharmaceutical ingredient, a gas-generating component, a swelling agent and viscolysing agent. The viscolysing agent initially and gel forming polymer further entraps the gas causing tablet/capsule to float so as to remain in the stomach/upper part of the small intestine. The hydrated gelling polymer creates a diffusion path for the drug resultmg in slow release of the drug. Such a pharmaceutical composition with combination of above excipients is referred to as controlled gas powered systems. JP 06024959 assigned to Bayer Yakuhin KK discloses a pharmaceutical composition to deliver the ciprofloxacin over a prolonged period of time by making the tablet to suspend in the stomach. The system contained two parts laminated to each other. One part contains a water-swellable gel-forming polymer and a water expandable foaming agent dispersed in the polymer and the other part contains the active agent. The results on this composition showed that only 46% of the drug was dissolved even after 24 hours losing its practicability to be effective as once daily ciprofloxacin formulation. U.S. Patent No. 5,651,985 assigned to Bayer AG, discloses a composition comprising a pharmaceutical active ingredient, polyvinylpyrrolidone, and methacrylic acid polymer. The composition also optionally contains a gas-forming additive. The composition absorbs many times its weight of aqueous acidic media and forms a highly swollen gel of high mechanical strength. Freeze drying technique has been utilized in the preparation of the gel-forming unit. The swelling of the polymer occurs to a size to prevent the passage of dosage form through the pylorus and gas forming agent gives the buoyancy to the dosage form leading to retention of the dosage form in the stomach for a prolonged period. Ciprofloxacin has been found to have low bulk density. In the present invention, wet granulation process has been adopted to increase the bulk density of the active agent ciprofloxacin. This could be a very useful technique for ciprofloxacin, which lacks proper characteristics of binding or bonding together into a compact entity. Wet granulation process is useful for ciprofloxacin, as it does not ordinarily possess the desired flow properties and compressibility required for direct compression tabletting. Wet granulation process is helpful for size enlargement of ciprofloxacin particles, which leads to • free flowing nature • increased mass to volume ratio • uniform mixture that does not separate rapidly • more compressibility • controlled rate of drug release • reduced dust/fines • product with improved quality/appearance Wet granulation process using an aqueous or non-aqueous granulating agent and a binder in addition to other pharmaceutical excipients for gas powered buoyant matrix tablets of ciprofloxacin for once a day administration can be advantageous over dry granulation and direct compression. The cohesiveness and compressibility of ciprofloxacin powder is improved due to added binder that coats the individual ciprofloxacin particle causing them to adhere each other so that they can be formed into granules. By this method, properties of the formulation components are so modified as to overcome tabletting deficiencies, as it is easy to compress granules leading to improved tooling life and decreased machine ware. As the dose of ciprofloxacin for once a day administration is very high, the direct compression technique cannot be used. The drug itself lacks the property required for direct compression. The dry granulation technique may lead to -5- xcess fines and tablets may show high friability due to lack of binding property of the drug, which may lead to problems during coating, packaging and shipping. As a result of this, ciprofloxacin, which is required to be taken at a high dose and has poor flow property and compressibility, can be preferably granulated by wet granulation process to obtain suitable flow and cohesive properties for required for compression into a tablet dosage form. In wet granulation, the composition of the each granule remains uniform. None of the gas powered buoyant matrix tablets of ciprofloxacin for once a day administration with the said composition has been prepared by means of wet granulation process using an aqueous or non-aqueous granulating agent and a binder in addition to other pharmaceutical excipients. Objects of the present invention It is an object of the present invention is to provide a process for the preparation and/ or manufacture of gas powered buoyant matrix tablets for once a day administration of ciprofloxacin, by wet granulation process. Another object of the invention is to provide a process for preparing gas powered buoyant matrix tablets for once a day administration of ciprofloxacin using an aqueous or non¬aqueous granulating agent and a binder in addition to other pharmaceutical excipients such as gas evolving agent, super gelling agent, rate retarding polymer, superdisintegrant and pharmaceutically acceptable lubricants. Another object of the present invention is to provide a process for the preparation of gas powered buoyant matrix tablets for once a day administration of ciprofloxacin wherein the said process involves binding of the drug particle with a binder using an aqueous or non-aqueous granulating agent to increase the bulk density, flow property and compressibility of ciprofloxacin so as to obtain tablets with desired pharmacotechnical properties. A further object of the present invention is to provide a composition of gas powered buoyant matrix tablets of ciprofloxacin prepared by the said process. Another object is to provide a composition of ciprofloxacin, prepared according to the present invention, wherein the tablets when comes in contact with aqueous acidic gastric fluid, generates a gas, which gets entrapped in the gel matrix of the tablet, leading to buoyancy of the tablet which floats on the surface of the gastric fluid. -6 — Yet another object of the present invention is to provide a process for preparation of gas powered buoyant matrix tablets for once a day ciprofloxacin that is intended to be retained in the stomach for prolonged period leading to controlled delivery of ciprofloxacin, a drug which has stomach and upper intestine as "absorption window". Still another object is to provide the use of such pharmaceutical composition prepared by the said process in the prophylaxis and/ or treatment of infections due to microorganisms in mammals. Summary of the invention The present invention relates to a pharmaceutical process for the preparation of gas powered buoyant matrix tablet of ciprofloxacin for once a day administration, by wet granulation process. The process involves the use of aqueous or non-aqueous granulating agent, a gas evolving agent and a binder in addition to other pharmaceutical excipients such as super gelling agent, rate retarding polymer, superdisintegrant and other pharmaceutically acceptable lubricants. The gas powered buoyant matrix tablet is intended to be retained in the stomach and/ or upper part of the small intestine for prolonged delivery of the drug. The dosage form prepared by the said process comprises of a binding agent in order to retain the shape of the dosage form intact. In a preferred embodiment, the gas powered buoyant matrix dosage form for oral controlled drug delivery system prepared by wet granulation process using an aqueous or non¬ aqueous granulating agent in the form of tablet comprises of a therapeutically effective amount of ciprofloxacin, about 0.5 % to 10 % of binder, about 0.5 % to 10 % by weight of at least one super gelling agent, 0.25 to 50% by wt of a rate retarding polymer, about 5 % to 40 % by weight of gas evolving component and about 0.5 % to 20 % of super disintegrant. In a preferred embodiment, the amount of ciprofloxacin is from 100 to 1100 mg. Binder used in the present invention is responsible for retaining the final integrity of the dosage form prepared by. wet granulation process and also provides the desired flow property, bulk density and compressibility to the granules of the drug so that the tablets with desired pharmacotechnical properties can be obtained. Super disintegrant used in the present invention functions to promote disintegration of a tablet by absorbing large amount of water. However, the composition also contains a gas-evolving component, which upon contact with aqueous hydrochloric acid of the stomach releases the carbon dioxide gas. Due to the presence of the rapid gelling agent in the composition, the -7- \tablet will not be allowed to burst out the drug, rather the generated gas will be entrapped in the "gel structure. As the composition contains binder which holds the individual particles intact and due to presence of rate retarding polymer, the drug is released slowly from the matrix dosage form. Entrapment of generated gas and due to swelling of the super disintegrant, a hydrodynamically balanced system is formed, leading to floating of the dosage form. Tablets prepared by wet granulation process with the said composition were found to be retained in the stomach for a prolonged period than previously known hydrophilic matrix tablets, floating capsules and bioadhesive tablets when these systems are administered with food. The formulation developed with the said process and composition results in release of the drug into the more absorptive regions of the gastrointestinal tract, i.e., into the stomach from where the maximum drug absorption occurs. It has been found that the gas powered buoyant matrix tablet prepared by wet granulation process for controlled release of those drugs that are absorbed only from the upper part of gastrointestinal tract, like ciprofloxacin, provides the desired absorption rate of drug such that effective plasma levels are maintained for a prolonged duration and the said formulation is especially suitable for once a day administration. Detailed Description of the Invention The present invention relates to a process for the preparation of gas powered buoyant matrix tablets of ciprofloxacin for once a day administration, by wet granulation process. The composition prepared by the process of the present invention comprises of a gas evolving agent, a binder and an aqueous or non-aqueous granulating agent in order to retain the shape of the dosage form intact. The pharmaceutical dosage prepared by the said process also contains, supergelling agent, release retarding polymer, super disintegrant and other pharmaceutically acceptable lubricant to extend the retention of the drug in the stomach or upper part of the small intestine for prolonged delivery of the drug. The pharmaceutical dosage form prepared by the said process of wet granulation contains binder/(s) that binds ciprofloxacin and other pharmaceutical excipients together to form granules. Binders are adhesives that are added to tablet formulations to provide cohesiveness required for bonding together of granules under compaction to form tablet. Suitable binders for the present invention can be natural polymers such as starch or gum including acacia, tragacanth, gelatin and the like or semisynthetic/ synthetic polymers like polyvinyl pyrrolidone, methyl cellulose, ethyl -8- cellulose, hydroxy propyl methylcellulose, sodium carboxymethyl cellulose, hydroxy propyl cellulose and the like. Preferably, the binder used is either cellulose derivatives or polyvinyl pyrrolidone, most preferably polyvinyl pyrrolidone. The binder may be present in an amount from about 0.5-10%, preferably from about 1-6% and more preferably 1.5-4%, by weight of the total weight of the composition.: The binder can be mixed with the drug powder and wetted with solvents like water, alcohol, organic solvents or a mixture of water and other organic solvents. In a preferred embodiment, organic solvents have been used and the preferred solvent of choice is isopropyl alcohol . Alternatively, the binder can be dissolved in the above solvent and added to the powder mixture. The gas evolving agent upon contact with the acidic gastric fluid evolves/releases carbon dioxide gas which is then entrapped by the supergelling agent. The gas-evolving agent comprises of sodium or calcium bicarbonates, alone, or in combination with citric/tartaric acid, or the salts of the same acid, to increase the efficacy of the gas-evolving compound. The gas-evolving agent may be present in an amount from about 5 to 40 %, and preferably in an amount from about 10 to 20 % by weight of the total weight of the composition. The release-retarding polymer used in the present process helps in slow and prolonged release of the drug ciprofloxacin, from the gas powered buoyant matrix dosage form. The required release rate of the drug can be achieved by varying the concentration of the release-retarding polymer. The composition prepared by the said process releases the drug for absorption at the intended site of absorption at a rate such that effective plasma concentration levels are maintained for prolonged period, making the dosage form suitable for once a day administration. The release-retarding polymer used in the present invention belongs to the class of cellulosics, which are either hydrophilic or hydrophobic and may either be water soluble or insoluble. The release-retarding polymer may be hydroxy propyl methylcellulose, hydroxy propyl cellulose, hydroxy ethyl cellulose, ethyl cellulose, carboxy methylcellulose, sodium carboxy methylcellulose and the like. Preferably the release-retarding polymer is hydroxy propyl methylcellulose. The release-retarding agent may be present in an amount from about 0.25 to 50% preferably from 0.25 to about 15 %, and more preferably from about 1 to 10% and most preferably about 3 to 8%, by weight of the total weight of the composition. The supergelling agent belongs to the class of natural gums, which upon contact with the aqueous gastric fluid forms a viscous gel and entraps the gas generated by the gas-evolving component. Examples of supergelling agent that may be used in the present process includes but - 9- are not limited to xanthan gum, tragacanth gum, guar gum and the like. The supergelling agent in the present process may be used in an amount from about 0.5 to about 20% and preferably from about 1 to 5% by weight of the total weight of the composition. Superdisintegrant used in the said process upon contact with the aqueous media swells and causes initial burst release of the drug. Superdisintegrating agents used in the present composition may include cross-linked polyvinyl pyrrolidone, sodium starch glycolate or cross-linked sodium carboxy methylcellulose. The superdisintegranting agent may be present in an amount from about 0.5 to about 20%, preferably from about 1 to 10% and more preferably from about 3 to 7 %, by weight of the total weight of the composition. Lubricants used in the present composition include stearic acid, talc, magnesium stearate, aerosil, glyceryl monosterate, glyceryl behenate and the like. The lubricant may be present in an amount from about 0.1 to about 10 % and more preferably from about 1 to 3% by weight of the total weight of the composition. The gas powered buoyant matrix tablets of ciprofloxacin prepared by wet granulation process according to the present invention, upon contact with the aqueous gastric fluid content generates carbon dioxide gas. The gas generated is entrapped within the matrix formed by supergelling agent initially and then by the rate retardmg/matrix-forming polymer. The binder maintains the integrity of the dosage form till the complete drug is released from the dosage form. As a result of the .gas entrapment, the dosage form achieves buoyancy and the whole dosage form floats on the surface of the gastric content. Process for preparation According to the present invention, the pharmaceutical dosage form was prepared by mixing ciprofloxacin with super gelling agent, rate retarding polymer, super disintegrant and gas evolving agent. The blend was then converted into dough mass using a binder in a particular solvent explained earlier. The mass was sieved and dried at 40-120°C using tray dryer or fluidized bed dryer for 10-180 min. After drying, the mass was sieved using desired ASTM sieve. These granules were then mixed with the lubricants and compressed into tablets. Alternatively, the drug can be mixed with super gelling agent and rate retarding polymer and converted into granules using the binder as explained earlier. The granules were then mixed with gas evolving agent and super disintegrant. The blend was then lubricated and compressed into tablets. - 10- Coating The present invention relating to a process for preparation gas powered buoyant pharmaceutical dosage form in the form of tablets as described above which may be coated with rapidly dissolving water-soluble pharmaceutical excipients to mask the bitter taste of the ciprofloxacin. A coating of low viscosity hydrophilic polymer is preferred for the faster hydration and release of the drug. The film former can be cellulose derivatives including hydroxy propyl methylcellulose, ethyl cellulose and the like. Highly water-soluble pharmaceutical excipients can be included in the coating to support the faster dissolution of the polymer. The water-soluble ingredient includes lactose, sucrose and the like. The solvent used for the coating solution in the present invention may be water, isopropyl alcohol or methylene chloride and mixture of the same. The tablet may be coated to a weight gain of about 1% to 5%, preferably about 1% to about 3%. Following non-limiting examples describe the process of the present invention and means of carrying out the said process to obtain a pharmaceutical dosage form of ciprofloxacin for once a day administration. Example 1 Table-1 Ingredients mg/tab 0/ /o Ciprofloxacin base 1000 82.30 Hydroxypropyl methylcellulose, HPMC (MethoceL K15M) 50 4.11 Sodium starch glycolate 30 2.46 Sodium bicarbonate 80 6.58 PVP-K30 . 30 2.46 Isopropyl Alcohol q.s q.Sv Stearic acid 13 1.06 Talc 12 0.98 Total 1215 100 All the ingredients used in the formulation were passed through a sieve (ASTM # 60). Ciprofloxacin and HPMC were mixed together and binded with PVK-30 solution in Isopropyl alcohol to obtain a dough mass. The mass was dried at 70°C for about 90 minutes in a tray drier. The dried mass was passed through a sieve (ASTM # 20). The granules were then mixed with sodium bicarbonate and sodium starch glycolate. The blend was then lubricated and compressed into tablets. The tablets were spray coated with a non-aqueous coating (Isopropyl alcohol and - 11- methylene chloride 50:50) dispersion containing HPMC 6cps 4%, Titanium dioxide 0.75%, talc 0.2% and PEG- 200 1.2%. so as to obtain a weight gain of 2% total tablet weight. Dissolution study of the coated tablets was conducted in 0.1N HC1 using USP Apparatus 1 with basket at 100 rpm. The dissolution results are given in Table -2 Table-2 Time (hr) % drug release 1 18.2 2 22.4 3 56.3 4 80.2 5 91.0 By the 6th hour 98.4 Example-2 Table-3 Ingredients mg/tab %w/w Ciprofloxacin base -1000 75.75 Xanthan gum 30 2.27 Hydroxypropyl methylcellulose (MethoceL K15M) 45 3.21 Sodium starch glycolate 75 4.73 Sodium bicarbonate 130 9.84 PVP-K90 30 2.27 Isopropyl alcohol q.s q.s Talc 10 0.75 Stearic acid 15 1.13 Total weight 1320 100.00 1 The tablet explained in the example 1 has showed faster dissolution rate, so further batch with rapid gelling agent (xanthan gum) has been tried. Ciprofloxacin, -Xanthan gum and HPMC K15 were mixed together and binded with PVK-90 solution in isopropyl alcohol to obtain dough mass. The mass was dried at 70°C for about 90 minutes in a tray drier. The dried mass was passed through a sieve (ASTM # 20). The granules were then mixed with sodium bicarbonate and sodium starch glycolate. The blend was then lubricated and compressed into tablets. The tablets were spray coated with a non-aqueous coating (Isopropyl alcohol and methylene chloride 50:50) dispersion containing HPMC 6cps 3%, -12- -Titanium dioxide 1%, talc 0.8% and PEG 200 1.2%. so as to obtain a weight gain of 2% total tablet weight. Dissolution study of the coated tablets was conducted in 0.1N HC1 using USP Apparatus 1 with basket at 100 rpm. The dissolution results are given in Table -4 Table-4 Time (hr) % Drug release 1 22.72 2 39.23 3 54.74 4 68.47 6 81.54 8 96.28 Example-3 Table 5 Ingredients mg/tab % Ciprofloxacin base 1000 72.72 Hydroxypropyl methylcellulose (Methocel, K15M) 80 5.81 Cros-Povidone 55 4.00 Sodium bicarbonate 150 10.90 PVP-K90 60 4.36 Isopropyl alcohol q.s q.s Stearic acid 20 1.45 Talc 10 0.72 Total 1375 100 In the above formula, the concentration of the rate-retarding polymer has been increased in order to obtain a prolonged release of the drug. The tablets were prepared according to the procedure explained in the Example 2. The tablets were spray coated with a non-aqueous coating (Isopropyl alcohol and methylene chloride 50:50) dispersion containing HPMC 6cps 2%, Titanium dioxide 1.5%, talc 0.2%, Aerosil 0.2% and PEG 200 0.3%. to weight gain of 2%of total tablet weight. Dissolution study of the coated tablets was conducted in 0.1N HC1 using USP Apparatus 1 with basket at 100 rpm. The dissolution results are given in Table -6. - 13— Table-6 Time (hr) % Drug release 1 22.86 2 43.03 4 72.72 6 87.34 8 90.33 10 93.39 12 98.76 Example-4 Table-7 Ingredients mg/tab % Ciprofloxacin base 1000 71.17 Xanthan gum 40 2.84 Hydroxypropyl methylcellulose (Methocel, K15M) 65 4.62 Cros-Povidone 85 6.04 Sodium bicarbonate 150 10.67 PVP K90 40 2.84 Isopropyl alcohol q.s q.s Magnesium stearate 15 1.06 Talc 10 0.71 Total 1405 100 The tablets were prepared according to the procedure explained in the Example 2. The tablets were spray coated with a non-aqueous coating (Isopropyl alcohol and methylene chloride 50:50) dispersion containing HPMC 6eps 0.5%, HPMC 3cps 1.5% Titanium dioxide 1.0%, talc 0.5%, Lactose 3% and PEG 200 0.39%to a weight gain of 2% of total tablet weight. Dissolutiohn study of the coated tablets was conducted in 0.1N HCl using USP Apparatus 1 with basket at 100 rpm. The dissolution results are given in Table -8 Table-8 Time (hr) % Drug release 1 25.29 2 38.5 6 4 61.77 6 75.41 8 85.30 10 91.24 12 94.221 14 100.98 -14- Exam ple-5 Table-9 Ingredients mg/tab % Ciprofloxacin base 1000 71.68 Xanthan gum 45 3.23 Hydroxypropyl methylcellulose (Methocel, K15M) 75 5.38 Cros-Povidone 60 4.30 Sodium bicarbonate 150 10.75 PVPK90 40 2.87 Isopropyl alcohol q.s q.s Magnesium stearate 15 1.08 Talc 10 0.72 Total 1423 100 The tablets were prepared according to the procedure explained in the Example 2. The tablets were spray coated with a non-aqueous coating (Isopropyl alcohol and methylene chloride 50:50) dispersion containing HPMC 6cps 1.0 % w/w, HPMC 3cps 1.0 % w/w, Titanium dioxide 1.0 % w/w, talc 1.0 % w/w, Lactose 3% w/w and PEG 200 0.8 % w/w, to a weight gain of 2% of total tablet weight. Dissolution study of the coated tablets was conducted in 0.1N HO using USP Apparatus 1 with basket at 100 rpm. The dissolution results are given in Table -8 Table-10 Time (hr) % Drug release 1 29.06 ■2 42.36 4 65.00 6 78.80 8 89.03 . 10 93.60 12 100.98 The in vitro dissolution depicted in the above examples of the present invention is similar to the dissolution profile for once a day dosing of ciprofloxacin from gas powered buyout matrix tablets as described in WO 01/64183 Al. -15- We claim: 1. A once a day buoyant gas powered matrix composition in the form of a tablet for oral administration in mammals for controlled release of ciprofloxacin which comprises ciproflaxin, from 5 to 40% by wt of a gas evolving agent and from 0.5 to 10% by wt of a binder, the balance consisting of pharmaceutically acceptable excipients, said composition having been granulated by a wet granulating process and compressed into tablets. 2. The composition as claimed in claim 1, wherein said binders comprise natural polymers selected from starch or gum including acacia, tragacanth, gelatin or synthetic polymers selected from polyvinyl pyrrolidone, methyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose sodium carboxymethylcellulose, hydroxypropyl cellulose. 3. The composition as claimed in claim 1 or 2 wherein the binder is present in an amount from 0.5-10% by wt of the composition. 4. The composition as claimed in any one of claims 1 to 3 wherein the amount of ciprofloxacin is from 100 to 110 mg. 5. The composition as claimed in any one of claims 1 to 4 wherein said release-retarding polymer used is a hydrophilic or hydrophobic cellulosics. 6. The composition as claimed in claim 5 wherein the release-retarding polymer is selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, ethylcellulose, carboxymethylcellulose, and sodium carboxymethylcellulose. 7. The composition as claimed in any one of claims 1 to 6 wherein the release-retarding agent is present in an amount from 1 to 50% by weight, preferably 3 to 10% by weight of the total weight of the composition. 8. The composition as claimed in any one of claims 1 to 7 wherein the supergelling agent belongs to the class of natural gums. 9. The composition as claimed in claim 8 wherein supergelling agents are selected from xanthan gum, tragacanth gum, guar gum, acacia, gelatin. -16- 10. The composition as claimed in claim 9 wherein said supergelling agent is present in an amount from 0.5 to about 10% by weight, preferably, 1 to 5% by weight of the total weight of the composition. 11. The composition as claimed in any preceding claim wherein said superdisintegrating agents used in the present composition are cross-linked polyvinyl pyrrolidone, sodium starch glycolate, cross-linked sodium carboxy methylcellulose. 12. The composition as claimed in claim 11 wherein the superdisintegrant agent is present in amount from 0.5 to 20% by weight, preferably, 1 to 10% by weight of the total weight of the composition. 13. The composition as claimed in any preceding claim wherein the gas-evolving agent comprises of sodium bicarbonate or calcium bicarbonate alone or in combination with citric aid or tartaric acid or the pharmaceutically acceptable salts of citric acid or tartaric acid. 14. The composition as claimed in any preceding claim wherein lubricant used is selected from stearic acid, talc, magnesium stearate, aerosil, glyceryl monosterate, glyceryl behenate. 15. The composition as claimed in claim 14 wherein the lubricant is present in an amount from 0.1 to about 10% by weight of the total weight of the composition. 16. The composition as claimed in claim 1 comprising of a therapeutically effective amount of ciprofloxacin, 1.5% to 4% polyvinyl pyrrolidone, 10% to 20% sodium bicarbonate, 3% to 8% hydroxypropyl methylcellulose, 1% to 5% xanthan gum, 3% to 7% cross-linked polyvinylpyrrolidone and 1% to 3% lubricants, said percentages being w/w of the composition. 17. A once a day buoyant gas powered matrix composition in the form of a tablet for oral administration in mammals for controlled release of ciprofloxacin as substantially herein described with reference to the forgoing examples. Dated this the 08th day of March 2004

Documents:

307-mum-2004-abstract(20-7-2007).pdf

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307-mum-2004-correspondence(19-05-2008).pdf

307-mum-2004-correspondence(ipo)-(07-09-2006).pdf

307-mum-2004-form 1(20-7-2007).pdf

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