Title of Invention	CONTROLLED POROSITY OSMOTIC PUMP BASED DRUG DELIVERY SYSTEM.
Abstract	Osmotic pump controlled porosity (CPOP) system have been disclosed for drugs that have varying solubility characteristics such as diclofenac sodium, pramipexole and nifedipine. Such systems in the form of tablets are intended for achieving controlled release of said drugs over 12-24 hours for the treatment of various chronic therepeutic conditions.

Full Text

COMPLETE AFTER PROVISIONAL LEFT ON 1/9/06 FORM 2 THE PATENT ACT 1970 (39 of 1970) & The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10 and rule 13) 1. TITLE OF THE INVENTION: "Controlled porosity osmotic pump based drug delivery system" 2. APPLICANTS (a) NAME : SEKHSARIA CHEMICALS LIMITED (b)NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956 (c) ADDRESS : 11-A Mittal Chambers, Nariman Point, Mumbai - 400 021, Maharashtra, India. (a) NAME : BAJAJ, AMRITA NARAYAN (b)NATIONALlTY: Indian (c) ADDRESS : C. U. Shah College of Pharmacy, S.N.D.T Women's University, Juhutara Road, Santacruz (W), Mumbai - 400 049, Maharashtra, India. 3. PREAMBLE TO THE DESCRIPTION The following specification particularly describes the invention and the manner in which it is to be performed. 1 SEP 06 Technical field of the invention: The present invention relates to osmotic pump based drug delivery system for active pharmaceutical ingredients. Particularly the invention relates to controlled porosity osmotic pump based drug delivery system applicable to active pharmaceutical ingredients with a wide range of solubility such as diclofenac sodium, pramipexole dihydochloride monohydrate and nifedipine. This invention is presented as an oral dosage form, particularly tablets, to achieve controlled release over a period of 12-24 hours. Background and prior art: Osmotically controlled drug delivery systems utilize osmotic pressure as driving force for controlled delivery of drugs. Drug release from these systems is independent of pH and other physiological parameters to a large extent, and it is possible to modulate the release characteristics of the drug by optimizing the properties of the system. Osmotic systems have a passageway in the membrane from where the drug release occurs. Depending on solubility characteristics of the drug, oral osmotic systems are designed as single osmotic pumps, multichamber osmotic pumps, and other special types of systems like controlled porosity osmotic pumps, osmotic systems with asymmetric membrane and such like, which modulate the rate of drug release utilizing osmotic pressure as the driving force. Controlled porosity osmotic pumps (CPOP) contain water-soluble additives in the membrane, which on coming in contact with water, dissolve, resulting in an in-situ formation of microporous membrane. The resulting membrane is substantially permeable to both water and dissolved solutes and the mechanism of drug release from these systems was found to be primarily osmotic, with simple diffusion playing a minor role. Another type of osmotic drug delivery system features a push-pull osmotic delivery system wherein a semi-permeable rate-controlling membrane is surrounding an osmotic core, which contains a push layer and a drug layer. 2 COO" NH CI Diclofenac sodium Diclofenac sodium is a non-steroidal anti-inflammatory drug (NSAID) used in arthritis and osteoarthritis. Its solubility is about 16.3mg/ml. It has relatively short half-life and it causes irritation to gastrointestinal tract leading to ulceration, which is its major side effect. The dose of diclofenac sodium is 50 mg twice a day, and 50 mg is recommended thrice a day in chronic conditions, further increasing ulceration possibilities. A pressing need exists for a dosage form of a therapeutic agent that can administer the required dose of the agent for treating osteoarthritis and rheumatoid arthritis, at a controlled rate in a constant dose per unit time over a prolonged period of time, substantially independent of the variable environment of the gastrointestinal tract. Prior art search reveals various patents for osmotic pump based drug delivery systems. A drug core surrounded by a wall formed by a hydrogel, or optionally a cross-linked hydrogel, a rate controlling laminated wall, a multi-lamella wall, a multi-chamber compartment and a first osmotic device enclosed within a second device are some of the techniques disclosed for osmotic drug delivery technology.(ref US patents 4327725, 4256108, 4200098, 4439196,4475916 and 6491949) US patent no 4344929 discloses a method of delivering drug with aid of effervescent activity generated in environment of use. A method is disclosed for delivering a drug, diclofenac sodium, substantially free of rapid precipitation from an osmotic device. The osmotic device comprises a semipermeable wall surrounding a compartment housing for a drug that exhibits limited solubility under neutral and acid conditions, and a compound capable of evolving carbon dioxide in the presence of an acid in the environment of use. US patent no 3916899 discloses a drug delivery preparation, wherein the release of the pharmaceutical agent occurs through openings in the wall of the tablet or capsule by the 3 osmotic pressure differential that is set up between the concentration of pharmaceutical agent in the tablet or capsule interior and the exterior fluid environment of the patient when the medicament is taken orally. The anti-inflammatory drugs on their delivery from the system immediately precipitate on contact with gastric fluid. The precipitated drug impedes the flow of saturated drug solution through the passage way and also impedes the imbibitions of fluid into the system. These phenomena seriously diminish the release of these drugs. The openings in the wall of the tablet are done by laser technology, adding an additional step in the manufacturing process and requiring specialized equipment for laser hole drilling. US patent no. 3845770 discloses a preparation for osmotic pressure differential delivery wherein the interior of a tablet has a hydrophobic core surrounded by a hydrophilic layer within the tablet wall. As such, water entering the tablet remained in the hydrophilic layer hence very little drug is actually released. Nifedipine Nifedipine is a dihydropyridine derivative belonging to the class of calcium channel blockers. It is a selective arteriolar dilator, and is used for the treatment of hypertension, angina pectoris and other cardiovascular disorders. It has a low solubility of l0ug/ml and a short biological half-life of 4-6 hours. Its dose is 20 mg twice or thrice a day depending on the severity of the condition. Considering the frequency of dosing which can cause fluctuations in the blood pressure of the patient and the short half-life of nifedipine, it is an ideal candidate for a controlled release drug delivery formulation. US patent no. 5698220, 5612059 and CA1338552 disclose a device for controlled release of an active substance through one or more asymmetric membrane by diffusion and/ or osmotic pumping. The coating polymer surrounding the core with the active substance 4 and the pore former in the coating solution are present in proportions of 10-20% and 20-40% respectively. These high proportions of excipients add to the cost of the formulation. US patent no. 6352721 discloses combined diffusion/osmotic pumping drug diffusion system. This essentially comprises a core and a multi-layered coating, which can release drug over a period of 12-24 hours. Pramipexole is a non-ergot dopamine agonist recently approved for the treatment of early and advanced Parkinson's disease (PD). Immediate release tablets in 0.125 mg, 0.25 mg, 0.5 mg, 1 mg, and 1.5 mg strengths designed as oral administration of single tablet three times a day to provide daily dose of 0.375 to 4.5 mg are available in the market. Suitable amounts per dose are likely to be found in a range from about 0.1 to about 10 mg, most preferably about 0.3 to 5 mg per day. Pramipexole dihydrochloride monohydrate is extremely water-soluble. Push-pull osmotic pump (PPOP) is used for drugs having extremes of water solubility, hence once a day push pull osmotic delivery system was developed for this drug. This push pull system provides desired controlled release of drug over a prolonged period of time. The drug is released in solution form that directly goes into systemic circulation, thereby reducing the dosing frequency. This aids the geriatric patient substantially, since he often forgets to take the medication, resulting in worsening of the disease condition. The push pull type of system reduces the fluctuations in plasma level; thereby various undesirable side effects caused due to pramipexole is minimized. United States Patent 6,217,905 discloses an osmotic device as a dosage form comprising an anti-Parkinson's disease drug for administering to a patient in need of anti-Parkinson's disease therapy. 5 A pressing need exists for a dosage form that can administer a drug for treating Parkinson's disease at a controlled rate in a constant dose per unit time over a prolonged period of time. The need exists for an oral dosage form that can administer an anti-Parkinson's disease drug for its therapeutic dopaminergic, anti-cholinergic, or anti-monoamine oxidase effect substantially independent of the variable environment of the gastrointestinal tract. It will be appreciated further by those versed in the dispensing art, that such a novel and unique dosage form that can administer an anti-Park in son's disease drug in a rate controlled dose over time, and simultaneously provide therapy in the brain, would represent an advancement and a valuable contribution to the art. The various osmotic delivery systems discussed hitherto involve multiple-step processing of multi-layered formulations, many requiring advanced laser drilling equipments to form pores through which drug delivery will occur. They also require fairly high concentrations of excipients to provide the desired release profile. Also, in certain formulations, the drug release rate is not controlled/predictable to produce sustained therapeutic action over a period of time. Objective of the invention: The objective of the present invention is to formulate controlled porosity osmotic pump (CPOP) drug delivery systems to achieve drug delivery over a period of 24 hours, thus presenting a once-a-day dosage regimen of the drug. A further objective of the invention is to formulate CPOP drug delivery systems for drugs with a wide range of solubility. One more objective of the invention is to provide an oral dosage form, particularly tablet, of insoluble drugs such as nifedipine and soluble drugs such as diclofenac sodium in the CPOP drug delivery system. Yet another objective of this invention is to provide for a novel and simple process for preparing a CPOP system based monolithic tablet which is further coated to provide the desired release profile of the drug, without having to adopt complex prior art procedures like laser drilling and use of high concentration of excipients. 6 Another objective of the invention is to provide a novel dosage form manufactured as an osmotic device using the push-pull technique of drug delivery that can administer an anti-Parkinson drug such as pramipexole dihydrochloride monohydrate to a human receptor in need of anti-Parkinson therapy. One other objective of the invention is to provide a once-a-day formulation of drugs recommended in chronic conditions, such that the sustained release of the drug results in desired therapeutic action, minimizing fluctuations in the action produced due to frequent dosing and reducing the severity of the unwanted effects of the drugs, thus improving patient compliance. Summary of the invention: In the present invention, controlled porosity osmotic pump (CPOP) formulations for soluble drugs such as diclofenac sodium as well as for insoluble drugs such as nifedipine are disclosed. The osmotic core tablets were prepared by direct compression process and they comprised the active ingredient, filler, swelling polymers, osmotic agents and lubricants. Such cores were coated with a coating solution comprising the coating polymer, plasticizer and pore-forming agent. The preferred swelling polymer in the case of diclofenac sodium tablets and nifedipine tablets was guar gum. The preferred filler in the case of diclofenac tablets was microcrystalline cellulose, whereas in the case of nifedipine tablets it was mannitol, also functioning as an osmotic agent. Diclofenac tablets were formulated using sodium bicarbonate as preferred osmotic agent, while nifedipine tablets employed sodium chloride. The coatings of both tablets were done using cellulose acetate as coating polymer. The difference lay in the coating solvent system used. Diclofenac tablets were coated employing acetone as coating solvent, while nifedipine was coated with a solvent system comprising of a combination of glycerol, ethanol, water, isopropyl alcohol and butanol. These tablets provided a sustained release of the active ingredient over a period of 12 -24 hours. In the push-pull technique of delivering pramipexole dihydrochloride monohydrate, the rate controlling membrane consisted of cellulose acetate with various water-soluble additives and the system was formulated as bilayered tablets prepared by wet granulation process. The pull layer comprised of active ingredient, filler, swelling polymers, osmotic agents and lubricants while the push layer consisted of swelling polymer, osmotic agent 7 and lubricants. The binder used was polyvinyl pyrolidone K 30. Such bilayer core tablets were coated with a coating solution comprising the coating polymer, plasticizer and pore-forming agent. The preferred swelling polymer of this bilayered tablet was HPMC K 4 M and HPMC K 100 M. The preferred fillers were microcrystalline cellulose or lactose, while sodium bicarbonate was used as preferred osmotic agent. The coatings of push pull osmotic tablets were done using cellulose acetate as coating polymer. The tablets were coated employing acetone as coating solvent. Detailed description of the invention: Osmotic pump controlled porosity (CPOP) systems have been disclosed for drugs that have varying solubility characteristics. Diclofenac with a good solubility of 16.3 mg/ml is selected to represent soluble drugs and nifedipine with a poor solubility of 10 mxg/ml represents insoluble drugs. The current invention discloses CPOP systems for nifedipine and diclofenac sodium to provide a 12-24-hour sustained release for the drugs. The formulations comprise the active ingredient, filler, swelling polymer, osmotic agent and lubricant in the core. The core tablets are coated with a coating polymer and a plasticizer in a solvent system comprising an organic solvent or a mixture of various organic solvents and water. Fillers in tablet core are selected from starch, modified starch, calcium salts such as dicalcium phosphate, tricalcium phosphate, cellulose derivatives such as microcrystalline cellulose, sugars such as sucrose, fructose and mannitol. In the present invention the preferred filler in diclofenac sodium cores is microcrystalline cellulose and in nifedipine cores is mannitol. Microcrystalline cellulose is in the range of 30 - 50 % w/w and mannitol is in the range of 40 - 50 % w/w The cores contain swelling polymer, selected from the various grades of hydroxy propyl methylcellulose such as K15M, K4M, K100M, 100 LVCR, hydroxypropyl cellulose and guar gum. In formulating diclofenac sodium CPOP system based tablets and nifedipine CPOP system tablets, naturally occurring indigenous polymer, guar gum is employed as swelling polymer. Guar gum is employed in the range of 3 - 8 % w/w The core tablets further contain osmotic agent elected from electrolytes such as potassium chloride, sodium chloride and sodium bicarbonate, others such as mannitol, citric acid, 8 fructose and dextrose. In the preferred embodiment of diclofenac sodium tablets, sodium bicarbonate is the osmotic agent and in nifedipine tablets, sodium chloride is the osmotic agent of choice. These are used in the range of 10 - 40 % w/w. The coating polymer used to coat the cores is cellulose acetate (CA). Amongst the various grades of cellulose acetate, the grade with 39.8% acetyl content was the preferred one. This coating agent formed the semi-permeable membrane around the core tablet. The coating formulation further comprised a plasticizer such as polyethylene glycol 400, which also played the role of a pore former. The coating solution was a solvent based preparation, wherein acetone was the preferred solvent for diclofenac sodium cores, whereas for nifedipine, the solvent system comprised a combination of glycerol, water butanol and ethanol, in the range of 0.4, 0.5,1.56 and 2.8 % w/w respectively, with volume being made up with acetone. The tablets were coated upto a weight gain of 5 -8% The process for preparing the CPOP system based sustained release tablets of diclofenac and nifedipine comprised of the following steps: Preparation of core tablets: mixing all the ingredients and tabletting by direct compression Coating in a conventional pan using the coating solution. During core preparation and coating various process parameters are monitored. These include conventional tablet granule parameters such as angle of repose, moisture, particle size, tablet compression process parameters such as hardness, disintegration time, thickness and friability and coating process parameters such as pan speed, temperature, nozzle pressure generated using Freezing point Osmometer and spraying rate. The coated tablets were also evaluated for osmotic pressure and coating characteristics using scanning electron microscopy. For pramipexole dihydrochloride monohydrate, a drug with a good solubility of 200 mg/ml the push-pull type osmotic delivery system was opted for to achieve a once-a-day formulation for the treatment of parkinsons ‘s disease. The formulation was in the form of tablets prepared by wet granulation technique and further coated. In the instant invention for pramipexole dihydrochloride monohydrate tablets, fillers in tablet core were selected from starch, modified starch, calcium salts such as dicalcium phosphate, tricalcium 9 phosphate, cellulose derivatives such as microcrystalline cellulose, sugars such as sucrose, fructose, spray dried lactose and mannitol. In the present invention the preferred filler in pramipexole dihydrochloride monohydrate cores was microcrystalline cellulose and lactose. Microcrystalline cellulose was used in range of 5- 20 % w/w and lactose in range of 25 - 50 % w/w The push and pull layers contained swelling polymer selected from the various grades of hydroxy propyl methylcellulose such as K.15M, K4M, K100M, 100 LVCR, hydroxypropyl cellulose. The osmotic agent is elected from electrolytes such as potassium chloride, sodium chloride, sodium bicarbonate and others such as mannitol, citric acid, fructose and dextrose. In the preferred embodiment of pramipexole dihydrochloride monohydrate tablets, sodium bicarbonate was the osmotic agent used in range of 2 - 15 % w/w. The coating polymer used to coat the cores is cellulose acetate. Amongst the various grades of cellulose acetate, the grade with 39.8% acetyl content was the preferred one. This coating agent formed the semi-permeable membrane around the core tablet. The coating formulation further comprised a plasticizer such as polyethylene glycol 400, which also played the role of a pore former. The coating solution was a solvent-based preparation, wherein acetone was the preferred solvent. The tablets were coated upto weigth gain of 5-15 % w/w. The process for preparing the Push pull osmotic system of pramipexole dihydrochloride monohydrate comprised of the following steps: Preparation of core tablets: mixing all the ingredients, granulating the powder and tabletting. Coating in a conventional pan using the coating solution. During core preparation and coating various process parameters were monitored. These included conventional tablet granules parameters such as angle of repose, moisture, particle size, tablet compression process parameters such as hardness, disintegration time, thickness and friability and coating process parameters such as pan speed, temperature, nozzle pressure generated using Freezing point Osmometer and spraying rate. The coated tablets were also evaluated for osmotic pressure and coating characteristics using scanning electron microscopy. The invention is exemplified as follows: Preferred embodiments 10 Example 1: Diclofenac tablets Table-1: Core Ingredient Quantity Diclofenac sodium 100 mg Microcrystalline cellulose HO mg Sodium bicarbonate 30 mg Guar gum 12.5 mg Magnesium stearate 6.5 mg Table 2: Coating solution Ingredient Quantity Cellulose acetate (39.8% acetyl content) 2 gm PEG 400 0.4 gm Acetone qs Example 2 Nifedipine tablets Table 3: Core Ingredient Quantity Nifedipine 60 mg Sodium chloride 275 mg Guar gum 25 mg Mannitol 300 mg Magnesium stearate 2.5 mg Table 4; Coating solution Ingredient Quantity Cellulose acetate (39.8% acetyl content) 2 gm Glycerol 0.4 gm 11 Water 0.5 gm Butanol 1.56 gm Ethanol 2.893 gm Acetone qs Example 3: Pramipexole hydrochloride tablets Table :5 Pull compartment Ingredients Quantity Pramipexole dihydrochloride monohydrate 5mg Lactose 100 mg Sodium bicarbonate 5mg HPMC K 4 M 5mg PVP K 30 20 mg Magnesium stearate 0.2 mg Push compartment HPMC K 4 M 45 mg Lactose 30 mg Sodium bicarbonate 25 mg PVP K 30 20 mg Ferric chloride q.s Magnesium stearate 0.2 mg The release profile obtained for the CPOP system based tablets of nifedipine and diclofenac sodium is tabulated herein: Table-6 Sr no. Time in hours Diclofenac tablets % drug release Nifedipine tablets % drug release 1 2 5-15 1-10 2 4 15-25 5-20 3 6 25-40 20-35 12 4 8 40-50 35-50 5 10 50-60 50-60 6 12 55-70 55-70 7 24 Above 70 Above 70 Table 7: Push pull osmotic tablet Percent drug release Time in Hrs 2 % CA + PEG 400 Dense coat 1 15 13 2 20 22 3 29.11 29.78 4 38.56 37.09 5 44.72 42.77 6 49.9 47.87 7 55.89 52.88 8 60.76 59.1 9 66.87 64.23 10 72.33 70.09 12 79.51 77.43 16 87.88 83.67 18 96.98 94.77 While the present invention is described above in connection with preferred or illustrative embodiments, these embodiments are not intended to be exhaustive or limiting of the invention. Rather, the invention is intended to cover all alternatives, modifications and equivalents included within its scope. 13 We Claim, 1. An osmotic drug delivery composition comprising soluble or insoluble drug and other pharmaceutical^ acceptable excipients for achieving controlled release of said drug over 12-24 hours for the treatment of various chronic therapeutic conditions. 2. An osmotic drug delivery composition as claimed in claim I wherein said composition comprises controlled porosity osmotic pump drug delivery system. 3. An osmotic drug delivery composition as claimed in claim 1 wherein said composition comprises push-pull type osmotic pump drug delivery system. 4. An osmotic drug delivery composition as claimed in claim 1 wherein said soluble drug is selected from diclofenac sodium and pramipexole dihydrochloride monohydrate. 5. An osmotic drug delivery composition as claimed in claim 1 wherein said insoluble drug is nifidepine. 6. An osmotic drug delivery composition as claimed in claim 1 wherein said composition is in the form of coated tablets prepared by conventional processes. 7. An osmotic drug delivery composition as claimed in claim 1 wherein said pharmaceutically acceptable excipients are selected from fillers, swelling polymers, osmotic agents, binders, lubricants, coating agents, plasticisers and coating solvents. 8. An osmotic drug delivery composition as claimed in claims 1 and 6 wherein said filler is selected from starch, modified starch, calcium salts such as dicalcium phosphate, tricalcium phosphate, cellulose derivatives such as microcrystalline cellulose, sugars such as sucrose, fructose, lactose and mannitol. 9. The filler as claimed in claim 7 wherein said filler is microcrystalline cellulose in diclofenac tablets in the range of 30-50%w/w, mannitol in nifedipine tablets in the 14 range of 40 - 50 % w/w and microcrystalline cellulose in the range of 5-20%w/w and lactose in the range of 25-50%w/w in pramipexole tablets. 10. An osmotic drug delivery composition as claimed in claims 1 and 6 wherein said swelling polymer is selected from hydroxyl propyl methylcellulose K15M, hydroxyl propyl methylcellulose K4M, hydroxyl propyl methylcellulose K100M, hydroxyl propyl methylcellulose 100 LVCR, hydroxylpropyl cellulose and guar gum. 11. The swelling polymer as claimed in claim 10 wherein said polymer is guar gum in the range of 3 - 8 % w/w. 12. An osmotic drug delivery composition as claimed in claims 1 and 6 wherein said osmotic agent is selected from electrolytes such as potassium chloride, sodium chloride, sodium bicarbonate, others such as mannitol, citric acid, fructose and dextrose. 13. The osmotic agent as claimed in claim 12 wherein said osmotic agent is sodium bicarbonate in diclofenac sodium tablets and pramipexole tablets in the range of 10-40%w/w and 2-15%w/w respectively, and sodium chloride in the range of 10 - 40 % w/w in nifedipine tablets. 14. An osmotic drug delivery composition as substantially described in foregoing examples 1 to 3 for the treatment of chronic therapeutic conditions. Dated this 1st day of September 2006 15 Abstract: Osmotic pump controlled porosity (CPOP) systems have been disclosed for drugs that have varying solubility characteristics such as diclofenac sodium, pramipexole and nifedipine. Such systems in the form of tablets are intended for achieving controlled release of said drugs over 12-24 hours for the treatment of various chronic therapeutic conditions. 16 -1 SEP 2006

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