Title of Invention	STABLE CONTROLLED RELEASE PHARMACEUTICAL COMPOSITION COMPRISING ACECLOFENAC
Abstract	1. A stable controlled release once-a-day pharmaceutical composition in solid dosage form comprising aceclofenac, dispersed in release controlling polymeric matrix along with pharmaceutically acceptable excipients; wherein the said polymeric matrix comprises of hydroxypropylmethyl cellulose, ethyl cellulose or their modified forms in the ratio of 3:1.

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FORM 2 THE PATENT ACT 1970 (39 of 1970) & The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10 and rulel3) 1. TITLE OF THE INVENTION: "Stable Controlled Release Pharmaceutical Composition Comprising Aceclofenac" 2. APPLICANT(S): (a) NAME: IPCA LABORATORIES LIMITED (b)NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956 (c) ADDRESS: 48, Kandivli Industrial Estate, Charkop, Kandivli (West), Mumbai-400 067, Maharashtra, India. 3. PREAMBLE TO THE DESCRIPTION: The following specification describes the nature of this invention and the manner in which it is to be performed: Original 189/mum/2005 Technical Field of Invention The present invention relates to stable controlled release pharmaceutical compositions of poorly water soluble drugs. Specifically, the present invention relates to stable pharmaceutical formulations of aceclofenac and the process for the preparation of such a controlled release formulation. Further, this is a simple readily manufacturable, robust, and rugged controlled release formulation of aceclofenac tablets designed to comprise of a matrix of material selected from polymeric cellulose derivatives. Preferably, the matrix comprises at least two of the aforementioned materials or components. Background and Prior art Aceclofenac is a generic name for a chemical called 2-[(2,6-dichloro phenyl)amino] phenyl acetoxyacetic acid and represented by formula shown below. Aceclofenac is a well-known non-steroidal anti-inflammatory (NSAID) drug. Its preparation and medical use has been first disclosed in US4548952. Aceclofenac is a poorly water soluble drug, has a low solubility and dissolution rate in digestive fluid thereby delayed its absorption and lowered the bioavailability. Hence, there have been various attempts to enhance solubility and dissolution rate of aceclofenac in digestive fluids. United States Patent No. 6,599,529 relates to an oral pharmaceutical modified release multiple-units composition for the administration of a therapeutically and/or prophylactically effective amount of a non-steroid anti-inflammatory drug substance to obtain both a relatively fast onset of the therapeutic effect and the maintenance of a therapeutically active plasma concentration for a relatively long period of time. The NSAID substance is selected from the group consisting of lornoxicam, diclofenac, nimesulide, ibuprofen, piroxicam, piroxicam complexed with betacyclodextrin, naproxen, ketoprofen, tenoxicam, aceclofenac, indometacin, nabumetone, acemetacin, momiflumate, meloxicam, flurbiprofen, tiaprofenic-acid, proglumetacin, mefenamic acid, fenbufen, etodolac, tolfenamic acid, sulindac, phenylbutazone, fenoprofen, tolmetin, acetylsalicylic acid, dexibuprofen, but specifically related to lornoxicam compositions were disclosed. Patent application No. US2004180961 describes compositions and preparation methods for oral aceclofenac immediate release dosage forms. The composition primarily comprises of aceclofenac, polyvinylpyrrolidone being the polymeric base and a surfactant. The said preparation is formulated into solid powder, compressed particles, granules or tablets, capsules, or semisolid form. United States Patent No. 6,713,089 provides a formulation for the rapid or quick release of the active substance in tablet form to obtain fast onset of therapeutic effect. Patent application number WO2004047834 relates to a method of solubilisation of aceclofenac and the solubilized composition thereof, such that the solubilisers improve the dissolution and the aceclofenac-containing liquid composition to be filled into a gelatin soft capsule. Upon oral administration, aceclofenac shows an onset time of shorter than 30 minutes, a time to maximum blood concentration (Tmax) of about 1.5-2. 5 hours. US Patent No. 6,365,184 is related to pharmaceutical preparations for use in the treatment and prophylaxis of gastrointestinal disorders associated with the use of non-steroidal anti¬inflammatory Drugs. This preparation comprises of an acid susceptible proton pump inhibitor in combination with one or more NSAID(s) in a new fixed unit tablet dosage form. This invention provides oral, fixed unit dosage forms, i.e. multiple unit tableted dosage forms, enteric coating layered tablets, multilayered tablets or capsules filled with more than one pharmaceutical^ active compound. US Patent No. 6,818,224 refers to a fluid pharmaceutical composition which allows the controlled release of at least one active substance which includes metronidazole, aceclofenac among others. This composition has the property of gelling instantly in aqueous phase. US Patent Nos. 6,471,970 and 6,509,028 also relate to other gellable compositions of aceclofenac. United States Patent No. 6,613,807 describes a novel polymer with a backbone comprising of anhydride linkage. This backbone comprises of one or more groups that will yield a biologically active compound upon hydrolysis of the polymer; provided that the biologically active compound is not an ortho-hydroxy aryl carboxylic acid or an alpha-hydroxy carboxylic acid. The biologically active compound is selected from an anti-inflammatory agent, an antibiotic, an anti-fungal agent, an anti-infective, an anti¬cancer agent, an anti-thrombotic, an immunomodulator, agent, or a psychotherapeutic agent, an antidiabetic agent, an antineoplastic and an antiosteoporotic. In the prior art, there are processes for extended release tablets disclosed which have an osmotically active drug core surrounded by a semipermeable membrane. These tablets function by allowing a fluid such as gastric or intestinal fluid to permeate the coating membrane and dissolve the active ingredient so it can be released through a passageway in the coating membrane or if the active ingredient is insoluble in the permeating fluid, pushed through the passageway by an expanding agent such as a hydrogel. Some representative examples of these osmotic tablet systems can be found in U.S. Pat. Nos. 6294201 and 6284276 describes an osmotic device wherein the active agent is released from a core surrounded by a semipermeable membrane only after sufficient pressure has developed within the membrane to burst or rupture the membrane at a weak portion of the membrane. Described in the prior art are immediate release tablet forms of aceclofenac. More common are the fluid and semi-solid gellable compositions. Although vast amounts of research have been performed on controlled or sustained release compositions and in particular on solid dosage forms, very little research has been performed in the area of controlled or sustained release compositions that employ NSAIDs. The present invention attempts, to prepare a novel controlled release formulation for the NSAIDs. Objectives of the invention The main objective of the present invention is intended to provide controlled release pharmaceutical compositions of a non-steroidal anti-inflammatory agent, aceclofenac in the form of tablets. Another objective of the present invention is to provide controlled release once-a-day dosage form which is especially effective in the treatment of inflammatory disorders. Further aspect of the present invention is to characterize that the controlled release pharmaceutical composition of the present invention is stable in accelerated conditions of stability for the studied period. Summary of the invention The present invention relates to stable controlled release pharmaceutical compositions of poorly water soluble drugs. Specifically, the present invention relates to stable pharmaceutical formulations of aceclofenac and the process for the preparation of such a controlled release formulation. Further, this controlled release formulation of aceclofenac tablets are prepared by providing a matrix of material selected from polymeric cellulose derivatives. Detailed Description of the Invention The present invention describes stable controlled release formulations of aceclofenac and the method of its preparation. The composition comprises active ingredient dispersed in polymeric matrix along with pharmaceutically acceptable excipients. Examples of suitable polymeric agents include but are not limited to pharmaceutically acceptable cellulose derivatives hydroxypropyl cellulose, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, cellulose acetate pthalate, hydroxy ethyl cellulose, ethyl cellulose and the like. The pharmaceutically acceptable excipients are selected from binders, release controlling polymers, lubricants, glidants, film formers and plasticizers either alone or in combinations thereof. The release controlling polymers are selected from hydroxypropylmethyl cellulose, ethyl cellulose, or their modified forms. The said polymers hydroxypropylmethyl cellulose and ethyl cellulose are present in a specified ratio of 3:1 in the formulation designed for controlled release. The preferred binder is polyvinylpyrrolidone having the K value of 30. The polyvinyl pyrrolidone is used in the range of 5-10%. The preferred lubricants and glidants are magnesium stearate and purified talc and used in the range of 0.8 to 1.5%. The dosage form of the present invention may be film coated tablets and the coating is achieved by alcoholic coating or aqueous coating. The film formers are selected from the group of polymers such as hydroxypropyl methyl cellulose. The plasticizers are selected from the family of glycols such as polyethylene glycol 6000. The controlled release pharmaceutical tablet exhibits the following dissolution profile when tested in a USP type 2 apparatus at 100 rpm in 900 ml of simulated intestinal fluid (pH 7.4 phosphate buffer) and at 37°C. The drug release profile is as follows; after 1 hour 0-25% of the drug is released; after 4 hours 10-45% of the drug is released; after 9 hours 30-85% of the drug is released; and after 24 hours not less than 95% of the drug is released. The present invention provides a process for preparation of stable pharmaceutical composition for the controlled release of aceclofenac. The process comprises, preparing the granules of the drug and polymer by a moist granulation process, wherein the drug and polymers are blended together using an alcoholic solution of povidone to achieve the granules, lubricants were incorporated to produce final compression blend. The granules so prepared can be compressed into tablets. The said compressed tablets can be coated with aqueous or alcoholic coating solution. The following examples are further illustrating the specific embodiments of the present invention: EXAMPLE1 Process: The active ingredient and the polymers were blended together and passed through relevant sieves. This resultant dry blend was further granulated in a high shear mixer with the binder solution prepared by dispersing polyvinyl pyrrolidone in isopropyl alcohol. After the wet mass was sized through suitable sieves, the solvent was evaporated from the granulate by drying at 50°C to achieve the desired moisture content of the granules, determined by loss on drying. The dried granules were reduced by sizing through suitable sieves and lubricated. The tablets of the present invention will also comprise the lubricants to improve flow properties of the granules and avoid sticking to the tooling in the tabletting process. Among the stearates, magnesium stearate is used which can ideally be taken as 1 to 2% of the weight of the tablet. But in order to achieve the desired tablet hardness with the requisite friability, magnesium stearate is used at about 1% of the weight of the tablet. Purified talc and magnesium stearate were incorporated as lubricants to produce the final compression blend. The function of the magnesium stearate in the core tablet is to act as a lubricant to prevent sticking to the tooling (punches and dies) in the tabletting process. The function of the povidone is to act as a binder to cause the drug and polymers to bind and compress into a sufficiently hard tablet under compression in the tabletting process. The resultant blend could be filled into hard gelatin capsule shells or compressed into tablets on a suitable tablet press. Alternatively, the tablets could be film coated with suitable coating solution. The composition of the said controlled release tablets are shown in table 1. The once-a-day dosage form tablet comprises 200gm of aceclofenac. Table 1 Ingredients Parts by weight of tablet Aceclofenac 67.56% Hydroxypropyl methyl cellulose 20.27% Ethyl cellulose 6.75% PVP K-30 3.37% Isopropyl alcohol qs Purified talc 1.01% Magnesium stearate 1.01% EXAMPLE 2 Tablets manufactured for clinical use were film-coated in a coating pan with an appropriate non-aqueous/alcoholic hydroxypropylmethylcellulose (HPMC) based film coat. The film coat was designed to mask any unpleasant taste of the tablet and was also applied for aesthetic purposes. The typical level of film coat applied to the tablets was 2% w/w. Film coating of uncoated tablets made in Example I was performed with the following coating solution: Table 2 Parts by weight of tablet 1.68% 0.13% 0.25% 0.09% qs qs Ingredients Hydroxypropyl methyl cellulose Talc Titanium dioxide Polyethylene glycol 6000 Isopropyl alcohol Methylene chloride Tablets of example 1 were coated with 2% of this solution per tablet weight using a film coating device to obtain the tablets of the present invention. EXAMPLE 3 Dissolution tests were then carried out for the tablets of Examples 1-2. The dissolution tests are conducted in an automated USP dissolution apparatus (Paddle type II, pH 7.4 phosphate buffer, 100 rpm). The results are given in Table 3. Table 3: Time in hours Tablet core % Release 1 14.25% 4 34.82% 9 58.70% 13 78.43% 24 104.03% From the dissolution profile, it is apparent that the formulation is capable of controlled release for upto 24 hours. EXAMPLE 4 Table 4: TEST SPECIFICAT ION INITIAL 25° C / 60 % RH 40° C / 75 % RH 1M 2M 3M 1M 2M 3M DESCRIP TION White to Off-White, round, bi-convex, uncoated tablet plain on both sides. Comp¬lies Comp -lies Comp -lies Comp -lies Comp -lies Comp¬lies Comp -lies DISSOLU TION NMT 40 % in lhr NLT 70 % in 12 hrs 10.73 % 88.18% 13.18% 89.47% 14.39 % 88.26% 12.83 % 93.60 % 9.05 % 94.24 % 10.46% 80.06 % 11.98% 88.31% ASSAY 90-110% 102.22% 101.67% 101.70% 101.0% 102.20% 101.88% 101.30% At accelerated conditions of stability, the formulation for the preparation was found to be stable for the studied period. The assay for aceclofenac was within limits during the period of study. The dissolution results were also in compliance with the standards. Although this invention has been described with reference to specific embodiments thereof, it is understood that other embodiments and variations of the invention as described and exemplified may be made by those skilled in the art without departing from the true spirit of the invention. It is intended that the appended claims be construed to include all such embodiments and variations. We claim, 1. A stable controlled release once-a-day pharmaceutical composition in solid dosage form comprising aceclofenac, dispersed in release controlling polymeric matrix along with pharmaceutically acceptable excipients; wherein the said polymeric matrix comprises of hydroxypropylmethyl cellulose, ethyl cellulose or their modified forms in the ratio of 3:1. 2. The stable controlled release composition as claimed in claim 1, wherein said composition is in the form of film-coated or uncoated tablets. 3. The stable controlled release composition as claimed in claim 1, wherein the strength of said aceclofenac is 200mg. 4. The stable controlled release composition as claimed in claim 1, wherein said pharmaceutically acceptable excipients are selected from binders, release controlling polymers, lubricants, glidants, film formers and plasticizers either alone or in combinations thereof. 5. The stable controlled release composition as claimed in claim 4, wherein said polymers hydroxypropylmethyl cellulose and ethyl cellulose are present in a specified ratio of 3:1 in the formulation. 6. The stable controlled release composition as claimed in claim 1 and 4, wherein the binder is polyvinylpyrrolidone having K value 30 used in the range of 5-10%. 7. The stable controlled release composition as claimed in claim 1 and 4, wherein the preferred lubricants and glidants are magnesium stearate and purified talc used are in the range of 0.8 to 1.5%. 8. The stable controlled release composition as claimed in claim 2, wherein said stable composition is in the form of film coated tablets. 9. The stable controlled release composition as claimed in claim 1, wherein the tablet is film coated by alcoholic or aqueous coating. 10. The stable controlled release composition as claimed in claims 8 and 9, wherein the film formers are selected from the group of polymers such as hydroxypropyl methyl cellulose and ethyl cellulose. 11. The stable controlled release composition as claimed in claims 8 to 10, wherein plasticizers are selected from the family of glycols such as polyethylene glycol 6000. 12. The stable controlled release composition as substantially described herein with reference to the foregoing examples 1 to 4. Dated this 21st day of February 2005 Dr. Gopakumar G. Nair Agent for the Applicant

Documents:

189-mum-2005-claims(granted)-(21-2-2005).doc

189-mum-2005-claims(granted)-(21-2-2005).pdf

189-mum-2005-correspondence(17-4-2008).pdf

189-mum-2005-correspondence(ipo)-(8-9-2008).pdf

189-mum-2005-form 1(17-4-2008).pdf

189-mum-2005-form 1(21-2-2005).pdf

189-mum-2005-form 18(19-1-2006).pdf

189-mum-2005-form 2(granted)-(21-2-2005).doc

189-mum-2005-form 2(granted)-(21-2-2005).pdf

189-mum-2005-form 26(10-1-2003).pdf

189-mum-2005-form 3(21-2-2005).pdf

189-mum-2005-form 9(21-5-2005).pdf