Title of Invention	MODIFIED RELEASE NSAID COMPOSITIONS
Abstract	A modified release pharmaceutical composition in the form of capsule, tablet, granules or pellets comprising a core, comprising non-steroidal anti-inflammatory drug such as Aceclofenac as first active ingredient; a barrier coat comprising at least one non-enteric water insoluble polymer and at least one channel forming agent and exhibiting modified release is disclosed. The invention also discloses the process to prepare such modified release pharmaceutical compositions.

Title of Invention

MODIFIED RELEASE NSAID COMPOSITIONS

Abstract

A modified release pharmaceutical composition in the form of capsule, tablet, granules or pellets comprising a core, comprising non-steroidal anti-inflammatory drug such as Aceclofenac as first active ingredient; a barrier coat comprising at least one non-enteric water insoluble polymer and at least one channel forming agent and exhibiting modified release is disclosed. The invention also discloses the process to prepare such modified release pharmaceutical compositions.

Full Text	COMPLETE AFTER PROVISIONAL LEFT ON 11/09/06 FORM-2 THE PATENTS ACT. 1970 (39 OF 1970) & The Patent Rules, 2003 COMPLETE SPECIFICATION (See Section 10 and Rule 13) "MODIFIED RELEASE PHARMACEUTICAL COMPOSITIONS" Themis Laboratories Pvt. Ltd. having its administrative office at Unit No. S - 4 , Khira Industrial Estate, B.M Bhargava Road, Santacruz West, Mumbai 400054, Maharashtra, India an Indian Company The following specification describes ttie invention. 1 1 SEP 2006 FIELD OF INVENTION This invention relates to modified release pharmaceutical compositions in the form of capsule, tablet, granules or pellets and process for producing these compositions containing a non-steroid anti-inflammatory drug (NSAID) such as Aceclofenac as first 5 active ingredient. BACKGROUND OF THE INVENTION NSAIDs are used for chronic as well as acute symptoms. Treatment with NSAIDs in conventional dosage forms is not generally tolerable due to severe gastric irritation, 10 nausea, vomiting and related undesirable effects. Release of NSAIDs in the stomach is considered responsible for such gastric discomfort in patients. Conventional dosage forms for administration of NSAIDs have serious problems. These are immediate release of the active followed by sub-minimal concentrations of the drug with time, requiring the patient to take multiple dosages in a day, which in turn further aggravates the problems due to 15 repeated gastric irritation. Previous attempts to provide controlled release formulations in the form of monolithic systems to modulate the NSAID release suffer from a few serious drawbacks. Accidental or intentional rupture of delivery system leads to dose dumping. Dose dumping can have toxic or fatal effects depending upon the active ingredient involved. Gastric 20 emptying of monolithic system is variable. It depends on many factors like presence or absence of food, type of food, physiological state, disease condition, posture etc. It ultimately results into more of localized release of NSAID and is indeed not a dosage form of a choice. Therefore, there is a need to have more reliable alternative dosage form and a 25 process to produce such dosage form. Such alternative dosage form containing active, comprises multiple smaller particles formulated with modified release characteristics. These multiple smaller particles are formulated into dosage form like capsule or tablet or are alternatively accommodated in sachet. Multiple unit system has distinct advantages over single unit system especially in 30 case of modified release systems. 1) Multiple unit system when administered gets distributed throughout the Gl tract thereby avoiding localized accumulation and local irritation. 2) Minimized inter and intra subject variation. 3) Incorporation of 2 or more drugs in a single dosage form. 35 4) Allows delivery of particles or small units having different release characteristics to achieve desired release profile. 2 5) Allows preparation of multi-dose formulation without any change in process or formulation. Problem of rupturing of small particles is resolved by imparting a protective coat if required. Such coat allows further processing of these small particles. 5 US 5,800,836 disclose a pelletized sustained release pharmaceutical composition with enteric coat and has enteric and water insoluble polymers. The core coating being such that the active ingredient is released in a controlled fashion over an extended period in the intestine but substantially no release occurs in the acid environment of the stomach. Use of enteric polymer is critical to the tune of 70% of the total weight of polymers used. 10 US 6531152, US 6632451 and US5840332 disclose device for immediate localized release of active that comprises a drug in combination with a swellable core material that carries enteric coat. The coating comprises a material that is not soluble, or minimally soluble, in aqueous solution, within which material, a hydrophilic, non-water-soluble, particulate is embedded. The essential feature of the coating is a relatively rigid 15 hydrophobic polymer that contains in it water insoluble hydrophilic particles which when in contact with water swell and form channel to connect core with surroundings outside the coat. This causes swelling of core leading to bursting of coat. US6599529 has two separate factions or two different types of units; one for immediate release where an antacid or alkaline portion is present and another for 20 sustained release purposes comprising units coated with substantially pH-independent water-insoluble, but water-diffusible coat. It is a unit dosage form comprising at least two NSAID-containing fractions, i) a first NSAID-containing fraction of multiple-units for quick release of the NSAID substance, and ii) a second NSAID-containing fraction of multiple-units for extended release of the NSAID substance, the first fraction which - when 25 subjected to dissolution method II employing 0.07 N HCI as dissolution medium - releases at least 50% w/w of the NSAID substance present in the fraction within the first 20 min of the test, the second fraction being in the form of coated delayed release multiple units for extended release of the NSAID substance. US6312728 teaches a sustained release formulation having an enteric coat. 30 US4713248 discloses a water based film comprising a homogeneous combination of water dispersible film forming agent and a polymeric substance that forms a film over a controlled release multiple release formulation containing a active substance but the release in first hour is not less than 23% of active and in case of NSAID, it will cause a great irritation. 35 Prior art has following approaches for providing sustained release compositions comprising of NSAIDs: 3 1) Make use of antacids; 2) Provide an immediate fraction and a sustained release faction; 3) Provide a matrix of one or more polymers for sustained release formulation; 4) Provide a formulation comprising of enteric coat to regulate the release. 5 These approaches provide for release of active in stomach and subsequent maintenance of levels and have drawbacks. For example use of antacids changes the pH profile locally which is highly undesirable. Active change in gastric fluid composition should be construed as intentionally altering the constitution by introduction of additional ingredient. For example in some patents an antacid layer is given around the active. Such 10 an antacid is an additional moiety that would alter pH to a greater extent and may therefore jeopardize aspects of absorption of some of the other ingredients. Many options indicate use of two types of particles of which one providing immediate release ensures gastric irritation. Some compositions though do not have two types of particles but contain active in such a way that on administration, there is 15 immediate release. These approaches do not solve the problems associated with NSAIDs like local irritation, gastric discomfort as indicated earlier in the document. Therefore there is a long standing need to develop a process and composition that does not have enteric coat, yet exhibiting modified release over a period of at least 7 hours such that Not more than (NMT) 10%w/w of active is released in acidic medium in 1 20 hour. OBJECTS OF THE INVENTION The object of the invention is to provide a modified release pharmaceutical composition devoid of enteric coating, containing a non-steroid anti-inflammatory drug 25 (NSAID) such as Aceclofenac as first active ingredient in the form of capsule, tablet, granules or pellets such that it exhibits in vitro drug release profile of NMT 10%w/w, preferably NMT 5%w/w release of aceclofenac at the end of one hour at pH of 1.5 and not less than (NLT) 60% w/w of aceclofenac at the end of seven hours at pH of 6.8 to 7.5. Another object of the invention is to provide a process to prepare a modified 30 release pharmaceutical composition devoid of enteric coating, containing a non-steroid anti-inflammatory drug (NSAID) such as Aceclofenac as first active ingredient in the form of capsule, tablet, granules or pellets such that it exhibits in vitro drug release profile of NMT 10%w/w, preferably NMT 5%w/w release of aceclofenac at the end of 1 hour at pH of 1.5 and NLT 60% w/w of aceclofenac at the end of seven hours at pH of 6.8 to 7.5. 35 Yet another object of the invention is to provide a means to release in 1 hour, NMT 10% w/w, preferably NMT 5 %w/w of first active at pH 1.5 in vitro and to release in 1, 4 and 7 hours NLT 15% w/w, 40 - 85 % w/w and NLT 60% w/w of first active in buffer of 4 pH 6.8, comprising a core, comprising non-steroidal anti-inflammatory drug such as Aceclofenac in an amount from 30-80%w/w of composition as first active ingredient; a barrier coat, comprising at least one non-enteric water insoluble polymer upto 25%w/w of composition and at least one channel forming agent. 5 Yet another object of the invention is to provide a modified release composition devoid of enteric coating and yet reduces the problem of gastric irritation without causing active change in gastric fluid composition and process to prepare such composition. Yet another object of the invention is to provide a once a day formulation or twice a day composition comprising of NSAID for better patient compliance. 10 Yet another object of the invention is to provide a composition and a process for producing such composition comprising NSAID and another active selected from proton pump inhibitor and / or prokinetic agent and / or another NSAID. Yet another object of the invention is to provide a composition comprising NSAID such as Aceclofenac and non-enteric water insoluble polymer to release in 1 hour, 4 hours 15 and 7 hours, Not less than (NLT) 15% w/w, 40-85%w/w and NLT 60%w/w of aceclofenac in pH buffer of 6.8 respectively and to provide the process to prepare such composition. SUMMARY OF INVENTION In accordance with the present invention modified release pharmaceutical 20 composition is provided that is devoid of enteric coating, containing a non-steroid anti inflammatory drug (NSAID) such as Aceclofenac as first active ingredient in the form of capsule, tablet, granules or pellets such that it exhibits in vitro drug release profile of NMT 10%w/w, preferably NMT 5%w/w release of aceclofenac at the end of one hour at pH of 1.5 and NLT 60% w/w of aceclofenac at the end of seven hours at pH of 6.8 to 7.5. 25 Surprisingly it is noticed that the composition comprising NSAID such as Aceclofenac and non-enteric water insoluble polymer releases in 1 hour, 4 hours and 7 hours NLT 15% w/w, 40-85%w/w and NLT 60%w/w of aceclofenac in pH buffer of 6.8. The invention further provides process for the preparation of modified release pharmaceutical composition in the form of capsule, tablet, granules or pellets comprising 30 steps of; a) Depositing on inert seeds or extruding and spheronizing, non-steroidal antiinflammatory drug such as Aceclofenac 30-80%w/w of composition as first active ingredient using binder, optionally with other pharmaceutically acceptable ingredients to obtain drug cores; 35 b) Optionally drying and/or coating the drug cores obtained in step a) with nonfunctional polymer to get hardened drug cores; and 5 c) Applying barrier coat comprising at least one non-enteric water insoluble polymer upto 25%w/w of composition and at least one channel forming agent, on drug cores or hardened drug cores obtained in step a) or b) respectively to obtain modified release microbeads. 5 The invention as disclosed in the present invention can as well be used for administration of more than one active. An NSAID can be effectively combined with prokinetic agent, or proton pump inhibitor or another NSAID. 10 DETAILED DESCRIPTION OF INVENTION The present invention provides a delayed modified release pharmaceutical composition comprising NSAID that releases active for a prolonged period. The compositions of the present invention are processed in such a way that though devoid of enteric polymer, release not more than 10% of active in acidic pH in vitro in 1 hour. This is 15 significantly different from prior art where presence of enteric polymer is must for arresting release of NSAID in acidic medium. Coating equipments like coating pan, fluid bed processors, extrusion and spheronizer, centrifugal coater, tangential coater can be used. This invention provides a means to release in one hour not more than 10% of first active ingredient at pH of 1.5 in vitro and to release in 1 hour, 4 hours, 7 hours NLT 15% 20 w/w, 40-85%w/w and NLT 60%w/w of first active in buffer of pH 6.8, comprising a core, comprising non-steroidal anti-inflammatory drug such as Aceclofenac in an amount from 30-80%w/w of composition as first active ingredient; a barrier coat, comprising at least one non-enteric water insoluble polymer upto 25%w/w of composition and at least one channel forming agent. 25 The objects of the invention are achieved by preparing and providing modified release solid oral dosage forms without the use of enteric polymer as described below in following steps: Step 1) Preparation of drug core Step 2) Application of optional coat 30 Step 3) Application of barrier coat STEP 1) Preparation of Drug Core: The first step is preparation of drug core by depositing on inert seeds, non-steroidal anti-inflammatory drug such as Aceclofenac 30-80%w/w of composition as first active 35 ingredient using binder, optionally with other pharmaceutical^ acceptable ingredients to obtain drug cores. Such deposition of NSAID can be simultaneous with binder or 6 alternating with binder. Binder may be in the form of aqueous or non-aqueous solution or dispersion. In another embodiment of the invention the drug cores can be prepared by extruding and spheronizing NSAID with pharmaceutically acceptable ingredients. 5 In simultaneous layering of NSAID, the binder solution or dispersion contains the NSAID in it, which is deposited on non pareil seeds. In this case, suspension comprising NSAID, binder and antitack agent in suitable aqueous or non-aqueous solvent can be coated as a single layer on sugar sphere to obtain drug cores. In alternate layering of NSAID, the pulverized NSAID is optionally mixed with inert 10 excipients to obtain an admixture, which is deposited on inert seeds in a coating pan using suitable aqueous or non-aqueous binder solution to obtain drug core. The process is continued till entire admixture containing drug is used for deposition. In yet another embodiment the NSAID is mixed with at least one pharmaceutically acceptable ingredient such as binders, fillers, disintegrants, lubricants, surfactants, 15 plasticizer and granulated using suitable media before extruded into pellets. Process and the composition disclosed enables incorporation of more than one NSAID. These NSAIDs are Paracetamol; Salicylates like Aspirin, Choline salicylate, Magnesium salicylate, Sodium salicylate, Choline magnesium trisalicylate; Indoles like indomethacin; Pyrazoles like Phenyl Butazone; Etodolac, Meclofenamate sodium, 20 Propionic acid derivatives like Naproxen sodium, Ibuprofen, Fenoprofen, Ketoprofen, Flubiprofen, Fenamates like mefenamic acid, flufenamic acid; ketorolac, pentazocine, Oxicam like Piroxicam, Tenoxicam, Meloxicam and similar compounds, Phenyl acetic acid Diclofenac, Aceclofenac; Cox-2 inhibitors like Rofecoxib, Torecoxib, Celecoxib, .Valdecoxib, Parecoxib, Etoricoxib, Lumiracoxib, Non COX selectives, preferential COX2 25 inhibitors like Nabumetone; Aminonicotinic acids like Flunixin; Pyrazolones like Phenylbutazone, Oxyphenbutazone, Dipyrone, Ramifenazone . The process is also useful in incorporating an active in addition to NSAID in the formulation wherein the said active can be a member of prokinetic agent such as cisapride, mosapride, Itopride, domperidone, or proton pump inhibitor such as 30 Omeprazole, Rabeprazole, Pantoprazole, Lansoprazole, Esomeprazole or another NSAID. These actives are processed into tablets, pellets, granules or capsules by the process known to a person skilled in the art. Proton pump inhibitors such as Omeprazole, Rabeprazole, Pantoprazole, Lansoprazole, Esomeprazole are in enteric release form and prokinetic agent such as cisapride, mosapride, Itopride, domperidone are preferably in 35 sustained release form. 7 The drug cores prepared above are suitably dried in equipments such as coating pan, tray drier or fluid bed drier or their likes to moisture content of less than 5%w/w preferably less than 3%w/w and more preferably less than 2%w/w. The dried drug cores are suitably sized to obtain drug cores of desired mesh size. 5 These sustained release compositions comprise NSAID in an amount from 30%w/w - 80%w/w of the composition. The pharmaceutically acceptable excipient comprise of one or more of filler, binder, disintegrant, lubricant, polymer, colorant, coating agent, preservatives and stabilizer, surfactant, anti-adherent, alkalizing agent, acidulant, pH modifiers, plasticizers, gums, 10 glidant, buffers and their mixtures thereof. Inert seeds such as sugar sphere comprising of sugar and starch is preferably used. Alternatively inert seeds comprising of microcrystalline cellulose or any other suitable inert material may also be used. The particle size of the sugar sphere used may be in the range of about 300 to 1680 microns preferably about 500 to 1200 microns. 15 Antitack agent used in the present invention is selected from talc, colloidal silicon dioxide, magnesium stearate, glyceryl behenate, glyceryl monostearate and their mixtures the preferable choice being talc with or without colloidal silicon dioxide and are used in the concentration range of about 0.1 - 20% w/w of composition. Inert fillers are selected from starch, lactose, microcrystalline cellulose, low 20 viscosity grade hydroxypropylcellulose, mannitol, pulverized sugar, sorbitol, rjonobasic sodium phosphate, dibasic sodium phosphate, tribasic sodium phosphate, crosslinked carboxymethylcellulose and its salts such as sodium, potassium and calcium salt; starch, sodium starch glycolate, pregelatinized starch, starch 1500, crospovidone, cyclodextrins and its derivatives, calcium sulfate and their mixtures. Inert excipient may be used alone 25 or in combination and is preferably starch and is used in concentration range of about 0.1 - 70% w/w of composition. Binder is selected from the group consisting of cellulose derivatives such as hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose, hydroxyethylcellulose, carboxymethylcellulose and its salt; sugar, acacia; polyvinylpyrollidone, polymethacrylates, 30 carbomer, gums like xanthan gum, guar gum, tragacanth, gelatin, carragenan, locust bean gum, karaya gum, agar, chitosan, alginic acid and its pharmaceutical acceptable salts such as sodium, potassium and calcium salt. Binder may be used alone or in combination and is preferably polyvinylpyrollidone used in the concentration upto about 0.1% to 20% w/w of composition. 35 Disintegrants is selected from but not limited to starch, cellulose derivatives such as alkyl cellulose, hydroxyalkylcellulose, crosslinked carboxymethylcellulose and its salts 8 such as sodium, potassium, calcium salt, microcrystalline cellulose, sodium starch glycolate, pre-gelatinized starch, starch 1500, crospovidone and their suitable mixture. Acidulant, alkalizing agents, pH modifiers and buffers are selected from but not limited to acetic, boric, carbonic, phosphoric, malic, maleic, citric, bicarbonic, tartaric, 5 succinic, benzoic, lactic, glyceric, glutamic, lauric, adipic, gluconic, fumaric, monocarboxylic, hydroxycarboxylic, polycarboxylic acids, glutaric acids, essential and nonessential amino acids and their pharmaceutical^ acceptable salts preferably sodium, potassium, calcium, magnesium and ammonium salt, alkali or alkali earth metal chlorides, sulfates, phosphates, bicarbonates, citrates, borates, acetates and succinates, sodium or 10 potassium hydrogen phosphate, sodium or potassium dihydrogen phosphate, hydrochloric acid sodium hydroxide, potassium hydroxides, tris buffer, organic acid buffer, alkali hydroxide, ammonia, and their mixtures. Glidants, anti-adherents and lubricants are selected from but not limited to talc, colloidal silicon dioxide, glyceryl monostearate, sodium benzoate, sodium lauryl sulfate, 15 glyceryl behenate, stearic acid and its salt such as magnesium stearate, calcium stearate and their suitable mixture. Preferably other pharmaceutically acceptable ingredient used in the invention is selected from talc, lactose, starch, sugar, microcrystalline cellulose, polyethylene glycol, polyvinylpyrollidone, colloidal silicon dioxide, magnesium stearate, glyceryl behenate, 20 glyceryl monostearate and their mixtures, preferably agent being talc. Although the solvent of preferred choice for processing NSAID is water, other solvents such as alcohol, hydroalcoholic mixture, organic solvent or their mixtures can also be used. For application of optional coat and barrier coat solvents such as water, isopropanol, acetone, ethanol, methanol, methylene chloride and their mixtures can be 25 used. STEP 2) Application of Optional Coat: The drug cores after drying and sizing are optionally coated with a layer of nonfunctional polymer and antitack agent to obtain hardened drug cores. 30 In another embodiment of the invention, non-functional polymer and antitack agent is deposited from aqueous media as a single layer on drug cores. Alternatively, non-functional polymer in water can be deposited with antitack agent as an alternate layer on drug cores to obtain hardened drug cores. The hardened drug cores are suitably dried in equipments such as coating pan, tray drier and fluid bed drier or 35 their likes to arrive a moisture content of less than 5%w/w preferably less than 3%w/w and more preferably less than 2%w/w. 9 Non-functional polymer is selected from the group of cellulose derivatives like hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose; polyvinylpyrrolidone, polymethacrylates and mixtures thereof, and is used in the concentration of upto about 6%w/w of composition. 5 STEP 3) Application of Barrier Coat: Drug cores or hardened drug cores so obtained as described in Step I or Step 2 respectively, are coated with a barrier coat comprising at least one non-enteric water insoluble polymer upto 25%w/w of composition and at least one channel forming agent. 10 Functional polymer is non-enteric water insoluble polymer and is selected from Ethyl cellulose, Polymethylacrylates and their mixtures. Polymethacrylates (Eudragit RTM) are selected from Poly (ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1 (Eudragit RS), Poly (ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.2 (Eudragit RL), Poly (ethyl acrylate, 15 methyl methacrylate) (Eudragit NE) or their mixtures. Ethyl cellulose is available in various grades depending on its viscosity from about 3 cps to about 100 cps. Ready to use aqueous dispersion of ethylcellulose such as Aquacoat ECD RTM of FMC and Surelease RTM of Colorcon can also be used. This ready dispersion further contains plasticizers, surfactants (sodium lauryl sulfate), stabilizing agents, ammonium hydroxide, oleic acid, 20 fumed silica, anti-foaming agent, cetyl alcohol as additives. The barrier coat comprises a mixture of non-enteric water insoluble polymer and channel forming agent in the ratio of 90:10 to 10:90, preferably in the ratio ranging from 80:20.to 50:50 and more preferably in the ratio from 70:30 to 40:60. In preferred embodiment, the barrier coat comprises a mixture of ethylcellulose and 25 hydroxypropylmethylcellulose in the ratio of 90:10 to 10:90, preferably in the ratio ranging from 80:20.to 50:50 and more preferably in the ratio from 70:30 to 40:60. Functional polymer is dissolved or dispersed in a suitable solvent such as water, alcohol, acetone, dichloromethane or mixtures thereof preferably in proportions of 1:9 to 9:1. 30 The channel forming agent is present in an amount upto 95%w/w of barrier coat and is selected from the group of cellulose derivatives such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose and its salt; sugars such as glucose, sucrose, lactose; polyvinylpyrollidone, polyethylene glycol, triacetin, triethylcitrate, diethylphthalate, acetyltribytylcitrate, hydrogenated oils, 35 polysorbates, propylene glycol, dibytylsebacate, meglumine, miglyol, cetyl alcohol and mixtures thereof. 10 Optionally antitack agent such as talc is added in the concentration of upto about 30%w/w of the barrier coat preferably when aqueous dispersion comprising of functional polymer is used. Optionally one can incorporate surfactants, pharmaceutically acceptable 5 preservatives and stabilizers for imparting associated properties. Colors, pigments and dyes used in the present invention are selected from pharmaceutically acceptable colors, pigments and dyes. The process described herein may be carried out completely or in part in aqueous or non-aqueous media such as methanol, ethanol, isopropanol, acetone, dichloromethane 10 or their mixtures. The above process can be carried out in equipment such as fluid bed bottom spray processor, extrusion spheronizer, coating pan and their likes. The process of the invention described herein is the viable continuous process for the preparation of modified release composition comprising of NSAID. Overall yield of the process not less than 95%. 15 In the description the words active, drug are used interchangeably. Words particles, microbeads, pellets are used interchangeably. The invention is now described with non - limiting examples. Illustration 1: Preparation of modified release Aceclofenac compositions by 20 alternate layering technique. Preparation of drug core: Ingredients Quantities (gm) Aceclofenac 459 Nonpareil Seeds 180 Sugar 22.5 Starch 22.5 Talc 11.25 PVPK-30 11.25 Purified water Quantity sufficient Term "qs" indicates quantity sufficient. 25 459 Gms of Aceclofenac was sifted through 200 mesh ASTM and mixed with 22.5 Gms of starch and 11.25 Gms of Talc in planetary mixer for about 10 minutes to obtain drug admixture. Sugar 22.5 Gms and 11.25 Gms of PVPK-30 was dispersed and dissolved in water to obtain binder solution. The concentration of PVPK-30 in water was 11 about 10%w/w. 180 Gms of Sugar spheres were loaded in coating pan. Binder solution was sprayed on sugar sphere. When desired level of wetting was observed, the drug admixture was layered till the wetted agglomerated sugar spheres were unagglomerated. This operation was repeated until the total quantity of drug admixture was used up. 5 Thereafter, the drug cores were dried in tray drier and checked for moisture content to be less than 3%. They are then sieved to get drug cores of desired size. Application of optional coat: Ingredients Quantities (gm) Aceclofenac Drug Core 260 HPMC E05 7.8 Talc 1.56 Purified water Quantity sufficient 10 7.8 Gms of HPMC was dispersed and dissolved in water and 1.56 Gms of talc was added to it. The drug core of undesirable size (utilizable residue) that was retained above and below the desired mesh was mixed with water and was added to HPMC suspension containing talc. The suspension was filtered through appropriate mesh and was sprayed on 260 Gms of drug cores in coating pan to obtain hardened drug core. The solid content 15 of this suspension in water may be upto 20% w/w. These hardened drug cores were dried in tray drier and checked for moisture content to be less than 3%. Preparation of modified release core: Ingredients Quantities (gm) Aceclofenac Hardened Drug core 230 Ethyl Cellulose 4.02 HPMC E05 1.73 Triacetin 0.4 Dichloromethane 49.03 Methanol 32.68 20 1.73 Gms of HPMC E05 & 4.02 Gms of Ethyl cellulose were dispersed and dissolved in the mixture of methanol and methylene chloride (2:3). 0.4 Gms of Triacetin was added to this solution. The solution was filtered through appropriate mesh and was sprayed on 230 Gms of hardened drug core in fluid bed bottom spray processor to obtain modified release microbeads. 12 The processing parameters during the coating process were adjusted to have an inlet air temperature of about 20°C to about 60°C, preferably about 30°C to 45°C outlet air temperature of about 20°C to about 45°C preferably 25°C to 40°C, atomization air pressure of not less than 0.5 bars, fluidization flap open from about 15 to about 90% w/w. 5 Modified release microbeads are dried in the same equipment maintaining the inlet temperature between about 50-80°C and outlet temperature between about 40 - 60°C to have moisture content of less than 5% and preferably less than 3% and more preferably less than 2%w/w. Alternatively the coating may also be carried out in other coating equipments such as coating pan. % of coating material to total weight of pellets produced 10 is about 2.45%. The modified release pellets so produced are spherical to almost spherical and support the filling in capsules which may be transparent especially if colored pellets are produced. 15 Illustration 2: Preparation of modified release Aceclofenac compositions using extrusion technique. Preparation of drug cores: Ingredients Quantities (gm) Aceclofenac 200 MCC 70 Lactose 15 PVPK-30 05 PEG 6000 10 Talc 05 Purified water 120 20 1) 200gms of Aceclofenac, 70gms of MCC and 15gms of Lactose were sifted through sieve 40. 2) 5 gms of PVPK-30 and 10 gms of PEG-6000 was dissolved in water to prepare binder solution. 25 3) Sifted ingredients obtained in step1 were blended in Kenwood planetary mixer for 5 minutes and granulated using binder solution obtained in step 2 to get dough. 4) The dough obtained in step 3 is extruded through 1.2 mm(radial) sieve with 50 rpm for 2 minutes. 5) These extrudates are spheronized at 600rpm for about 2 minutes. Talc is sprinkled on 30 extrudates while carrying out spheronization. 13 Preparation of modified release pellets 1.25 %w/w coating solution of Ethyl Cellulose: HPMC in 75:25 ratio is used for preparation of modified release pellets. Quantitative composition of modified release coat is as follows: Ingredients Quantities (gm) Aceclofenac Drug pellets 305 Ethyl Cellulose 2.85 HPMC E05 0.95 Triacetin 0.29 Methylene Chloride 46.84 Methanol 31.23 5 1) Disperse and dissolve ethyl cellulose in mixture of methylene chloride and methanol. 2) Dissolve HPMC E05 in the solution obtained from step 1). 3) Add triacetin to solution obtained in step 2) and stir for 5 minutes to dissolve it. 4) Filter the solution obtained in step 3) through 100 mesh sieve. 10 5) The process of coating is carried out in fluid bed processor with process parameters of 3 rpm, atomization pressure at 2, inlet and outlet temperatures at 45°C and 33°C respectively, and % flap opened at 45%. Illustration 3: Dissolution testing results of Aceclofenac pellets prepared as per 15 illustration 2, in 6.8 pH buffer, USP basket type. Time in hour % w/w release of Aceclofenac 1 hour 38.3% 4 hour 72.4% 7 hour 85.9% Illustration 4: Dissolution testing of Aceclofenac pellets prepared as per illustration 1, in 1.5. pH, 7.5 pH buffer, USP basket type. PH Time in hour % w/w release of Aceclofenac 1.5 1st Hour 1.25% 7.5 2"° Hour 55.00% 7.5 4m Hour 84.25% 7.5 6m Hour 95.21% 20 14 Dissolution testing was performed in pH of 1.5 first followed by pH of buffer 7.5. Illustration 5: Preparation of modified release pellets containing Aceclofenac 70% w/w. Ingredients Quantities (gm) Aceclofenac 520 Nonpareil Seeds 120 Talc 48 PVPK-30 48 IPA 540 Water 180 5 Preparation of drug core: 520 gms of Aceclofenac and 48 gms of Talc were mixed in Kenwood mixer for 10 minutes before passing through mesh 40. 48gms of PVPK-30 were dissolved in mixture of IPA:Water (3:1) to get a binder solution. 10 120 gms of nonpareil seeds were loaded in coating pan. Binder solution was sprayed on nonpareil seeds. When desired level of wetting was observed, the admixture of Aceclofenac and talc was layered till the wetted agglomerated nonpareil seeds were un-agglomerated. This operation was repeated until the total quantity of admixture was used up. The coating process parameters of pan rpm 16-20, Atomization pressure of 0.5 to 3 15 bars, pan angle of 15-20 were observed. Thereafter, the drug cores were dried in oven at 50°C for an hour. Application of optional (seal) coat: Ingredients Quantities (gm) Aceclofenac drug pellets 610 HPMC E05 36.6 Talc 3.66 Water 534.88 20 The drug cores of undesirable size (utilizable residue) that was retained above and below the desired mesh (mesh 14 and 20) was mixed with water and was added to nonfunctional polymer (HPMC E05) suspension containing talc. The suspension was filtered through appropriate mesh and was sprayed on drug cores in coating pan to obtain hardened drug core. The solid content of this suspension in water may be upto 20% w/w. These 15 hardened drug cores were dried in coating pan for 30 minutes keeping blower temperature to 70°C and checked for moisture content and particle size. Preparation of modified release core: Ingredients Quantities (gm) Aceclofenac seal coat Pellets 196.140 Ethyl Cellulose 4.86 HPMC E05 2.08 Triacetin 0.46 Methylene chloride 84.44 Methanol 56.30 5 2.08 Gms of HPMC E05 & 4.86 Gms of Ethyl cellulose were dispersed and dissolved in the mixture of methanol and methylene chloride (2:3). 0.23 Gms of Triacetin was added to this solution. The polymer content in barrier coat is 3.4%w/w of the composition. The solution was filtered through appropriate mesh and was sprayed on 196.14 Gms of 10 hardened drug core in coating pan to obtain modified release pellets. Methanol and methylene chloride are used preferably in the ratio of 2:3. The processing parameters during the coating process were adjusted to have an inlet air temperature of about 20°C to about 60°C, preferably about 25°C to 45°C, atomization air pressure of not less than 0.5 bars, fluidization flap open from about 15 to about 90% w/w. 15 Modified release pellets are dried in the same equipment maintaining the inlet temperature between about 50-80°C and outlet temperature between about 40 - 60°C to have moisture content of less than 5% and preferably less than 3% and more preferably less than 2%w/w. Alternatively the coating may also be carried out in coating pan to obtain modified release microbeads comprising of NSAID. 20 16 Claims: We Claim, 1) A modified release pharmaceutical composition in the form of capsule, tablet, granules or pellets comprising 5 a) a core, comprising non-steroidal anti-inflammatory drug such as Aceclofenac in an amount from 30-80%w/w of composition as first active ingredient; b) a barrier coat, comprising at least one non-enteric water insoluble polymer upto 25%w/w of composition and at least one channel forming agent; such that it exhibits in vitro drug release profile of not more than 10%w/w of 10 aceclofenac at the end of one hour at pH of 1.5 and not less than 60% w/w of aceclofenac at the end of seven hours at pH of 6.8 to 7.5. 2) A composition as claimed in claim 1 wherein the non-enteric water insoluble polymer is selected from Ethyl cellulose, Polymethylacrylates and their mixtures. 15 3) A composition as claimed in claim 1 wherein the channel forming agent is present in an amount upto 95%w/w of barrier coat. 4) A composition as claimed in claims 1 and 3 wherein channel forming agent is selected 20 from the group of cellulose derivatives such as hydroxypropylmethylcellulose carboxymethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose; sugar such as glucose, sucrose, lactose; polyvinylpyrollidone, polyethylene glycol, triacetin, triethylcitrate, diethylphthalate, acetyltribytyIcitrate, hydrogenated oils, polysorbates, propylene glycol, dibytylsebacate, meglumine, miglyol, cetyl alcohol and mixtures 25 thereof. 5) A composition as claimed in claims 1,3-4 wherein the barrier coat comprises a mixture of ethylcellulose and hydroxypropylmethylcellulose in the ratio of 90:10 to 10:90, preferably in the ratio ranging from 80:20.to 50:50 and more preferably in the 30 ratios ranging from 70:30 to 40:60. 6) A process for the preparation of modified release pharmaceutical composition in the form of capsule, tablet, granules or pellets comprising steps of; a) Depositing on inert seeds or extruding and spheronizing, non-steroidal anti- 35 inflammatory drug such as Aceclofenac 30-80%w/w of composition as first active ingredient using binder, optionally with other pharmaceutical^ acceptable 17 ingredients to obtain drug cores; b) Optionally drying and/or coating the drug cores obtained in step a) with nonfunctional polymer to get hardened drug cores; and c) Applying barrier coat comprising at least one non-enteric water insoluble polymer 5 upto 25%w/w of composition and at least one channel forming agent, on drug cores or hardened drug cores obtained in step a) or b) respectively. 7) A process as claimed in claim 6 wherein the non-enteric water insoluble polymer is selected from Ethyl cellulose, Polymethylacrylates and their mixtures; channel forming 10 agent is selected from the group of cellulose derivatives such as hydroxypropylmethylcellulose carboxymethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose; sugars, polyvinylpyrollidone, polyethylene glycol, triacetin, triethylcitrate, diethylphthalate, acetyltribytylcitrate, hydrogenated oils, polysorbates, propylene glycol, dibytylsebacate, meglumine, miglyol, cetyl alcohol and mixtures 15 thereof in an amount upto 95%w/w of barrier coat; binder and non-functional polymer is selected from polyvinylpyrollidone, hydroxypropylcellulose, sugar, hydroxypropylmethylcellulose, acrylic acid, polymethacrylates and their mixtures, preferably hydroxypropylmethylcellulose. 20 8) A process as claimed in claim 6, wherein the pharmaceutically acceptable ingredient is selected from talc, lactose, starch, sugar such as glucose, sucrose, lactose; Microcrystalline cellulose, Polyethylene glycol, Polyvinylpyrollidone, colloidal silicon dioxide, magnesium stearate, glyceryl behenate, glyceryl monostearate and their mixtures, preferably agent being talc. 25 9) A process as claimed in claims 6-7 wherein the barrier coat comprises a mixture of ethylcellulose and hydroxypropylmethylcellulose in the ratio of 90:10 to 10:90, preferably in the ratio ranging from 80:20.to 50:50 and more preferably in the ratio ranging from 70:30 to 40:60. 30 10)A composition in the form of capsule, tablet, granules or pellets as claimed in claim 1, further comprises another active ingredient selected from proton pump inhibitors such as Omeprazole, Rabeprazole, Pantoprazole, Lansoprazole, Esomeprazole or prokinetic agent such as cisapride, mosapride, Itopride, domperidone or other non- 35 steroidal anti-inflammatory drug. 18 11) A means to release in one hour not more than 10%w/w, preferably not more ttian 5%w/w of first active ingredient at pH of 1.5 in vitro and to release in 1 hour, 4 hours, 7 hours NLT 15% w/w, 40-85%w/w and NLT 60%w/w of first active in buffer of pH 6.8, comprising a) a core, comprising non-steroidal anti-inflammatory drug such as Aceclofenac in an amount from 30-80%w/w of composition as first active ingredient; b) a barrier coat, comprising at least one non-enteric water insoluble polymer upto 25%w/w of composition and at least one channel forming agent. 10 15 Dated this 11m day of September 2006 Milind Sathe Manager, IPR For Themis Laboratories Private Limited 19 I ABSTRACT A modified release pharmaceutical composition in the form of capsule, tablet, granules or 5 pellets comprising a core, comprising non-steroidal anti-inflammatory drug such as Aceclofenac as first active ingredient; a barrier coat comprising at least one non-enteric water insoluble polymer and at least one channel forming agent and exhibiting modified release is disclosed. The invention also discloses the process to prepare such modified release pharmaceutical compositions. 10

Full Text

COMPLETE AFTER PROVISIONAL
LEFT ON 11/09/06
FORM-2

THE PATENTS ACT. 1970
(39 OF 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
(See Section 10 and Rule 13)

"MODIFIED RELEASE PHARMACEUTICAL COMPOSITIONS"
Themis Laboratories Pvt. Ltd. having its administrative office at Unit No. S - 4 , Khira Industrial Estate, B.M Bhargava Road, Santacruz West, Mumbai 400054, Maharashtra, India an Indian Company
The following specification describes ttie invention.

1 1 SEP 2006

FIELD OF INVENTION
This invention relates to modified release pharmaceutical compositions in the form of capsule, tablet, granules or pellets and process for producing these compositions containing a non-steroid anti-inflammatory drug (NSAID) such as Aceclofenac as first
5 active ingredient.
BACKGROUND OF THE INVENTION
NSAIDs are used for chronic as well as acute symptoms. Treatment with NSAIDs in conventional dosage forms is not generally tolerable due to severe gastric irritation,
10 nausea, vomiting and related undesirable effects. Release of NSAIDs in the stomach is considered responsible for such gastric discomfort in patients. Conventional dosage forms for administration of NSAIDs have serious problems. These are immediate release of the active followed by sub-minimal concentrations of the drug with time, requiring the patient to take multiple dosages in a day, which in turn further aggravates the problems due to
15 repeated gastric irritation.
Previous attempts to provide controlled release formulations in the form of monolithic systems to modulate the NSAID release suffer from a few serious drawbacks. Accidental or intentional rupture of delivery system leads to dose dumping. Dose dumping can have toxic or fatal effects depending upon the active ingredient involved. Gastric
20 emptying of monolithic system is variable. It depends on many factors like presence or absence of food, type of food, physiological state, disease condition, posture etc. It ultimately results into more of localized release of NSAID and is indeed not a dosage form of a choice.
Therefore, there is a need to have more reliable alternative dosage form and a
25 process to produce such dosage form.
Such alternative dosage form containing active, comprises multiple smaller particles formulated with modified release characteristics. These multiple smaller particles are formulated into dosage form like capsule or tablet or are alternatively accommodated in sachet. Multiple unit system has distinct advantages over single unit system especially in
30 case of modified release systems.
1) Multiple unit system when administered gets distributed throughout the Gl tract thereby avoiding localized accumulation and local irritation.
2) Minimized inter and intra subject variation.
3) Incorporation of 2 or more drugs in a single dosage form.
35 4) Allows delivery of particles or small units having different release characteristics to achieve desired release profile.
2

5) Allows preparation of multi-dose formulation without any change in process or formulation.
Problem of rupturing of small particles is resolved by imparting a protective coat if
required. Such coat allows further processing of these small particles.
5 US 5,800,836 disclose a pelletized sustained release pharmaceutical composition
with enteric coat and has enteric and water insoluble polymers. The core coating being such that the active ingredient is released in a controlled fashion over an extended period in the intestine but substantially no release occurs in the acid environment of the stomach. Use of enteric polymer is critical to the tune of 70% of the total weight of polymers used.
10 US 6531152, US 6632451 and US5840332 disclose device for immediate localized
release of active that comprises a drug in combination with a swellable core material that carries enteric coat. The coating comprises a material that is not soluble, or minimally soluble, in aqueous solution, within which material, a hydrophilic, non-water-soluble, particulate is embedded. The essential feature of the coating is a relatively rigid
15 hydrophobic polymer that contains in it water insoluble hydrophilic particles which when in contact with water swell and form channel to connect core with surroundings outside the coat. This causes swelling of core leading to bursting of coat.
US6599529 has two separate factions or two different types of units; one for immediate release where an antacid or alkaline portion is present and another for
20 sustained release purposes comprising units coated with substantially pH-independent water-insoluble, but water-diffusible coat. It is a unit dosage form comprising at least two NSAID-containing fractions, i) a first NSAID-containing fraction of multiple-units for quick release of the NSAID substance, and ii) a second NSAID-containing fraction of multiple-units for extended release of the NSAID substance, the first fraction which - when
25 subjected to dissolution method II employing 0.07 N HCI as dissolution medium - releases at least 50% w/w of the NSAID substance present in the fraction within the first 20 min of the test, the second fraction being in the form of coated delayed release multiple units for extended release of the NSAID substance.
US6312728 teaches a sustained release formulation having an enteric coat.
30 US4713248 discloses a water based film comprising a homogeneous combination
of water dispersible film forming agent and a polymeric substance that forms a film over a controlled release multiple release formulation containing a active substance but the release in first hour is not less than 23% of active and in case of NSAID, it will cause a great irritation.
35 Prior art has following approaches for providing sustained release compositions
comprising of NSAIDs:
3

1) Make use of antacids;
2) Provide an immediate fraction and a sustained release faction;
3) Provide a matrix of one or more polymers for sustained release formulation;
4) Provide a formulation comprising of enteric coat to regulate the release.
5 These approaches provide for release of active in stomach and subsequent
maintenance of levels and have drawbacks. For example use of antacids changes the pH profile locally which is highly undesirable. Active change in gastric fluid composition should be construed as intentionally altering the constitution by introduction of additional ingredient. For example in some patents an antacid layer is given around the active. Such
10 an antacid is an additional moiety that would alter pH to a greater extent and may therefore jeopardize aspects of absorption of some of the other ingredients.
Many options indicate use of two types of particles of which one providing
immediate release ensures gastric irritation. Some compositions though do not have two
types of particles but contain active in such a way that on administration, there is
15 immediate release. These approaches do not solve the problems associated with NSAIDs
like local irritation, gastric discomfort as indicated earlier in the document.
Therefore there is a long standing need to develop a process and composition that does not have enteric coat, yet exhibiting modified release over a period of at least 7 hours such that Not more than (NMT) 10%w/w of active is released in acidic medium in 1
20 hour.
OBJECTS OF THE INVENTION
The object of the invention is to provide a modified release pharmaceutical composition devoid of enteric coating, containing a non-steroid anti-inflammatory drug
25 (NSAID) such as Aceclofenac as first active ingredient in the form of capsule, tablet, granules or pellets such that it exhibits in vitro drug release profile of NMT 10%w/w, preferably NMT 5%w/w release of aceclofenac at the end of one hour at pH of 1.5 and not less than (NLT) 60% w/w of aceclofenac at the end of seven hours at pH of 6.8 to 7.5.
Another object of the invention is to provide a process to prepare a modified
30 release pharmaceutical composition devoid of enteric coating, containing a non-steroid anti-inflammatory drug (NSAID) such as Aceclofenac as first active ingredient in the form of capsule, tablet, granules or pellets such that it exhibits in vitro drug release profile of NMT 10%w/w, preferably NMT 5%w/w release of aceclofenac at the end of 1 hour at pH of 1.5 and NLT 60% w/w of aceclofenac at the end of seven hours at pH of 6.8 to 7.5.
35 Yet another object of the invention is to provide a means to release in 1 hour, NMT
10% w/w, preferably NMT 5 %w/w of first active at pH 1.5 in vitro and to release in 1, 4
and 7 hours NLT 15% w/w, 40 - 85 % w/w and NLT 60% w/w of first active in buffer of
4

pH 6.8, comprising a core, comprising non-steroidal anti-inflammatory drug such as
Aceclofenac in an amount from 30-80%w/w of composition as first active ingredient; a
barrier coat, comprising at least one non-enteric water insoluble polymer upto 25%w/w of
composition and at least one channel forming agent.
5 Yet another object of the invention is to provide a modified release composition
devoid of enteric coating and yet reduces the problem of gastric irritation without causing
active change in gastric fluid composition and process to prepare such composition.
Yet another object of the invention is to provide a once a day formulation or twice a
day composition comprising of NSAID for better patient compliance.
10 Yet another object of the invention is to provide a composition and a process for
producing such composition comprising NSAID and another active selected from proton
pump inhibitor and / or prokinetic agent and / or another NSAID.
Yet another object of the invention is to provide a composition comprising NSAID
such as Aceclofenac and non-enteric water insoluble polymer to release in 1 hour, 4 hours 15 and 7 hours, Not less than (NLT) 15% w/w, 40-85%w/w and NLT 60%w/w of aceclofenac
in pH buffer of 6.8 respectively and to provide the process to prepare such composition.
SUMMARY OF INVENTION
In accordance with the present invention modified release pharmaceutical
20 composition is provided that is devoid of enteric coating, containing a non-steroid anti
inflammatory drug (NSAID) such as Aceclofenac as first active ingredient in the form of
capsule, tablet, granules or pellets such that it exhibits in vitro drug release profile of NMT
10%w/w, preferably NMT 5%w/w release of aceclofenac at the end of one hour at pH of
1.5 and NLT 60% w/w of aceclofenac at the end of seven hours at pH of 6.8 to 7.5.
25 Surprisingly it is noticed that the composition comprising NSAID such as
Aceclofenac and non-enteric water insoluble polymer releases in 1 hour, 4 hours and 7 hours NLT 15% w/w, 40-85%w/w and NLT 60%w/w of aceclofenac in pH buffer of 6.8.
The invention further provides process for the preparation of modified release pharmaceutical composition in the form of capsule, tablet, granules or pellets comprising
30 steps of;
a) Depositing on inert seeds or extruding and spheronizing, non-steroidal antiinflammatory drug such as Aceclofenac 30-80%w/w of composition as first active ingredient using binder, optionally with other pharmaceutically acceptable ingredients to obtain drug cores;
35 b) Optionally drying and/or coating the drug cores obtained in step a) with nonfunctional polymer to get hardened drug cores; and
5

c) Applying barrier coat comprising at least one non-enteric water insoluble polymer upto 25%w/w of composition and at least one channel forming agent, on drug cores or hardened drug cores obtained in step a) or b) respectively to obtain modified release microbeads.
5
The invention as disclosed in the present invention can as well be used for administration of more than one active. An NSAID can be effectively combined with prokinetic agent, or proton pump inhibitor or another NSAID.
10 DETAILED DESCRIPTION OF INVENTION
The present invention provides a delayed modified release pharmaceutical composition comprising NSAID that releases active for a prolonged period. The compositions of the present invention are processed in such a way that though devoid of enteric polymer, release not more than 10% of active in acidic pH in vitro in 1 hour. This is
15 significantly different from prior art where presence of enteric polymer is must for arresting release of NSAID in acidic medium. Coating equipments like coating pan, fluid bed processors, extrusion and spheronizer, centrifugal coater, tangential coater can be used.
This invention provides a means to release in one hour not more than 10% of first active ingredient at pH of 1.5 in vitro and to release in 1 hour, 4 hours, 7 hours NLT 15%
20 w/w, 40-85%w/w and NLT 60%w/w of first active in buffer of pH 6.8, comprising a core, comprising non-steroidal anti-inflammatory drug such as Aceclofenac in an amount from 30-80%w/w of composition as first active ingredient; a barrier coat, comprising at least one non-enteric water insoluble polymer upto 25%w/w of composition and at least one channel forming agent.
25 The objects of the invention are achieved by preparing and providing modified
release solid oral dosage forms without the use of enteric polymer as described below in following steps:
Step 1) Preparation of drug core Step 2) Application of optional coat
30 Step 3) Application of barrier coat
STEP 1) Preparation of Drug Core:
The first step is preparation of drug core by depositing on inert seeds, non-steroidal
anti-inflammatory drug such as Aceclofenac 30-80%w/w of composition as first active
35 ingredient using binder, optionally with other pharmaceutical^ acceptable ingredients to
obtain drug cores. Such deposition of NSAID can be simultaneous with binder or
6

alternating with binder. Binder may be in the form of aqueous or non-aqueous solution or dispersion.
In another embodiment of the invention the drug cores can be prepared by extruding and spheronizing NSAID with pharmaceutically acceptable ingredients.
5 In simultaneous layering of NSAID, the binder solution or dispersion contains the NSAID in it, which is deposited on non pareil seeds. In this case, suspension comprising NSAID, binder and antitack agent in suitable aqueous or non-aqueous solvent can be coated as a single layer on sugar sphere to obtain drug cores.
In alternate layering of NSAID, the pulverized NSAID is optionally mixed with inert
10 excipients to obtain an admixture, which is deposited on inert seeds in a coating pan using suitable aqueous or non-aqueous binder solution to obtain drug core. The process is continued till entire admixture containing drug is used for deposition.
In yet another embodiment the NSAID is mixed with at least one pharmaceutically acceptable ingredient such as binders, fillers, disintegrants, lubricants, surfactants,
15 plasticizer and granulated using suitable media before extruded into pellets.
Process and the composition disclosed enables incorporation of more than one NSAID. These NSAIDs are Paracetamol; Salicylates like Aspirin, Choline salicylate, Magnesium salicylate, Sodium salicylate, Choline magnesium trisalicylate; Indoles like indomethacin; Pyrazoles like Phenyl Butazone; Etodolac, Meclofenamate sodium,
20 Propionic acid derivatives like Naproxen sodium, Ibuprofen, Fenoprofen, Ketoprofen, Flubiprofen, Fenamates like mefenamic acid, flufenamic acid; ketorolac, pentazocine, Oxicam like Piroxicam, Tenoxicam, Meloxicam and similar compounds, Phenyl acetic acid Diclofenac, Aceclofenac; Cox-2 inhibitors like Rofecoxib, Torecoxib, Celecoxib, .Valdecoxib, Parecoxib, Etoricoxib, Lumiracoxib, Non COX selectives, preferential COX2
25 inhibitors like Nabumetone; Aminonicotinic acids like Flunixin; Pyrazolones like Phenylbutazone, Oxyphenbutazone, Dipyrone, Ramifenazone .
The process is also useful in incorporating an active in addition to NSAID in the formulation wherein the said active can be a member of prokinetic agent such as cisapride, mosapride, Itopride, domperidone, or proton pump inhibitor such as
30 Omeprazole, Rabeprazole, Pantoprazole, Lansoprazole, Esomeprazole or another NSAID. These actives are processed into tablets, pellets, granules or capsules by the process known to a person skilled in the art. Proton pump inhibitors such as Omeprazole, Rabeprazole, Pantoprazole, Lansoprazole, Esomeprazole are in enteric release form and prokinetic agent such as cisapride, mosapride, Itopride, domperidone are preferably in
35 sustained release form.
7

The drug cores prepared above are suitably dried in equipments such as coating
pan, tray drier or fluid bed drier or their likes to moisture content of less than 5%w/w
preferably less than 3%w/w and more preferably less than 2%w/w. The dried drug cores
are suitably sized to obtain drug cores of desired mesh size.
5 These sustained release compositions comprise NSAID in an amount from 30%w/w
- 80%w/w of the composition.
The pharmaceutically acceptable excipient comprise of one or more of filler, binder, disintegrant, lubricant, polymer, colorant, coating agent, preservatives and stabilizer, surfactant, anti-adherent, alkalizing agent, acidulant, pH modifiers, plasticizers, gums,
10 glidant, buffers and their mixtures thereof.
Inert seeds such as sugar sphere comprising of sugar and starch is preferably
used. Alternatively inert seeds comprising of microcrystalline cellulose or any other
suitable inert material may also be used. The particle size of the sugar sphere used may
be in the range of about 300 to 1680 microns preferably about 500 to 1200 microns.
15 Antitack agent used in the present invention is selected from talc, colloidal silicon
dioxide, magnesium stearate, glyceryl behenate, glyceryl monostearate and their mixtures the preferable choice being talc with or without colloidal silicon dioxide and are used in the concentration range of about 0.1 - 20% w/w of composition.
Inert fillers are selected from starch, lactose, microcrystalline cellulose, low
20 viscosity grade hydroxypropylcellulose, mannitol, pulverized sugar, sorbitol, rjonobasic sodium phosphate, dibasic sodium phosphate, tribasic sodium phosphate, crosslinked carboxymethylcellulose and its salts such as sodium, potassium and calcium salt; starch, sodium starch glycolate, pregelatinized starch, starch 1500, crospovidone, cyclodextrins and its derivatives, calcium sulfate and their mixtures. Inert excipient may be used alone
25 or in combination and is preferably starch and is used in concentration range of about 0.1
- 70% w/w of composition.
Binder is selected from the group consisting of cellulose derivatives such as hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose, hydroxyethylcellulose, carboxymethylcellulose and its salt; sugar, acacia; polyvinylpyrollidone, polymethacrylates,
30 carbomer, gums like xanthan gum, guar gum, tragacanth, gelatin, carragenan, locust bean gum, karaya gum, agar, chitosan, alginic acid and its pharmaceutical acceptable salts such as sodium, potassium and calcium salt. Binder may be used alone or in combination and is preferably polyvinylpyrollidone used in the concentration upto about 0.1% to 20%
w/w of composition.
35 Disintegrants is selected from but not limited to starch, cellulose derivatives such as
alkyl cellulose, hydroxyalkylcellulose, crosslinked carboxymethylcellulose and its salts
8

such as sodium, potassium, calcium salt, microcrystalline cellulose, sodium starch glycolate, pre-gelatinized starch, starch 1500, crospovidone and their suitable mixture.
Acidulant, alkalizing agents, pH modifiers and buffers are selected from but not limited to acetic, boric, carbonic, phosphoric, malic, maleic, citric, bicarbonic, tartaric,
5 succinic, benzoic, lactic, glyceric, glutamic, lauric, adipic, gluconic, fumaric, monocarboxylic, hydroxycarboxylic, polycarboxylic acids, glutaric acids, essential and nonessential amino acids and their pharmaceutical^ acceptable salts preferably sodium, potassium, calcium, magnesium and ammonium salt, alkali or alkali earth metal chlorides, sulfates, phosphates, bicarbonates, citrates, borates, acetates and succinates, sodium or
10 potassium hydrogen phosphate, sodium or potassium dihydrogen phosphate, hydrochloric acid sodium hydroxide, potassium hydroxides, tris buffer, organic acid buffer, alkali hydroxide, ammonia, and their mixtures.
Glidants, anti-adherents and lubricants are selected from but not limited to talc, colloidal silicon dioxide, glyceryl monostearate, sodium benzoate, sodium lauryl sulfate,
15 glyceryl behenate, stearic acid and its salt such as magnesium stearate, calcium stearate and their suitable mixture.
Preferably other pharmaceutically acceptable ingredient used in the invention is selected from talc, lactose, starch, sugar, microcrystalline cellulose, polyethylene glycol, polyvinylpyrollidone, colloidal silicon dioxide, magnesium stearate, glyceryl behenate,
20 glyceryl monostearate and their mixtures, preferably agent being talc.
Although the solvent of preferred choice for processing NSAID is water, other
solvents such as alcohol, hydroalcoholic mixture, organic solvent or their mixtures can
also be used. For application of optional coat and barrier coat solvents such as water,
isopropanol, acetone, ethanol, methanol, methylene chloride and their mixtures can be
25 used.
STEP 2) Application of Optional Coat:
The drug cores after drying and sizing are optionally coated with a layer of nonfunctional polymer and antitack agent to obtain hardened drug cores.
30 In another embodiment of the invention, non-functional polymer and antitack agent is deposited from aqueous media as a single layer on drug cores.
Alternatively, non-functional polymer in water can be deposited with antitack agent as an alternate layer on drug cores to obtain hardened drug cores. The hardened drug cores are suitably dried in equipments such as coating pan, tray drier and fluid bed drier or
35 their likes to arrive a moisture content of less than 5%w/w preferably less than 3%w/w and more preferably less than 2%w/w.
9

Non-functional polymer is selected from the group of cellulose derivatives like
hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose;
polyvinylpyrrolidone, polymethacrylates and mixtures thereof, and is used in the concentration of upto about 6%w/w of composition.
5
STEP 3) Application of Barrier Coat:
Drug cores or hardened drug cores so obtained as described in Step I or Step 2 respectively, are coated with a barrier coat comprising at least one non-enteric water insoluble polymer upto 25%w/w of composition and at least one channel forming agent.
10 Functional polymer is non-enteric water insoluble polymer and is selected from
Ethyl cellulose, Polymethylacrylates and their mixtures. Polymethacrylates (Eudragit RTM) are selected from Poly (ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1 (Eudragit RS), Poly (ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.2 (Eudragit RL), Poly (ethyl acrylate,
15 methyl methacrylate) (Eudragit NE) or their mixtures. Ethyl cellulose is available in various grades depending on its viscosity from about 3 cps to about 100 cps. Ready to use aqueous dispersion of ethylcellulose such as Aquacoat ECD RTM of FMC and Surelease RTM of Colorcon can also be used. This ready dispersion further contains plasticizers, surfactants (sodium lauryl sulfate), stabilizing agents, ammonium hydroxide, oleic acid,
20 fumed silica, anti-foaming agent, cetyl alcohol as additives.
The barrier coat comprises a mixture of non-enteric water insoluble polymer and channel forming agent in the ratio of 90:10 to 10:90, preferably in the ratio ranging from 80:20.to 50:50 and more preferably in the ratio from 70:30 to 40:60.
In preferred embodiment, the barrier coat comprises a mixture of ethylcellulose and
25 hydroxypropylmethylcellulose in the ratio of 90:10 to 10:90, preferably in the ratio ranging from 80:20.to 50:50 and more preferably in the ratio from 70:30 to 40:60.
Functional polymer is dissolved or dispersed in a suitable solvent such as water, alcohol, acetone, dichloromethane or mixtures thereof preferably in proportions of 1:9 to 9:1.
30 The channel forming agent is present in an amount upto 95%w/w of barrier coat
and is selected from the group of cellulose derivatives such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose and its salt; sugars such as glucose, sucrose, lactose; polyvinylpyrollidone, polyethylene glycol, triacetin, triethylcitrate, diethylphthalate, acetyltribytylcitrate, hydrogenated oils,
35 polysorbates, propylene glycol, dibytylsebacate, meglumine, miglyol, cetyl alcohol and mixtures thereof.
10

Optionally antitack agent such as talc is added in the concentration of upto about 30%w/w of the barrier coat preferably when aqueous dispersion comprising of functional polymer is used.
Optionally one can incorporate surfactants, pharmaceutically acceptable
5 preservatives and stabilizers for imparting associated properties.
Colors, pigments and dyes used in the present invention are selected from pharmaceutically acceptable colors, pigments and dyes.
The process described herein may be carried out completely or in part in aqueous or non-aqueous media such as methanol, ethanol, isopropanol, acetone, dichloromethane
10 or their mixtures.
The above process can be carried out in equipment such as fluid bed bottom spray processor, extrusion spheronizer, coating pan and their likes. The process of the invention described herein is the viable continuous process for the preparation of modified release composition comprising of NSAID. Overall yield of the process not less than 95%.
15 In the description the words active, drug are used interchangeably. Words particles,
microbeads, pellets are used interchangeably.
The invention is now described with non - limiting examples.
Illustration 1: Preparation of modified release Aceclofenac compositions by 20 alternate layering technique.
Preparation of drug core:

Ingredients Quantities (gm)
Aceclofenac 459
Nonpareil Seeds 180
Sugar 22.5
Starch 22.5
Talc 11.25
PVPK-30 11.25
Purified water Quantity sufficient
Term "qs" indicates quantity sufficient.
25 459 Gms of Aceclofenac was sifted through 200 mesh ASTM and mixed with 22.5
Gms of starch and 11.25 Gms of Talc in planetary mixer for about 10 minutes to obtain drug admixture. Sugar 22.5 Gms and 11.25 Gms of PVPK-30 was dispersed and dissolved in water to obtain binder solution. The concentration of PVPK-30 in water was
11

about 10%w/w. 180 Gms of Sugar spheres were loaded in coating pan. Binder solution was sprayed on sugar sphere. When desired level of wetting was observed, the drug admixture was layered till the wetted agglomerated sugar spheres were unagglomerated. This operation was repeated until the total quantity of drug admixture was used up.
5 Thereafter, the drug cores were dried in tray drier and checked for moisture content to be less than 3%. They are then sieved to get drug cores of desired size.
Application of optional coat:

Ingredients Quantities (gm)
Aceclofenac Drug Core 260
HPMC E05 7.8
Talc 1.56
Purified water Quantity sufficient
10 7.8 Gms of HPMC was dispersed and dissolved in water and 1.56 Gms of talc was
added to it. The drug core of undesirable size (utilizable residue) that was retained above and below the desired mesh was mixed with water and was added to HPMC suspension containing talc. The suspension was filtered through appropriate mesh and was sprayed on 260 Gms of drug cores in coating pan to obtain hardened drug core. The solid content
15 of this suspension in water may be upto 20% w/w. These hardened drug cores were dried in tray drier and checked for moisture content to be less than 3%.
Preparation of modified release core:

Ingredients Quantities (gm)
Aceclofenac Hardened Drug core 230
Ethyl Cellulose 4.02
HPMC E05 1.73
Triacetin 0.4
Dichloromethane 49.03
Methanol 32.68
20 1.73 Gms of HPMC E05 & 4.02 Gms of Ethyl cellulose were dispersed and
dissolved in the mixture of methanol and methylene chloride (2:3). 0.4 Gms of Triacetin was added to this solution. The solution was filtered through appropriate mesh and was sprayed on 230 Gms of hardened drug core in fluid bed bottom spray processor to obtain modified release microbeads.
12

The processing parameters during the coating process were adjusted to have an inlet air temperature of about 20°C to about 60°C, preferably about 30°C to 45°C outlet air temperature of about 20°C to about 45°C preferably 25°C to 40°C, atomization air pressure of not less than 0.5 bars, fluidization flap open from about 15 to about 90% w/w.
5 Modified release microbeads are dried in the same equipment maintaining the inlet temperature between about 50-80°C and outlet temperature between about 40 - 60°C to have moisture content of less than 5% and preferably less than 3% and more preferably less than 2%w/w. Alternatively the coating may also be carried out in other coating equipments such as coating pan. % of coating material to total weight of pellets produced
10 is about 2.45%.
The modified release pellets so produced are spherical to almost spherical and support the filling in capsules which may be transparent especially if colored pellets are produced.
15 Illustration 2: Preparation of modified release Aceclofenac compositions using extrusion technique.
Preparation of drug cores:
Ingredients Quantities (gm)
Aceclofenac 200
MCC 70
Lactose 15
PVPK-30 05
PEG 6000 10
Talc 05
Purified water 120
20
1) 200gms of Aceclofenac, 70gms of MCC and 15gms of Lactose were sifted through
sieve 40.
2) 5 gms of PVPK-30 and 10 gms of PEG-6000 was dissolved in water to prepare binder
solution.
25 3) Sifted ingredients obtained in step1 were blended in Kenwood planetary mixer for 5 minutes and granulated using binder solution obtained in step 2 to get dough.
4) The dough obtained in step 3 is extruded through 1.2 mm(radial) sieve with 50 rpm for
2 minutes.
5) These extrudates are spheronized at 600rpm for about 2 minutes. Talc is sprinkled on
30 extrudates while carrying out spheronization.
13

Preparation of modified release pellets
1.25 %w/w coating solution of Ethyl Cellulose: HPMC in 75:25 ratio is used for preparation of modified release pellets. Quantitative composition of modified release coat is as follows:

Ingredients Quantities (gm)
Aceclofenac Drug pellets 305
Ethyl Cellulose 2.85
HPMC E05 0.95
Triacetin 0.29
Methylene Chloride 46.84
Methanol 31.23
5
1) Disperse and dissolve ethyl cellulose in mixture of methylene chloride and methanol.
2) Dissolve HPMC E05 in the solution obtained from step 1).
3) Add triacetin to solution obtained in step 2) and stir for 5 minutes to dissolve it.
4) Filter the solution obtained in step 3) through 100 mesh sieve.
10 5) The process of coating is carried out in fluid bed processor with process parameters of 3 rpm, atomization pressure at 2, inlet and outlet temperatures at 45°C and 33°C respectively, and % flap opened at 45%.
Illustration 3: Dissolution testing results of Aceclofenac pellets prepared as per 15 illustration 2, in 6.8 pH buffer, USP basket type.

Time in hour % w/w release of Aceclofenac
1 hour 38.3%
4 hour 72.4%
7 hour 85.9%
Illustration 4: Dissolution testing of Aceclofenac pellets prepared as per illustration 1, in 1.5. pH, 7.5 pH buffer, USP basket type.

PH Time in hour % w/w release of Aceclofenac
1.5 1st Hour 1.25%
7.5 2"° Hour 55.00%
7.5 4m Hour 84.25%
7.5 6m Hour 95.21%
20
14

Dissolution testing was performed in pH of 1.5 first followed by pH of buffer 7.5.
Illustration 5: Preparation of modified release pellets containing Aceclofenac 70% w/w.

Ingredients Quantities (gm)
Aceclofenac 520
Nonpareil Seeds 120
Talc 48
PVPK-30 48
IPA 540
Water 180
5
Preparation of drug core:
520 gms of Aceclofenac and 48 gms of Talc were mixed in Kenwood mixer for 10 minutes
before passing through mesh 40.
48gms of PVPK-30 were dissolved in mixture of IPA:Water (3:1) to get a binder solution.
10 120 gms of nonpareil seeds were loaded in coating pan. Binder solution was sprayed on nonpareil seeds. When desired level of wetting was observed, the admixture of Aceclofenac and talc was layered till the wetted agglomerated nonpareil seeds were un-agglomerated. This operation was repeated until the total quantity of admixture was used up. The coating process parameters of pan rpm 16-20, Atomization pressure of 0.5 to 3
15 bars, pan angle of 15-20 were observed. Thereafter, the drug cores were dried in oven at 50°C for an hour.
Application of optional (seal) coat:

Ingredients Quantities (gm)
Aceclofenac drug pellets 610
HPMC E05 36.6
Talc 3.66
Water 534.88
20 The drug cores of undesirable size (utilizable residue) that was retained above and below the desired mesh (mesh 14 and 20) was mixed with water and was added to nonfunctional polymer (HPMC E05) suspension containing talc. The suspension was filtered through appropriate mesh and was sprayed on drug cores in coating pan to obtain hardened drug
core. The solid content of this suspension in water may be upto 20% w/w. These
15

hardened drug cores were dried in coating pan for 30 minutes keeping blower temperature to 70°C and checked for moisture content and particle size.
Preparation of modified release core:

Ingredients Quantities (gm)
Aceclofenac seal coat Pellets 196.140
Ethyl Cellulose 4.86
HPMC E05 2.08
Triacetin 0.46
Methylene chloride 84.44
Methanol 56.30
5
2.08 Gms of HPMC E05 & 4.86 Gms of Ethyl cellulose were dispersed and dissolved in the mixture of methanol and methylene chloride (2:3). 0.23 Gms of Triacetin was added to this solution. The polymer content in barrier coat is 3.4%w/w of the composition. The solution was filtered through appropriate mesh and was sprayed on 196.14 Gms of
10 hardened drug core in coating pan to obtain modified release pellets. Methanol and methylene chloride are used preferably in the ratio of 2:3.
The processing parameters during the coating process were adjusted to have an inlet air temperature of about 20°C to about 60°C, preferably about 25°C to 45°C, atomization air pressure of not less than 0.5 bars, fluidization flap open from about 15 to about 90% w/w.
15 Modified release pellets are dried in the same equipment maintaining the inlet temperature between about 50-80°C and outlet temperature between about 40 - 60°C to have moisture content of less than 5% and preferably less than 3% and more preferably less than 2%w/w. Alternatively the coating may also be carried out in coating pan to obtain modified release microbeads comprising of NSAID.
20
16

Claims:
We Claim,
1) A modified release pharmaceutical composition in the form of capsule, tablet, granules
or pellets comprising
5 a) a core, comprising non-steroidal anti-inflammatory drug such as Aceclofenac in an
amount from 30-80%w/w of composition as first active ingredient; b) a barrier coat, comprising at least one non-enteric water insoluble polymer upto
25%w/w of composition and at least one channel forming agent;
such that it exhibits in vitro drug release profile of not more than 10%w/w of
10 aceclofenac at the end of one hour at pH of 1.5 and not less than 60% w/w of
aceclofenac at the end of seven hours at pH of 6.8 to 7.5.
2) A composition as claimed in claim 1 wherein the non-enteric water insoluble polymer is
selected from Ethyl cellulose, Polymethylacrylates and their mixtures.
15
3) A composition as claimed in claim 1 wherein the channel forming agent is present in an
amount upto 95%w/w of barrier coat.
4) A composition as claimed in claims 1 and 3 wherein channel forming agent is selected
20 from the group of cellulose derivatives such as hydroxypropylmethylcellulose
carboxymethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose; sugar such as
glucose, sucrose, lactose; polyvinylpyrollidone, polyethylene glycol, triacetin,
triethylcitrate, diethylphthalate, acetyltribytyIcitrate, hydrogenated oils, polysorbates,
propylene glycol, dibytylsebacate, meglumine, miglyol, cetyl alcohol and mixtures
25 thereof.
5) A composition as claimed in claims 1,3-4 wherein the barrier coat comprises a
mixture of ethylcellulose and hydroxypropylmethylcellulose in the ratio of 90:10 to
10:90, preferably in the ratio ranging from 80:20.to 50:50 and more preferably in the
30 ratios ranging from 70:30 to 40:60.
6) A process for the preparation of modified release pharmaceutical composition in the
form of capsule, tablet, granules or pellets comprising steps of;
a) Depositing on inert seeds or extruding and spheronizing, non-steroidal anti-
35 inflammatory drug such as Aceclofenac 30-80%w/w of composition as first active
ingredient using binder, optionally with other pharmaceutical^ acceptable
17

ingredients to obtain drug cores;
b) Optionally drying and/or coating the drug cores obtained in step a) with
nonfunctional polymer to get hardened drug cores; and
c) Applying barrier coat comprising at least one non-enteric water insoluble polymer
5 upto 25%w/w of composition and at least one channel forming agent, on drug cores
or hardened drug cores obtained in step a) or b) respectively.
7) A process as claimed in claim 6 wherein the non-enteric water insoluble polymer is selected from Ethyl cellulose, Polymethylacrylates and their mixtures; channel forming
10 agent is selected from the group of cellulose derivatives such as
hydroxypropylmethylcellulose carboxymethylcellulose, hydroxypropylcellulose,
hydroxyethylcellulose; sugars, polyvinylpyrollidone, polyethylene glycol, triacetin, triethylcitrate, diethylphthalate, acetyltribytylcitrate, hydrogenated oils, polysorbates, propylene glycol, dibytylsebacate, meglumine, miglyol, cetyl alcohol and mixtures
15 thereof in an amount upto 95%w/w of barrier coat; binder and non-functional polymer
is selected from polyvinylpyrollidone, hydroxypropylcellulose, sugar, hydroxypropylmethylcellulose, acrylic acid, polymethacrylates and their mixtures, preferably hydroxypropylmethylcellulose.
20 8) A process as claimed in claim 6, wherein the pharmaceutically acceptable ingredient is selected from talc, lactose, starch, sugar such as glucose, sucrose, lactose; Microcrystalline cellulose, Polyethylene glycol, Polyvinylpyrollidone, colloidal silicon dioxide, magnesium stearate, glyceryl behenate, glyceryl monostearate and their mixtures, preferably agent being talc.
25
9) A process as claimed in claims 6-7 wherein the barrier coat comprises a mixture of ethylcellulose and hydroxypropylmethylcellulose in the ratio of 90:10 to 10:90, preferably in the ratio ranging from 80:20.to 50:50 and more preferably in the ratio ranging from 70:30 to 40:60.
30
10)A composition in the form of capsule, tablet, granules or pellets as claimed in claim 1,
further comprises another active ingredient selected from proton pump inhibitors such
as Omeprazole, Rabeprazole, Pantoprazole, Lansoprazole, Esomeprazole or
prokinetic agent such as cisapride, mosapride, Itopride, domperidone or other non-
35 steroidal anti-inflammatory drug.
18

11) A means to release in one hour not more than 10%w/w, preferably not more ttian 5%w/w of first active ingredient at pH of 1.5 in vitro and to release in 1 hour, 4 hours, 7 hours NLT 15% w/w, 40-85%w/w and NLT 60%w/w of first active in buffer of pH 6.8, comprising
a) a core, comprising non-steroidal anti-inflammatory drug such as Aceclofenac in an amount from 30-80%w/w of composition as first active ingredient;
b) a barrier coat, comprising at least one non-enteric water insoluble polymer upto 25%w/w of composition and at least one channel forming agent.
10

15

Dated this 11m day of September 2006
Milind Sathe Manager, IPR For Themis Laboratories Private Limited

19

I

ABSTRACT
A modified release pharmaceutical composition in the form of capsule, tablet, granules or
5 pellets comprising a core, comprising non-steroidal anti-inflammatory drug such as Aceclofenac as first active ingredient; a barrier coat comprising at least one non-enteric water insoluble polymer and at least one channel forming agent and exhibiting modified release is disclosed. The invention also discloses the process to prepare such modified release pharmaceutical compositions.
10

Documents:

1119-mum-2005-abstract(granted)-(26-2-2009).pdf

1119-mum-2005-abstract.doc

1119-mum-2005-abstract.pdf

1119-MUM-2005-CANCELLED PAGES(19-5-2008).pdf

1119-mum-2005-claims(granted)-(26-2-2009).pdf

1119-mum-2005-claims.doc

1119-mum-2005-claims.pdf

1119-mum-2005-correspondance-received-ver-080906.pdf

1119-mum-2005-correspondance-received-ver-260705.pdf

1119-MUM-2005-CORRESPONDENCE(12-5-2011).pdf

1119-MUM-2005-CORRESPONDENCE(2-5-2007).pdf

1119-MUM-2005-CORRESPONDENCE(22-9-2009).pdf

1119-MUM-2005-CORRESPONDENCE(IPO)-(22-9-2009).pdf

1119-mum-2005-description (complete).pdf

1119-mum-2005-description (provisional).pdf

1119-mum-2005-description(granted)-(26-2-2009).pdf

1119-MUM-2005-FORM 1(11-9-2006).pdf

1119-MUM-2005-FORM 1(19-5-2008).pdf

1119-MUM-2005-FORM 13(17-11-2009).pdf

1119-MUM-2005-FORM 13(4-5-2007).pdf

1119-MUM-2005-FORM 18(4-5-2007).pdf

1119-mum-2005-form 2(granted)-(26-2-2009).pdf

1119-MUM-2005-FORM 2(TITLE PAGE)-(COMPLETE)-(11-9-2006).pdf

1119-mum-2005-form 2(title page)-(granted)-(26-2-2009).pdf

1119-MUM-2005-FORM 2(TITLE PAGE)-(PROVISIONAL)-(15-9-2005).pdf

1119-MUM-2005-FORM 3(11-9-2006).pdf

1119-MUM-2005-FORM 5(11-9-2006).pdf

1119-MUM-2005-FORM 6(1-5-2009).pdf

1119-mum-2005-form-1.pdf

1119-mum-2005-form-2 (complete).pdf

1119-mum-2005-form-2 (provisional).pdf

1119-mum-2005-form-26.pdf

1119-mum-2005-form-3-ver-080906.pdf

1119-mum-2005-form-3-ver-150905.pdf

1119-mum-2005-form-5-ver-080906.pdf

1119-mum-2005-form-5-ver-150905.pdf

1119-MUM-2005-REPLY TO FIRST EXAMINATION REPORT(19-5-2008).pdf

1119-MUM-2005-SPECIFICATION(AMENDED)-(19-5-2008).pdf

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Patent Number

230382

Indian Patent Application Number

1119/MUM/2005

PG Journal Number

13/2009

Publication Date

27-Mar-2009

Grant Date

26-Feb-2009

Date of Filing

15-Sep-2005

Name of Patentee

THEMIS LABORATORIES PRIVATE LIMITED

Applicant Address

UNIT NO. S-4, KHIRA INDUSTRIAL ESTATE, B.M BHARGAVA ROAD, SANTACRUZ WEST, MUMBAI-400054,

Inventors:

#	Inventor's Name	Inventor's Address
1	ANTARKAR AMIT KRISHNA	HOUSE NO. C/4, RANI LAXMI NAGER NAGPUR 440 022

PCT International Classification Number

A61K9/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA