Title of Invention	A PROCESS FOR MAKING A NOVEL PHARMACEUTICAL COMPOSITION AS CAPSULE DOSAGE FORM
Abstract	A process for making anovel pharmaceutical composition as capsule dosage form, containing a final blend of statin, treated with plurality of antioxidant, along with delayed release tablet of aspirin, the process steps comprising of-sieving a statin through 40# mesh and treating with a plurality of antioxidants by spraying the solution of said plurality of antioxidants on said statin for uniform treatment, sieving the resulting wet mass through 8# mesh to get wet granules, air-drying said wet granules at 30°C to 40°C, then drying said granules in tray drier at 40°C to 45°C until loss on drying up to 2.5%, passing dried granules through 20 # mesh and mixing with plurality of diluents in a high-speed mixer, dispersing binder in isopropyl alcohol making 5 % solution and adding to the dry mix under slow speed, sieving plurality of lubricants through 60 # mesh and mixing with said 20# mesh passed dried granules for 10 min in a planetary mixer to get said final blend of statin for filling in capsule, sieving aspirin, with plurality of diluents though 40 # mesh, mixing in a blender for 10 min, compressing the above mixture using 5 mm or 6 mm D type standard concave tooling on a rotary tablet compression machine to get core tablet of aspirin, subcoating said core tablets of aspirin to provide seal coat to get seal coated aspirin tablet, further enteric coating said seal coated tablet of aspirin up to 10% to 14% of total weight of core to get said delayed release tablet of aspirin, and filling, said delayed release aspirin tablets along with said final blend of statin, in hard gelatin capsule using a special type of hard gelatin capsule filling machine equipped with tablet loader.

Title of Invention

A PROCESS FOR MAKING A NOVEL PHARMACEUTICAL COMPOSITION AS CAPSULE DOSAGE FORM

Abstract

A process for making anovel pharmaceutical composition as capsule dosage form, containing a final blend of statin, treated with plurality of antioxidant, along with delayed release tablet of aspirin, the process steps comprising of-sieving a statin through 40# mesh and treating with a plurality of antioxidants by spraying the solution of said plurality of antioxidants on said statin for uniform treatment, sieving the resulting wet mass through 8# mesh to get wet granules, air-drying said wet granules at 30°C to 40°C, then drying said granules in tray drier at 40°C to 45°C until loss on drying up to 2.5%, passing dried granules through 20 # mesh and mixing with plurality of diluents in a high-speed mixer, dispersing binder in isopropyl alcohol making 5 % solution and adding to the dry mix under slow speed, sieving plurality of lubricants through 60 # mesh and mixing with said 20# mesh passed dried granules for 10 min in a planetary mixer to get said final blend of statin for filling in capsule, sieving aspirin, with plurality of diluents though 40 # mesh, mixing in a blender for 10 min, compressing the above mixture using 5 mm or 6 mm D type standard concave tooling on a rotary tablet compression machine to get core tablet of aspirin, subcoating said core tablets of aspirin to provide seal coat to get seal coated aspirin tablet, further enteric coating said seal coated tablet of aspirin up to 10% to 14% of total weight of core to get said delayed release tablet of aspirin, and filling, said delayed release aspirin tablets along with said final blend of statin, in hard gelatin capsule using a special type of hard gelatin capsule filling machine equipped with tablet loader.

Full Text	FORM 2 The Patents Act, 1970 (39 OF 1970) [Refer Section 10; Rule 13] COMPLETE SPECIFICATION A Process for making a Novel Pharmaceutical Composition as capsule dosage form M/s Aristo Pharmaceutical Ltd 23-A, Shah Industrial Estate, Off Veera Desai road, Andheri (W), Mumbai - 400 053. Name of the inventors - 1) Mr. Manutosh Manohar Acharya, Indian, residing at 4/7, Amaltas Parisar Shahpura, Bhopal (MP), India. GRANTED 28-3-2005 The following complete specification describes the nature of this invention and the manner in which it is to be performed. Original 888/MUM/2003 Complete Specifications BACKGROUND OF THE INVENTION (1) Gastro esophageal reflux disease (GERD) is among the most common disorders seen by the gastroenterologists and general practitioners. This disease is characterized as the backward flow of the stomach contents into the esophagus. One of the most important factors in the pathogenesis of gastro-esophageal reflux disease is a reduction in the pressure barrier due to the failure of the lower esophageal sphincter. Failure of the lower esophageal sphincter can arise due to a low basal pressure, sphincter relaxation, or to a non-compensated increase in intragastric pressure. (2) Other factors in the pathogenesis of the disease are delayed gastric emptying, insufficient esophageal clearing due to impaired peristalsis and the corrosive nature of the reflux material which can damage esophageal mucosa. (3) Mosapride, i.e., 4-amino-5-chloro-2-ethoxy-N- [[4- (4-fluorophenyl) methyl]-2-morpholinyl] methylj-benzamide, is disclosed in European Patent No. 243959 and United States Patent No. 4870074 as gastrointestinal prokinetic agent. Mosapride formulations in market are in which mosapride citrate dihydrate is equivalent to mosapride. In the present invention, mosapride and or its salts here after will be termed as "mosapride". Mosapride is a new 5-HT4 agonist intended for oral treatment of gastrointestinal motility dysfunction e.g. gastro-esophageal reflux. (4) It is known to exert its action by facilitating acetylcholine release from the enteric cholinergic neurons. With respect to the therapeutic actions mosapride enhances gastric emptying and also improves total acid clearance time. Conditions or symptoms relieved by the promotion of gastric emptying include but are not limited to gastric stasis, flatulence, dyspepsia, peptic ulcer and reflux oesophagitis. Conventionally mosapride is given 5 mg three times daily for decreasing acid reflux in the esophagus in patients with gastro-esophageal reflux disease. Maintenance therapy is often necessary to prevent recurrent symptoms and reflux oesophagitis. It is more convenient for patients to receive long-term effective controlled release mosapride dosage forms once a day than the conventional mosapride dosage forms administered three times a day. Mosapride has a short biological half-life of about 1.4-2 hours and shows linear pharmacokinetics upto a dose of 40 mg. Thus, it is suitable for formulation into oral controlled release dosage form. A once-a-day controlled release dosage form eliminates the inconvenience to the patient in taking multiple dosing at different times and thus ensures patient compliance to the prescribed dosage regimen. (005) An optimum design of an oral controlled release dosage form of mosapride for once-a-day therapy in humans also requires that the dosage form provide a control on the plasma levels such that the mean residence time (i. e. the mean time that a drug spends in the body) is within a desirable range for said once-a-day therapy in humans. Hence, an oral controlled release dosage form for mosapride that releases the mosapride in a controlled manner so as to provide control over mosapride plasma levels, such that the ratio of peak plasma levels to the plasma levels at 24 hours after administration, and the mean residence time of mosapride, are within a desirable range for once-a-day therapy in humans, is thus required. (006) Earlier controlled release once-a-day dosage form of the prokinetic agent, Mosapride is given in European patent no WO 03011256. The mosapride is released according to the following dissolution profile (a) not less then 15% of the mosapride is released after 4 hours; (b) between 35% and 55% of the mosapride is released after 8 hours; and (c) between 50% and 75% of the mosapride is released after 12 hours (c) Not less than 90% of mosapride is released after 24 hours; The release pattern of the drug has been tested in vitro as per United States Pharmacopoeia Type II apparatus at 100 rpm using 0.1 N HC1 as dissolution medium at 37°C for 24 hours. However, loading dose and maintenance dose fractions, rationale for choosing in vitro dissolution media for Mosapride Citrate Dihydrate is not mentioned. SUMMARY OF THE INVENTION (7) Conventionally mosapride citrate dihydrate expressed as mosapride is given 5 mg t.i.d. The present invention provides oral single unit dosage form of a prokinetic agent, mosapride and or its pharmaceutically acceptable salts expressed as mosapride with pharmaceutical compositions in dosage forms to provide a loading dose and a controlled release of maintenance dose for once a day administration. (8) A process for making oral single unit dosage form of a prokinetic agent, mosapride and or its pharmaceutically acceptable salts with pharmaceutically acceptable excipients wherein the single unit dosage form comprises of a bilayer tablet, or a tablet, and blend or granules in a capsule, where the total dose of mosapride is split, partitioned or distributed in the dosage forms to provide a loading dose and a controlled release of maintenance dose for once a day administration wherein mosapride release is according to the following dissolution profile, (a) Not less than 35 % of the drug is release within 15 minute, which is a loading dose, (b) between 35% and 50% of the drug should be release between 2 to 3 hours, (c) between 50 - 80 % of the drug should be released between 3-5 hours, (d) Between 80 - 90 % of the drug should be released between 5-8 hours. The said bilayer tablet comprises of two part in which one part is immediate release containing loading dose with pharmaceutically acceptable excipients, which contains mosapride citrate dihydrate expressed as mosapride in concentration ranging from 15 to 25 %, preferably 18.9 % of the total dose of mosapride (total dose 15 mg expressed as mosapride) and the other part is a controlled or sustained release fraction and this fraction can also be a gastro retentive floating device releasing the prokinetic agent, in sustained or controlled release form with suitable pharmaceutically acceptable excipients with release rate controlling polymers and the mosapride in this layer ranges from 75 to 85%, preferably 81.1% of the total mosapride dose (total dose 15 mg expressed as mosapride). The process of preparation ofbilayer tablet is as follows- Mosapride citrate dihydrate, Hydroxy propyl methyl cellulose USP viscosity 1,00,000 cps (Methocel K100 M Premium) and Microcrystalline cellulose sieved through 60 no. mesh and blended for 5 minutes. Polyvinyl pyrrolidone (K 30) was dissolved in Isopropyl alcohol (5 % w/v) and the above blend was granulated. The granules were passed through mesh no. 8, air dried and then dried at 40° C till the loss on drying (LOD) of desired value reached of NMT 2.5 % at 95 C. The dried granules were sieved through 20 mesh. Finally magnesium stearate and colloidal silicon dioxide (passed through 60 no. mesh) were added and the whole mixture blended for 5 minutes. The immediate release blend was processed as follows—Mosapride citrate dihydrate, colour lake of quinoline yellow and Microcrystalline cellulose sieved through 60 no. mesh and blended for 5 minutes. Polyvinyl pyrrolidone (K 30) was dissolved in Isopropyl alcohol (5 % w/v) and the above blend was granulated. The granules were passed from mesh no. 8, air dried and then dried at 40° C till the loss on drying (LOD) of desired value reached of NMT2.5 % at 95° C. The dried granules were sieved through 20 mesh. Finally magnesium stearate, colloidal silicon dioxide and sodium starch glycollate (passed through 60 no. mesh) were added and the whole mixture blended for 5 minutes. These blend was compressed into tablets using 8.0 mm flat faced beveled edge punch 27-station rotatory bilayer tablet machine. The hardness limit for tablets was 4-6 kg/cm . The whole procedure was carried out in controlled conditions of temperature (25 °C ±2°C), relative humidity (40%±5% RH) and protected from direct exposure to light. (9) Omitted and merged with (008) (10) The present invention also comprises a formulation of a single unit capsule dosage form containing of two fractions, in which one fraction comprises blend or granules of mosapride or its pharmaceutically acceptable salts as immediate release fraction for loading dose, and the other fraction comprises of mosapride or its pharmaceutically acceptable salts which is a controlled or sustained release fraction formulated with biocompatible, hydrophilic polymer compressed into a tablet on a tableting machine. Both fractions are presented in a capsule (tablet and blend/granules in a capsule). The present invention also comprises a formulation of a single unit capsule dosage form comprising of two fractions, in which one fraction comprises blend or granules of mosapride or its pharmaceutically acceptable salts as immediate release fraction for loading dose, and the second part is a gastric retentive floating device comprises of mosapride or its pharmaceutical acceptable salts which is a controlled or sustained release fraction formulated with biocompatible polymers, compressed into a tablet on a tableting machine. Both fractions are presented in a capsule (tablet and blend/granules in a capsule). Capsule part comprises of two part in which one part is immediate release containing loading dose with pharmaceutically acceptable excipients, which contains mosapride citrate dihydrate expressed as mosapride in concentration ranging from 25 to 35 %, preferably 30.5 % of the total dose of mosapride (preferably 15 mg) and the other part is a controlled or sustained release fraction and this fraction can also optionally be a gastro retentive floating device releasing the prokinetic agent, in sustained or controlled release form with suitable pharmaceutically acceptable excipients with release rate controlling polymers and the mosapride in this layer ranges from 65 to 55%, preferably 69.5% of the total mosapride dose (total dose 15 mg expressed as mosapride) The process optionally comprised of following sequence of events- Mosapride sustained release tablet comprises Mosapride citrate dihydrate, Hydroxypropylmethyl cellulose viscosity l,00,000cps (Methocel K 100 M Premium), Hydroxypropylmethyl cellulose (E 15 cps) Sodium Carboxy methyl cellulose (Low viscosity grade), Sodium Carboxy methyl cellulose (Medium viscosity grade)and Microcrystalline cellulose sieved through 60 no. mesh and blended for 5 minutes. Povidone (PVPK-30) was dissolved in Isopropyl Alcohol (5 % w/v) and the above blend was granulated. The granules were passed from mesh no. 8, air dried and then dried at 40° C till the loss on drying (LOD) of desired value reached of NMT 2.5 % (Make: Mettler Toledo LJ16 moisture analyzer) at 105° C. The dried granules were sieved through 20 mesh. Finally magnesium stearate and colloidal silicon dioxide (passed through 60 no. mesh) were added and the whole mixture blended for 5 minutes. The tablets were compressed on 16 station compression machine. The hardness of tablets found to be 3-5 kg/cm. Mosapride immediate release blend part comprises Mosapride citrate dihydrate, Lactose DC 11 and Avicel pH 200 sieved through 60 no. mesh and blended for 5 minutes. Talc and magnesium stearate (passed through 60 no. mesh) were added and the whole mixture blended for 5 minutes. The size '1' hard gelatin capsules were filled with mosapride sustained release tablet and mosapride immediate release blend. The whole procedure was carried out in control condition of temperature (25 °C + 2°C), relative humidity (40%±5% RH) and protected from direct exposure to light. (Oil) Omitted and merged with(010) (12) The present invention also comprises of single unit capsule dosage form comprising a fraction of mosapride or its pharmaceutically acceptable salts which is a immediate release tablet for loading dose and second part is a blend and or granules comprising a fraction of mosapride or its pharmaceutically acceptable salts which is a gastric retentive floating fluffy mass which release the fraction of mosapride or its pharmaceutically acceptable salts which is a controlled or sustained release formulated with biocompatible polymers (tablet and blend/granules in a capsule). (13) The oral controlled release dosage forms of the present invention comprises mosapride or its pharmaceutically acceptable salts and release controlling pharmaceutically acceptable excipients, wherein the mosapride is released as per the following in vitro dissolution profile.(a) Not less than 30 % of the drug is release within 15 minute, which is a loading dose, (b) between 40% and 60% of the drug should be release between 2 to 3 hours, (c) between 60 - 80 % of the drug should be released between 3-5 hours, (d) Between 80-100 % of the drug should be released between 5-8 hours. The invitro release profile of the formulation has been tested as per United States Pharmacopoeia with Type I apparatus at 100 rpm using 900ml of sodium acetate buffer pH 3.5 as dissolution medium at 37°C ± 0.5°C for 8 hours. DETAILED DESCRIPTION OF THE INVENTION (0017) The present invention will now be further explained in the examples. Following description contains many specifications, these should not be construed as limitation in the scope of invention, but rather as an exemplification of the prepared embodiments thereof, many other modifications can be possible including use of any statins such as pravastatin or lovastatin or simvastatin or cerivastatin or fluvastatin apart from atorvastatin and rosuvastatin described below. (18) The compatibility (physical and chemical) study was done taking suitable ratio of aspirin or statin with the individual excipients. The sample mixtures were blended and triturated gently in glass mortar and pestle and these were filled in glass vials and sealed with high viscosity polyethylene closures. Few pinholes were made on the cap for maintaining the relative humidity and the vials were placed on 40° C ± 2° C / 75 % ± 5% RH. Samples were analyzed on differential scanning calorimeter and visual inspection was carried out initially and at the intervals of 15 days for one month. The results were compared to check the compatibility (physical and chemical) of the drug with excipients. It was found that the vials containing drug and excipients blend triturate were satisfactory in appearance as compared to individual control samples. (19) In order to screen for formulation stability we have formulated different types of process for the formulation. The analysis was done by HPLC (Make-Agilient series) using Inertsil ODS 150 X 4.6 mm C8 Column, at 215 nm using 0.05 M KH2P04 Buffer: Acetonitrile in 3:2 ratio respectively. The stability studies were done as per ICH guidelines for 6 months. (20) The in vitro dissolution medium was selected using detailed study of saturation solubility along with solution state stability data of the active drugs in the said medium and pH of the site of absorption in vivo. Dissolution Studies: Acid Stage: 2 hours in 900 ml 0.1N HC1 at 100 RPM using USP I apparatus at 100 RPM temperature 37± 0.5o C. or 4F or 4G or 4H or 41 was filled up to the required filled weight. The capsules were sealed, polished and packed. (0036) The capsules prepared as mentioned in this example had Assay within 90% to 100 % of label claim for Aspirin and Rosuvastatin Free salicylic acid NMT 3 % determined using method described in USP 27th edition: Dissolution Studies: (37) Acid Stage for Aspirin: 2 hours in 900 ml 0.1N HC1 at 100 RPM using USP I apparatus temperature 37 ± 0.5° C release complies with the specification i.e, NMT 10%. Buffer Stage for Aspirin: 45 Min 900 ml Phosphate buffer pH 6.8 at 100 RPM using USP I apparatus temperature 37±0.5° C release complies with the specification i.e., NLT 80% Rosuvastatin: 45 min in 900 ml 0.1 N HC1 at 100 RPM using USP I apparatus temperature 37 ± 0.5°C release complies with the specification i.e., NLT 80 %. (38) The tablets were placed on accelerated stability studies according to the ICH guidelines on 40°C ± 2° Cl 75 % ± 5 % relative humidity (RH), 30°C ± 2° C/60 % ± 5 % relative humidity (RH) and Controlled room temperature (CRT). Six-month studies have been done for the assay, dissolution, and free salicylic acid content and have shown good stability of assay, dissolution and free salicylic acid content within the prescribed limit. (39) Accordingly, the scope of the invention should be determined not by embodiments(s) and example(s) illustrated, but by the appended claims and their legal equivalents. Examplel Formulation of Bilayer Tablet containing Mosapride citrate dihydrate by non¬aqueous granulation. (18) The dosage forms generally comprises of a bilayer tablet have one layer comprises of mosapride or its pharmaceutically acceptable salts as immediate release fraction for loading dose, and the other layer comprises of the fraction of mosapride or its pharmaceutically acceptable salts which is a controlled or sustained release fraction formulated with biocompatible, hydrophilic polymer both layers compressed as bilayer tablet on a bilayer tableting machine. The sustained release layer that releases the drug within 8-12 hours to provide a maintenance dose for maintaining prolonged duration of action. (19) Sustained release layer comprises hydrophilic matrix polymer, which act as major rate controlling polymer. Mosapride citrate dihydrate, Hydroxy propyl methyl cellulose (Methocel K100 M Premium USP) and Microcrystalline cellulose sieved through 60 no. Mesh and blended for 5 minutes. Polyvinyl pyrrolidone (K 30) was dissolved in Isopropyl alcohol (5 % w/v) and the above blend was granulated. The granules were passed through mesh no. 8, air dried and then dried at 40° C till the loss on drying (LOD) of desired value reached of NMT 2.5 % (Make: Mettler Toledo LJ16 moisture analyzer) at 95° C. The dried granules were sieved through 20 mesh. Finally magnesium stearate and colloidal silicon dioxide (passed through 60 no. Mesh) were added and the whole mixture blended for 5 minutes. Table 1: Mosapride SR Layer mg/tablet Mosapride Citrate Dihydrate 12.840 Methocel K 100 M 15.0 Micro Crystalline Cellulose 46.66 Povidone (PVPK-30) 4.0 Isopropyl Alcohol q.s. Magnesium Stearate 1.0 Colloidal Silicon Dioxide 1.0 Av. Weight of SR layer 80.0 mg Mosapride IR Layer Mosapride Citrate Dihydrate 3.0 Colour lake of Quinoline yellow 1.0 Microcrystalline cellulose 87.5 PVPK 30 2.5 Isopropyl alcohol q.s. Magnesium Stearate 0.5 Colloidal silicon dioxide 0.5 Sodium starch glycollate 5.0 Average weight of IR layer 100.0 mg Total weight of tablet 180 mg Tools: 8.0 mm flat faced beveled edge punch (020) Immediate release layer comprises fast disintegrating excipients to ensure instant release of the drug for loading dose. Mosapride citrate dihydrate, colour lake of Quinoline yellow and Microcrystalline cellulose sieved through 60 no. Mesh and blended for 5 minutes. Polyvinyl pyrrolidone (K 30) Was dissolved in Isopropyl alcohol (5 % w/v) and the above blend was granulated. The granules were passed from mesh no. 8, air dried and then dried at 40° C till the loss on drying (LOD) of desired value reached of NMT 2.5 % (Make: Mettler Toledo LJ16 moisture analyzer) at 95° C. The dried granules were sieved through 20 mesh. Finally magnesium stearate, colloidal silicon dioxide and sodium starch glycollate (passed through 60 no. Mesh) were added and the whole mixture blended for 5 minutes. (021) The blend was compassed into tablets using 8.0 mm flat-faced beveled edge punch 27-station rotatory bilayer tablet machine (Make: Cadmach). The hardness limit for tablets was 4-6 kg/cm2. The whole procedure was carried out in controlled conditions of temperature (25 °C ± 2°C), relative humidity (40%±5% RH) and protected from direct exposure to light. The dissolution of above formulation was carried out by using USP type I (basket) apparatus at 100 rpm in 900 ml acetate buffer pH 3.5 at 37.0°C ± 0.5°C .The percent drug release of the above formulation found to be: Time % drug release of the labeled amount 1 hr 37.97 % (preferably30%-40%) 2 hr 49.43 % (preferably40%-55%) 3 4 hr 65.27 % (preferably60%-70%) 4 6 hr 79.37 % (preferably75%-85%) 8 hr 89.40 % (preferably not less than 80%) Example 2 Formulation of Tablet in capsule containing Mosapride citrate dihydrate by non¬aqueous granulation. (022) The present invention also comprises a formulation of a single unit capsule dosage form containing of two fractions, in which one fraction comprises blend or granules of mosapride or its pharmaceutically acceptable salts as immediate release fraction for loading dose, and the other fraction comprises of mosapride or its pharmaceutically acceptable salts which is a controlled or sustained release fraction formulated with biocompatible, hydrophilic polymer compressed into a tablet on a tableting machine. Both fractions are presented in a capsule (tablet and blend/granules in a capsule). Table 2: Mosapride SR Tablet Part mg/tablet Mosapride Citrate Dihydrate 11.0 Methocel K 100M 5.0 HPMC E 15 cps 10.0 Micro Crystalline Cellulose 37.0 Povidone (PVPK-30) 5.0 Isopropyl Alcohol q.s. Magnesium Stearate 1.0 Colloidal Silicon Dioxide 1.0 Average weight of SR tablet 70.0 mg Tools: 5.0 mm standard concave punch Mosapride IR Blend Part Mosapride Citrate Dihydrate 4.840 Lactose DC 11 138.1 Avicel pH 200 135.0 Magnesium Stearate 1.0 Colloidal silicon dioxide 1.0 Capsule filled weight (blend) 280.0 mg Average weight of capsule 426 mg Hard gelatin Capsule size ' 1' (023) Mosapride sustained release tablet comprises Mosapride citrate dihydrate, Hydroxypropylmethyl cellulose (Methocel K 100 M Premium), Hydroxypropylmethyl cellulose (E 15 cps) and Microcrystalline cellulose sieved through 60 no. mesh and blended for 5 minutes. Povidone (PVPK-30) was dissolved in Isopropyl Alcohol (5 % w/v) and the above blend was granulated. The granules were passed from mesh no. 8, air dried and then dried at 40° C till the loss on drying (LOD) of desired value reached of NMT 2.5 % (Make: Mettler Toledo LJ16 moisture analyzer) at 105° C. The dried granules were sieved through 20 mesh. Finally magnesium stearate and colloidal silicon dioxide (passed through 60 no. mesh) were added and the whole mixture blended for 5 minutes. The tablets were compressed on 16 station compression machine (Make:Cadmach). The hardness of tablets found to be 3-5 kg/cm2. (24) Mosapride immediate release blend part comprises Mosapride citrate dihydrate, Lactose DC 11 and Avicel pH 200 sieved through 60 no. mesh and blended for 5 minutes. Talc and magnesium stearate (passed through 60 no. mesh) were added and the whole mixture blended for 5 minutes. (25) The size '1' capsules were filled with mosapride sustained release tablet and mosapride immediate release blend. The whole procedure was carried out in control condition of temperature (25 °C ± 2°C), relative humidity (40%±5% RH) and protected from direct exposure to light. The dissolution of above formulation was carried out by using USP type I (basket) apparatus at 100 rpm in 900 ml acetate buffer pH 3.5 at 37.0 + 0.5°C . In vitro drug release profile of Mosapride citrate sustained release found to be: Time % drug release of the labeled amount 1 hr 38.5 % (preferably 30%-40%) 2 hr 48.8% (preferably 40%-55%) 4 hr 63.7 % (preferably 60%-70%) 6 hr 77.2% (preferably 75%-8 5%) 8 hr 88.2% (preferably not less than 80 %) Example 3 Formulation of Gastroretentive Bilayer Tablet containing Mosapride citrate dihydrate by non-aqueous granulation. (026) The present invention also comprises a formulation of a bilayer tablet in which one layer comprises of mosapride or its pharmaceutically acceptable salts as immediate release fraction for loading dose, and the other layer is a gastric retentive floating device comprises of the fraction of mosapride or its pharmaceutically acceptable salts which is a controlled or sustained release fraction formulated with biocompatible polymers, both layers compressed as single tablet on a bilayer tableting machine. Table 3: Mosapride Floating Tablet Layer mg/tablet Mosapride Citrate Dihydrate 11.0 Methocel K 100 M 5.0 HPMC E 15 cps 5 Sodium Carboxy methyl cellulose (Low viscosity grade) 15.0 Sodium Carboxy methyl cellulose (Medium viscosity grade) 5.0 Sodium alginate 5.0 Micro Crystalline Cellulose 27.0 Povidone (PVPK-30) 5.0 Isopropyl Alcohol q.s. Magnesium Stearate 1.0 Colloidal Silicon Dioxide 1.0 Average weight 80.0 mg Mosapride Immediate release layer mg/tablet Mosapride Citrate Dihydrate 4.84 Microcrystalline cellulose 86.6 PVPK 30 2.5 Isopropyl alcohol q.s. Magnesium Stearate 0.5 Colloidal silicon dioxide 0.5 Sodium starch glycollate 5.0 Average weight 100.0 mg Tablet weight 180mg Tools: 8.0 mm flat faced beveled ec ge punch (027) Mosapride sustained release floating layer comprises Mosapride citrate dihydrate, Hydroxypropylmethyl cellulose (Methocel K 100 M Premium), Hydroxypropylmethyl cellulose (E 15 cps) Sodium Carboxy methyl cellulose (Low viscosity grade), Sodium Carboxy methyl cellulose (Medium viscosity grade)and Microcrystalline cellulose sieved through 60 no. mesh and blended for 5 minutes. Povidone (PVPK-30) was dissolved in Isopropyl Alcohol (5 % w/v) and the above blend was granulated. The granules were passed from mesh no. 8, air dried and then dried at 40° C till the loss on drying (LOD) of desired value reached of NMT 2.5 % (Make: Mettler Toledo LJ16 moisture analyzer) at 105° C. The dried granules were sieved through 20 mesh. Finally magnesium stearate and colloidal silicon dioxide (passed through 60 no. Mesh) were added and the whole mixture blended for 5 minutes. (28) Mosapride immediate release blend part comprises Mosapride citrate dihydrate, Lactose DC 11 and Avicel pH 200 sieved through 60 no. Mesh and blended for 5 minutes. Talc and magnesium stearate (passed through 60 no. Mesh) were added and the whole mixture blended for 5 minutes. (29) The blend was compressed into tablets using 8.0 mm flat-faced beveled edge punch on 27-station rotatory bilayer tablet machine (Make: Cadmach). The hardness of tablet found to be 4-6 kg/cm2. The whole procedure was carried out in control condition of temperature (25 °C ± 2°C), relative humidity (40%±5% RH) and protected from direct exposure to light. The dissolution of above formulation was carried out by using USP type II (paddle) apparatus at 100 rpm in 900 ml acetate buffer pH 3.5 at 37.0 ± 0.5°C. In vitro drug release profile of Mosapride citrate sustained release found to be: Time % drug release of the labeled amount 1 hr 39.2 % (preferably 30%-40%) 2 hr 45.1% (preferably 40%-55%) 4 hr 62.3% (preferably 60%-70%) 6 hr 75.9 % (preferably 75%-85%) 8 hr 85.1% (preferably not less than 80%) Example 4 Formulation of Floating Tablet in Capsule containing Mosapride citrate dihydrate by non-aqueous granulation. (030) The present invention also comprises a formulation of a single unit capsule dosage form comprising of two fractions, in which one fraction comprises blend or granules of mosapride or its pharmaceutically acceptable salts as immediate release fraction for loading dose, and the second part is a gastric retentive floating device comprises of mosapride or its pharmaceutically acceptable salts which is a controlled or sustained release fraction formulated with biocompatible polymers, compressed into a tablet on a tableting machine. Both fractions are presented in a capsule (tablet and blend/granules in a capsule). Table 4: Mosapride Tablet Part mg/tablet Mosapride Citrate Dihydrate 11.0 Methocel K 100 M 5.0 HPMC E 15 cps 5 Sodium Carboxy methyl cellulose (Low viscosity grade) 15.0 Sodium Carboxy methyl cellulose (Medium viscosity grade) 5.0 Xanthan gum 5.0 Micro Crystalline Cellulose 27.0 Povidone (PVPK-30) 5.0 Isopropyl Alcohol q.s. Magnesium Stearate 1.0 Colloidal Silicon Dioxide 1.0 Tablet weight 80.0 mg Tools: 5.0 mm standard concave punch Mosapride Blend Part Mosapride Citrate Dihydrate 4.84 Lactose DC 11 133.1 Avicel pH 200 130.0 Magnesium Stearate 1.0 Colloidal silicon dioxide 1.0 Capsule filled weight 270.0 mg Average weight of Capsule 426 mg Hard gelatin Capsule size ' 1' (031) Mosapride sustained release floating tablet comprises Mosapride citrate dihydrate, Hydroxypropylmethyl cellulose (Methocel K 100 M Premium), Hydroxypropylmethyl cellulose (E 15 cps) Sodium Carboxy methyl cellulose (Low viscosity grade), Sodium Carboxy methylcellulose (Medium viscosity grade) and Microcrystalline cellulose sieved through 60 no. mesh and blended for 5 minutes. Povidone (PVPK-30) was dissolved in Isopropyl Alcohol (5 % w/v) and the above blend was granulated. The granules were passed from mesh no. 8, air dried and then dried at 40° C till the loss on drying (LOD) of desired value reached of NMT 2.5 % (Make: Mettler Toledo LJ16 moisture analyzer) at 105 C. The dried granules were sieved through 20 mesh. Finally magnesium stearate and colloidal silicon dioxide (passed through 60 no. Mesh) were added and the whole mixture blended for 5 minutes. The tablets were compressed on 16-station compression machine (Make: Cadmach). The hardness of tablets found to be 3-5 kg/cm2. (32) Mosapride immediate release blend part comprises Mosapride citrate dihydrate, Lactose DC 11 and Avicel pH 200 sieved through 60 no. Mesh and blended for 5 minutes. Talc and magnesium stearate (passed through 60 no. Mesh) were added and the whole mixture blended for 5 minutes. (33) The size '1' capsules were filled with mosapride-sustained release floating tablet and mosapride immediate release blend. The whole procedure was carried out in control condition of temperature (25 °C ± 2°C), relative humidity (40%±5% RH) and protected from direct exposure to light. The dissolution of above formulation was carried out by using USP type I (basket) apparatus at 100 rpm in 900 ml acetate buffer pH 3.5 at 37.0 + 0.5°C. In vitro drug release profile of Mosapride citrate sustained release found to be: Time % drug release of the labeled amount lhr 35.6% (preferably 30%-40%) 2hr 43.5% (preferably 40%-5 5%) 4hr 60.1% (preferably 60%-70%) 6hr 73.9% (preferably 75%-85%) 8hr 83.2% (preferably not less than 80 %) Example 5 Formulation of Tablet and floating mass in Capsule containing Mosapride citrate dihydrate by non-aqueous granulation. (034) The present invention also comprises of single unit capsule dosage form comprising a fraction of mosapride or its pharmaceutically acceptable salts which is a immediate release tablet for loading dose and second part is a blend and or granules comprising a fraction of mosapride or its pharmaceutically acceptable salts which is a gastric retentive floating fluffy mass which release the fraction of mosapride or its pharmaceutically acceptable salts which is a controlled or sustained release formulated with biocompatible polymers (tablet and blend/granules in a capsule). Table 5: Mosapride Immediate release tablet part mg/tablet Mosapride Citrate Dihydrate 4.84 Microcrystalline cellulose 66.6 PVPK 30 2.5 Isopropyl alcohol q.s. Magnesium Stearate 0.5 Colloidal silicon dioxide 0.5 Sodium starch glycollate 5.0 Average weight 80.0 mg Tools: 5.0 mm standard concave punch Mosapride Floating mass capsule part mg Mosapride Citrate Dihydrate 11.0 Methocel K 100 M 5.0 Sodium alginate 10.0 Sodium Carboxy methyl cellulose (Low viscosity grade) 20.0 Sodium Carboxy methyl cellulose (Medium viscosity grade) 5.0 Xanthan gum 10.0 Micro Crystalline Cellulose 206.0 Povidone (PVPK-30) 5.0 Isopropyl Alcohol q.s. Magnesium Stearate 1.0 Colloidal Silicon Dioxide 1.0 Filled weight 274.0 mg Average weight of capsule 430 mg Hard gelatin Capsule size ' 1' (035) Mosapride Immediate release tablet comprises Mosapride citrate dihydrate, Microcrystalline cellulose sieved through 60 no. mesh and blended for 5 minutes. Povidone (PVPK-30) was dissolved in Isopropyl Alcohol (5 % w/v) and the above blend was granulated. The granules were passed from mesh no. 8, air dried and then dried at 40° C till the loss on drying (LOD) of desired value reached of NMT 2.5 % (Make: Mettler Toledo LJ16 moisture analyzer) at 105° C. The dried granules were sieved through 20 mesh. Finally magnesium stearate, sodium starch glycollate and colloidal silicon dioxide (passed through 60 no. Mesh) were added and the whole mixture blended for 5 minutes. The tablets were compressed on 16-station compression machine (Make: Cadmach). The hardness of tablets found to be 3-5 kg/cm2. (36) Mosapride sustained release floating mass comprises Mosapride citrate dihydrate, Hydroxypropylmethyl cellulose (Methocel K 100 M Premium), Sodium alginate, Sodium Carboxy methyl cellulose (Low viscosity grade), Sodium Carboxy methyl cellulose (Medium viscosity grade), xanthan gum, microcrystalline cellulose sieved through 60 no. mesh and blended for 5 minutes. Povidone (PVPK-30) was dissolved in Isopropyl Alcohol (5 % w/v) and the above blend was granulated. The granules were passed from mesh no. 8, air dried and then dried at 40° C till the loss on drying (LOD) of desired value reached of NMT 2.5 % (Make: Mettler Toledo LJ16 moisture analyzer) at 105° C. The dried granules were sieved through 20 mesh. Finally magnesium stearate and colloidal silicon dioxide (passed through 60 no. mesh) were added and the whole mixture blended for 5 minutes. (37) The size T capsules were filled with mosapride immediate release tablet and mosapride sustained release blend, which will form a floating mass upon the imbibition of dissolution media. The whole procedure was carried out in control condition of temperature (25 °C ± 2°C), relative humidity (40%±5% RH) and protected from direct exposure to light. The dissolution of above formulation was carried out by using USP type I (basket) apparatus at 100 rpm in 900 ml acetate buffer pH 3.5 at 37.0 ± 0.5°C . In vitro drug release profile of Mosapride citrate sustained release found to be: Time % drug release of the labeled amount lhr 36.1 % (preferably 30%-40%) 2hr 43.8 % (preferably 40%-55%) 4hr 60.8 % (preferably 60%-70%) 6hr 71.9% (preferably 75%-85%) 8hr 84.2 % (preferably not less than 80 %) (038) The oral controlled release dosage forms of the present invention comprises mosapride or its pharmaceutically acceptable salts and release controlling pharmaceutically acceptable excipients, wherein the mosapride is released as per the following in vitro dissolution profile.(a) Not less than 30 % of the drug is release within 15 minute, which is a loading dose, (b) between 40% and 60% of the drug should be release between 2 to 3 hours, (c) between 60 - 80 % of the drug should be released between 3-5 hours, (d) Between 80 - 100 % of the drug should be released between 5-8 hours. The in vitro release profile of the formulation has been tested as per United States Pharmacopoeia with Type I apparatus at 100 rpm using 900ml of acetate buffer pH 3.5 as dissolution medium at 37 ± 0.5°C for 8 hours. Claims We claim: 1. A process for making anovel pharmaceutical composition as capsule dosage form, containing a final blend of statin, treated with plurality of antioxidant, along with delayed release tablet of aspirin, the process steps comprising of-sieving a statin through 40# mesh and treating with a plurality of antioxidants by spraying the solution of said plurality of antioxidants on said statin for uniform treatment, sieving the resulting wet mass through 8# mesh to get wet granules, air-drying said wet granules at 30°C to 40°C, then drying said granules in tray drier at 40°C to 45°C until loss on drying up to 2.5%, passing dried granules through 20 # mesh and mixing with plurality of diluents in a high-speed mixer, dispersing binder in isopropyl alcohol making 5 % solution and adding to the dry mix under slow speed, sieving plurality of lubricants through 60 # mesh and mixing with said 20# mesh passed dried granules for 10 min in a planetary mixer to get said final blend of statin for filling in capsule, sieving aspirin, with plurality of diluents though 40 # mesh, mixing in a blender for 10 min, compressing the above mixture using 5 mm or 6 mm D type standard concave tooling on a rotary tablet compression machine to get core tablet of aspirin, subcoating said core tablets of aspirin to provide seal coat to get seal coated aspirin tablet, further enteric coating said seal coated tablet of aspirin up to 10% to 14% of total weight of core to get said delayed release tablet of aspirin, and filling, said delayed release aspirin tablets along with said final blend of statin, in hard gelatin capsule using a special type of hard gelatin capsule filling machine equipped with tablet loader. 2. A process as claimed in claim 1, wherein said statin is either atorvastatin in the dose range of 5 mg to 40 mg or rosuvastatin in the dose range of 5 mg to 45 mg. 3. A process as claimed in claim 1, wherein said delayed release tablet comprising of aspirin in the dose range of 75 mg to 150 mg. A process as claimed in claim 1, wherein said antioxidants are butylated hydroxyanisole used in the range of 0.05% to 5.0% of the dose of said statin, more preferably 0.2 % to 0.8% of the dose of said statin and butylated hydroxytoluene used in the range of 0.05% to 5.0% of the dose of statin, more preferably 0.2 % to 0.8% of the dose of said statin. A process as claimed in claim 1, wherein said subcoating given for preparation of said delayed release tablet of aspirin comprises of hydroxypropyl methylcellulose E6 polymer is used in the range of 1-10% of tablet weight of said core tablet of aspirin more preferably 3% of weight of said core tablet of aspirin, additionally polyvinylpyrrolidone K30 is used in the range of 1-5% more preferably 2% of weight of said hydroxy propyl methyl cellulose E6 polymer, additionally propylene glycol is used in the range of 10-50% more preferably 25% of weight of said hydroxy propyl methyl cellulose E6 polymer, and titanium dioxide is used in the range of 1-10%, more preferably 2% of weight of said hydroxy propyl methyl cellulose E6 polymer A process as claimed in claim 1, wherein said enteric coating comprises of plurality of polymer, plurality of plasticizer, and an antisticking agent, wherein said polymer is either eudragit L-100 55 used in the range of 10-20% weight of said core tablet of aspirin, more preferably 13% of weight of said core tablet of aspirin or hydroxypropyl methylcellulose phthalate used in the range of 10-20% weight of said core tablet of aspirin, more preferably 13% weight of said core tablet of aspirin, additionally said plasticizer is polyethelene glycol 6000 used in the range of 1-5% of weight of said polymer, more preferably 1.5% of weight of said polymer and triacetin used in the range ofl% to 5% of weight of said polymer, more preferably 1.5% of said polymer, additionally said antisticking agent is talc used in the range of 8-20% of polymer weight more preferably 10% of weight of polymer. A process as claimed in claim 1, wherein said binder is polyvinylpyrrolidone K30 in the range of 1-5% fill weight of the said statin blend. A process as claimed in claim 1, wherein said plurality of diluents incorporated in said final blend of statin are microcrystalline cellulose used in the range of 5-95% of weight of said final blend of statin, more preferably 30% to 50% of weight of said final blend of statin, additionally pregelatinized starch is used in the range of 1-35% of weight of said final blend of statin, more preferably 22 % to 28% of weight of said final blend of statin, additionally sodium starch glycolate is used in the range of 1-20% weight of said final blend of statin, more preferably 8% to 12% of weight of said final blend of statin and additionally polyvinylpyrrolidone K 30 is used in the range of 1-20% of weight of said final blend of statin, more preferably 1.5 to 3% of weight of said final blend of statin. A process as claimed in claim 1, wherein said plurality of diluents used to prepare said delayed release tablet are maize starch is used in the range of 5% tol7% of weight of said core tablet of aspirin, additionally sodium starch glycolate used in the range of 3% to 5% of weight of said core tablet of aspirin, additionally talc is used in the range of 4% to 8% of weight of said core tablet of aspirin, and additionally colloidal silicon dioxide is used in the range of 2% to 6% of weight of said core tablet of aspirin. A process as claimed in claim 1, wherein said plurality of lubricants used is magnesium stearate is used in the range of 0.5% to 5 % of weight of said final blend of statin, more preferably up to 2% of weight of said final blend of statin, additionally colloidal silicon dioxide is used in the range of 0.5% to 5 % of weight of said final blend of statin, more preferably up to 2% of weight of said final blend of statin, additionally crosspovidone is used in the range of 1.0 % to 10 % of weight of said final blend of statin, more preferably up to 3% of weight of said final blend of statin. Mr. Manutosh Manohar Acharya Name of the inventor: Assignee: Aristo Pharmaceuticals Ltd Mercantile Chambers, 3rd Floor, 12, J. N. Heredia Marg, Ballard Estate, Mumbai - 400 001 (INDIA)

Full Text

FORM 2
The Patents Act, 1970
(39 OF 1970)
[Refer Section 10; Rule 13]
COMPLETE SPECIFICATION
A Process for making a Novel Pharmaceutical Composition as capsule dosage form
M/s Aristo Pharmaceutical Ltd 23-A, Shah Industrial Estate, Off Veera Desai road, Andheri (W), Mumbai - 400 053.
Name of the inventors -
1) Mr. Manutosh Manohar Acharya, Indian, residing at 4/7, Amaltas Parisar Shahpura, Bhopal (MP), India.
GRANTED

28-3-2005
The following complete specification describes the nature of this invention and the manner in which it is to be performed.
Original 888/MUM/2003

Complete Specifications BACKGROUND OF THE INVENTION
(1) Gastro esophageal reflux disease (GERD) is among the most common disorders seen by the gastroenterologists and general practitioners. This disease is characterized as the backward flow of the stomach contents into the esophagus. One of the most important factors in the pathogenesis of gastro-esophageal reflux disease is a reduction in the pressure barrier due to the failure of the lower esophageal sphincter. Failure of the lower esophageal sphincter can arise due to a low basal pressure, sphincter relaxation, or to a non-compensated increase in intragastric pressure.
(2) Other factors in the pathogenesis of the disease are delayed gastric emptying, insufficient esophageal clearing due to impaired peristalsis and the corrosive nature of the reflux material which can damage esophageal mucosa.
(3) Mosapride, i.e., 4-amino-5-chloro-2-ethoxy-N- [[4- (4-fluorophenyl) methyl]-2-morpholinyl] methylj-benzamide, is disclosed in European Patent No. 243959 and United States Patent No. 4870074 as gastrointestinal prokinetic agent. Mosapride formulations in market are in which mosapride citrate dihydrate is equivalent to mosapride. In the present invention, mosapride and or its salts here after will be termed as "mosapride". Mosapride is a new 5-HT4 agonist intended for oral treatment of gastrointestinal motility dysfunction e.g. gastro-esophageal reflux.
(4) It is known to exert its action by facilitating acetylcholine release from the enteric cholinergic neurons. With respect to the therapeutic actions mosapride enhances gastric emptying and also improves total acid clearance time. Conditions or symptoms relieved

by the promotion of gastric emptying include but are not limited to gastric stasis, flatulence, dyspepsia, peptic ulcer and reflux oesophagitis. Conventionally mosapride is given 5 mg three times daily for decreasing acid reflux in the esophagus in patients with gastro-esophageal reflux disease. Maintenance therapy is often necessary to prevent recurrent symptoms and reflux oesophagitis. It is more convenient for patients to receive long-term effective controlled release mosapride dosage forms once a day than the conventional mosapride dosage forms administered three times a day. Mosapride has a short biological half-life of about 1.4-2 hours and shows linear pharmacokinetics upto a dose of 40 mg. Thus, it is suitable for formulation into oral controlled release dosage form. A once-a-day controlled release dosage form eliminates the inconvenience to the patient in taking multiple dosing at different times and thus ensures patient compliance to the prescribed dosage regimen.
(005) An optimum design of an oral controlled release dosage form of mosapride for
once-a-day therapy in humans also requires that the dosage form provide a control on the
plasma levels such that the mean residence time (i. e. the mean time that a drug spends in
the body) is within a desirable range for said once-a-day therapy in humans. Hence, an
oral controlled release dosage form for mosapride that releases the mosapride in a
controlled manner so as to provide control over mosapride plasma levels, such that the
ratio of peak plasma levels to the plasma levels at 24 hours after administration, and the
mean residence time of mosapride, are within a desirable range for once-a-day therapy in
humans, is thus required.
(006) Earlier controlled release once-a-day dosage form of the prokinetic agent,
Mosapride is given in European patent no WO 03011256. The mosapride is released
according to the following dissolution profile (a) not less then 15% of the mosapride is
released after 4 hours; (b) between 35% and 55% of the mosapride is released after 8
hours; and (c) between 50% and 75% of the mosapride is released after 12 hours (c) Not
less than 90% of mosapride is released after 24 hours; The release pattern of the drug has
been tested in vitro as per United States Pharmacopoeia Type II apparatus at 100 rpm
using 0.1 N HC1 as dissolution medium at 37°C for 24 hours. However, loading dose
and maintenance dose fractions, rationale for choosing in vitro dissolution media for
Mosapride Citrate Dihydrate is not mentioned.

SUMMARY OF THE INVENTION
(7) Conventionally mosapride citrate dihydrate expressed as mosapride is given 5 mg t.i.d. The present invention provides oral single unit dosage form of a prokinetic agent, mosapride and or its pharmaceutically acceptable salts expressed as mosapride with pharmaceutical compositions in dosage forms to provide a loading dose and a controlled release of maintenance dose for once a day administration.
(8) A process for making oral single unit dosage form of a prokinetic agent, mosapride and or its pharmaceutically acceptable salts with pharmaceutically acceptable excipients wherein the single unit dosage form comprises of a bilayer tablet, or a tablet, and blend or granules in a capsule, where the total dose of mosapride is split, partitioned or distributed in the dosage forms to provide a loading dose and a controlled release of maintenance dose for once a day administration wherein mosapride release is according to the following dissolution profile, (a) Not less than 35 % of the drug is release within 15 minute, which is a loading dose, (b) between 35% and 50% of the drug should be release between 2 to 3 hours, (c) between 50 - 80 % of the drug should be released between 3-5 hours, (d) Between 80 - 90 % of the drug should be released between 5-8 hours. The said bilayer tablet comprises of two part in which one part is immediate release containing loading dose with pharmaceutically acceptable excipients, which contains mosapride citrate dihydrate expressed as mosapride in concentration ranging from 15 to 25 %, preferably 18.9 % of the total dose of mosapride (total dose 15 mg expressed as mosapride) and the other part is a controlled or sustained release fraction and this fraction can also be a gastro retentive floating device releasing the prokinetic agent, in sustained or controlled release form with suitable pharmaceutically acceptable excipients with release rate controlling polymers and the mosapride in this layer ranges from 75 to 85%, preferably 81.1% of the total mosapride dose (total dose 15 mg expressed as mosapride). The process of preparation ofbilayer tablet is as follows- Mosapride citrate dihydrate, Hydroxy propyl methyl cellulose USP viscosity 1,00,000 cps (Methocel K100 M Premium) and Microcrystalline cellulose sieved through 60 no. mesh and blended for 5 minutes.

Polyvinyl pyrrolidone (K 30) was dissolved in Isopropyl alcohol (5 % w/v) and the above blend was granulated. The granules were passed through mesh no. 8, air dried and then dried at 40° C till the loss on drying (LOD) of desired value reached of NMT 2.5 % at 95 C. The dried granules were sieved through 20 mesh. Finally magnesium stearate and colloidal silicon dioxide (passed through 60 no. mesh) were added and the whole mixture blended for 5 minutes. The immediate release blend was processed as follows—Mosapride citrate dihydrate, colour lake of quinoline yellow and Microcrystalline cellulose sieved through 60 no. mesh and blended for 5 minutes. Polyvinyl pyrrolidone (K 30) was dissolved in Isopropyl alcohol (5 % w/v) and the above blend was granulated. The granules were passed from mesh no. 8, air dried and then dried at 40° C till the loss on drying (LOD) of desired value reached of NMT2.5 % at 95° C. The dried granules were sieved through 20 mesh. Finally magnesium stearate, colloidal silicon dioxide and sodium starch glycollate (passed through 60 no. mesh) were added and the whole mixture blended for 5 minutes. These blend was compressed into tablets using 8.0 mm flat faced beveled edge punch 27-station rotatory bilayer tablet machine. The hardness limit for tablets was 4-6 kg/cm . The whole procedure was carried out in controlled conditions of temperature (25 °C ±2°C), relative humidity (40%±5% RH) and protected from direct exposure to light.
(9) Omitted and merged with (008)
(10) The present invention also comprises a formulation of a single unit capsule dosage form containing of two fractions, in which one fraction comprises blend or granules of mosapride or its pharmaceutically acceptable salts as immediate release fraction for loading dose, and the other fraction comprises of mosapride or its pharmaceutically acceptable salts which is a controlled or sustained release fraction formulated with biocompatible, hydrophilic polymer compressed into a tablet on a tableting machine. Both fractions are presented in a capsule (tablet and blend/granules in a capsule). The present invention also comprises a formulation of a single unit capsule dosage form comprising of two fractions, in which one fraction comprises blend or granules of mosapride or its pharmaceutically acceptable salts as immediate release fraction for loading dose, and the second part is a gastric retentive floating

device comprises of mosapride or its pharmaceutical acceptable salts which is a controlled or sustained release fraction formulated with biocompatible polymers, compressed into a tablet on a tableting machine. Both fractions are presented in a capsule (tablet and blend/granules in a capsule). Capsule part comprises of two part in which one part is immediate release containing loading dose with pharmaceutically acceptable excipients, which contains mosapride citrate dihydrate expressed as mosapride in concentration ranging from 25 to 35 %, preferably 30.5 % of the total dose of mosapride (preferably 15 mg) and the other part is a controlled or sustained release fraction and this fraction can also optionally be a gastro retentive floating device releasing the prokinetic agent, in sustained or controlled release form with suitable pharmaceutically acceptable excipients with release rate controlling polymers and the mosapride in this layer ranges from 65 to 55%, preferably 69.5% of the total mosapride dose (total dose 15 mg expressed as mosapride) The process optionally comprised of following sequence of events- Mosapride sustained release tablet comprises Mosapride citrate dihydrate, Hydroxypropylmethyl cellulose viscosity l,00,000cps (Methocel K 100 M Premium), Hydroxypropylmethyl cellulose (E 15 cps) Sodium Carboxy methyl cellulose (Low viscosity grade), Sodium Carboxy methyl cellulose (Medium viscosity grade)and Microcrystalline cellulose sieved through 60 no. mesh and blended for 5 minutes. Povidone (PVPK-30) was dissolved in Isopropyl Alcohol (5 % w/v) and the above blend was granulated. The granules were passed from mesh no. 8, air dried and then dried at 40° C till the loss on drying (LOD) of desired value reached of NMT 2.5 % (Make: Mettler Toledo LJ16 moisture analyzer) at 105° C. The dried granules were sieved through 20 mesh. Finally magnesium stearate and colloidal silicon dioxide (passed through 60 no. mesh) were added and the whole mixture blended for 5 minutes. The tablets were compressed on 16 station compression machine. The hardness of tablets found to be 3-5 kg/cm. Mosapride immediate release blend part comprises Mosapride citrate dihydrate, Lactose DC 11 and Avicel pH 200 sieved through 60 no. mesh and blended for 5 minutes. Talc and magnesium stearate (passed through 60 no. mesh) were added and the whole mixture blended for 5 minutes. The size '1' hard gelatin capsules were filled with mosapride sustained release tablet and mosapride immediate release blend. The whole procedure was

carried out in control condition of temperature (25 °C + 2°C), relative humidity (40%±5% RH) and protected from direct exposure to light.
(Oil) Omitted and merged with(010)

(12) The present invention also comprises of single unit capsule dosage form comprising a fraction of mosapride or its pharmaceutically acceptable salts which is a immediate release tablet for loading dose and second part is a blend and or granules comprising a fraction of mosapride or its pharmaceutically acceptable salts which is a gastric retentive floating fluffy mass which release the fraction of mosapride or its pharmaceutically acceptable salts which is a controlled or sustained release formulated with biocompatible polymers (tablet and blend/granules in a capsule).
(13) The oral controlled release dosage forms of the present invention comprises mosapride or its pharmaceutically acceptable salts and release controlling pharmaceutically acceptable excipients, wherein the mosapride is released as per the following in vitro dissolution profile.(a) Not less than 30 % of the drug is release within 15 minute, which is a loading dose, (b) between 40% and 60% of the drug should be release between 2 to 3 hours, (c) between 60 - 80 % of the drug should be released between 3-5 hours, (d) Between 80-100 % of the drug should be released between 5-8 hours. The invitro release profile of the formulation has been tested as per United States Pharmacopoeia with Type I apparatus at 100 rpm using 900ml of sodium acetate buffer pH 3.5 as dissolution medium at 37°C ± 0.5°C for 8 hours.

DETAILED DESCRIPTION OF THE INVENTION
(0017) The present invention will now be further explained in the examples.
Following description contains many specifications, these should not be construed
as limitation in the scope of invention, but rather as an exemplification of the
prepared embodiments thereof, many other modifications can be possible including
use of any statins such as pravastatin or lovastatin or simvastatin or cerivastatin or
fluvastatin apart from atorvastatin and rosuvastatin described below.
(18) The compatibility (physical and chemical) study was done taking suitable ratio of aspirin or statin with the individual excipients. The sample mixtures were blended and triturated gently in glass mortar and pestle and these were filled in glass vials and sealed with high viscosity polyethylene closures. Few pinholes were made on the cap for maintaining the relative humidity and the vials were placed on 40° C ± 2° C / 75 % ± 5% RH. Samples were analyzed on differential scanning calorimeter and visual inspection was carried out initially and at the intervals of 15 days for one month. The results were compared to check the compatibility (physical and chemical) of the drug with excipients. It was found that the vials containing drug and excipients blend triturate were satisfactory in appearance as compared to individual control samples.
(19) In order to screen for formulation stability we have formulated different types of process for the formulation. The analysis was done by HPLC (Make-Agilient series) using Inertsil ODS 150 X 4.6 mm C8 Column, at 215 nm using 0.05 M KH2P04 Buffer: Acetonitrile in 3:2 ratio respectively. The stability studies were done as per ICH guidelines for 6 months.
(20) The in vitro dissolution medium was selected using detailed study of saturation solubility along with solution state stability data of the active drugs in the said medium and pH of the site of absorption in vivo.
Dissolution Studies:
Acid Stage: 2 hours in 900 ml 0.1N HC1 at 100 RPM using USP I apparatus at 100 RPM temperature 37± 0.5o C.

or 4F or 4G or 4H or 41 was filled up to the required filled weight. The capsules were sealed, polished and packed.
(0036) The capsules prepared as mentioned in this example had Assay within 90% to
100 % of label claim for Aspirin and Rosuvastatin Free salicylic acid NMT 3 %
determined using method described in USP 27th edition:
Dissolution Studies:
(37) Acid Stage for Aspirin: 2 hours in 900 ml 0.1N HC1 at 100 RPM using USP I apparatus temperature 37 ± 0.5° C release complies with the specification i.e, NMT 10%. Buffer Stage for Aspirin: 45 Min 900 ml Phosphate buffer pH 6.8 at 100 RPM using USP I apparatus temperature 37±0.5° C release complies with the specification i.e., NLT 80% Rosuvastatin: 45 min in 900 ml 0.1 N HC1 at 100 RPM using USP I apparatus temperature 37 ± 0.5°C release complies with the specification i.e., NLT 80 %.
(38) The tablets were placed on accelerated stability studies according to the ICH guidelines on 40°C ± 2° Cl 75 % ± 5 % relative humidity (RH), 30°C ± 2° C/60 % ± 5 % relative humidity (RH) and Controlled room temperature (CRT). Six-month studies have been done for the assay, dissolution, and free salicylic acid content and have shown good stability of assay, dissolution and free salicylic acid content within the prescribed limit.
(39) Accordingly, the scope of the invention should be determined not by embodiments(s) and example(s) illustrated, but by the appended claims and their legal equivalents.

Examplel
Formulation of Bilayer Tablet containing Mosapride citrate dihydrate by non¬aqueous granulation.
(18) The dosage forms generally comprises of a bilayer tablet have one layer comprises of mosapride or its pharmaceutically acceptable salts as immediate release fraction for loading dose, and the other layer comprises of the fraction of mosapride or its pharmaceutically acceptable salts which is a controlled or sustained release fraction formulated with biocompatible, hydrophilic polymer both layers compressed as bilayer tablet on a bilayer tableting machine. The sustained release layer that releases the drug within 8-12 hours to provide a maintenance dose for maintaining prolonged duration of action.
(19) Sustained release layer comprises hydrophilic matrix polymer, which act as major rate controlling polymer. Mosapride citrate dihydrate, Hydroxy propyl methyl cellulose (Methocel K100 M Premium USP) and Microcrystalline cellulose sieved through 60 no. Mesh and blended for 5 minutes. Polyvinyl pyrrolidone (K 30) was dissolved in Isopropyl alcohol (5 % w/v) and the above blend was granulated. The granules were passed through mesh no. 8, air dried and then dried at 40° C till the loss on drying (LOD) of desired value reached of NMT 2.5 % (Make: Mettler Toledo LJ16 moisture analyzer) at 95° C. The dried granules were sieved through 20 mesh. Finally magnesium stearate and colloidal silicon dioxide (passed through 60 no. Mesh) were added and the whole mixture blended for 5 minutes.

Table 1:

Mosapride SR Layer mg/tablet
Mosapride Citrate Dihydrate 12.840
Methocel K 100 M 15.0
Micro Crystalline Cellulose 46.66
Povidone (PVPK-30) 4.0
Isopropyl Alcohol q.s.
Magnesium Stearate 1.0
Colloidal Silicon Dioxide 1.0
Av. Weight of SR layer 80.0 mg
Mosapride IR Layer
Mosapride Citrate Dihydrate 3.0
Colour lake of Quinoline yellow 1.0
Microcrystalline cellulose 87.5
PVPK 30 2.5
Isopropyl alcohol q.s.
Magnesium Stearate 0.5
Colloidal silicon dioxide 0.5
Sodium starch glycollate 5.0
Average weight of IR layer 100.0 mg
Total weight of tablet 180 mg
Tools: 8.0 mm flat faced beveled edge punch
(020) Immediate release layer comprises fast disintegrating excipients to ensure instant release of the drug for loading dose. Mosapride citrate dihydrate, colour lake of Quinoline yellow and Microcrystalline cellulose sieved through 60 no. Mesh and blended for 5 minutes. Polyvinyl pyrrolidone (K 30) Was dissolved in Isopropyl alcohol (5 % w/v) and the above blend was granulated. The granules were passed from mesh no. 8, air dried and then dried at 40° C till the loss on drying (LOD) of desired value reached of NMT 2.5 % (Make: Mettler Toledo LJ16 moisture analyzer) at 95° C. The dried granules were sieved through 20 mesh. Finally magnesium stearate, colloidal silicon dioxide and sodium starch glycollate (passed through 60 no. Mesh) were added and the whole mixture blended for 5 minutes.

(021) The blend was compassed into tablets using 8.0 mm flat-faced beveled edge punch 27-station rotatory bilayer tablet machine (Make: Cadmach). The hardness limit for tablets was 4-6 kg/cm2. The whole procedure was carried out in controlled conditions of temperature (25 °C ± 2°C), relative humidity (40%±5% RH) and protected from direct exposure to light. The dissolution of above formulation was carried out by using USP type I (basket) apparatus at 100 rpm in 900 ml acetate buffer pH 3.5 at 37.0°C ± 0.5°C .The percent drug release of the above formulation found to be: Time % drug release of the labeled amount
1 hr 37.97 % (preferably30%-40%)
2 hr 49.43 % (preferably40%-55%)
3 4 hr 65.27 % (preferably60%-70%)
4 6 hr 79.37 % (preferably75%-85%)
8 hr 89.40 % (preferably not less than 80%)
Example 2
Formulation of Tablet in capsule containing Mosapride citrate dihydrate by non¬aqueous granulation.
(022) The present invention also comprises a formulation of a single unit capsule dosage form containing of two fractions, in which one fraction comprises blend or granules of mosapride or its pharmaceutically acceptable salts as immediate release fraction for loading dose, and the other fraction comprises of mosapride or its pharmaceutically acceptable salts which is a controlled or sustained release fraction formulated with biocompatible, hydrophilic polymer compressed into a tablet on a tableting machine. Both fractions are presented in a capsule (tablet and blend/granules in a capsule).

Table 2:

Mosapride SR Tablet Part mg/tablet
Mosapride Citrate Dihydrate 11.0
Methocel K 100M 5.0
HPMC E 15 cps 10.0
Micro Crystalline Cellulose 37.0
Povidone (PVPK-30) 5.0
Isopropyl Alcohol q.s.
Magnesium Stearate 1.0
Colloidal Silicon Dioxide 1.0
Average weight of SR tablet 70.0 mg
Tools: 5.0 mm standard concave punch
Mosapride IR Blend Part
Mosapride Citrate Dihydrate 4.840
Lactose DC 11 138.1
Avicel pH 200 135.0
Magnesium Stearate 1.0
Colloidal silicon dioxide 1.0
Capsule filled weight (blend) 280.0 mg
Average weight of capsule 426 mg
Hard gelatin Capsule size ' 1'
(023) Mosapride sustained release tablet comprises Mosapride citrate dihydrate, Hydroxypropylmethyl cellulose (Methocel K 100 M Premium), Hydroxypropylmethyl cellulose (E 15 cps) and Microcrystalline cellulose sieved through 60 no. mesh and blended for 5 minutes. Povidone (PVPK-30) was dissolved in Isopropyl Alcohol (5 % w/v) and the above blend was granulated. The granules were passed from mesh no. 8, air dried and then dried at 40° C till the loss on drying (LOD) of desired value reached of NMT 2.5 % (Make: Mettler Toledo LJ16 moisture analyzer) at 105° C. The dried granules were sieved through 20 mesh. Finally magnesium stearate and colloidal silicon dioxide (passed through 60 no. mesh) were added and the whole mixture blended for 5 minutes. The tablets were compressed on 16 station compression machine (Make:Cadmach). The hardness of tablets found to be 3-5 kg/cm2.

(24) Mosapride immediate release blend part comprises Mosapride citrate dihydrate, Lactose DC 11 and Avicel pH 200 sieved through 60 no. mesh and blended for 5 minutes. Talc and magnesium stearate (passed through 60 no. mesh) were added and the whole mixture blended for 5 minutes.
(25) The size '1' capsules were filled with mosapride sustained release tablet and mosapride immediate release blend. The whole procedure was carried out in control condition of temperature (25 °C ± 2°C), relative humidity (40%±5% RH) and protected from direct exposure to light. The dissolution of above formulation was carried out by using USP type I (basket) apparatus at 100 rpm in 900 ml acetate buffer pH 3.5 at 37.0 + 0.5°C . In vitro drug release profile of Mosapride citrate sustained release found to be: Time % drug release of the labeled amount
1 hr 38.5 % (preferably 30%-40%)
2 hr 48.8% (preferably 40%-55%)
4 hr 63.7 % (preferably 60%-70%)
6 hr 77.2% (preferably 75%-8 5%)
8 hr 88.2% (preferably not less than 80 %)
Example 3
Formulation of Gastroretentive Bilayer Tablet containing Mosapride citrate
dihydrate by non-aqueous granulation.
(026) The present invention also comprises a formulation of a bilayer tablet in which one
layer comprises of mosapride or its pharmaceutically acceptable salts as immediate
release fraction for loading dose, and the other layer is a gastric retentive floating device
comprises of the fraction of mosapride or its pharmaceutically acceptable salts which is a
controlled or sustained release fraction formulated with biocompatible polymers, both
layers compressed as single tablet on a bilayer tableting machine.

Table 3:

Mosapride Floating Tablet Layer mg/tablet
Mosapride Citrate Dihydrate 11.0
Methocel K 100 M 5.0
HPMC E 15 cps 5
Sodium Carboxy methyl cellulose (Low viscosity grade) 15.0
Sodium Carboxy methyl cellulose (Medium viscosity grade) 5.0
Sodium alginate 5.0
Micro Crystalline Cellulose 27.0
Povidone (PVPK-30) 5.0
Isopropyl Alcohol q.s.
Magnesium Stearate 1.0
Colloidal Silicon Dioxide 1.0
Average weight 80.0 mg
Mosapride Immediate release layer mg/tablet
Mosapride Citrate Dihydrate 4.84
Microcrystalline cellulose 86.6
PVPK 30 2.5
Isopropyl alcohol q.s.
Magnesium Stearate 0.5
Colloidal silicon dioxide 0.5
Sodium starch glycollate 5.0
Average weight 100.0 mg
Tablet weight 180mg
Tools: 8.0 mm flat faced beveled ec ge punch
(027) Mosapride sustained release floating layer comprises Mosapride citrate dihydrate, Hydroxypropylmethyl cellulose (Methocel K 100 M Premium), Hydroxypropylmethyl cellulose (E 15 cps) Sodium Carboxy methyl cellulose (Low viscosity grade), Sodium Carboxy methyl cellulose (Medium viscosity grade)and Microcrystalline cellulose sieved through 60 no. mesh and blended for 5 minutes. Povidone (PVPK-30) was dissolved in

Isopropyl Alcohol (5 % w/v) and the above blend was granulated. The granules were passed from mesh no. 8, air dried and then dried at 40° C till the loss on drying (LOD) of desired value reached of NMT 2.5 % (Make: Mettler Toledo LJ16 moisture analyzer) at 105° C. The dried granules were sieved through 20 mesh. Finally magnesium stearate and colloidal silicon dioxide (passed through 60 no. Mesh) were added and the whole mixture blended for 5 minutes.
(28) Mosapride immediate release blend part comprises Mosapride citrate dihydrate, Lactose DC 11 and Avicel pH 200 sieved through 60 no. Mesh and blended for 5 minutes. Talc and magnesium stearate (passed through 60 no. Mesh) were added and the whole mixture blended for 5 minutes.
(29) The blend was compressed into tablets using 8.0 mm flat-faced beveled edge punch on 27-station rotatory bilayer tablet machine (Make: Cadmach). The hardness of tablet found to be 4-6 kg/cm2. The whole procedure was carried out in control condition of temperature (25 °C ± 2°C), relative humidity (40%±5% RH) and protected from direct exposure to light. The dissolution of above formulation was carried out by using USP type II (paddle) apparatus at 100 rpm in 900 ml acetate buffer pH 3.5 at 37.0 ± 0.5°C. In vitro drug release profile of Mosapride citrate sustained release found to be:
Time % drug release of the labeled amount
1 hr 39.2 % (preferably 30%-40%)
2 hr 45.1% (preferably 40%-55%)
4 hr 62.3% (preferably 60%-70%)
6 hr 75.9 % (preferably 75%-85%)
8 hr 85.1% (preferably not less than 80%)
Example 4
Formulation of Floating Tablet in Capsule containing Mosapride citrate dihydrate
by non-aqueous granulation.
(030) The present invention also comprises a formulation of a single unit capsule dosage
form comprising of two fractions, in which one fraction comprises blend or granules of
mosapride or its pharmaceutically acceptable salts as immediate release fraction for

loading dose, and the second part is a gastric retentive floating device comprises of mosapride or its pharmaceutically acceptable salts which is a controlled or sustained release fraction formulated with biocompatible polymers, compressed into a tablet on a tableting machine. Both fractions are presented in a capsule (tablet and blend/granules in a capsule). Table 4:

Mosapride Tablet Part mg/tablet
Mosapride Citrate Dihydrate 11.0
Methocel K 100 M 5.0
HPMC E 15 cps 5
Sodium Carboxy methyl cellulose (Low viscosity grade) 15.0
Sodium Carboxy methyl cellulose (Medium viscosity grade) 5.0
Xanthan gum 5.0
Micro Crystalline Cellulose 27.0
Povidone (PVPK-30) 5.0
Isopropyl Alcohol q.s.
Magnesium Stearate 1.0
Colloidal Silicon Dioxide 1.0
Tablet weight 80.0 mg
Tools: 5.0 mm standard concave punch
Mosapride Blend Part
Mosapride Citrate Dihydrate 4.84
Lactose DC 11 133.1
Avicel pH 200 130.0
Magnesium Stearate 1.0
Colloidal silicon dioxide 1.0
Capsule filled weight 270.0 mg
Average weight of Capsule 426 mg
Hard gelatin Capsule size ' 1'
(031) Mosapride sustained release floating tablet comprises Mosapride citrate dihydrate, Hydroxypropylmethyl cellulose (Methocel K 100 M Premium), Hydroxypropylmethyl cellulose (E 15 cps) Sodium Carboxy methyl cellulose (Low viscosity grade), Sodium Carboxy methylcellulose (Medium viscosity grade) and Microcrystalline cellulose sieved

through 60 no. mesh and blended for 5 minutes. Povidone (PVPK-30) was dissolved in Isopropyl Alcohol (5 % w/v) and the above blend was granulated. The granules were passed from mesh no. 8, air dried and then dried at 40° C till the loss on drying (LOD) of desired value reached of NMT 2.5 % (Make: Mettler Toledo LJ16 moisture analyzer) at 105 C. The dried granules were sieved through 20 mesh. Finally magnesium stearate and colloidal silicon dioxide (passed through 60 no. Mesh) were added and the whole mixture blended for 5 minutes. The tablets were compressed on 16-station compression machine (Make: Cadmach). The hardness of tablets found to be 3-5 kg/cm2.
(32) Mosapride immediate release blend part comprises Mosapride citrate dihydrate, Lactose DC 11 and Avicel pH 200 sieved through 60 no. Mesh and blended for 5 minutes. Talc and magnesium stearate (passed through 60 no. Mesh) were added and the whole mixture blended for 5 minutes.
(33) The size '1' capsules were filled with mosapride-sustained release floating tablet and mosapride immediate release blend. The whole procedure was carried out in control condition of temperature (25 °C ± 2°C), relative humidity (40%±5% RH) and protected from direct exposure to light. The dissolution of above formulation was carried out by using USP type I (basket) apparatus at 100 rpm in 900 ml acetate buffer pH 3.5 at 37.0 + 0.5°C. In vitro drug release profile of Mosapride citrate sustained release found to be: Time % drug release of the labeled amount
lhr 35.6% (preferably 30%-40%)
2hr 43.5% (preferably 40%-5 5%)
4hr 60.1% (preferably 60%-70%)
6hr 73.9% (preferably 75%-85%)
8hr 83.2% (preferably not less than 80 %)
Example 5
Formulation of Tablet and floating mass in Capsule containing Mosapride citrate
dihydrate by non-aqueous granulation.
(034) The present invention also comprises of single unit capsule dosage form
comprising a fraction of mosapride or its pharmaceutically acceptable salts which is a

immediate release tablet for loading dose and second part is a blend and or granules comprising a fraction of mosapride or its pharmaceutically acceptable salts which is a gastric retentive floating fluffy mass which release the fraction of mosapride or its pharmaceutically acceptable salts which is a controlled or sustained release formulated with biocompatible polymers (tablet and blend/granules in a capsule).
Table 5:

Mosapride Immediate release tablet part mg/tablet
Mosapride Citrate Dihydrate 4.84
Microcrystalline cellulose 66.6
PVPK 30 2.5
Isopropyl alcohol q.s.
Magnesium Stearate 0.5
Colloidal silicon dioxide 0.5
Sodium starch glycollate 5.0
Average weight 80.0 mg
Tools: 5.0 mm standard concave punch
Mosapride Floating mass capsule part mg
Mosapride Citrate Dihydrate 11.0
Methocel K 100 M 5.0
Sodium alginate 10.0
Sodium Carboxy methyl cellulose (Low viscosity grade) 20.0
Sodium Carboxy methyl cellulose (Medium viscosity grade) 5.0
Xanthan gum 10.0
Micro Crystalline Cellulose 206.0
Povidone (PVPK-30) 5.0
Isopropyl Alcohol q.s.
Magnesium Stearate 1.0
Colloidal Silicon Dioxide 1.0
Filled weight 274.0 mg
Average weight of capsule 430 mg
Hard gelatin Capsule size ' 1'

(035) Mosapride Immediate release tablet comprises Mosapride citrate dihydrate,
Microcrystalline cellulose sieved through 60 no. mesh and blended for 5 minutes.
Povidone (PVPK-30) was dissolved in Isopropyl Alcohol (5 % w/v) and the above blend
was granulated. The granules were passed from mesh no. 8, air dried and then dried at
40° C till the loss on drying (LOD) of desired value reached of NMT 2.5 % (Make:
Mettler Toledo LJ16 moisture analyzer) at 105° C. The dried granules were sieved
through 20 mesh. Finally magnesium stearate, sodium starch glycollate and colloidal
silicon dioxide (passed through 60 no. Mesh) were added and the whole mixture blended
for 5 minutes. The tablets were compressed on 16-station compression machine (Make:
Cadmach). The hardness of tablets found to be 3-5 kg/cm2.
(36) Mosapride sustained release floating mass comprises Mosapride citrate dihydrate, Hydroxypropylmethyl cellulose (Methocel K 100 M Premium), Sodium alginate, Sodium Carboxy methyl cellulose (Low viscosity grade), Sodium Carboxy methyl cellulose (Medium viscosity grade), xanthan gum, microcrystalline cellulose sieved through 60 no. mesh and blended for 5 minutes. Povidone (PVPK-30) was dissolved in Isopropyl Alcohol (5 % w/v) and the above blend was granulated. The granules were passed from mesh no. 8, air dried and then dried at 40° C till the loss on drying (LOD) of desired value reached of NMT 2.5 % (Make: Mettler Toledo LJ16 moisture analyzer) at 105° C. The dried granules were sieved through 20 mesh. Finally magnesium stearate and colloidal silicon dioxide (passed through 60 no. mesh) were added and the whole mixture blended for 5 minutes.
(37) The size T capsules were filled with mosapride immediate release tablet and mosapride sustained release blend, which will form a floating mass upon the imbibition of dissolution media. The whole procedure was carried out in control condition of temperature (25 °C ± 2°C), relative humidity (40%±5% RH) and protected from direct exposure to light. The dissolution of above formulation was carried out by using USP type I (basket) apparatus at 100 rpm in 900 ml acetate buffer pH 3.5 at 37.0 ± 0.5°C . In vitro drug release profile of Mosapride citrate sustained release found to be:

Time

% drug release of the labeled amount

lhr 36.1 % (preferably 30%-40%)
2hr 43.8 % (preferably 40%-55%)
4hr 60.8 % (preferably 60%-70%)
6hr 71.9% (preferably 75%-85%)
8hr 84.2 % (preferably not less than 80 %)
(038) The oral controlled release dosage forms of the present invention comprises mosapride or its pharmaceutically acceptable salts and release controlling pharmaceutically acceptable excipients, wherein the mosapride is released as per the following in vitro dissolution profile.(a) Not less than 30 % of the drug is release within 15 minute, which is a loading dose, (b) between 40% and 60% of the drug should be release between 2 to 3 hours, (c) between 60 - 80 % of the drug should be released between 3-5 hours, (d) Between 80 - 100 % of the drug should be released between 5-8 hours. The in vitro release profile of the formulation has been tested as per United States Pharmacopoeia with Type I apparatus at 100 rpm using 900ml of acetate buffer pH 3.5 as dissolution medium at 37 ± 0.5°C for 8 hours.

Claims
We claim:
1. A process for making anovel pharmaceutical composition as capsule dosage form, containing a final blend of statin, treated with plurality of antioxidant, along with delayed release tablet of aspirin, the process steps comprising of-sieving a statin through 40# mesh and treating with a plurality of antioxidants by spraying the solution of said plurality of antioxidants on said statin for uniform treatment, sieving the resulting wet mass through 8# mesh to get wet granules, air-drying said wet granules at 30°C to 40°C, then drying said granules in tray drier at 40°C to 45°C until loss on drying up to 2.5%, passing dried granules through 20 # mesh and mixing with plurality of diluents in a high-speed mixer, dispersing binder in isopropyl alcohol making 5 % solution and adding to the dry mix under slow speed, sieving plurality of lubricants through 60 # mesh and mixing with said 20# mesh passed dried granules for 10 min in a planetary mixer to get said final blend of statin for filling in capsule, sieving aspirin, with plurality of diluents though 40 # mesh, mixing in a blender for 10 min, compressing the above mixture using 5 mm or 6 mm D type standard concave tooling on a rotary tablet compression machine to get core tablet of aspirin, subcoating said core tablets of aspirin to provide seal coat to get seal coated aspirin tablet, further enteric coating said seal coated tablet of aspirin up to 10% to 14% of total weight of core to get said delayed release tablet of aspirin, and filling, said delayed release aspirin tablets along with said final blend of statin, in hard gelatin capsule using a special type of hard gelatin capsule filling machine equipped with tablet loader.
2. A process as claimed in claim 1, wherein said statin is either atorvastatin in the dose range of 5 mg to 40 mg or rosuvastatin in the dose range of 5 mg to 45 mg.
3. A process as claimed in claim 1, wherein said delayed release tablet comprising of aspirin in the dose range of 75 mg to 150 mg.

A process as claimed in claim 1, wherein said antioxidants are butylated hydroxyanisole used in the range of 0.05% to 5.0% of the dose of said statin, more preferably 0.2 % to 0.8% of the dose of said statin and butylated hydroxytoluene used in the range of 0.05% to 5.0% of the dose of statin, more preferably 0.2 % to 0.8% of the dose of said statin.
A process as claimed in claim 1, wherein said subcoating given for preparation of said delayed release tablet of aspirin comprises of hydroxypropyl methylcellulose E6 polymer is used in the range of 1-10% of tablet weight of said core tablet of aspirin more preferably 3% of weight of said core tablet of aspirin, additionally polyvinylpyrrolidone K30 is used in the range of 1-5% more preferably 2% of weight of said hydroxy propyl methyl cellulose E6 polymer, additionally propylene glycol is used in the range of 10-50% more preferably 25% of weight of said hydroxy propyl methyl cellulose E6 polymer, and titanium dioxide is used in the range of 1-10%, more preferably 2% of weight of said hydroxy propyl methyl cellulose E6 polymer
A process as claimed in claim 1, wherein said enteric coating comprises of plurality of polymer, plurality of plasticizer, and an antisticking agent, wherein said polymer is either eudragit L-100 55 used in the range of 10-20% weight of said core tablet of aspirin, more preferably 13% of weight of said core tablet of aspirin or hydroxypropyl methylcellulose phthalate used in the range of 10-20% weight of said core tablet of aspirin, more preferably 13% weight of said core tablet of aspirin, additionally said plasticizer is polyethelene glycol 6000 used in the range of 1-5% of weight of said polymer, more preferably 1.5% of weight of said polymer and triacetin used in the range ofl% to 5% of weight of said polymer, more preferably 1.5% of said polymer, additionally said antisticking agent is talc used in the range of 8-20% of polymer weight more preferably 10% of weight of polymer.
A process as claimed in claim 1, wherein said binder is polyvinylpyrrolidone K30 in the range of 1-5% fill weight of the said statin blend.

A process as claimed in claim 1, wherein said plurality of diluents incorporated in said final blend of statin are microcrystalline cellulose used in the range of 5-95% of weight of said final blend of statin, more preferably 30% to 50% of weight of said final blend of statin, additionally pregelatinized starch is used in the range of 1-35% of weight of said final blend of statin, more preferably 22 % to 28% of weight of said final blend of statin, additionally sodium starch glycolate is used in the range of 1-20% weight of said final blend of statin, more preferably 8% to 12% of weight of said final blend of statin and additionally polyvinylpyrrolidone K 30 is used in the range of 1-20% of weight of said final blend of statin, more preferably 1.5 to 3% of weight of said final blend of statin.
A process as claimed in claim 1, wherein said plurality of diluents used to prepare said delayed release tablet are maize starch is used in the range of 5% tol7% of weight of said core tablet of aspirin, additionally sodium starch glycolate used in the range of 3% to 5% of weight of said core tablet of aspirin, additionally talc is used in the range of 4% to 8% of weight of said core tablet of aspirin, and additionally colloidal silicon dioxide is used in the range of 2% to 6% of weight of said core tablet of aspirin.
A process as claimed in claim 1, wherein said plurality of lubricants used is magnesium stearate is used in the range of 0.5% to 5 % of weight of said final blend of statin, more preferably up to 2% of weight of said final blend of statin, additionally colloidal silicon dioxide is used in the range of 0.5% to 5 % of weight of said final blend of statin, more preferably up to 2% of weight of said final blend of statin, additionally crosspovidone is used in the range of 1.0 % to 10 % of weight of said final blend of statin, more preferably up to 3% of weight of said final blend of statin.

Mr. Manutosh Manohar Acharya
Name of the inventor:

Assignee: Aristo Pharmaceuticals Ltd
Mercantile Chambers, 3rd Floor, 12, J. N. Heredia Marg, Ballard Estate, Mumbai - 400 001 (INDIA)

Documents:

888-mum-2003-cancelled pages(28-3-2005).pdf

888-mum-2003-claims(granted)-(28-3-2005).doc

888-mum-2003-claims(granted)-(28-3-2005).pdf

888-mum-2003-correspondence(ipo)-(29-10-2004).pdf

888-mum-2003-form 1(2-9-2003).pdf

888-mum-2003-form 13(15-9-2004).pdf

888-mum-2003-form 13(28-9-2005).pdf

888-mum-2003-form 19(3-2-2004).pdf

888-mum-2003-form 2(granted)-(28-3-2005).doc

888-mum-2003-form 2(granted)-(28-3-2005).pdf

888-mum-2003-form 3(26-8-2003).pdf

888-mum-2003-form 4(1-9-2004).pdf

888-mum-2003-form 5(28-9-2004).pdf

888-mum-2003-other documents(15-9-2004).pdf

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Patent Number

206650

Indian Patent Application Number

888/MUM/2003

PG Journal Number

40/2008

Publication Date

03-Oct-2008

Grant Date

04-May-2007

Date of Filing

02-Sep-2003

Name of Patentee

ARISTO PHARMACEUTICAL LTD.

Applicant Address

ARISTO PHARMACEUTICAL LTD., 3RD FLOOR, MERCANTILE CHAMBERS, 12, J.N. MARG, BALLARD ESTATE, MUMBAI 400 001

Inventors:

#	Inventor's Name	Inventor's Address
1	MR. MANUTOSH MANOHAR ACHARYA	4/7, AMALTAS PARISAR SHAHPURA, BHOPAL (MP), INDIA

PCT International Classification Number

A61K 3/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA