Title of Invention

A PROCESS FOR MAKING A NOVEL PHARMACEUTICAL COMPOSITION OF A PROTON PUMP INHIBITOR WITH A PROKINETIC AGENT

Abstract

A process, for making novel pharmaceutical composition, comprising enteric coated tablet of proton pump inhibitor pantoprazole sodium sesquihydrate expressed as pantoprazole and sustained release blend of prokinetic agent itopride in a single unit formulation as capsule, comprising of several steps as described follows - sieving of said proton pump inhibitor, plurality of diluents and plurality of disintegrants through 60 no. mesh and blending for 5 minutes to get a blend, dissolving a binder in purified water to make 10 % w/v solution and granulating said blend to get wet mass, sieving said wet mass through mesh no. 8 to get wet granules, air drying of said wet granules and further drying of said wet granules at 40° C till the loss on drying of desired value reached at not more than 3.0 % at 105° C to get dried granules, sieving said dried granules through 20 mesh, finally mixing the said dried granules with plurality of lubricants and blending whole mixture for 5 minutes to get final blend, compressing said final blend by using tablet compression machine to get core tablets, seal coating of said core tablets of pantoprazole to get seal coated pantoprazole tablet, further enteric coating of said seal coated pantoprazole tablet up to 10% to 14% of total weight of core to get said enteric coated tablet of proton pump inhibitor pantoprazole, and sieving of said prokinetic agent itopride hydrochloride, plurality of polymers, plurality of diluents through 60 no. mesh and blending for 5 minutes to get a blend, dissolving binder in isopropyl alcohol to get 5 % w/v binder solution, granulating said blend with said binder solution to get wet mass, sieving said wet mass through mesh no. 8 to get wet granules, air drying said wet granules and further drying in trey drier at 40° C till the loss on drying of desired value reached of not more than 2.5 % at 105° C to get dry granules, sieving said dry granules through 20 mesh, finally mixing of said dried granules with plurality of lubricants and blending of whole mixture for 5 minutes to get said sustained release blend of itopride, and filling of said capsules with said enteric coated tablet of proton pump inhibitor pantoprazole and said sustained release

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 of a Proton Pump inhibitor with a Prokinetic Agent 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, Amaitas Parisar Shahpura, Bhopal (MP), India. The following complete specification describes the nature of this invention and the manner in which it is to be performed. ORG A Process for making a Novel Pharmaceutical Composition of a Proton Pump Inhibitor with a Prokinetic Agent BACKGROUND OF THE INVENTION (01) Gastro esophageal reflux disease (GERD), reflux oesophagitis, peptic ulcer, gastric ulcer and other gastric acid related disorders are disorders having a pathogenesis related to reduced gastric motility, i.e., reduced clearing capacity of the stomach, and release of excessive gastric acid. Besides from behavioral changes, GERD and gastric ulcer have been successfully treated with a range of gastric acid inhibitors, such as ranitidine and omeprazole, which are known as H2 blocker or acid-suppressing drugs. Stimulation of gastric motility has been proposed to accelerate the healing of gastric ulcer. Prokinetic drugs, such as itopride, cisapride, are known to enhance gastrointestinal motility and prevent duodenogastric reflux, and are widely used to treat GERD. Ranitidine and prokinetic drugs have been used in combination to treat gastric ulcer and other related disorders. (2) H2 receptor antagonists are widely prescribed for GERD. Their higher cost has been compensated by the clinical results obtained both in terms of symptom relief and healing. These advantages have been related to their mode of action, which offered more potent and longer duration of effect on gastric acidity. (3) Pyridin-2-ylmethylsulfinyl-lH-benzimidazoles, as disclosed, for example, in EP-A 0005129, EP-A 0166287 and EP-A 0268956 are becoming increasingly important, because of their H+/K+ ATPase-inhibiting action, for the therapy of diseases, which originate from increased gastric acid secretion. The present invention comprises of proton pump inhibitor is pantoprazole. The pantoprazole sodium sesquihydrate is expressed as pantoprazole. The pantoprazole and or its salts here after will be termed as "pantoprazole". (004) Pantoprazole is a proton pump inhibitor, which rapidly takes share from H2 receptor antagonists, particularly in reflux oesophagitis and healing and prevention of relapse for reflux oesophagitis. (5) Itopride, i. e., N-[p-[2-(dimethylamino) ethoxy] benzyl] veratramide hydrochloride, CAS Registry no 1222898-67-3 is a gastrointestinal prokinetic agent. Itopride hydrochloride and its pharmaceutically acceptable salts will be here after termed as. "itopride". Itopride increases the release of acetylcholine (ACh) through dopamine D2-receptor antagonistic action and inhibits decomposing released ACh through its acetylcholine esterase (AChE) inhibitory action, resulting in enhancement of gastrointestinal motility. (6) A combination therapy comprising an acid suppressing agent and a prokinetic agent is attractive, rational and effective. An acid suppressing agent plus a prokinetic agent could be an alternative to each of them separately in case of failure. However, because of the large number of therapeutical tablets/pills that must be taken each day in such a therapy, the compliance of such a treatment may be a problem. It is well known that patient compliance is a main factor in receiving good results in medical treatments. Administration of two, three or even more different tablets to the patient is not convenient or satisfactory to achieve the most optimal results. The present invention now provides new oral dosage forms comprising two different active substances combined in one fixed unit dosage form, preferably tablet and blend/ granule in a capsule. (7) The US Patent 6,132,771 discloses oral pharmaceutical composition comprising a proton pump inhibitor & a prokinetic agent, the proton pump inhibitor claimed is omeprazole & its salt and proknetic agent is Mosapride and Cisapride, the dosage form is 2 a multiple unit tableted dosage forms, multilayered tablets, or a capsule filled with more than one pharmaceutically active compound but both in conver|tional dosage form. The dose for proton pump inhibitor mentioned here is omeprazole is the dose is 10/20mg once a day and prokinetic agent mosapride is to be given 5mg thrice a day hence combining the two will have problem of dose adjustment and frequency. Our patent discloses once a day dosage form containing proton pump inhibitor Pantoprazole 20 /40 mg with Itopride 150 mg SR, which eliminates the problem of dose adjustment & frequency. SUMMARY OF INVENTION (8) The present invention comprises co-administration of a proton pump inhibitor, pantoprazole and a prokinetic agent, itopride in a single unit formulation, wherein the proton pump inhibitor and prokinetic agents are formulated and presented in a manner to minimize interaction of pantoprazole with itopride and a single unit dosage form to deliver a enteric coated proton pump inhibitor Pantoprazole along with the immediate release and or sustained/controlled/floating gastroretentive sustained or controlled release prokinetic agent Itopride. (9) It is well known that some of the gastric acid suppressing agents, such as proton pump inhibitors are susceptible to degradation/transformation in acid reacting and neutral media. In respect of the stability properties, it is obvious that the one of the active substances being an acid susceptible proton pump inhibitor must be protected from contact with acidic gastric juice by an enteric coating layer. (10) There are problems to produce a fixed unit dosage form comprising a rather high amount of active substance. Different active substances with differing physical properties in the same preparation give further problems. In order to obtain a pharmaceutical dosage form of pantoprazole, which prevents it from contact with the itopride and acidic gastric juice, the pantoprazole must be enteric coated or delayed release. (11) In order to enhance the storage stability of the enteric coated tablet of pantoprazole, the cores of the tablet must also contain alkalizing agent. When such an alkaline core is enteric coated with an amount of a conventional enteric coating polymer such as, for example, cellulose acetate phthalate, that permits the dissolution of the coating and the active drug contained in the cores in the proximal part of the small intestine, it also will allow some diffusion of water of gastric juice through the enteric coating into the cores, during the time the dosage form resides in the stomach before it is emptied into the small intestine. The diffused water of gastric juice will dissolve parts of the core in the close proximity of the enteric coating layer and there form an alkaline solution inside the 4 coated dosage form. The alkaline nature of core will interfere with the enteric coating and eventually dissolve it. The 3-4% of the seal coat of hydroxyl propyl methyl cellulose is done in order to prevent the incompatibility of the alkaline nature of the core with the enteric coating. 5 (012) The present invention contains a single unit dosage form of a capsule which contains two parts (tablet and blend/granules in a capsule), first part comprises of a proton pump inhibitor pantoprazole with pharmaceutically acceptable excipient and alkalizing agent compressed in tablet and it is enteric coated and second part comprises of the blend and or granules of itopride with pharmaceutically acceptable excipients in a single unit formulation. DETAILED DESCRIPTION OF THE INVENTION (013) Pantoprazole is a proton pump inhibitor, which rapidly takes share from H2 receptor antagonists, particularly in reflux oesophagitis and healing and prevention of relapse for reflux oesophagitis. Itopride increases the release of acetylcholine (ACh) through dopamine D2-receptor antagonistic action and inhibits decomposing released ACh through its acetylcholine esterase (AChE) inhibitory action, resulting in enhancement of gastrointestinal motility. (14) A combination therapy comprising an acid suppressing agent and a prokinetic agent is attractive, rational and effective. An acid suppressing agent plus a prokinetic agent could be an alternative to each of them separately in case of failure. However, because of the large number of therapeutical tablets/pills that must be taken each day in such a therapy, the compliance of such a treatment may be a problem. It is well known that patient compliance is a main factor in receiving good results in medical treatments. Administration of two, three or even more different tablets to the patient is not convenient or satisfactory to achieve the most optimal results. The present invention now provides new oral dosage forms comprising two different active substances combined in one fixed unit dosage form, preferably tablet and blend/ granule in a capsule. (15) The compatibility (physical and chemical) study was done taking suitable ratio of itopride hydrochloride and Pantoprazole sodium sesquihydrate with the individual excipients and the combination drugs. 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 analysed on differential scanning calorimeter and visually for initially, and at the interval 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. 6 (16) In order to screen for formulation stability we have formulated five different types of process for the formulation. The analysis of pantoprazole part was done by HPLC (Make: Agilent 1100 series) using 4.6 X 250 mm, Hypersil BDS C18, 5 u. column using buffer and acetonitrile as mobile phase in ratio of 62:38 respectively and detection was done at 280 nm. The analysis of itopride sustained release part was done by HPLC (Make: Agilent 1100 series) using 4.6 X 150 mm, ds, Zorbax XBD column using buffer (prepared 0.01M potassium di-hydrogen orthophosphatebuffer and adjusted the pH3.0 with diluted ortho-phosphoric acid) and acetonitrile as mobile phase in ratio of 80:20 respectively and detection was done at 260 nm.The stability studies were done as per ICH guidelines for 6 months. (17) The dissolution testing of pantoprazole enteric coated tablet part was carried out in 0.1 N hydrochloric acid for 2 hrs and in phosphate buffer pH 6.8 for 45 minutes. As per United States Pharmacopoeia criteria the quantity of the dissolution medium used should be not less than three times that required to form a saturated solution of the drug substance, which complies when used 0.1 N HC1 for itopride hydrochloride, based on the solubility equilibrium of the drug substance. The dissolution of dosage forms carried out by using 900 ml 0.1 N HC1 which complies with the sink conditions mentioned in USP. (Ref. USP/NF, Vol. 27, 2004 Page no. 2514). Example 1 Pantoprazole 20mg//40 mg delayed release + Itopride 150 mg sustained release Capsule (018) The present invention contains a single unit dosage form of a capsule which contains two parts (tablet and blend/granules in a capsule), first part comprises of a proton pump inhibitor pantoprazole with pharmaceutically acceptable excipient and alkalizing agent compressed in tablet and it is enteric coated and second part comprises of the sustained release or controlled release blend and or granules of itopride with 7 pharmaceutically acceptable excipients in a single unit formulation which releases the drug within 8-12 hours to maintain a prolonged duration of action. (019) Pantoprazole enteric coated tablet formulation comprises alkaline excipients. Pantoprazole, mannitol, sodium carbonate anhydrous, crosspovidone, sodium lauryl sulphate, sieved through 60 no. mesh and blended for 5 minutes. HPMC E06 was dissolved in purified water to make 10 % w/v solution 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 3.0 % (Make: Mettler Toledo LJ16 moisture analyzer) at 105° C. The dried granules were sieved through 20 mesh. Finally Crospovidone, Calcium Stearate, Sodium Lauryl Sulphate, 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. Tablel Table 1A Pantoprazole Part mg/tablet Pantoprazole Sodium sesquihydrate 22.6 to 45.20 Mannitol DC 14.4 to 37.0 Sodium Carbonate anhydrous 5.00 Crospovidone 5.20 Sodium Lauryl Sulphate 0.45 Colloidal Silicon Dioxide 0.85 Hydroxypropylmethyl Cellulose E 06 1.0 Purified Water q.s. Crospovidone 10.0 Calcium Stearate 1.60 Sodium Lauryl Sulphate 0.45 Colloidal Silicon dioxide 0.85 Tablet weight 85.0 mg Enteric Coating Ac ueous solution EudragitL100 55 12-15% of tablet wt PEG 6000 1-1.5% of polymer Sodium hydroxide To adjust pH 5.5 Talcum Titanium Dioxide 8-10 % of polymer 8-10 % of polymer Colour Tratrazine supra 0.1-0.5% of polymer Purified water q.s. to make 25 % solution of the polymer Itopride Sustained release Part Itopride hydrochloride 150.0 MethocelK 100 M 10.0 HPMCE15 cps 20.0 Sodium carboxy methyl cellulse (medium viscosity grade) 10.0 Sodium carboxy methyl cellulse (low viscosity grade) 25.0 Xanthan gum 20.0 8 5.0 mm standard concave punch Sub coat solution(3 % w/v) Hydroxypropylmethylcellulose E06 3 % of tablet weight PVPK30 2 % of polymer Propylene Glycol 25 % of the polymer Purified Water 1:2 to 1:3 ratio Isopropyl Alcohol Titanium Dioxide l-2%of polymer Micro Crystalline Cellulose 124.0 Povidone (PVPK-30) 12.0 Isopropyl Alcohol q.s. Magnesium Stearate 5.0 Colloidal silicon dioxide 4.0 Capsule filled weight 380.0 mg Hard gelatin capsule size '0' (020) Itopride sustained release part of capsule comprises itopride hydrochloride, Hydroxypropylmethyl cellulose (Methocel K 100 M Premium), Hydroxypropylmethyl cellulose (E 15 cps), Sodium carboxy methyl cellulse (medium viscosity grade), Sodium carboxy methyl cellulse (low viscosity grade), xanthan gum 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. (021) The capsules were filled with pantoprazole enteric coated tablet, itopride sustained 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 sunlight. The dissolution of above formulation was carried out by using USP type I (basket) apparatus at 100 rpm in 900 ml 0.1 N HCl at 37.0 ± 0.5°C for itopride, while for pantoprazole in 0.1 N HCl for two hrs (% drug released found not more than 10.0% of labeled amount) and then in phosphate buffer pH 6.8 for 45 minutes (% drug released found not less than 80.0% of labeled amount). In vitro drug release profile of itopride sustained release found to be: 9 Time % drug release of the labeled amount l hr 31.65% (preferably30%-50%) 2 hr 42.51% (preferably40%-60%) 4 hr 61.25 % (preferably60%-70%) 6 hr 73.12% (preferably70%-85%) 8 hr 89.21 % (preferably not less than 80%) Example 2 Pantoprazole 20mg//40 mg delayed release + Itopride ISO mg sustained release Capsule (18) The present invention contains a single unit dosage form of a capsule which contains two parts (tablet and blend/granules in a capsule), first part comprises of a proton pump inhibitor pantoprazole with pharmaceutically acceptable excipient and alkalizing agent compressed in tablet and it is enteric coated and second part comprises of the sustained release or controlled release blend and or granules of itopride with pharmaceutically acceptable excipients in a single unit formulation which releases the drug within 8-12 hours to maintain a prolonged duration of action. (19) Pantoprazole enteric coated tablet formulation comprises alkaline excipients. Pantoprazole, mannitol, sodium carbonate anhydrous, crosspovidone, sodium lauryl sulphate, sieved through 60 no. mesh and blended for 5 minutes. HPMC E06 was dissolved in purified water to make 10 % w/v solution 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 3.0 % (Make: Mettler Toledo LJ16 moisture analyzer) at 105° C. The dried granules were sieved through 20 mesh. Finally Crospovidone, Calcium Stearate, Sodium Lauryl Sulphate, 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/cm . 10 Table 2 Table 2A Pantoprazole Part mg/tablet Pantoprazole Sodium sesquihydrate 22.6 to 45.20 Mannitol DC 14.4 to 37.0 Sodium Carbonate anhydrous 5.00 Crospovidone 5.20 Sodium Lauryl Sulphate 0.45 Colloidal Silicon Dioxide 0.85 Hydroxypropylmethyl Cellulose E 06 1.0 Purified Water q.s. Crospovidone 10.0 Calcium Stearate 1.60 Sodium Lauryl Sulphate 0.45 Colloidal Silicon dioxide 0.85 Tablet weight 85.0 mg 5.0 mm standard concave punch Sub coat solution(3 % w/v) Hydroxypropylmethylcellulose E06 3 % of tablet weight PVPK30 2 % of polymer Propylene Glycol 25 % of the polymer Purified Water 1:2 to 1:3 ratio Isopropyl Alcohol Titanium Dioxide l-2%of polymer Enteric Coating on-aqueous Hydroxypropylmethylcellul ose Phthalate 12-15% of tablet wt PEG 6000 1-1.5 % of polymer Talcum 8-10 % of polymer Acetone: Isopropyl alcohol q.s. to make 5 % solution of the polymer in 1:1 ratio Titanium dioxide 8-10% of polymer Colour Tratrazine supra 0.1-0.5 % of polymer Itopride Sustained release Part Itopride hydrochloride 150.0 MethocelK 100 M 10.0 HPMCE15cps 20.0 Sodium carboxy methyl cellulse (medium viscosity grade) 10.0 Sodium carboxy methyl cellulse (low viscosity grade) 25.0 Xanthan gum 20.0 Micro Crystalline Cellulose 124.0 Povidone (PVPK-30) 12.0 Isopropyl Alcohol q.s. Magnesium Stearate 5.0 Colloidal silicon dioxide 4.0 Capsule filled weight 380.0 mg Hard gelatin capsule size '0' (020) Itopride sustained release part of capsule comprises itopride hydrochloride, Hydroxypropylmethyl cellulose (Methocel K 100 M Premium), Hydroxypropylmethyl cellulose (E 15 cps), Sodium carboxy methyl cellulse (medium viscosity grade), Sodium carboxy methyl cellulse (low viscosity grade), xanthan gum 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 11 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. (021) The capsules were filled with pantoprazole enteric coated tablet, itopride sustained 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 sunlight. The dissolution of above formulation was carried out by using USP type I (basket) apparatus at 100 rpm in 900 ml 0.1 N HCl at 37.0 ± 0.5°C for itopride, while for pantoprazole in 0.1 N HCl for two hrs (% drug released found not more than 10.0% of labeled amount) and then in phosphate buffer pH 6.8 for 45 minutes (% drug released found not less than 80.0% of labeled amount). In vitro drug release profile of itopride sustained release found to be: Time % drug release of the labeled amount 1 hr 32.45 % (preferably30%-50%) 2 hr 43.51% (preferably40%-60%) 4 hr 62.51% (preferably60%-70%) 6 hr 75.61 % (preferably70%-85%) 8 hr 84.51 % (preferably not less than 80%) Example 3 Pantoprazole 20mg//40 mg delayed release + Itopride 150 mg sustained release Capsule (018) The present invention contains a single unit dosage form of a capsule which contains two parts (tablet and blend/granules in a capsule), first part comprises of a proton pump inhibitor pantoprazole with pharmaceutically acceptable excipient and alkalizing agent compressed in tablet and it is enteric coated and second part comprises of the sustained release or controlled release blend and or granules of itopride with pharmaceutically acceptable excipients in a single unit formulation which releases the drug within 8-12 hours to maintain a prolonged duration of action. 12 (019) Pantoprazole enteric coated tablet formulation comprises alkaline excipients. Pantoprazole, mannitol, sodium carbonate anhydrous, crosspovidone,. sodium lauryl sulphate, L-arginine sieved through 60 no. mesh and blended for 5 minutes. HPMC E06 was dissolved in purified water to make 10 % w/v solution 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 3.0 % (Make: Mettler Toledo LJ16 moisture analyzer) at 105° C. The dried granules were sieved through 20 mesh. Finally Crospovidone, Calcium Stearate, Sodium Lauryl Sulphate, 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. Table 3 Table 3A Pantoprazole Part mg/tablet Pantoprazole Sodium sesquihydrate 22.6 to 45.20 Mannitol DC 9.4 to 32.0 Sodium Carbonate anhydrous 5.00 Crospovidone 5.20 Sodium Lauryl Sulphate 0.45 Colloidal Silicon Dioxide 0.85 L-arginine 5 to 15 mg Hydroxypropylmethyl Cellulose E 06 1.0 Purified Water q. s. Crospovidone 10.0 Calcium Stearate 1.60 Sodium Lauryl Sulphate 0.45 Colloidal Silicon dioxide 0.85 Tablet weight 85.0 mg 5.0 mm standard concave punch Sub coat solution(3 % w/v) Hydroxypropylmethylcellulose E06 3 % of tablet weight PVPK30 2% of polymer Enteric Coating Aqueous solution EudragitL100 55 12-15% of tablet wt PEG 6000 1-1.5 % of polymer Sodium hydroxide To adjust pH 5.5 Talcum Titanium Dioxide 8-10% of polymer 8-10 % of polymer Colour Tratrazine supra 0.1-0.5% of polymer Purified water q.s. to make 25 % solution of the polymer Itopride Sustained release Part Itopride hydrochloride 150.0 Methocel K 100 M 10.0 HPMCE15cps 20.0 Sodium carboxy methyl cellulse (medium viscosity grade) 10.0 Sodium carboxy methyl cellulse (low viscosity grade) 25.0 Xanthan gum 20.0 Micro Crystalline Cellulose 124.0 Povidone (PVPK-30) 12.0 Isopropyl Alcohol q.s. 13 Propylene Glycol 25 % of the polymer Purified Water 1:2 to 1:3 ratio Isopropyl Alcohol Titanium Dioxide l-2%of polymer Magnesium Stearate 5.0 Colloidal silicon dioxide 4.0 Capsule filled weight 380.0 mg Hard gelatin capsule size '0' (020) Itopride sustained release part of capsule comprises itopride hydrochloride, Hydroxypropylmethyl cellulose (Methocel K 100 M Premium), Hydroxypropylmethyl cellulose (E 15 cps), Sodium carboxy methyl cellulse (medium viscosity grade), Sodium carboxy methyl cellulse (low viscosity grade), xanthan gum 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. (021) The capsules were filled with pantoprazole enteric coated tablet, itopride sustained 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 sunlight. The dissolution of above formulation was carried out by using USP type I (basket) apparatus at 100 rpm in 900 ml 0.1 N HCl at 37.0 ± 0.5°C for itopride, while for pantoprazole in 0.1 N HCl for two hrs (% drug released found not more than 10.0% of labeled amount) and then in phosphate buffer pH 6.8 for 45 minutes (% drug released found not less than 80.0% of labeled amount). In vitro drug release profile of itopride sustained release found to be: Time % drug release of the labeled amount 1 hr 34.21 % (preferably30%-50%) 2 hr 41.56% (preferably40%-60%) 4 hr 62.54 % (preferably60%-70%) 6 hr 75.48 % (preferably70%-85%) 8 hr 85.26 % (preferably not less than 80%) 14 We claim: 1. A process, for making novel pharmaceutical composition, comprising enteric coated tablet of proton pump inhibitor pantoprazole sodium sesquihydrate expressed as pantoprazole and sustained release blend of prokinetic agent itopride in a single unit formulation as capsule, comprising of several steps as described follows - sieving of said proton pump inhibitor, plurality of diluents and plurality of disintegrants through 60 no. mesh and blending for 5 minutes to get a blend, dissolving a binder in purified water to make 10 % w/v solution and granulating said blend to get wet mass, sieving said wet mass through mesh no. 8 to get wet granules, air drying of said wet granules and further drying of said wet granules at 40° C till the loss on drying of desired value reached at not more than 3.0 % at 105° C to get dried granules, sieving said dried granules through 20 mesh, finally mixing the said dried granules with plurality of lubricants and blending whole mixture for 5 minutes to get final blend, compressing said final blend by using tablet compression machine to get core tablets, seal coating of said core tablets of pantoprazole to get seal coated pantoprazole tablet, further enteric coating of said seal coated pantoprazole tablet up to 10% to 14% of total weight of core to get said enteric coated tablet of proton pump inhibitor pantoprazole, and sieving of said prokinetic agent itopride hydrochloride, plurality of polymers, plurality of diluents through 60 no. mesh and blending for 5 minutes to get a blend, dissolving binder in isopropyl alcohol to get 5 % w/v binder solution, granulating said blend with said binder solution to get wet mass, sieving said wet mass through mesh no. 8 to get wet granules, air drying said wet granules and further drying in trey drier at 40° C till the loss on drying of desired value reached of not more than 2.5 % at 105° C to get dry granules, sieving said dry granules through 20 mesh, finally mixing of said dried granules with plurality of lubricants and blending of whole mixture for 5 minutes to get said sustained release blend of itopride, and filling of said capsules with said enteric coated tablet of proton pump inhibitor pantoprazole and said sustained release i blend of prokinetic agent itopride, by using hard gelatine capsule filling machine equipped with tablet loader. 2. A process as claimed in claim 1, wherein said proton pump inhibitor pantoprazole is used in the dose range of 10 mg to 40 mg and said prokinetic agent is itopride used in dose range from 50-200 mg. 3. A process as claimed in claim 1, wherein said core tablet of pantoprazole comprising said plurality of diluent is manitol in the range of 20- 90% of weight of said core tablet of pantoprazole more preferably 25 % 45 % of weight of said core tablet of pantoprazole , additionally sodium carbonate used in the range of 1- 40% of weight of said core tablet of pantoprazole more preferably 3% to 6% weight of said core tablet of pantoprazole , additionally L-arginine is used in the range of 1- 40% weight of said core tablet of pantoprazole, more preferably 4% to 15 % of weight of said core tablet of pantoprazole, sodium lauryl sulphate used in the range of 0.1-5.0% of weight of said core tablet of pantoprazole, said plurality of disintegrant used is sodium starch glycollate used in the range of 1 - 20% of weight of said core tablet of pantoprazole additionally crosspovidione in the range of 1 - 20% of weight of said core tablet of pantoprazole, said binder is hydroypropyl methylcellulose in the range of 0.1- 20% of weight of said core tablet of pantoprazole, said plurality of lubricant is talc used in the range of 0.1-10% of weight of said core tablet of pantoprazole, additionally colloidal silicon dioxide used in the range of 0.1- 10% of weight of said core tablet of pantoprazole, additionally calcium stearate used in the range of 1-10% weight of said core tablet of pantoprazole. 4. A process as claimed in claim 1, wherein said seal coating comprising of hydroxypropyl methylcellulose used in the range of 3% of weight of said core tablet of pantoprazole, additionally contains triacetin used in the range of 0.5- 10% of weight of the hydroxylpropyl methylcellulose, said enteric coating layer comprises of a eudragit L 100 55 used in the range of 10% to 12 % of weight of said core tablet of pantoprazole, additionally contains titanium dioxide in the range of 8 to 10% of weight of said eudragit L 100 55, talc in the range of 8 to 10% of weight of said eudragit L 100 55 , additionally contains polyethelene glycol in the range of 1 to 3% of weight of said eudragit L 100 55 and coloring agent lake of dyes in amount of 0.1-10% said of eudragit L 100 55. 5. A process as claimed in claim 1, wherein said sustained release blend of itopride comprises said plurality of polymer which is hydroxypropyl methylcellulose K100M (viscosity grade 100000 cps) used in range of 5 to 30%, preferably 19 % of weight of said sustained release blend of itopride, additionally hydroxypropyl methylcellulose (viscosity grade 15 cps) in used in the range of 10 to 50% of weight of said sustained release blend. 6. A process as claimed in claim 1, wherein said sustained release blend of itopride comprises said plurality of diluent which is microcrystalline cellulose used in the range of 30 to 80% of weight of said sustained release blend, said binder is polyvinylpyrrolidine K30 used in the range of 0.5 to 5% of weight of said sustained release blend, said lubricants is magnesium stearate used in the range of 0.1 to 5% of weight of said sustained release blend, additionally colloidal silicon dioxide used in the range of 0.1 to 5% of weight of said sustained release blend. 7. A process as claimed in claim 1, wherein said sustained release blend of itopride optionally be a gastro retentive floating fraction comprising of sodium carboxy methylcellulose is used in the range of 3 to 25% of weight of said sustained release blend, additionally containing xanthan gum used in the range of 1 to 10% of the total weight of said sustained release blend. Dated this 2nd day of September, 2003 bignsfture OPIMRfttGEUTICAlStli aid

Documents:

889-mum-2003-claims(granted)-(01-09-2004).doc

889-mum-2003-claims(granted)-(01-09-2004).pdf

889-mum-2003-correspondence(ipo)-(12-09-2007).pdf

889-mum-2003-form 1(02-09-2004).pdf

889-mum-2003-form 13(07-04-2005).pdf

889-mum-2003-form 13(15-09-2004).pdf

889-mum-2003-form 19(03-02-2004).pdf

889-mum-2003-form 2(granted)-(01-09-2004).doc

889-mum-2003-form 2(granted)-(01-09-2004).pdf

889-mum-2003-form 3(26-08-2003).pdf

889-mum-2003-form 4(01-09-2004).pdf

889-mum-2003-form 5(28-09-2004).pdf

889-mum-2003-power of attoreny(15-09-2004).pdf