Title of Invention

A PROCESS FOR MAKING ORAL SINGLE DOSAGE FORM OF A PROKINETIC AGENT

Abstract

A process for making novel pharmaceutical composition, comprising coadministration of a proton pump inhibitor and a prokinetic agent in a single unit formulation, wherein one, the proton pump inhibitor containing an alkalizing agent with pKa value more than 8 like arginine, lysine, tyrosine, cysteine to enhance the stability during storage, is enteric coated to bypass stomach's acid environment where pantoprazole is degraded and release the drug in small intestine where the environment is alkaline and, prokinetic agent is sustained or controlled release are formulated and presented in a manner to minimize interaction of proton pump inhibitor with prokinetic agent and to provide the ease of once a day administration to reduce the inconvenience of multiple dosing at multiple frequency in a day.

Full Text

FORM 2 The Patents Act, 1970 (39 OF 1970) [Refer Section 10; Rule 13] COMPLETE SPECIFICATION A Process for making Oral single dosage form of 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, Amaltas 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. A Process for making Oral single dose form of a Prokinetic Agent 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) Itopride, i. e., N-[p-[2-(dimethylamino) ethoxy] benzyl] veratramide hydrochloride, CAS Registry no 1222898-67-3 is a gastrointestinal prokinetic agent. Itopride and its pharmaceutically acceptable salts will be here after termed as "itopride". Itopride formulations in market are in which Itopride hydrochloride. 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. Unlike Cisapride & Mosapride the Itopride has no affinity for the 5-HT4 receptors. (4) Itopride has stimulatory action on colonic perstalisis, propelling colonic luminal content different from that of cisapride & mosapride. Therefore, itopride may be useful drug for the treatment of functional bowel disorders such as functional constipation. (5) Conventionally itopride is given 50 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 oesophagitis. It is more convenient for patients to receive long-term effective controlled release of itopride dosage forms/ once-a-day than the conventional itopride dosage forms administered three times a day; (6) Itopride has a biological half-life of about 5-6 hours. Its gastroprokinetic threshold dose was as large as 3-10 times those of cisapride, domperidone and metoclopramide. 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. (7) An optimum design of an oral controlled release dosage form of itopride 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 itopride that releases the itopride in a controlled manner so as to provide control over itopride 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 itopride, are within a desirable range for once-a-day therapy in humans, is thus required. There is no earlier controlled release once-a-day dosage form of itopride. SUMMARY OF THE INVENTION (008) The present invention provides oral single unit dosage form of a prokinetic agent, itopride and or its pharmaceutically acceptable salts with pharmaceutical compositions in dosage forms to provide a loading dose and a controlled release of maintenance dose for once a day administration. (009) The dosage forms generally comprises of a bilayer tablet have one layer comprises of itopride or its pharmaceutically acceptable salts as immediate release fraction for loading dose, and the other layer comprises of the fraction ofitopride or its pharmaceutically acceptable salts which is a controlled or sustained release fraction formulated with biocompatible, hydrophilic polymer both layers compressed as single tablet on a bilayer tableting machine. Sustained or controlled release layer comprises hydrophilic matrix polymer which act as major rate controlling polymer. Itopride hydrochloride, Hydroxy propyl methyl cellulose (Methocel K100 M Premium USP), Hydroxy propyl methyl cellulose (Methocel K4 M Premium USP), and Microcrystalline cellulose sieved through 60 no. mesh and blended for 5 minutes. Polyvinylpyrrolidone (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. Immediate release layer comprises fast disintegrating excipients to ensure instant release of the drug for loading dose. Itopride hydrochloride, colour lake of quinoline yellow and microcrystalline cellulose sieved through 60 no. mesh and blended for 5 minutes. Polyvinylpyrrolidone (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 105° 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. Both the blends were compressed into bilayer tablets using 11.0 mm standard concave punch 27-station rotatory bilayer tablet machine (Make: Cadmach). 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. (010) The present invention also comprises a formulation of a bilayer tablet in which one layer comprises of itopride 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 itopride 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. (Oil) The present invention also comprises of single unit capsule dosage form comprising a fraction of itopride 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 itopride or its pharmaceutically acceptable salts which is a gastric retentive floating fluffy mass which release the fraction of itopride or its pharmaceutically acceptable salts which is a controlled or sustained release blend and or granules formulated with biocompatible polymers (tablet and blend/granules in a capsule). Immediate release tablet part comprises Itopride hydrochloride, 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. The sustained release floating part comprises Itopride hydrochloride, 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 ofNMT2.5 % (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 size 'V capsules were filled with itopride immediate release tablet and itopride 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. (012) The oral controlled release dosage forms of the present invention comprises itopride or its pharmaceutically acceptable salts and release controlling pharmaceutically acceptable excipients, wherein the itopride is released as per the following in vitro dissolution profile- Time (hours) % Release of itopride 1 30-50 2 40-60 3 50-65 4 60- 70 5 65- 75 6 70-85 7 85-90 8 90-100 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 0.1 N HC1 as dissolution medium at 37 ± 0.5°C for 8 hours. DETAILED DESCRIPTION OF THE INVENTION (13) Following description contains many examples, 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. 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. Itopride has stimulatory action on colonic peristalsis propelling colonic luminal content different from that of cisapride & mosapride. Therefore, itopride may be useful drug for the treatment of functional bowel disorders such as functional constipation. Unlike Cisapride & Mosapride the itopride has no affinity for the 5-HT4 receptors. Itopride has a biological half-life of about 5-6 hours. Its gastroprokinetic threshold dose was as large as 3-10 times those of cisapride, domperidone and metoclopramide It is more convenient for patients to receive long-term effective controlled release itopride dosage forms once-a-day than the conventional itopride dosage forms administered three times a day. 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. (14) The compatibility (physical and chemical) study was done taking suitable, ratio of itopride hydrochloride 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. (15) In order to screen for formulation stability we have formulated five different types of process for the formulation. The analysis was done by HPLC (Make: Agilent 1100 series) using 4.6 X 150 mm, Ci8j Zorbax XBD column using buffer (prepared 0.01M potassium di-hydrogen orthophosphate buffer 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 run. The stability studies were done as per ICH guidelines for 6 months. (16) 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 Formulation of bilayer tablet containing itopride hydrochloride by non-aqueous granulation. (017) The dosage forms generally comprises of a bilayer tablet have one layer comprises of itopride or its pharmaceutically acceptable salts as immediate release fraction for loading dose, and the other layer comprises of the fraction of itopride 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. (018) Sustained release layer comprises hydrophilic matrix polymer, which act as major rate controlling polymer. Itopride hydrochloride, Hydroxypropyl methylcellulose (Methocel K100 M Premium USP), Hydroxypropyl methylcellulose (Methocel K4 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 Itopride SR Layer mg/tablet Itopride hydrochloride 110.0 Methocel K 100 M 20.0 Methocel K 4 M 40.0 Micro Crystalline Cellulose 40.0 Povidone (PVPK-30) 5.0 Isopropyl Alcohol q.s. Magnesium Stearate 2.5 Colloidal Silicon Dioxide 2.5 Av. Weight of SR layer 220.0 mg Itopride IR Layer Itopride hydrochloride 40.0 Colour lake of quinoline yellow 1.5 Microcrystalline cellulose 123.5 PVPK 30 5.0 Isopropyl alcohol q.s. Magnesium Stearate 2.0 Colloidal silicon dioxide 2.0 Sodium starch glycollate 6.0 Average weight of IR layer 180.0 mg Total weight of tablet 400 mg Tools: 11,0 mm standard concave punch (019) Immediate release layer comprises fast disintegrating excipients to ensure instant release of the drug for loading dose. Itopride hydrochloride, 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 105 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. (020) The blend was compressed into tablets using 11.0 mm standard concave 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 0.1 NHC1 at 37.0 ± 0.5°C.The percent drug release of the above formulation found to be: Time % drug release of the labeled amount 1 hr 32.21 % (preferably 30%-50%) 2hr 44.80% (preferably 40%-60%) 4hr 64.21% (preferably 60%-70%) 6hr 75.35% (preferably 70%-8 5%) 8 hr 98.16% (preferably not less than 80%) Example 2 Formulation of Gastroretentive Bilayer Tablet containing Itopride hydrochloride by non-aqueous granulation. (021) The present invention also comprises a formulation of a bilayer tablet in which one layer comprises of itopride 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 itopride 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. 9 Table 2 Itopride SR gastroretentive Layer mg/tablet Itopride hydrochloride 110.0 Methocel K l00 M 10.0 Methocel K4M 25.0 Sodium carboxy methyl cellulse (medium viscosity grade) 20.0 Xanthan gum 15.0 Micro Crystalline Cellulose 30.0 Povidone (PVPK-30) 5.0 Isopropyl Alcohol q.s. Magnesium Stearate 2.5 Colloidal Silicon Dioxide 2.5 Av. Weight of SR layer 220.0 mg Itopride IR Layer Itopride hydrochloride 40.0 Colour lake of quinoline yellow 1.5 Microcrystalline cellulose 123.5 PVPK 30 5.0 Isopropyl alcohol q.s. Magnesium Stearate 2.0 Colloidal silicon dioxide 2.0 Sodium starch glycollate 6.0 Average weight of IR layer 180.0 mg Total weight of tablet 400 mg Tools: 11.0 mm standard concave punch (022) Itopride sustained release floating layer comprises Itopride hydrochloride, Hydroxypropylmethyl cellulose (Methocel K 100 M Premium), Hydroxypropylmethyl cellulose (Methocel K 4 M Premium), Xanthan gum, 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. (23) Immediate release layer comprises fast disintegrating excipients to ensure instant release of the drug for loading dose. Itopride hydrochloride, colour lake of quinoline yellow and Microcrystallirie 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 105° 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. (24) The blend was compressed into tablets using 11.0 mm standard concave 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 0.1 N HCl at 37.0 ± 0.5°C .The percent drug release of the above formulation found to be: Time % drug release of the labeled amount 1 hr 34.74 % (preferably 30%-50%) 2 hr 43.21% (preferably 40%-60%) 4 hr 65.89 % (preferably 60%-70%) 6 hr 76.21 % (preferably 70%-85%) 8 hr 93.21% (preferably not less than 80%) Example 3 Formulation of tablet and floating mass in capsule containing itopride hydrochloride by non-aqueous granulation. (025) The present invention also comprises of single unit capsule dosage form comprising a fraction of itopride 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 itopride or its pharmaceutically acceptable salts which is a gastric retentive floating fluffy mass which release the fraction of itopride or its pharmaceutically acceptable salts which is a controlled or sustained release formulated with biocompatible polymers (tablet and blend/granules in a capsule). Table 3 Itopride Immediate release tablet part mg/tablet Itopride hydrochloride 40.0 Microcrystalline cellulose 29.0 PVPK 30 4.0 Isopropyl alcohol q.s. Magnesium Stearate 1.0 Colloidal silicon dioxide 1.0 Sodium starch glycollate 5.0 Average weight 80.0 mg Tools: 5.0 mm standard concave punch Itopride SR Floating mass capsule part mg Itopride hydrochloride 110.0 Methocel K 100 M 20.0 Sodium alginate 15.0 Sodium Carboxy methyl cellulose (Low viscosity grade) 20.0 Sodium Carboxy methyl cellulose (Medium viscosity grade) 10.0 Xanthan gum 10.0 Micro Crystalline Cellulose 76.0 Povidone (PVPK-30) 8.0 Isopropyl Alcohol q.s. (028) The size ' 1' capsules were filled with itopride immediate release tablet and itopride 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 0.1 N HC1 at 37.0 ± 0.5°C . In vitro drug release profile of itopride sustained release found to be: Time % drug release of the labeled amount lhr 35.56 % (preferably 3 0%-50%) 2hr 42.15% (preferably 40%-60%) 4hr 68.26 % (preferably 60%-70%) 6hr 71.24% (preferably 70%-85%) 8hr 85.41 % (preferably not less than 80%) (029) 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. claim: 1. A process for making oral single unit dosage form of a prokinetic agent, itopride in the form of either bilayer tablet or as a capsule containing final sustained release blend and final immediate release blend, wherein the process steps comprises of- sieving of itopride hydrochloride, a plurality of polymers and a diluent through 60 no. mesh and blended for 5 minutes to get a blend, dissolving a bonder in isopropyl alcohol to make 5 % w/v solution and granulating said blend with said binder solution to get wet mass, passing said wet mass through mesh no. 8 to get wet granules, air drying and further drying of said wet granules at 40° C till the loss on drying of desired value reached of NMT 2.5 % at 95° C to get dried granules, sieving of said dried granules through 20 mesh, finally missing said dried granules with plurality of lubricants and blending whole mixture for 5 minutes to get said final sustained release blend, sieving of itopride hydrochloride, colour lake of quinoline yellow and a diluent through 60 no. mesh and blending for 5 minutes to get a dry blend, dissolving a binder in isopropyl alcohol to make 5 % w/v solution and granulating said dry blend with binder solution to get wet mass, sieving said wet mass through mesh no. 8 to get wet granules, air drying and further drying said wet granules at 40° C till the loss on drying of desired value reached of NMT 2.5 % at 105° C to get dried granules, sieving said dried granules through 20 mesh, finally mixing and blending with plurality of lubricants to get final immediate release blend, and compressing said final sustained release blend and said immediate release blend intosaid bilayer tablets by using bilayer tablet machine, optionally compressing said immediate release blend by using tablet compression machine and filling along with said sustained release blend in a hard gelatine capsule by using capsule filling machine equipped with tablet loader to get said capsule. 2. A process as claimed in claim 1 wherein said final immediate release blend contains loading dose of itopride hydrochloride ranging from 20 to 40 %, preferably 26.66 % of the total dose of itopride and said final sustained release blend which optionally be a gastro retentive floating fraction containing itopride ranging from 60 to 85%, preferably 73.34% of the total itopride dose, wherein said total itopride dose is 150 mg. 3. A process as claimed in claim 1, wherein said plurality of polymer is hydroxypropyl methylcellulose K100M (viscosity grade 100000 cps) used in amount ranging from 5 to 30%, preferably 19 % additionally hydroxypropyl methylcellulose K4M (viscosity grade 4000 cps) in said amount ranging from 10 to 50%, preferably 40% of weight of final sustained release blend, 4. A process as claimed in claim 1, wherein said diluent is microcrystalline cellulose used in the concentration range of 30 to 80% of weight of final sustained release blend, said binder used is polyvinylpyrrolidine K30 used in the concentration range of 0.5 to 5% of weight of final sustained release blend, said plurality lubricant is magnesium stearate used in the range of 0.1 to 5% of weight of final sustained release blend, and colloidal silicon dioxide used in the concentration range of 0.1 to 5% of weight of final sustained release blend, said disintegrant is sodium starch glycollate used in the concentration of 1 to 8% of weight of said bilayer tablet or said capsule. 5. A process as claimed in claim 2, wherein said gastro retentive floating fraction optionally contains sodium carboxmethylcellulose used in amount ranging from 3 to 25% of weight of said final sustained release blend, additionally sodium alginate in said amount ranging from 2 to 25% of weight of said final sustained release blend, additionally xanthan gum is used in amount ranging from 1 to 10% of weight of said final sustained release blend. COMPELETE AFTER PROVISNAL EFT ON 1 SEP 2004 A Novel Pharmaceutical Composition of a proton pump inhibitor with a Prokinetic Agent A Novel pharmaceutical composition, comprising co-administration of a proton pump inhibitor pantoprazole and a prokinetic agent, mosapride in a single unit formulation for once a dose, wherein the proton pump inhibitor and prokinetic agents are formulated and presented in a manner to minimize interaction of pantoprazole with mosapride and a single unit dosage form to deliver a enteric coated proton pump inhibitor pantoprazole along with the sustained/controlled/floating gastroretentive sustained or controlled release prokinetic agent mosapride for once a day administration. BACKGROUND OF THE INVENTION (1) 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. Aside from behavioral changes, GERD and gastric ulcer have been successfully treated with a range of gastric acid inhibitors, such as ranitidine and omeprazol, 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 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. (003) The pantoprazole sodium sesquihydrate is equivalent to pantoprazole. The pantoprazole and or its salts here after will be termed as "pantoprazole". 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. (004) The prokinetic agents in the present invention, mosapride citrate dihydate is equivalent to mosapride citrate and or its salts here after will be termed as "mosapride" in this application. They are a benzamide-type gastroprokinetic agent that enhances the gastrointestinal motility by stimulating the 5-hydroxytryptamine-4 (5-HT4) receptor. (005)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 a multiple unit tableted dosage forms, multilayered tablets, or a capsule filled with more than one pharmaceutically active compound but both in conventional 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 Mosapride 15mg SR, which eliminates the problem of dose adjustment & frequency. (6) 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 H7K+ ATPase-inhibiting action, for the therapy of diseases which originate from increased gastric acid secretion. The present invention comprises of proton pump inhibitor, pantoprazole. (7) 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 2 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. SUMMARY OF THE INVENTION (8) The present invention comprises co-administration of a proton pump inhibitor pantoprazole and a prokinetic agent, mosapride 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 mosapride 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 mosapride for once a day administration. (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 or delayed release. (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 mosapride and acidic gastric juice, the pantoprazole must be enteric coated. (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 coated dosage form. The alkaline nature of core will interfere with the enteric coating and 4 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. (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 a prokinetic agent, mosapride 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. The prokinetic agents in the present invention, mosapride citrate dihydate is equivalent to mosapride citrate and or its salts here after will be termed as "mosapride" in this application. They are a benzamide-type gastroprokinetic agent that enhances the gastrointestinal motility by stimulating the 5-hydroxytryptamine-4 (5-HT4) receptor. (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 for once a day dosing. (15) The compatibility (physical and chemical) study was done taking suitable ratio of Mosapride citrate dihydrate 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 6 drug and excipients blend triturate were satisfactory in appearance as compared to individual control samples. (016) 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 Ci8, 5 n column using buffer and acetonitrile as mobile phase in ratio of 62:38 respectively and detection was done at 280 nm. While the analysis of mosapride sustained release part was done by HPLC (Make: Agilent 1100 series) using 4.6 X 150 mm, Inersil Cg, 5 n column using buffer and acetonitrile as mobile phase in ratio of 62:38 respectively and detection was \ done at 275 nm The stability studies were done as per ICH guidelines for 6 months. Rationale for In vitro dissolution media (017) 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. The quantity of mosapride citrate dihyrate is expressed in terms of equivalent amount of mosapride citrate. The solubility studies of mosapride citrate dihydrate was carried out as, in distilled water found to be very slightly soluble, in 0.1 N HC1 and phosphate buffer pH 6.8 practically insoluble while in sodium acetate buffer pH 3.5 it is found to be slightly soluble, the results are interpreted as per the criteria defined in USP. 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 sodium acetate buffer pH 3.5 for mosapride citrate dihydrate, based on the solubility equilibrium of the drug substance, which complies when used sodium acetate buffer pH 3.5. Hence the dissolution of dosage forms carried out by using 900 ml sodium acetate buffer pH 3.5 which complies with the sink conditions mentioned in USP. However USP allows use of dissolution media up to 2000 ml volume for drugs having limited solubility. (Ref. USP/NF, Vol. 27,2004 Page no. 2514). 7 Example 1 Pantoprazole 20mg//40 mg delayed release + Mosapride 15 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 immediate release blend and or granules to provide a loading dose of the mosapride, a prokinetic agent, and sustained release tablet which releases the drug within 8-12 hours to provide a maintenance dose for maintaining 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/cm2. 8 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 5.0 mm standard concave punch Sub coat solution(3 % w/v) Hydroxypropylmethylcellulose E 06 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 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 Mosapride Sustained release Tablet Part Mosapride Citrate Dihydrate 11.0 Methocel K 100 M 5.0 HPMCE15cps 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 Tablet weight 70.0 mg Mosapride immediate release blend Part Mosapride Citrate Dihydrate 4.84 Lactose DC 11 98.1 Avicel pH 200 95.0 Magnesium Stearate 1.0 Colloidal silicon dioxide 1.0 Capsule filled weight 200.0 mg Hard gelatin capsule size ' 1' (020) 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 9 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. (21) 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. (22) The capsules were filled with pantoprazole enteric coated tablet, 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 sunlight. 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 for mosapride, while for pantoprazole in 0.1 N HC1 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 Mosapride citrate sustained release found to be: Time % drug release of the labeled amount 1 hr 39.0 % (preferably 30%-40%) 2 hr 49.4 % (preferably 40%-55%) 4hr 63.7% (preferably 60%-70%) 6 hr 77.2 % (preferably 75%-85%) 8 hr 88.2 % (preferably not less than 80 %) 10 Example 2 Pantoprazole 20 mg/40 mg delayed release + Mosapride 15 mg sustained release Capsule (23) 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 immediate release blend and or granules to provide a loading dose of the mosapride, a prokinetic agent, and sustained release tablet which releases the drug within 8-12 hours to provide a maintenance dose for maintaining prolonged duration of action. (24) 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 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. 11 Table 2 Table 2A Pantoprazole Part 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 Sub coat solution(3 % w/v) Hydroxypropylmethylcellulose E 06 3 % of tablet weight PVPK30 2 % of polymer Propylene Glycol 25 % of the polymer Titanium Dioxide l-2%of polymer Purified Water 1:2 to 1:3 ratio Isopropyl Alcohol Enteric Coating N on-aqueous Hydroxypropylmethylcellul ose Phthalate 12-15 % of tablet weight Titanium Dioxide 8-10% of polymer Triacetin 1-1.5 %of polymer Acetone Isopropyl alcohol q.s. to make 5 % solution of the polymer in 1:1 ratio Talcum 8-10% of polymer Colour Tratrazine supra 0.1-0.5 %ofpolymer Mosapride Sustained release Tablet Part Mosapride Citrate Dihydrate 11.0 Methocel K 100 M 5.0 HPMCE15cps 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 Tablet weight 70.0 mg Mosapride Immediate release blend Part Mosapride Citrate Dihydrate 4.84 Lactose DC 11 98.1 Avicel pH 200 95.0 Magnesium Stearate 1.0 Colloidal silicon dioxide 1.0 Capsule filled weight 200.0 mg Capsule size ' 1' (025) 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 12 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. (26) 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. (27) The capsules were filled with pantoprazole enteric coated tablet, 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 sunlight. 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 for mosapride, while for pantoprazole in 0.1 N HC1 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 Mosapride citrate sustained release found to be: Time % drug release of the labeled amount 1 hr 40.2 % (preferably 30%-40%) 2 hr 48.1% (preferably 40%-55%) 4 hr 64.1% (preferably 60%-70%) 6 hr 78.2 % (preferably 75%-85%) 8 hr 89.1 % (preferably not less than 80%) Example 3 Pantoprazole 20mg//40 mg delayed release + Mosapride 15 mg sustained release Capsule (028) 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 13 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 immediate release blend and or granules to provide a loading dose of the mosapride, a prokmetic agent, 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 which releases the drug within 8-12 hours to provide a maintenance dose for maintaining prolonged duration of action. (029) 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 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 . 14 Table 3 Table 3A 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 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 Mosapride Sustained release (floating) tablet part Mosapride Citrate Dihydrate 11.0 Methocel K l00M 5.0 Sodium Carboxy methyl cellulose (Low viscosity grade) 10.0 HPMC E l5cps 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 70.0 mg Mosapride immediate release blend Part Mosapride Citrate Dihydrate 4.84 Lactose DC 11 98.1 Avicel pH 200 95.0 Magnesium Stearate 1.0 Colloidal silicon dioxide 1.0 Capsule filled weight 200.0 mg Capsule size ' 1' 15 (030) Mosapride sustained release tablet comprises Mosapride citrate dihydrate, Hydroxypropylmethyl cellulose (Methocel K 100 M Premium), Hydroxypropylmethyl cellulose (E 15 cps), Sodium Carboxy methyl cellulose (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. The tablets were compressed on 16 station compression machine (Make:Cadmach). The hardness of tablets found to be 3-5 kg/cm2. (31) 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. (32) The capsules were filled with pantoprazole enteric coated tablet, 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 sunlight. 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 for mosapride, while for pantoprazole in 0.1 N HC1 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 Mosapride citrate sustained release found to be: 16 Time % drug release of the labeled amount l hr 38.4 % (preferably 30%-40%) 2 hr 44.2 % (preferably 40%-55%) 4 hr 68.1% (preferably 60%-70%) 6 hr 76.1% (preferably 75%-85%) 8 hr 90.0% (preferably not less than 80 %) Example 4 Pantoprazole 20 mg/40 mg delayed release + Mosapride 15 mg sustained release Capsule (33) 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 immediate release blend and or granules to provide a loading dose of the mosapride, a prokinetic agent, and sustained release tablet which releases the drug within 8-12 hours to provide a maintenance dose for maintaining prolonged duration of action. (34) 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 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. 17 Table 4 Table 4A Pantoprazole Part 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 Sub coat solution(3 % w/v) Hydroxypropylmethylcellulose E06 3 % of tablet weight PVPK30 2 % of polymer Propylene Glycol 25 % of the polymer Titanium Dioxide l-2%of polymer Purified Water 1:2 to 1:3 ratio Isopropyl Alcohol Enteric Coating > on-aqueous Hydroxypropylmethylcellul ose Phthalate 12-15 % of tablet weight Titanium Dioxide 8-10% of polymer Triacetin 1-1.5 %of polymer Acetone Isopropyl alcohol q.s. to make 5 % solution of the polymer in 1:1 ratio Talcum 8-10 % of polymer Colour Tratrazine supra 0.1-0.5 %of polymer Mosapride Sustained release (floating) tablet part Mosapride Citrate Dihydrate 11.0 Methocel K l00M 5.0 Sodium Carboxy methyl cellulose (Low viscosity grade) 10.0 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 70.0 mg Mosapride Immediate release blend Part Mosapride Citrate Dihydrate 4.84 Lactose DC 11 98.1 Avicel pH 200 95.0 Magnesium Stearate 1.0 Colloidal silicon dioxide 1.0 Capsule filled weight 200.0 mg Capsule size ' 1' 18 (035) Mosapride sustained release tablet comprises Mosapride citrate dihydrate, Hydroxypropylmethyl cellulose (Methocel K 100 M Premium), Sodium Carboxy methyl cellulose (Low viscosity grade), Sodium Carboxy methyl cellulose (Medium 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. The tablets were compressed on 16 station compression machine (Make:Cadmach). The hardness of tablets found to be 3-5 kg/cm2. (36) 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. (37) The capsules were filled with pantoprazole enteric coated tablet, 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 sunlight. 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 for mosapride, while for pantoprazole in 0.1 N HC1 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 Mosapride citrate sustained release found to be: 19 Time % drug release of the labeled amount 1 hr 37.9.2 % (preferably 30%-40%) 2 hr 44.3 % (preferably 40%-55%) 4 hr 62.5% (preferably 60%-70%) 6 hr 76.4% (preferably 75%-85%) 8 hr 86.0 % (preferably not less than 80%) Example 5 Pantoprazole 20mg//40 mg delayed release + Mosapride 15 mg sustained release Capsule (38) 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 such as sodium carbonate anhydrous, sodium hydroxide, L-arginine compressed in tablet and it is enteric coated and second part comprises of the immediate release blend and or granules to provide a loading dose of the mosapride, a prokinetic agent, and sustained release tablet which releases the drug within 8-12 hours to provide a maintenance dose for maintaining prolonged duration of action. (39) Pantoprazole enteric coated tablet formulation comprises alkaline excipients. Pantoprazole, mannitol, sodium carbonate anhydrous, L-arginine, crosspovidone, sodium lauryl sulphate, sieved through 60 no. mesh and blended for 5 minutes. HPMC E06 was dissolved in purified water 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 . 20 Table 5 Table 5A Pantoprazole Part mg/tablet Pantoprazole Sodium sesquihydrate 22.6 to 45.20 Mannitol DC , 9.4 to 32.0 Sodium Carbonate anhydrous 5.00 L-arginine 5.0 to 15.0 mg 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 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 Mosapride Sustained release Tablet Part Mosapride Citrate Dihydrate 11.0 Methocel K l00M 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 Tablet weight 70.0 mg Mosapride immediate release blend Part Mosapride Citrate Dihydrate 4.84 Lactose DC 11 98.1 Avicel pH 200 95.0 Magnesium Stearate 1.0 Colloidal silicon dioxide 1.0 Capsule filled weight 200.0 mg Capsule size ' 1' (040) 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 (solution 5 % w/v) and the above blend was granulated. The granules were passed from 21 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. (41) 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. (42) The capsules were filled with pantoprazole enteric coated tablet, 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 sunlight. 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 for mosapride, while for pantoprazole in 0.1 N HC1 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 Mosapride citrate sustained release found to be: Time % drug release of the labeled amount 1 hr 39.0 % (preferably 30%-40%) 2 hr 49.4 % (preferably 40%-55%) 4 hr 63.7% (preferably 60%-70%) 6 hr 77.2 % (preferably 75%-85%) 8 hr 88.2 % (preferably not less than 80 %) (043) 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 22 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 1. A process for making novel pharmaceutical composition, comprising coadministration of a proton pump inhibitor and a prokinetic agent in a single unit formulation, wherein one, the proton pump inhibitor containing an alkalizing agent with pKa value more than 8 like arginine, lysine, tyrosine, cysteine to enhance the stability during storage, is enteric coated to bypass stomach's acid environment where pantoprazole is degraded and release the drug in small intestine where the environment is alkaline and, prokinetic agent is sustained or controlled release are formulated and presented in a manner to minimize interaction of proton pump inhibitor with prokinetic agent and to provide the ease of once a day administration to reduce the inconvenience of multiple dosing at multiple frequency in a day. 2. A process as defined in claim 1 wherein the proton pump inhibitor is pantoprazole and its pharmaceutically acceptable salts in dose range from 20- 40 mg and wherein the prokinetic agent is mosapride and its pharmaceutically acceptable \salts in dose range from 10- 50 mg, preferably 15 mg, to be coadministered once a 3. A process as defined in claim 1 wherein single unit formulation comprises 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 seal & enteric coated and second part comprises of two parts 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 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). 4. The pharmaceutical composition as defined in claim 3 wherein the enteric coated or delayed Release tablet contains the pantoprazole is with one or more excipients. 5. The pharmaceutical composition as defined in claim 4 wherein the enteric coated tablet includes, a core and a coating layers, surrounding said core. 6. The pharmaceutical composition as defined in claim 3 wherein the pantoprazole is present in the core. 7. The pharmaceutical composition as defined in claim 6 wherein the core comprises pantoprazole, and excipients comprising of diluent, alkalizing agent, solubility enhancer, lubricant, disintegrant, binder and glidant 8. The pharmaceutical composition as defined in claim 7 wherein the core comprises of said diluent is manitol in said amount of 20- 90%, alkalizing agent is sodium hydroxide, and or sodium carbonate and or L-arginine, lysine, tyrosine, cysteine in said amount of 1- 40% and solubility enhancer sodium lauryl sulphate in said amount of 0.1-5.0%, disintegrant is sodium starch glycollate and or crosspovidione (kollidion CL) in said amount of 1 - 20%, binder is Hydroypropyl methyl cellulose (HPMC E 06) in said amount of 0.1- 20% and or ethyl cellulose in said amount of 0.1 - 5%, glidant is talc and/or colloidal silicon dioxide in said amount of 0.1- 10%, lubricant is calcium stearate or magnesium stearate in said amount of 1-10%. 9. The pharmaceutical composition as defined in claim 6 wherein the coating layer comprises of sub coating and enteric coating. The sub coating layer comprises of subcoating polymer and a plastisizer. Sub coating layer comprises of hydroxy 25 propyl methyl cellulose of in said amount of 0.5- 4% of the tablet weight, plastisizer comprises of triacetin in said amount of 0.5- 10% of the hydroxyl propyl methyl cellulose. The enteric coating layer comprises of a Methacrylic acid copolymer USP Type A, B or C and or combinations of A,B and C, titanium dioxide, talc, triacetin and coloring agent in said amount of 8-15% of tablet weight. The enteric coating layer comprises Methacrylic acid copolymer USP type A, B or C and or combinations of Type A, B or C (Eudragit L 100, Eudragit L 100 55 and different grades including aqueous enteric coating grade) in said amount of 8-15% of tablet weight and titanium dioxide in said amount of 1-20%, triacetin in said amount of 1-20%, talc in said amount of 1-20%, and coloring agent is Lake of dyes in said amount of 0.1-10% of Eudragit L 100 55. 10. A process claimed in claim 3 where the second part of capsule comprises of two part in which one part is a controlled or sustained release tablet comprises of release rate controlling biocompatible, hydrophilic polymer which is hydroxypropyl methyl cellulose(HPMC), a mixture of polymer hydroxy propyl methyl cellulose of different grades that is HPMC K100M (viscosity grade 100000 cps) in said amount ranging from 5 to 30%, preferably 19 % and or HPMC K4M (viscosity grade 4000 cps) in said amount ranging from 10 to 50%, preferably 40% and or with HPMC (viscosity grade 15 cps) in said amount ranging from 10 to 50% of the sustained release layer weight (as in example 1, Tablel, the sustained release layer weight is 80 mg ). Other pharmaceutical acceptable excipients are microcrystalline cellulose as a diluent and a wecking agent in the concentration range of 30 to 80%, binder used is polyvinylpyrrolidine K25 or K30 or K90 in the concentration range of 0.5 to 5% lubricants and glidants are magnesium stearate and colloidal silicon dioxide repectively in the concentration range of 0.1 to 5%. disintegrants are either sodium starch glycollate, croscarmellose sodium, crospovidone, alone or mixture in the concentration of 1 to 8 % of the total tablet weight in both the layers. 26 11. A process as claimed in claim 3 where the second part of capsule comprises of two part in which one part is a controlled or sustained release fraction and this fraction can also be a gastro retentive floating device which contains alongwith release rate controlling excipients as mentioned in claim 5 additionally contains sodium or calcium carboxmethylcellulose of low or medium viscosity grade in said amount ranging from 3 to 25%, and or sodium or calcium alginate , alginic acid in said amount ranging from 2 to 25%, methylcellulose of different viscosity grade in said amount ranging from 3 to 35%, also may contain xanthan or vee gum in said amount ranging from 1 to 10% of the total weight of controlled release fraction for floating gastroretentive layer. 12. A process as claimed in claim 3 where the immediate release layer of capsule part comprises of microcrystalline cellulose, lactose DC 11 as a diluent and a wecking agent in the concentration range of 30 to 80% of total tablet weight and or individual layers, polyvinylpyrrolidine K25 or K30 or K90 as binder 0.5 to 5% of total tablet weight and or individual layers, magnesium stearate and colloidal silicon dioxide as glidant and lubricant in the concentration range of 0.1 to 5% of total tablet weight and or individual layers, also immediate release layer contains disintegrants either sodium starch glycollate, croscarmellose sodium, crosspovidone, alone or mixture in the concentration of 1 to 8% of total layer weight. Name of the inventor: Mr. Manutosh Manohar Acharya Mr. Vijay Vitthal Nangare Assignee: Aristo Pharmaceuticals Ltd 12, J. N. Heredia Marg, Ballard Estate, Mumbai - 400001 (INDIA)

Documents:

887-mum-2003-claims(granted)-(4-4-2005).doc

887-mum-2003-claims(granted)-(4-4-2005).pdf

887-mum-2003-correspondence(ipo)-(23-7-2007).pdf

887-mum-2003-form 2(granted)-(4-4-2005).doc

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

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

887-mum-2003-form 13(4-4-2005).pdf

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

887-mum-2003-form 2(granted)-(4-4-2005).pdf

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

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

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

887-mum-2003-other document(15-9-2004).pdf