Title of Invention

A NOVAL PHARMACEUTICAL COMPOSITION OF A PROTON PUMP INHIBITOR WITH A PROKINETIC AGENT

Abstract A process, for making novel pharmaceutical composition in the form of capsule, comprising of enteric coated tablet of rabeprazole and a sustained release tablet of mosapride and a final immediate release blend of mosapride, wherein process steps comprising of coating of rabeprazole sodium, with plurality of alkalizing agent, sieving plurality of diluents, a surface active agent, and a disintegrant through 60 mesh, blending for 5 minutes, dissolving a binder in purified water to make 10% w/v solution and granulating above said blend with said binder to get wet mass, passing said wet mass through mesh no. 8 to get wet granules, air drying, further drying said wet granules at 40° C in a tray drier till the loss on drying of desired value reached at not more than 3.0 % at 70 C, sifting the said dried granules through 20# sieve to get dry pass granules, finally mixing and blending of said dried granules with a disintegrant, a surface active agent and plurality of lubricants to get a lubricated blend , compressing the said lubricated blend into tablets by using compression machine to get core uncoated tablets of rabeprazole, seal coating of said uncoated tablets of rabeprazole by using a polymer and a plasticizer to get seal coated tablets of rabeprazole, enteric coating of said seal coated tablets of rabeprazole by using enteric coating polymer , a plasticizer, opacifying agent, anti-sticking agent and a coloring agent, in a conventional coating pan to get said enteric coated tablet of rabeprazole,
Full Text FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION
A Novel process for making a.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, India, Residing at 4/7,Amaltas Parisar Shahpura, Bhopal.
2. Mr.Suresh Kumar Paswan , India Residing at QTR - 790/05, Baconager Dist. Korba, Chattisgarh, India.
3. Mr.Vijay Vithal Nangare , Indian , Residfing at Tadwale, Tal-khatav, Dist-Satara. MH.
The following specification describes the nature of this invention and the manner in which it is to be performed.

ORIGINAL
891/MUMNP/2003

GRANTED
2-9-2003

A Novell Pharmaceutical Composition of a Proton Pump Inhibitor with a Prokinetic Agent
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 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 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 rabeprazole sodium. The rabeprazole sodium and or its other salts here after will be termed as "rabeprazole".
(4) Rabeprazole 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) The US patent 6,132,771 discloses oral pharmaceutical composition comprising of a proton pump inhibitor and a prokinetic agent, the proton pump inhibitor claimed is omeprazole and its salts and prokinetic agent is Mosapride or Cisapride, the dosage form is multiple unit tablet dosage form, multilayered tablets or capsules filled with more than one pharmaceutically active compounds in a conventional dosage form. The dose of proton pump inhibitor mentioned herein is Omeprazole and its dose is 10/20 nig once a day and a prokinetic agent Mosapride is to be given 5 mg thrice a day. Hence comprising the two will lead to a problem of dose adjustment and frequency.
Our patent discloses once a day dosage form containing proton pump inhibitor Rabeprazole 10/20 mg with Mosapride 15 mg SR, which eliminates the problem of dose adjustment and frequency.
(6) 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 are a benzamide-type gastroprokinetic agent that enhances the gastrointestinal motility by stimulating the 5-hydroxytryptamine-4 (5-HT4) receptor.
(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 therapeutic 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 with blend/ granule in a capsule.

SUMMARY OF INVENTION
(8) The present invention comprises co-administration of a proton pump inhibitor, rabeprazole 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 rabeprazole with mosapride a single unit dosage form to deliver a enteric coated proton pump inhibitor rabeprazole 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.

(9) 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 rabeprazole, which prevents it from contact with the mosapride and acidic gastric juice, the rabeprazole must be enteric coated or delayed release.
(10) In order to enhance the storage stability of the enteric coated tablet of rabeprazole , 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 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.
(011) 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 Rabeprazole 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. Rabeprazole enteric-coated tablet formulation comprises alkaline excipients. Rabeprazole, was coated with L-Arginine and / or Sodium Hydroxide dissolved in minimum amount of water and the blend was air dried to remove the solvent and dried till all solvent was evaporated Mannitol, sodium carbonate anhydrous, Light Magnesium Carbonate Crospovidone, sodium lauryl sulphate were sieved through 60 mesh and blended for 5 minutes. HPMC E06 and /or HPC were dissolved in purified water to make 10 % w/v solution and the above blend was granulated. The granules were wet 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 3.0 % (Make: Mettler Toledo LJ16 moisture analyzer) at 70' C. The dried granules were sieved through 20# Sieve. Finally Crospovidone, Magnesium Stearate, Sodium Lauryl Sulphate, Colloidal Silicon dioxide (passed through 60 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. Mosapride sustained release tablet comprises Mosapride citrate dihydrate, Hydroxypropylmethyl cellulose (Methocel K 100 M Premium), Hydroxypropylmethyl cellulose (E15 cps) and Microcrystalline cellulose sieved through 60 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. Mosapride immediate release blend part comprises Mosapride citrate dihydrate, Lactose DC 11 and Avicel pH 200 sieved through 60 no. mesh and blended for 5 minutes. Talc and magnesium stearate (passed through 60 no. mesh) were added and the whole mixture blended for 5 minutes. The capsules were filled with Rabeprazole enteric-coated tablet, mosapride sustained release tablet and mosapride immediate release blend. 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.

DETAILED DESCRIPTION OF THE INVENTION
(12) 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. Rabeprazole Sodium 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.
(13) 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 therapeutic 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.
(14) The compatibility (physical and chemical) study was done taking suitable ratio of Mosapride citrate dihydrate and Rabeprazole sodium 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 analyzed 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.
(015) In order to screen for formulation stability we have formulated five different types
of process for the formulation. The analysis of Rabeprazole part was done by HPLC
(Make: Agilent 1100 series) using 4.6 X 250 mm, Symmetry Cis, 5 column using
buffer and acetonitrile as mobile phase in ratio of 70:30 respectively and detection was
done at 288 nm. While the analysis of mosapride sustained release part was done by
HPLC (Make: Agilent 1100 series) using 4.6 X 150 mm, Inersil Cs, 5 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
(016) The dissolution testing of Rabeprazole sodium enteric coated tablet part was carried
out in 0.1 N hydrochloric acid for 2 hrs and in phosphate buffer pH 7.8: n- Propanol (8:2)
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).

Example 1
Rabeprazole 10mg//20 mg delayed release + Mosapride 15 mg sustained release Capsule
(17) 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 Rabeprazole Sodium 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 prokinetfc agent, and sustained release tablet which re/eases the drug within 8-12 hours to provide a maintenance dose for maintaining prolonged duration of action.
(18) Rabeprazole enteric-coated tablet formulation comprises alkaline excipients. Rabeprazole, was coated with L-Arginine and / or Sodium Hydroxide dissolved in minimum amount of water and the blend was air dried to remove the solvent and dried till all solvent was evaporated Mannitol, sodium carbonate anhydrous, Light Magnesium Carbonate Crospovidone, sodium lauryl sulphate were sieved through 60 mesh and blended for 5 minutes. HPMC E06 and / or HPC were dissolved in purified water to make 10 % w/v solution and the above blend was granulated. The granules were wet 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 3.0 % (Make: Mettler Toledo LJ16 moisture analyzer) at 70° C. The dried granules were sieved through 20# Sieve. Finally Crospovidone, Magnesium Stearate, Sodium Lauryl Sulphate, Colloidal Silicon dioxide (passed through 60 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






(019) 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 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.
(20) 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.
(21) The capsules were filled with Rabeprazole enteric-coated tablet, mosapride sustained release tablet and mosapride immediate release blend. The whole procedure was carried out in controlled conditions of temperature (25 °C ± 2 C), relative humidity (40%±5% RH) and protected from direct exposure to light. The dissolution of above formulation was carried out by using USP type I (basket) apparatus at 100 rpm in 900 ml acetate buffer pH 3.5 at 37.0 ± 0.5°C for mosapride, while for Rabeprazole 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 7.8: n- Propanol (8:2) 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 % mosapride release of the labeled amount
1 hr 34.0 % (preferably 30%-40%)
2 hr 51.4 % (preferably 40%-55%) 4 hr 62.7 % (preferably 60%-70%) 6hr 81.2% (preferably 75%-85%)
8hr 87.2% (preferably not less than 80 %)

Example 2
Rabeprazole 10 mg/20 mg delayed release + Mosapride 15 mg sustained release Capsule
(022) Rabeprazole enteric-coated tablet formulation comprises alkaline excipients. Rabeprazole was coated with L-Arginine and / or Sodium Hydroxide dissolved in minimum amount of ethanol and the blend was air dried to remove the solvent Mannitol, sodium carbonate anhydrous, Light Magnesium Carbonate, Crospovidone, sodium lauryl sulphate were sieved through 60 no. Mesh and blended for 5 minutes. HPMC E06 and / or HPC were dissolved in Isopropyl alcohol: Dichloroniethane (1:1 ratio) to make 10 % w/v solution and the above blend was granulated. The granules were wet 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 3.0 % (Make: Mettler Toledo LJ16 moisture analyzer) at 70° C. The dried granules were sieved through 20 mesh. Finally Crospovidone, Magnesium 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 1A







(023) Mosapride sustained release tablet comprises Mosapride citrate dihydrate, Hydroxypropylmethyl cellulose (Methocel K 100 M Premium), Hydroxypropylmethyl cellulose (E 15 cps) and Microcrystalline cellulose sieved through 60 no. Mesh and blended for 5 minutes. Povidone (PVPK-30) was dissolved in Isopropyl Alcohol (5 % w/v) and the above blend was granulated. The granules were passed from mesh no. 8, air dried and then dried at 40° C till the loss on drying (LOD) of desired value reached of NMT 2.5 % (Make: Mettler Toledo LJ16 moisture analyzer) at 105° C. The dried granules were sieved through 20 mesh. Finally magnesium stearate and colloidal silicon dioxide (passed through 60 no. Mesh) were added and the whole mixture blended for 5 minutes. The tablets were compressed on 16-station compression machine (Make: Cadmach). The hardness of tablets found to be 3-5 kg/cm .

(24) Mosapride immediate release blend part comprises Mosapride citrate dihydrate, Lactose DC 11 and Avicel pH 200 sieved through 60 no. Mesh and blended for 5 minutes. Talc and magnesium stearate (passed through 60 no. Mesh) were added and the whole mixture blended for 5 minutes.
(25) The capsules were filled with Rabeprazole 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 light. The dissolution of above formulation was carried out by using USP type 1 (basket) apparatus at 100 rpm in 900 ml acetate buffer pH 3.5 at 37.0 ± 0.5°C for mosapride, while for Rabeprazole in 0.1 N HC1 for two hrs (% drug released found not more than 10.0% of labeled amount) phosphate buffer pH 7.8 n- Propanol (8:2) 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 % mosapride release of the labeled amount
1 hr 40.2 % (preferably 30%-40%)
2hr 48.1% (preferably 40%-5 5%)
4hr 64.1% (preferably 60%-70%)
6hr 78.2% (preferably 75%-85%)
8 hr 89.1 % (preferably not less than 80%)
Example 3
Rabeprazole 10mg//20 mg delayed release + Mosapride 15 mg sustained release Capsule
(026) 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 Rabeprazole 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 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.
(027) Rabeprazole enteric coated tablet formulation comprises alkaline excipients. Rabeprazole was coated with L-Arginine and / or Sodium Hydroxide dissolved in minimum amount of water and the blend was air dried to remove the solvent and dried till all solvent was evaporated Mannitol, sodium carbonate anhydrous, Light Magnesium Carbonate Crospovidone, sodium lauryl sulphate were sieved through 60 no. Mesh and blended for 5 minutes. HPMC E06 and / or HPC were dissolved in purified water to make 10 % w/v solution and the above blend was granulated. The granules were wet 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 3.0 % (Make: Mettler Toledo LJ16 moisture analyzer) at 70 C. The dried granules were sieved through 20 mesh. Finally Crospovidone, Magnesium 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







(028) 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.
(29) 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.
(30) The capsules were filled with Rabeprazole 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 light. The dissolution of above formulation was carried out by using USP type I (basket) apparatus at 100 rpm in 900 ml acetate buffer pH 3.5 at 37.0 ± 0.5°C for mosapride, while for Rabeprazole 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 7.8: n- Propanol (8:2) 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 % mosapride release of the labeled amount

1 hr 38.4 % (preferably 30%-40%)
2hr 44.2 % (preferably 40%-55%)
4hr 68.1% (preferably 60%-70%)
6hr 76.1% (preferably 75%-85%)
8hr 90.0% (preferably not less than 80 %)

Example 4
Rabeprazole 10 mg/20 mg delayed release + Mosapride 15 mg sustained release Capsule
(31) 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 Rabeprazole with pharmaceutical 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.
(32) Rabeprazole enteric coated tablet formulation comprises alkaline excipients. Rabeprazole was coated with L-Arginine and / or Sodium Hydroxide dissolved in minimum amount of water and the blend was air dried to remove the solvent and dried till all solvent was evaporated Mannitol, sodium carbonate anhydrous, Light Magnesium Carbonate Crospovidone, sodium lauryl sulphate were sieved through 60 no. Mesh and blended for 5 minutes. HPMC E06 and / or HPC was dissolved in purified water to make 10 % w/v solution and the above blend was granulated. The granules were wet 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 3.0 % (Make: Mettler Toledo LJ16 moisture analyzer) at 70° C. The dried granules were sieved through 20 mesh. Finally Crospovidone, Magnesium 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 .

Table 4 Table 4A




(033) 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/cm .
(34) 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.
(35) The capsules were filled with Rabeprazole 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 light. The dissolution of above formulation was carried out by using USP type I (basket) apparatus at 100 rpm in 900 ml acetate buffer pH 3.5 at 37.0 ± 0.5°C for mosapride, while for Rabeprazole in 0.1 N HC1 for two hrs (% drug released found not more than 10.0% of labeled amount) and then in phosphate buffer pH7.8: n- Propanol (8:2) 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 % mosapride release of the labeled amount
1 hr 37.92 % (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
Rabeprazole 10mg/20mg delayed release + Mosapride 15 mg sustained release Capsule
(36) 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 Rabeprazole 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.
(37) Rabeprazole enteric-coated tablet formulation comprises alkaline excipients. Rabeprazole, mannitol, sodium carbonate anhydrous, L-arginine, Crospovidone, 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.



fable 5 Table 5A

(038) 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 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 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.
(39) Mosapride immediate release blend part comprises Mosapride citrate dihydrate, Lactose DC 11 and Avicel pH 200 sieved through 60 mesh and blended for 5 minutes. Talc and magnesium stearate (passed through 60mesh) were added and the whole mixture blended for 5 minutes.
(40) The capsules were filled with Rabeprazole 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 light. The dissolution of above formulation was carried out by using USP type I (basket) apparatus at 100 rpm in 900 ml acetate buffer pH 3.5 at 37.0 ± 0.5°C for mosapride, while for Rabeprazole in 0.1 N HCI for two hrs (% drug released found not more than 10.0% of labeled amount) and then in phosphate buffer pH 7.8 : n-Propanol(8:2) 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 % mosapride 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 %)
(041) The oral controlled release dosage forms of the present invention comprises
mosapride or its pharmaceutically acceptable salts and release'controlling
pharmaceutically acceptable excipients, wherein the mosapride is released as per the
following in vitro dissolution profile, (a) Not less than 30 % of the drug is release'within
15 minute, which is a loading dose, (b) between 40% and 60% of the drug should be

release between 2 to 3 hours, (c) between 60 - 80 % of the drug should be released between 3-5 hours, (d) Between 80 - 100 % of the drug should be released between 5-8 hours. The in vitro release profile of the formulation has been tested as per United States Pharmacopoeia with Type I apparatus at 100 rpm using 900ml of acetate buffer pH 3.5 as dissolution medium at 37 ± 0.5°C for 8 hours.
(042) 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.


A process, for making novel pharmaceutical composition in the form of capsule, comprising of enteric coated tablet of rabeprazole and a sustained release tablet of mosapride and a final immediate release blend of mosapride, wherein process steps comprising of-
coating of rabeprazole sodium, with plurality of alkalizing agent, sieving plurality of diluents, a surface active agent, and a disintegrant through 60 mesh, blending for 5 minutes, dissolving a binder in purified water to make 10% w/v solution and granulating above said blend with said binder to get wet mass, passing said wet mass through mesh no. 8 to get wet granules, air drying, further drying said wet granules at 40° C in a tray drier till the loss on drying of desired value reached at not more than 3.0 % at 70 C, sifting the said dried granules through 20# sieve to get dry pass granules, finally mixing and blending of said dried granules with a disintegrant, a surface active agent and plurality of lubricants to get a lubricated blend , compressing the said lubricated blend into tablets by using compression machine to get core uncoated tablets of rabeprazole, seal coating of said uncoated tablets of rabeprazole by using a polymer and a plasticizer to get seal coated tablets of rabeprazole, enteric coating of said seal coated tablets of rabeprazole by using enteric coating polymer , a plasticizer, opacifying agent, anti-sticking agent and a coloring agent, in a conventional coating pan to get said enteric coated tablet of rabeprazole,
sieving a part of said mosapride, plurality of polymers and a diluent through 60 no. mesh and blending for 5 minutes, dissolving a binder in isopropyl alcohol to make 5 % w/v solution and granulating said blend to get wet mass and sieving said wet mass through mesh no. 8, air drying the said wet granules and further drying at 40° C in a tray drier till the loss on drying not more than 2.5 % at 95° C is achieved to get dried granules, passing said dried granules through 20 mesh, finally mixing with plurality of lubricants and blending the whole mixture for 5 minutes to obtain a final sustained release blend, compressing said final sustained release blend into

tablets by using tablet compression machine to get said sustained release tablet of mosaprlde,
sieving another part of said mosaprlde citrate dlhydrate, and plurality of diluent through 60 no. mesh and blending for 5 minutes, dissolving a binder in Isopropyl alcohol to make 5 % w/v solution and granulating said blend to get wet mass , sieving said wet mass through mesh no. 8 to obtain wet granules, air drying said wet granules and further drying at 40° C till the loss on drying observed not more than 2.5 % at 95° C is achieved to obtain dried granules, sieving said dried granules through 20 no. mesh, finally sieving the plurality of lubricants through 60 no. mesh and mixing with said dried 20 mesh passed granules and blending whole mixture for 5 minutes to get a said final immediate release blend, and filling of said enteric coated tablet of rabeprazole, said sustained release tablet of mosaprlde, along with said immediate release blend of mosaprlde in a hard gelatin capsule by using capsule filling machine equipped with a tablet loader.
2. A process as claimed in claim 1, wherein said mosaprlde is in the form of mosaprlde citrate dlhydrate, comprising of said Immediate release blend containing mosaprlde citrate dlhydrate ranging from 25 to 35 %, preferably 30.5 % of the total dose of mosaprlde and said sustained release which optionally is gastro retentive floating, tablet, comprising of mosaprlde citrate dlhydrate ranging from 65 to 55%, preferably 69.5% of the total mosaprlde dose, wherein said total dose of mosaprlde is 15 mg.
3. A process as claimed in claim 1, wherein said enteric coated tablets of rabeprazole comprises of rabeprazole sodium in the dose range of 10 mg to 20 mg per tablet.
4. A process as described in claim 1, wherein said enteric coated tablet of rabeprazole comprises of said diluent which is mannitol used in the range of


20- 90%, said plurality of alkalizing agent is sodium hydroxide used in the range of 0.1 to 5% of weight of said core tablet of rabeprazole, additionally L-arginine used in the range of 0.1 to 5% of weight of said core tablet of rabeprazole, said surfactant is sodium lauryl sulphate used in the range of 0.1 to 5% of weight of said core tablet of rabeprazole, said disintegrant is crospovidone used in range of 1 - 20% of weight of said core tablet of rabeprazole, said binder is either hydroxypropyl methyl cellulose or hydroxypropyl cellulose used in range of 0.1- 20% of weight of said core tablet of rabeprazole, said plurality of lubricant is talc used in the range of 1 to 5% of weight of said core tablet of rabeprazole, additionally colloidal silicon dioxide used in the range of 1 to 10% of weight of said core tablet of rabeprazole, additionally magnesium stearate used in the range of 1 to 5% of weight of said core tablet of rabeprazole.
5. A process as claimed in claim 1, wherein said seal coated tablet of rabeprazole comprises of said polymer which is hydroxypropyl methylcellulose used in the range of 1 to 5% of weight of said core tablet of rabeprazole, said plasticizer comprises oftriacetin used in range of 0.5- 10% of weight of said polymer, said enteric coating polymer comprises of either eudragit L 100 55 or hydroxy methylcellulose phthalate used in the range of 5% to 15% of weight of said seal coated tablet of rabeprazole , said opecifying agent is titanium dioxide used in the range of 8 to 10 % of weight of said enteric coating polymer, said antisticking agent is talc used in the range of 8- 10 % of weight of enteric coating polymer, and said coloring agent is tartrazine supra used in the range of 0.1 to 10% of weight of said enteric coating polymer
6. A process claimed in claim 1, wherein said sustained release tablet of mosapride comprises of a plurality of polymer which is hydroxypropyl methylcellulose K100M (viscosity grade 100000 cps) in amount ranging from 5 to 30% of the said final sustained release layer weight, preferably 8.33 % of the said final sustained release layer weight, and additionally hydroxypropyl methylcellulose (viscosity grade 15 cps) in amount ranging from 10 to 50% of the said final sustained release layer weight, preferably 16.66% of the Said final sustained

release layer weight, said diluent is microcrystalline cellulose used in the concentration range of 30 to 80%, said binder used is polyvinylpyrrolidine K30 in the concentration range of 0.5 to 5%, said lubricants is magnesium stearate used in the range of 0.1 to 5% of weight of said sustained release tablet of mosapride additionally colloidal silicon dioxide used in concentration range of 0.1 to 5% of weight of said sustained release tablet of mosapride. A process as claimed in claim 2, wherein said sustained release tablet of mosapride optionally be a gastro retentive floating tablet comprising of which sodium car boxy methylcellulose used in amount ranging from 3 to 25%, additionally contains contain xanthan gum in amount ranging from 1 to 10% of weight of said gastro retentive floating tablet.
A process as claimed in claim 1, wherein said immediate release blend of mosapride comprises of said plurality of diluents which is microcrystalline cellulose used in the range of 30 to 80% of weight of immediate release blend, and lactose DC 11 used in the concentration range of 30 to 80% of weight of immediate release blend, said binder is polyvinylpyrrolidone K30 used in the range of 0.5 to 5% of weight of immediate release blend, said plurality lubricant is magnesium stearate used in the concentration range of 0.1 to 5% of weight of immediate release blend and additionally colloidal silicon dioxide used in the concentration range of 0.1 to 5% of weight of immediate release blend.
this 2nd day of September, 2003

Documents:

891-mum-2003-claims(granted)-(02-09-2003).doc

891-mum-2003-claims(granted)-(02-09-2003).pdf

891-mum-2003-correspondence(20-04-2005).pdf

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

891-mum-2003-form 1(02-09-2003).pdf

891-mum-2003-form 13(04-04-2005).pdf

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

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

891-mum-2003-form 2(granted)-(02-09-2003).doc

891-mum-2003-form 2(granted)-(02-09-2003).pdf

891-mum-2003-form 23(11-09-2007).pdf

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

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

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

891-mum-2003-form 8(20-04-2005).pdf


Patent Number 209904
Indian Patent Application Number 891/MUM/2003
PG Journal Number 43/2008
Publication Date 24-Oct-2008
Grant Date 11-Sep-2007
Date of Filing 02-Sep-2003
Name of Patentee ARISTO PHARMACEUTICAL LTD
Applicant Address ARISTO PHARMACEUTICAL LTD., 3RD FLOOR, MERCANTILE CHAMBERS, 12, J N HEREDIA MARG, BALLARD ESTATE, MUMBAI 400 001.
Inventors:
# Inventor's Name Inventor's Address
1 MR. MANUTOSH MANOHAR ACHARYA 4/7, AMALTAS PARISAR SHAHPURA, BHOPAL (MP) INDIA.
PCT International Classification Number A61K 3/00
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA