FORM 2
COMPLETE
Oral Single Unit Dosage Form for Once a day Delivery of Itopride, a Prokinetic Agent.
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.
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 gastroesophageal 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
(8) 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.
(9) 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 single tablet on a bilayer tableting machine.
(10) 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.

(11) 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).
(12) 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 invitro 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 HCl as dissolution medium at 37 ± 0.5°C for 8 hours.

DETAILED DESCRIPTION OF THE INVENTION
(13) 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 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. 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, C18, Zorbax XBD column using buffer (prepared 0.01M

potassiumdi-hydrogen orthophosphatebuffer and adjusted the pH3.0 with diluted ortho-phosphoric acid) and acetonitrile as mobile phase in ratio of 80:20 respectively and detection was done at 260 nm. The stability studies were done as per ICH guidelines for 6 months.
(016) 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).
Examplel
Formulation of Bilayer Tablet containing Itopride hydrochloride by non-aqueous
granulation.
(17) 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 which releases the drug within 8-12 hours to provide a maintenance dose for maintaining prolonged duration of action.
(18) Sustained 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. 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/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 sunlight. The dissolution of above formulation was carried out by using USP type I (basket) apparatus at 100 rpm in 900 ml 0.1 N HC1 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 % (preferably30%-50%)
2 hr 44.80 % (preferably40%-60%) 4hr 64.21% (preferably60%-70%) 6 hr 75.35 % (preferably70%-85%)
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.

Table 2

Itopride SR gastroretentive Layer mg/tablet
Itopride hydrochloride 110.0
Methocel K 100 M 10.0
Methocel K 4 M 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 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.
(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/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 sunlight. The dissolution of above formulation was carried out by using USP type I (basket) apparatus at 100 rpm in 900 ml 0.1 N HC1 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.

Contd.. Table 3 :
Magnesium Stearate 2.5
Colloidal Silicon Dioxide 2.5
Filled weight 274.0 mg
Average weight of capsule 430 mg
Hard gelatin Capsule size ' 1'
(026) Itopride Immediate release tablet comprises Itopride hydrocloride, 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. S, 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.
(027) Itopride sustained release floating mass 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 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.

(028) The size ' 1' capsules were filled with itopride immediate release tablet and itopide 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 sunlight. The dissolution of above formulation was carried out by using USP type I (basket) apparatus at 100 rpm in 900 ml 0.1 N HCl at 37.0 ± 0.5°C . In vitro drug release profile of itopride sustained release found to be:
Time % drug release of the labeled amount
1 hr 35.56 % (preferably 30%-50%)
2 hr 42.15 % (preferably 40%-60%) 4 hr 68.26 % (preferably 60%-70%) 6 hr 71.24 % (preferably 70%-85%)
8 hr 85.41% (preferably not less than 80%)

Claims
1. A process for making oral single unit dosage form of a prokinetic agent, itopride and or its pharmaceutically acceptable salts with pharmaceutically acceptable excipients wherein the single unit dosage form comprises of a bilayer tablet, or a tablet, and blend or granules in a capsule, where the total dose of itopride is split, partitioned or distributed in the dosage forms to provide a loading dose and a controlled release of maintenance dose for once a day administration wherein itopride release is according to the following dissolution profile, (a) Not less than 30 % of the drug is release within 15 minute, which is a loading dose, (b) between 40% and 65 % of the drug should be release between 2 to 3 hours, (c) between 50 - 75 % of the drug should be released between 3-5 hours, (d) Between 70 - 90 % of the drug should be released between 6-8 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 0.1 N HC1 as dissolution medium at 37 ± 0.5°C for 8 hours. This media provides the proper "sink conditions" criteria as defined in United States Pharmacopoeia (Ref. United States Pharmacopoeia 27, Page No. 2514).
2. An oral controlled release composition as claimed in claim 1 wherein the amount of itopride and its pharmaceutically acceptable salts expressed as "itopride" is in range of 50 - 200 mg.
3. A process as claimed in claim 1 wherein the said bilayer tablet comprises of two part in which one part is immediate release containing loading dose with pharmaceutically acceptable excipients, which contains itopride in concentration ranging from 20 to 40 %, preferably 26.66 % of the total dose of itopride (total dose 150 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 itopride in this layer ranges from 60 to 85%, preferably 73.34% of the total itopride dose

(total dose 150 mg). The capsule part comprises of two part in which one part is immediate release tablet containing loading dose with pharmaceutically acceptable excipients, which contains itopride hydrochloride expressed as itopride in concentration ranging from 20 to 40 %, preferably 26.66 % of the total dose of itopride (preferably 150 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 itopride in this layer ranges from 60 to 85%, preferably 73.34% of the total itopride dose (total dose 150 mg).
4. A process as claimed in claim 3 where the bilayer tablet controlled or sustained release layer 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. 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.
5. A process as claimed in claim 3 where the 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 release rate controlling excipients as explained in claim 4 and 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. As claimed in claim 3 bilayer tablet in which 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 contain the said excipients.
6. A process as claimed in claim 3 where the capsule part comprises immediate release tablet comprising microcrystalline cellulose, 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)