FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule!3)
1. TITLE OF THE INVENTION: "ITOPRIDE HYDROCHLORIDE CONTROLLED RELEASE TABLETS"
2. APPLICANT
(a) NAME: LYKA LABS LIMITED
(b) NATIONALITY: Indian Company incorporated under the Indian
Companies ACT, 1956
(c) ADDRESS: 77, Nehru Road, Vile Parle (East), Mumbai - 400 099,
Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner
in which it is to be perform.


Technical Field:
This invention relates to controlled release oral solid dosage form of Itopride or its pharmaceutically acceptable salts, preferably Itopride Hydrochloride where in the drug release is controlled over an extended period of 24 hours to attain dissolution profile for better patient convenience and compliance. Further the invention relates to a process for preparation of controlled release tablets of Itopride or its pharmaceutically acceptable salts.
Background and Prior Art:
Gastrointestinal motility (GI) is a coordinated neuromuscular process that transports nutrients through the digestive system. Impaired GI motility, which may be involved in gastroesophageal reflux disease, gastroparesis (e.g., diabetic and postsurgical), irritable bowel syndrome and constipation. Impaired GI motility can also lead to post operative ileus and colonic pseudo-obstruction.
Very few compounds such as cisapride monohydrate, metoclopramide, erythromycin, domperidone, ondansetrone, tropisetrone, mosapride and Itopride etc. are useful for treating impaired GI motility.
Itopride which is chemically known as N-[p-[2-(Dimethylamino) ethoxy] benzyl] veratramide is a gastro-prokinetic drug of choice.
WO 0028984 by Kato et al. discloses medicines for treating and/or preventing digestive tract functional disorder induced by drugs such as antidepressive drugs, antihistaminic agents and antiarrhythmic agents which contain as the active ingredient Itopride or its salt; and medicinal composition which contain a drug inducing digestive tract functional disorder together with itopride or its salt so as to relieve or regulate the digestive tract functional disorder.
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US patent no 6548501 by Hakkinen et al. (Pfizer Inc.) describes methods for stimulating the motility of the gastrointestinal system in a patient which comprises administering a growth hormone secretagogue, a prodrug thereof or a pharmaceutically acceptable salt of the secretagogue or the prodrug. The prodrug is selected from prokinetic agents such as metoclopramide, erythromycin, domperidone, ondansetron, topisetron, mosapride and itopride.
Colonic motor dysfunction remedies comprising aminothiazole derivatives as active ingredients are discussed by Ueki et al. in US patent no 6673368. The above patent relates to combinations of itopride with other active ingredient for stomach ailments but does not disclose any controlled release pharmaceutical composition of itopride.
Itopride hydrochloride increases release of Acetylcholine (Ach) through dopamine D2 receptor antagonistic action and inhibits decomposing of released Ach through its Acetylcholine esterase (AChE) inhibitory action, resulting in enhancement of gastrointestinal motility activation of the gastric emptying ability. This causes reduction in gastric emptying time. Usual oral dose for adults of Itopride hydrochloride is 150mg daily in three divided doses before meals. 50mg Itopride hydrochloride conventional release tablets is already available in the market. These tablets are to be taken three times a day. Since biological half life for Itopride Hcl is 5.77 hrs, there is a need for developing a controlled release dosage form of Itopride Hcl for patient convenience and better patient compliance. There is no prior art on controlled release dosage form of the prokinetic agent, itopride, and there is a need for such a dosage form.
Objectives of this Invention:
Our main objective is to develop controlled release dosage form of a Prokinetic agetnt comprising Itopride or its pharmaceutically acceptable salts, which will release the drug for an extended period of time of over 8 hrs, 12 hrs or preferably 24 hours.
Another objective is to develop controlled release tablets which will help to maintain a steady peak plasma concentration for a longer period of time such as 24 hours, avoids fluctuations and dose dumping at one time thus eliminates risk of side effects/adverse
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reactions. Moreover the release of Itopride is so controlled that the ratio of peak plasma level to plasma level at 24 hrs, after administration and the mean residence time of Itopride are within desirable range for once-a -day therapy in humans.
Yet another objective is to eliminate the inconvenience to patients in taking multiple doses at different times, thus, ensuring patient compliance to prescribed dosage regimen.
Summary of the invention:
The present invention discloses an oral controlled release composition comprising
of Itopride or its pharmaceutically acceptable salt in the range of 50mg to 300mg, rate
controlling exicipient selected from polymers or fatty compounds or gum or mixture
thereof, and
one or more pharmaceutically acceptable excipients.
The rate controlling polymers are selected from cellulose ethers such as Methyl Cellulose, Ethyl Cellulose, Hydroxy Ethyl Cellulose, Hydroxy Propyl Cellulose, Hydroxy Propyl Methyl Cellulose, Hydroxy Propyl Ethyl Cellulose, CarboxyMethyl Cellulose, Crosslinked Carboxymethyl cellulose and its alkali salts, cellulose acetate, Ethyl hydroxyethyl cellulose, Hydroxy Ethyl Methyl Cellulose, Hydrophobically modified hydroxyethyl cellulose (HMHEC), hydrophobically modified ethylhydroxy ethyl cellulose (HMEHEC) Carboxymethyl Hydroxyethyl cellulose, Carboxymethyl hydrophobically modified Hydroxyethyl Cellulose and like, vinyl pyrollidone polymers such as polyvinyl pyrolidine, copolymers of vinyl pyrolidone and vinyl acetate, alkylene oxide homopolymers such as polypropylene oxide, ethylene oxide homopolymers etc. gums of natural origin such as guargum, gum arabic, gum tragacanth, karaya gum, locust bean gum, Pectin, Agar, Alginates, Carrageenan, Furcellaran derived from marine plants;
Poly saccharides such as dextran, gellan gum, rhamsan gum, welan gum, xanthan gum modified starches like carboxymethyl starch, sodium carboxymethyl starch; Acrylic acid polymer such as cross linked polymer of acrylic acid commercially known as
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Carbopols. Poly methacrylates commercially known as Eudragit OD, particularly Eudragit RS and Eudragit RL; etc.
Fatty compounds such as substituted or unsubstituted hydrocarbons, such as fatty acids, fatty alcohols, waxes such as glyceryl esters of fatty acids, mineral oil, vegetable oils and like, may also be used to control the release of drug either alone or in combination with rate controlling polymer .
The rate controlling polymer is added in the range from 0.5% to 50%. The pharmaceutically acceptable excipients are diluents, binders and Lubricants. The diluents are selected from Lactose, Micro crystalline cellulose, Maize starch and may be used in the range of 5%to90% of total weight of tablet.
The lubricant is selected from Magnesium Stearate, steric acid, Talc, Colloidal Silicon Dioxide, Polyethylene Glycols and their mixtures and may be used in the range of 0.5% to 5% of total weight of tablet.
The Binder is selected from Starch, gelatin, sugars, cellulose derivatives or polyvinyl pyrolidone and may be used in the range of 0.5% to 20% of total weight of tablet.
Detailed Description of the Invention:
The oral controlled release dosage form of the present invention comprising Itopride or its pharmaceutically acceptable salts, rate controlling polymer and pharmaceutically acceptable excipients, which releases 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 desirable range for once-a-day therapy in humans.
The tablets comprise of a mixture of Itopride or its pharmaceutically acceptable salt as active ingredient and a rate controlling hydrophilic polymer that forms a matrix system in suitable concentration, along with other tabletting excipients.The polymer rapidly absorbs water and swells to form a soft mucilagenous mass called 'hydrogel'system.
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The drug is entrapped in this matrix system and its release is controlled from this matrix system. The drug release profile is balance between swelling and slow erosion of polymer. Varying the concentration of the rate controlling polymer, the release of drug is extended for several hours (8hrs, 12hrs, 24hrs and like). A cellulose polymer like HPMC in combination with low and high viscosity polymers are used to extend the release for 24hrs.
In the present invention Itopride is released according to the following dissolution profile, when tested invitro in USP Type II Apparatus at 75 rpm using 0.1N hydrochloric acid as dissolution medium at 37°c.
Dissolution profile :
Time in hours % drug released
4hrs NLT15%
8 hrs 30% - 70%
24 hrs NLT 90%
More particularly, release of Itopride hydrochloride is controlled so as to follow the dissolution profile as below, when tested invitro in USP type II apparatus at 75 rpm using 0.1N hydrochloric acid as dissolution medium at 37°c which is given below:
Time in hours % drug released
4 hrs NLT 15%
8 hrs 35% - 55%
12 hrs 50% - 75%
24 hrs NLT 90%
Itopride or its pharmaceutically acceptable salt, preferably Itopride Hydrochloride may be used in controlled release tablets in the range of 50mg to 300mg. Itopride Hydrochloride may be used preferably in the range of 50 mg tO 150 mg, in particular it was used in an amount of 150mg.
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The rate controlling polymers was any material that slows the drug release rate of the dosage form. Usually it is a polymer or fatty compound or gums or a mixture thereof. Examples of rate controlling polymers include cellulose ethers such as Methyl Cellulose, Ethyl Cellulose, Hydroxy Ethyl Cellulose, Hydroxy Propyl Cellulose, Hydroxy Propyl Methyl Cellulose, Hydroxy Propyl Ethyl Cellulose, Carboxy Methyl Cellulose, Crosslinked Carboxymethyl cellulose and its alkali salts, cellulose acetate, Ethyl hydroxyethyl cellulose, Hydroxy Ethyl Methyl Cellulose, Hydrophobically modified hydroxy ethyl cellulose (HMHEC), hydrophobically modified ethyl hydroxy ethyl cellulose (HMEHEC) Carboxymethyl Hydroxyethyl cellulose, Carboxymethyl hydrophobically modified Hydroxyethyl Cellulose and like; Polyvinyl alcohol, vinyl pyrollidone polymers such as polyvinyl pyrolidone cross linked Poly vinyl pyrrolidone, copolymers of vinyl pyrolidone and vinyl acetate, alkylene oxide homopolymers such as polypropylene oxide, ethylene oxide homo polymers;
gums of natural origin such as guargum, gum arabic, gum tragacanth, karaya gum, locust bean gum, Pectin, Agar, Alginates, Carrageenan, Furcellaran derived from marine plants;
Poly saccharides such as dextran, gellan gum, rhamsan gum, welan gum, xanthan gum modified starches like carboxymethyl starch, sodium carboxymethyl starch; Acrylic acid polymer such as cross linked polymer of acrylic acid commercially known as Carbopols. Poly methacrylates commercially known as Eudragit OD, particularly Eudragit RS and Eudragit RL; etc.
Fatty compounds such as substituted or unsubstituted hydrocarbons, such as fatty acids, fatty alcohols, waxes such as glyceryl, esters of fatty acids, mineral oil, vegetable oils and like waxes may also be used to control the release of drug either alone or in combination with rate controlling polymer.
For present invention, more preferred rate controlling polymer was the cellulose ethers such as Hydroxy Propyl Methyl Cellulose polymer. Several grades of the same varying in viscosity (20cps to 1, 00, OOOcps) and extent of substitution are available. It may be
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used alone or in combination mixture. The concentration of rate controlling polymer was added in the range from 0.5% to 50% of total weight of the tablet.
Particularly for one of the embodiment, preferred rate controlling polymer is a combination of high viscosity, greater than 50,000 cps.Preferably 100,000 cps, commercially available as Methocel K100M of Dow Chemical and Metolose 90SH 100,000 of ShinEtsu and a low viscosity grade of HPMC having viscosity less than 10,000 cps, preferably 4,000 cps commercially available as Methocel K4M of Dow Chemical and Metolose 90SH 4,000 of ShinEtsu are used.
In yet another embodiment of present invention the combination of grades of HPMC used has viscosity of about 15,000 cps commercially known as Methocel K15M of Dow Chemical and Metolose 90SH 15000 of ShinEtsu and viscosity as high as 100,000 cps commercially known as Methocel K100M of Dow Chemical and Metolose 90SH 1,00,000 of ShinEtsu.
The rate controlling polymer is added in the range from 0.5% to 50%.
The other excipients for tabletting used in embodiments of present invention include diluents such as Lactose, Micro crystalline cellulose, Maize starch etc; Lubricants such as Magnesium Stearate, stearic acid Talc and Colloidal Silicon Dioxide, Polyethylene Glycols and their mixtures; Binders such as Starch, gelatin, sugars, cellulose derivatives Polyvinyl pyrolidone and like.
The diluents may be added in the range of 5%to90% of total weight of tablet particularly was added in the range of 20% to 30% by weight of the total composition.
The lubricant may be added in the range of 0.5% to 5% of total weight of tablet particularly was added in the range of 1% to 2% by weight of the total composition.
The Binder may be added in the range of 0.5% to 20% of total weight of tablet particularly was added in the range of 1% to 6% by weight of the total composition.
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A process for preparation of the controlled release tablet comprises steps of:
1. Itopride Hydrochloride was passed through 100 mesh sieve.
2. Lactose Monohydrate, Microcrystalline Cellulose, Maize Starch, Hydroxy Propyl methyl cellulose HPMC K15M and Hydroxy Propyl methyl cellulose HPMC K100M, Povidone (PVP K-30) were passed through 40 mesh sieve and mixed together.

3. Ingredients of step 1 were mixed with blend of step 2 in geometric proportion.
4. The blend of step 3 was granulated with Isopropyl alcohol till wet mass of suitable consistency obtained.
5. The wet mass was passed through 12# sieve.
6. The granules were dried in drier first at ambient temp then at 35°C-40°C for suitable period of time and the dried granules were passed through 20 mesh sieve.
7. Talc, Magnesium Stearate and Colloidal Silicon Dioxide were sifted through 40# Sieve and mixed with dried granules of step 6 to obtain lubricated granules.
8. The lubricated granules were compressed into a tablet. The lubricated granules can be filled in capsule, or may be used as granules in any suitable form.
A circular, biconvex tablet is having Diameter = 10.4 mm, Average Wt = 345 mg, and Hardness = 2-6 kg / cm2 .
The controlled released tablets of present invention so obtained showed drug release profile as follows when dissolution is checked in a USP type II dissolution apparatus at 75 rpm, In 0.1 M HCL as dissolution medium at 37°C.
Time in hours % drug released
4hrs NLT15%
8 hrs 35% - 55%
12 hrs 50% - 75%
24 hrs NLT 90%
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It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be falling within the scope of the invention.
Example 1

Sr.
No. Ingredients Qty. (in mg)
1) Itopride Hydrochloride s 150 mg
2) Lactose Monohydrate 64 mg
3) Macrocrystalline Cellulose / 25 mg
4) Maize Starch 30 mg
5) Hydroxy Propyl Methyl Cellulose (HPMC K15M)
< Metolose90SH 15,000 40 mg
6) Hydroxy propyl methyl cellulose (HPMC K100M) Metolose 90SH 100,000 / 25 mg
7) Povidone (PVP K-30) 5mg
8) Magnesium Stearate 2mg
9) Colloidal Silicon Dioxide y 2mg
10) Talc 2mg
11 Isopropyl alcohol Volatile
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STEP1
Itopride Hydrochloride was passed through 100 mesh sieve.
STEP 2
Lactose Monohydrate, Microcrystalline Cellulose, Maize Starch, Hydroxy Propyl methyl cellulose HPMC K15M and Hydroxy Propyl methyl cellulose HPMC K100M, Povidone (PVP K-30) were passed through 40 mesh sieved and mixed together.
STEP 3
Ingredients of step 1 were mixed with blend of step 2 in geometric proportion.
STEP 4
The blend of step 3 was granulated with Isopropyl alcohol till wet mass of suitable consistency obtained.
STEP 5
The wet mass was passed through 12# sieve.
STEP 6
The granules were dried in dryer first at ambient temp then at 35°C-40°C for suitable period of time and the dried granules were passed through 20 mesh sieve.
STEP 7
Talc, Magnesium Stearate and Colloidal Silicon Dioxide were sifted through 40# Sieve and mixed with dried granules of step 6 to obtain lubricated granules.
STEP 8
The lubricated granules were compressed to obtain Circular, Biconvex tablets.
Diameter = 10.4 mm
Average Wt. = 345 mg
Hardness = 2-6 kg / cm2
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Example 2

Sr.
No. Ingredients Qty. (in mg)
1) Itopride Hydrochloride 150 mg
2) Lactose Monohydrate 57 mg
3) Microcrystalline Cellulose 17 mg
4) Maize Starch 15 mg
5) Hydroxy Propyl Methyl Cellulose (HPMC K4M) Metolose 90SH 4,000 70 mg
6) Hydroxy propyl methyl cellulose (HPMC K100M) Metolose 90SH 100,000 25 mg
7) Povidone (PVP K-30) 5mg
8) Magnesium Stearate 2mg
9) Colloidal Silicon Dioxide 1 mg
10) Talc 3mg
H) Isopropyl alcohol Volatile
STEP1
Itopride Hydrochloride was passed through 100 mesh sieve.
STEP 2
Lactose Monohydrate, Microcrystalline Cellulose, Maize Starch, Hydroxy propyl methyl cellulose HPMC K4M and Hydroxy Propyl methyl cellulose HPMC K100M, Povidone (PVP K-30) were passed through 40 mesh sieved and mixed together.
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STEP 3
Ingredients of step 1 were mixed with blend of step 2 in geometric proportion.
STEP 4
The blend of step 3 was granulated with Isopropyl alcohol till wet mass of suitable consistency obtained.
STEPS
The wet mass was passed through 12# sieve.
STEP 6
The granules were dried in dryer first at ambient temperature then at 35°C-40°C for suitable period of time and the dried granules were passed through 20 mesh sieve.
STEP 7
Talc, Magnesium Stearate and Colloidal Silicon Dioxide were sifted through 40# Sieve and mixed with dried granules of step 6 to obtain lubricated granules.
STEP 8
The lubricated granules were compressed to obtain Circular, Biconvex tablets.
Diameter = 10.4 mm
Average Wt. = 345 mg
Hardness = 2-6 kg / cm2
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We Claim,
1. A controlled release oral dosage form comprising Itopride or its pharmaceutical^ acceptable salt in the range of 50 mg to 300 mg; wherein said dosage form is characterized by having a rate controlling polymer in an amount of 0.5 % - 50% of total weight of dosage form to control the rate of drug release over the period of 24 hours along with one or more pharmaceutically acceptable excipients.
2. The controlled release dosage form as claimed in claim 1, wherein said rate controlling polymers are optionally in combination with fatty components or gums.
3. The controlled release dosage form as claimed in claim 2, wherein said rate controlling polymers are selected from cellulose ethers such as Methyl Cellulose, Ethyl Cellulose, Hydroxy Ethyl Cellulose, Hydroxy Propyl Cellulose, Hydroxy Propyl Methyl Cellulose, Hydroxy Propyl Ethyl Cellulose, Carboxymethyl Cellulose, Crosslinked Carboxymethyl cellulose and its alkali salts, cellulose acetate, Ethyl hydroxyethyl cellulose, Hydroxy Ethyl Methyl Cellulose, Hydrophobically modified hydroxyl ethyl cellulose (HMHEC), hydrophobically modified ethylhydroxy ethyl cellulose (HMEHEC) Carboxymethyl Hydroxyethyl cellulose, Carboxymethyl hydrophobically modified Hydroxyethyl Cellulose and Polyvinyl alcohol, vinyl pyrrolidone polymers such as polyvinyl pyrrolidone, copolymers of vinyl pyrrolidone and vinyl acetate, alkylene oxide homopolymers such as propylene oxide and ethylene oxide homopolymers.
4. The controlled release dosage form as claimed in claim 2, wherein said fatty compounds are selected from substituted or unsubstituted hydrocarbons, such as fatty acids, fatty alcohols, waxes such as glyceryl esters of fatty acids, mineral oil or vegetable oil.
5. The controlled release dosage form as claimed in claim 2, wherein said gums are of natural origin such as guar gum, gum arabic, gum tragacanth, karaya gum, locust bean gum, pectin, agar, alginates, carrageenan, furcellaran derived from marine plants.

6. The controlled release dosage form as claimed in claim I, wherein the pharmaceutical/ acceptable excipients are diluents selected from Lactose, Microcrystalline Cellulose, Maize Starch in the range of 5% to 90% of total weight of dosage form; binders selected from Starch, gelatin, sugars, cellulose derivatives or polyvinyl pyrrolidone in the range of 0.5% to 20% of total weight of dosage form and lubricants selected from Magnesium stearate, stearic acid, talc, colloidal silicon dioxide, polyethylene glycols and their mixtures in the range of 0.5% to 5% of total weight of dosage form.
7. The controlled release dosage form according to any of preceding claims, wherein the dosage form of said composition, is in the form of granules, tablet or capsules.
8. The controlled release dosage form comprising Itopride or its pharmaceutically acceptable salt as substantially described herein with reference to foregoing examples 1 and 2.
Dated this the 23rd day of March 2005