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FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
PROVISIONAL SPECIFICATION
[Section 10, and Rule 13]
Title
PROLONGED RELEASE FORMULATION OF AMISULPRIDE
Applicant
Name: Torrent Pharmaceuticals Limited
Nationality: Indian
Address: Torrent House, Off Ashram Road, Near Dinesh
Hall, Ahmedabad 380 009, Gujarat, India
The following specification describes the nature of the invention


PROLONGED RELEASE FORMULATION OF AMISULPRIDE
FIELD OF THE INVENTION
The present invention relates to a prolonged release dosage form comprising amisulpride preferably in the form of a multiunit pellets or micro tablets filled into capsule or bilayered tablet. It also relates to the process for preparing the said dosage form.
BACKGROUND OF THE INVENTION
Amisulpride is a selective dopamine antagonist used in the treatment of psychoses, more particularly in the treatment of paranoid and productive schizophrenias or acute delirious psychoses and in the treatment of schizophrenia deficiency states, residual psychotic changes and inhibitory states with slowing. It is commercially available in the dosage range from 50 mg to 400 mg as immediate release tablets in the trade name of Solian® Tablets. Amisulpride shows linear pharmacokinetics with bioavailability of 48%, low protein binding (17%) and an elimination half-life of ~12 h. It is predominantly eliminated in the urine as the parent compound. Its dosage ranges from 200 to 1200 mg/day. Hence patients would be required to take several tablets daily, which results in patient incompliance.
Therefore, it would be of considerable clinical benefit to design orally deliverable dosage form of amisulpride as a prolonged release dosage form.
Further, the administration of amisulpride by the oral route can lead to a low and/or irregular bioavailability. The term "bioavailability" is understood here as meaning the
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fraction of active principle which is absorbed from its pharmaceutical form and which reaches the plasma.
The low or irregular bioavailability can be the outcome of several factors amongst which are discussed below: low solubility or a very slow dissolution of the active agent; instability of the active agent, either over the entire length of the gastrointestinal tract, or in one part of it only; enzymatic degradation in the mucous membrane or at the hepatic level of the active agent; slow or incomplete absorption of the active agent due to a slow passive diffusion through the intestine, or, in the case of an active mechanism, a saturation of the transport system.
It is known that the bioavailability of certain active agents can be modified by means of a prolonged release formulation which releases the active agent over the entire length of the gastrointestinal tract.
French patent 7801632 discloses the compound amisulpride, its isomers and some of its derivatives.
US6069165 discloses a pharmaceutical composition of amisulpride comprising of a lipophilic phase, The lipid materials that can be used in the present invention may be one or more of fatty acids, glycerides, mineral oils or other oils. It claims to increase the bioavailability of the drug by incorporating the lipid phase in the dosage form.
JP62178518 discloses a once a day formulation of a sulpiride. The doses form comprises of more than two hydrogel forming excipients like gelatin, hydroxypropyl cellulose, methylcellulose, etc. It discloses the use of mixtures of water and ethanol for the granulation of the active compound with that of the hydrogel forming excipients.
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US20010046473 discloses a gastric retained dosage form of amisulpride comprising of carbon dioxide gas generating system and a polymeric composition capable of retaining the generated gas. So it provides a floating dosage form of amisulpride. According to applicant benzamides, such as amisulpride are generally poorly absorbed at the colonic level in man, but that, on the other hand, they are better absorbed in the small intestine. For certain of these benzamides, absorption takes place quasi-exclusively in the upper parts of the small intestine, that is to say the jejunum, the duodenum or the proximal ileum. Hence, applicant has considered improving the bioavailability of the amisulpride by formulating them in the form of a pharmaceutical composition for gastric residence favouring absorption at the level of the small intestine, or evens, more specifically, the upper parts of the small intestine. However, there are some disadvantages associated with gastroretentive system, like the tablet may get stuck in the pylorus; variability in bioavailability, depending on standing or sleeping position of patient.
US6861072 discloses a controlled release gastric retained dosage form of an active agent covering amisulpride. The dosage form of the invention comprises a gas generating system, hydrophilic polymer matrix and an excipient which is capable of modifying the release profile of the active agent.
US2006153925 A1 discloses an orodispersible dosage form of amisulpride comprising of coated particles of the drug along with excipients used conventionally in the preparation of rapidly disintegrating dosage forms. It affords immediate release of the drug.
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Hence there is a need for the further development of prolonged release dosage form of amisulpride that is simple and easy to manufacture, provide better clinical effects and improved patient compliance.
SUMMARY OF THE INVENTION
The first aspect of the present invention is to provide a prolonged release dosage form of amisulpride.
Another aspect of the present-invention is to provide a prolonged release dosage form of amisulpride in the form of a bilayer tablet comprising of a prolonged release blend and an immediate release blend.
In yet another aspect, the present invention provides a prolonged release formulation of amisulpride that can be administered orally once or twice daily.
Another aspect of the present invention to provide a method of preparation of a prolonged release formulation of amisulpride, which comprises of two parts , wherein the first part is immediate release part which is manufactured by mixing amisulpride with suitable diluents and optionally disintegrants, then granulating with a binder solution and drying the granules. The dried granules may be milled or suitably size reduced and mixed with lubricants and optionally with other pharmaceutically acceptable ingredients.
The second part is prolonged release part which is manufactured by mixing amisulpride with suitable diluents, release controlling agents and optionally other pharmaceutically acceptable excipient and granulating with a binder solution and
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drying the granules. The dried granules may be milled or suitably size reduced and mixed with lubricants and optionally with other pharmaceutical ly acceptable ingredients.
The above said parts of amisulpride may be formulated into a suitable dosage form. For example, they can be formulated into bilayered tablets, tablet in a tablet, inlay tablets and the like.
Yet another aspect of the present invention is to provide a method of treating an animal, particularly a human being in need thereof, comprising administering the said dosage form.
DETAILED DESCRIPTION
In one general embodiment, the present invention provides prolonged release dosage form of amisulpride, more particularly a bilayer tablet of amisulpride which comprises of: a) Immediate release blend and b) Prolonged release blend.
The term "dosage form" denotes any physical form of the formulation that contains an amount sufficient to produce a therapeutic effect with a single administration. It may be in the form of solid dosage form like tablets, capsules etc. The preferred dosage form of the present invention is a tablet like multilayered tablets, compression coated tablets or inlay tablets. The most preferred dosage form is a bilayer tablet.
The term "immediate release blend" or "immediate release part" as used herein or elsewhere encompasses mixtures of excipients and active agent which provide immediate release of the active agent when administered to a patient. It can be clear to
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a person of ordinary skill that immediate release blend can be prepared by dry granulation process or by wet granulation process or by direct compression process. The preferred process is a wet granulation process.
The term "prolonged release blend" or "prolonged release part" as used herein or elsewhere encompass mixtures of active agent, rate controlling polymers and pharmaceuticaily acceptable excipients. The term prolonged release blend can be conveniently replaced by similar terms like modified release, controlled release, prolonged release, timed release, retarded release, extended release and delayed release, etc. The prolonged release blend of the present invention can be prepared by conventional methods like polymer matrix composition, coating composition or likewise. "Prolonged release" is defined herein as release of an active agent in a continuous manner over a prolonged period of time. By "prolonged period of time" it is meant a continuous period of time of greater than about 1 hour, preferably, greater than about 4 hours, more preferably, greater than about 8 hours.
The term "prolonged release oral dosage" as used herein refers to the release of an active ingredient such as a drug from a composition, formulation or dosage form in which the active ingredient is released according to a desired profile over an extended period of time and is taken to encompass sustained release, modified release, controlled release, delayed release and the like. "Prolonged release oral dosage" is defined herein as release of an active agent in a continuous manner over a prolonged period of time.
For the bilayered tablet composition, 25- 28 % w/w of active agent is used in immediate release part and 75 to 72% w/w of active agent is used in prolonged release part.
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According to instant invention, the desired release profile of Amisulpride is as below:
1 hour - Not more than 50%
4 hour - Not more than 85%
8 hour - More than 90%
The dissolution condition being:
Apparatus: USP Type II (Paddle); RPM: 50 0 - 2hr, 900 mL, 0.01 N HC1 followed by
2 - 3hr, 900 mL, 4.5 pH Acetate buffer followed by
3 - 8 hr, 900 mL, 6.8 pH Phosphate buffer
The term "amisulpride" or "active agent" as used herein is to encompass free base, metabolites, optically active enantiomer or pharmaceutically acceptable acid addition salts or mixtures thereof. It is also intended to include various polymorphic forms of amisulpride or its pharmaceutically acceptable acid addition salts.
The particle size of 90% particles of amisulpride is less than 30 microns; preferably particle size of 90% particles of levosulpride is less than 20 microns; more preferably particle size of 90% particles of levosulpride is less than 10 microns.
According to instant invention, the most preferred particle size of amisulpride is as follows: A Particle size of 90% particles of amisulpride is less than 10 microns.
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The excipients that can be used as the release controlling agent within the granule(s) and over the tablet as coating are described in greater detail herein below.
The release controlling agents as used herein in the granulation or coating are selected from pH independent polymer and pH dependent polymer more preferably pH independent polymer. The release controlling agent may be hydrophillic or hydrophobic in nature.
The pH dependent polymer that can be employed in the present invention may be such as, for example, an alginate material, a carboxyvinyl polymer or a sodium salt of carboxymethyl cellulose.
The pH independent release controlling polymer may be selected from the group comprising of hydroxy propyl methyl cellulose, hydroxy propyl ethyl cellulose, hydroxy propyl cellulose, hydroxy ethyl cellulose, methyl cellulose, xantham gum or polyethylene oxide, ammonio methacrylate copolymers type A and B as described in USP, polyacrylate dispersion 30% as described in Ph. Eur., or combination thereof.
The preferred release controlling agent of the present invention is hydroxy propyl methyl cellulose sold under the brand name of Hypromellose.
The combination of hydrophillic polymer like low viscosity hypromellose and disintegrants like crospovidone are used in instant invention to achieve desired prolonged release profile, wherein hydrophillic polymer will act as matrix to retard the dissolution of active agent and disintegrant will absorb water which will cause faster hydration of the hydrophillic matrix.
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A dosage form as described herein may comprise one or more pharmaceutically acceptable excipients, during granulation, compression or coating, and may be selected from diluent/filler, glidants, disintegrant, binder, lubricant, release controlling agents, plasticizers, opaciflers, stabilizers, anti-tacking agent, surfactant, coloring agent and others known to the skilled person in the art. As will be appreciated by those skilled in the art, the exact choice of excipient and their relative amounts will depend to some extent on the final oral dosage form.
Examples of "diluents" or "fillers" include but not limited to dibasic calcium phosphate, lactose anhydrous, lactose monohydrate, pregelatinized starch, mannitol, microcrystalline cellulose, powdered cellulose, sorbitol, starch or mixtures thereof. The diluent may be present in an amount ranging from 1 % to 80 % by weight of the composition.
Examples of "binders" include but not limited to polyvinylpyrrolidone, copovidone, cellulose derivatives, shellac, zein, gelatin, polymethacrylates, synthetic resins, acrylates or mixtures thereof. The binder may be present in an amount ranging from 0.1 % to 10 % by weight of the composition.
Examples of "glidants" or "anti-tacking agents" include but not limited to colloidal silica, talc, calcium silicate, magnesium silicate, colloidal silicondioxide or mixtures thereof. The glidant or anti-tacking agent may be present in an amount ranging from 0.1 % to 5 % by weight of the composition.
Examples of "lubricants" include but not limited to Stearic acid, Polyethylene glycol, Magnesium stearate, Calcium stearate, Zinc stearate, Talc or Silica, Hydrogenated
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castor oil or mixtures thereof. The lubricant may be prese'nt in an amount ranging from 0.1 %to 5 % by weight of the composition.-
Examples of "surfactants" include but not limited to sodium dodecyl sulfate, ammonium lauryl sulfate, and other alkyl sulfate, dodecyl betaine, dodecyl dimethylamine oxide, alkyl poly (ethylene oxide), copolymers of poly (ethylene oxide) and poly (propylene oxide) commercially called as poloxamers. The preferred surfactants are inhibitor of the P-glycoprotein like polyethoxylated tocopheryl succinate, polyoxyethylene castor oil or polyethoxylated castor oil, polyoxyethylene sorbitan monolaurate (Tween®20), polyoxyethylene sorbitan monopalmitate (Tween®40), polyoxyethylene sorbitan monostearate (Tween®60). polyoxyethylene sorbitan monooleate (Tween®80), polyethylene glycol monostearate (Polyoxyl 40 stearate),polyoxyethylene-polyoxypropylene copolymers, octylphenolethoxylate, etc. The most preferable surfactant in the present invention is polyethylene glycol monostearate (Polyoxyl 40 Stearate). The surfactant may be present preferably in the range of 0.25-5%.
Plasticizer may be used in a coat to increase the flexibility and strength of the layer and may be selected from Triethyl citrate, PEG 6000, Glyceryl monopalmetostearate / Glyceryl monostearate, Dibutyl phthalate, Macrogol or other materials known to one of ordinary skill in the art.
Examples of opacifier includes but not limited to titanium dioxide or talc.
Examples of solvents used to prepare solution of release controlling agent for the granulation or coating includes aqueous or organic solvent or combination thereof.
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The immediate release blend or prolonged release blend of the present invention can be prepared by any method known to the person skilled in art such as wet granulation, direct compression, extrusion spheronization or any other possible methods. Preferably wet granulation method is applied.
Jn another general embodiment, the present invention provides process for preparing the prolonged release dosage form according to present invention.
The general manufacturing process is as below:
The pharmaceutical composition is prepared in two parts. The first part is immediate release part which is manufactured by mixing Amisulpride with suitable diluents and optionally disintegrants, then granulating with a binder solution and drying the granules. The dried granules may be milled or suitably size reduced and mixed with lubricants and optionally with other pharmaceutically acceptable ingredients.
The second part is prolonged release part which is manufactured by mixing Amisulpride with suitable diluents, release controlling agent(s) and optionally other pharmaceutically acceptable excipient and granulating with a binder solution and drying the granules. The dried granules may be milled or suitably size reduced and mixed with lubricants and optionally with other pharmaceutically acceptable ingredients.
The above said parts of amisulpride may be formulated into a suitable dosage form. For example, they can be formulated into bilayered tablets, tablet in a tablet, inlay tablets and the like.
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In another embodiment, the immediate release pharmaceutical composition of amisulpride is coated over prolonged release pharmaceutical composition of amisulpride.
In another embodiment, the immediate release pharmaceutical composition of amisulpride and prolonged release pharmaceutical composition of amisulpride is filled into capsules in the form of granules, beads, pellets and the like..
In another embodiment, the prolonged release pharmaceutical composition of amisulpride is manufactured as single layer tablet dosage form or monolithic tablet dosage form.
The invention will be further illustrated by the following Examples, however, without
restricting its scope to these embodiments.
EXAMPLE-1
Table I

Sr.No Ingredients Mg/Tab
Immediate release (IR) blend
Dry mix
1. Amisulpride 112.00
2. Lactose Monohydrate 54.60
3. Micro crystal line Cellulose 54.26
4. Colloidal Silicon Dioxide 5.25
5. Ferric oxide red 0.90
Granulation
1. Polyoxyl 40 Stearate 1.75
2. Hydroxy propyl methyl cellulose 10.29
Purified Water* q.s.
Blending
I. Sodium Starch Glycol ate 25.05
2. Microcrystalline cellulose (PH 200) 19.19
3. Colloidal Silicon Dioxide 5.SS
4. Talc ■ 5.88
5. Magnesium Stearate 7.35
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Table I (Contd.)

Sr.No Ingredients Mg/Tab
Prolonged Release Blend
Dry Mix
1. Amisulpride 288.00
2. Lactose Monohydrate 55.68
3. Microcrystalline Cellulose 37.44
4. Hydroxy Propyl Methyl Cellulose (K 100LV) 115.20
5. Crospovidone 23.04
Granulation
1. Hydroxy Propyl Methyl Cellulose 11.52
2. Isopropyl Alcohol* q.s
3. Water* q.s
Blending
1. Microcrystalline Cellulose 28.80
2. Colloidal Silicon Dioxide 11.52
3. Magnesium Stearate 14.40
Compression
1 Immediate Release (IR) Blend 302.40
2 Prolonged release Blend 585.60
Total weight 888.00
Manufacturing Process:
1) Preparation of Immediate Release (IR) Blend:
1. Amisulpride, Lactose Monohydrate, Microcrystalline Cellulose, Colloidal Silicon Dioxide and Ferric oxide red were sifted through appropriate sieves and mixed.
2. Polyoxyl 40 Stearate was mixed with some quantity of warm purified water with a stirrer. Hydroxy propyl methyl cellulose was dispersed in the remaining quantity of water with stirring till there is no lump. Then the solution of Polyoxyl 40 stearate was added in the dispersion of hydroxy propyl methyl cellulose with stirring.
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3. Materials of Step No-1 was loaded in RMG and granulated with the binder solution of Step No-2.
4. The wet mass obtained from the Step No- 3 was dried and sized through appropriate sieve.
5. Sodium Starch Glycolate, Microcrystalline Cellulose, Talc and Colloidal Silicon Dioxide were sifted through appropriate sieve.
6. Magnesium Stearate was sifted through appropriate sieve.
7. Granules of Step No-4 were blended with the mixtures obtained from the Step No-5 in a blender.
8. Blend of Step No-7 was lubricated with the Magnesium Stearate obtained from Step No-6 in a blender.
Preparation of Prolonged Release Blend:
1. Amisulpride, Lactose Monohydrate, Microcrystalline Cellulose, Hydroxy Propyl Methyl Cellulose (K100LV) and Crospovidone were sifted through appropriate sieves and mixed.
2. Hydroxy Propyl Methyl Cellulose was dispersed with the solvent mixtures of Isopropyl alcohol and water with stirring till there are no lumps.
3. Materials of Step No-1 was loaded in a RMG and granulated with the binder solution of Step No-2.
4. Wet mass of Step No-3 was dried and sieved through appropriate sieve.
5. Microcrystalline Cellulose and Colloidal Silicon dioxide were sifted through appropriate sieves.
6. Magnesium Stearate was sifted through appropriate sieve.
7. Granules of Step No-4 were blended with ingredients of Step No-5 in a blender.
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8. Blend obtained from Step No-7 was lubricated with Magnesium Stearate of Step No-6.
Compression:
1. The ]R blend and the prolonged release blend were compressed to tablets using suitable punches and compression machine.
The dissolution data of Example 1 is as below:

Dissolution Medium Time (hrs) % Drug Dissolved
0.01NHC1 1 41

2 54
pH 4.5 Acetate Buffer i 3 69
pH6.8 Phosphate Buffer 4 82

6 92

8 101

10 105
Dated this 26th day of August, 2008

Praveen Chand Gandhi,
Torrent Pharmaceuticals Limited,
Torrent Research Centre
P.O. Bhat - 382428, Gandhinagar
Gujarat, India
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