FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
PROVISIONAL SPECIFICATION
[Section 10, and Rule 13]
Title
PROLONGED RELEASE COMPOSITION OF LEVOSULPIRIDE


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 COMPOSITION OF LEVOSULPIRIDE
FIELD OF THE INVENTION
The present invention relates to prolonged release oral dosage form comprising levosulpiride, 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
Levosulpiride is a levo-enantiomer form of racemic sulpiride, substituted benzamide derivative and a highly selective antagonist of D2 receptors with antipsychotic, antidepressant and antiemetic activity.
Levosulpiride is used at low doses in dyspepsia (25mg) and at higher dose as an antipsychotics (50 & 100mg).
Levosulpiride is commercially available in the dose strength of 25/50/100mg tablets as Levopraid®. Levosupiride has plasma half life of about 9.7 hours and has shown linear kinetics over the dose range of 25 to 100 mg. The bioavailability is about 20-30%. It has been observed that poor oral bioavailability is primarily due to the factors such as less aqueous solubility, incomplete absorption in the GIT, predominant absorption from upper GIT, presence of food and consequent change in gastric transit time. The normal dosage frequency of levosulpiride is three times daily for gastrointestinal disorders. This dosage frequency leads to patient incompliance.
Therefore, it would be of considerable clinical benefit to design orally deliverable dosage form of levosulpiride as once daily dosage form. However due to absorption
1

window, the development of prolonged release dosage form which gives immediate as well as long lasting effect is challenging. Presently, the prolonged release composition of levosulpiride is not available commercially.
French patent 5916 disclose the compound levosulpiride.
GB2151920 discloses a pharmaceutical composition of sulpiride comprising of microgranules of the active agent. The microgranules of the invention comprises of excipients such as saccharose, starch, lactose, stearic acid. These core microgranules are again coated with microporous polymers such as ethyl cellulose, shellac, methacrylate etc.
GB2129301 discloses a galenic dosage form of sulpiride having controlled and programmed release profile. The claimed dosage form comprises of microgranules. Microgranules of the present invention are formed by inert core of saccharide excipients like saccharose, lactose. Then the inert core comprises of first layer of sulpiride and second layer of microporous synthetic polymer.
EP0145558 discloses a novel galenic form of sulpiride comprising of inert cores made up of saccharose and starch grains. It involves spraying of alcoholic polyvinyl pyrollidone sulpiride solution onto the inert core. Again these granules are coated with methacrylate polymer solution.
JP62175424 discloses a pharmaceutical composition of sulpiride prepared by dissolving the active agent in methanolic solution of methyl methacrylate/methacrylic acid copolymer and completely removing the solvent by freeze drying process. It claims to increase bioavailability of the drug in the intestinal region and also capable of maintaining stable blood concentration of the drug.
2

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.
Hence there is a need for prolonged release dosage form of levosulpiride, which gives immediate as well as long lasting effect, simple and easy to manufacture, provide better clinical effects and improve patient compliance. Inventors of the present invention have developed a dosage form of levosulpiride, which contains both immediate release layer and prolonged release layer. Drug from the immediate release layer is helpful in achieving instant therapeutic benefit in acute condition while the prolonged release layer maintains therapeutic effective concentration for a longer period of time.
SUMMARY OF THE INVENTION
One general aspect of the present invention is to provide a prolonged release dosage form comprising levosulpiride.
Another aspect of the present invention is to provide a prolonged release dosage form comprising levosulpiride in the form of a bilayer tablet comprising of a prolonged release blend and an immediate release blend.
In Another aspect, the present invention provides a prolonged release formulation of levosulpiride 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 levosulpiride, which comprises of two parts ,
3

wherein the first part is immediate release which is manufactured by mixing Levosulpride 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 which is manufactured by mixing Levosulpride with suitable diluents, release controlling agents 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 levosulpride may be formulated into a suitable dosage form. For example, they can be formulated into bilayered tablets, tablet in a tablet, inlay tablets or mini-tablets filled in a capsule and other dosage.
In yet another aspect, the present invention provides a prolonged release formulation of levosulpiride in monolithic form.
Yet another aspect of the present invention is to provide a method of treating an animal, particularly a human being in need thereof, cornprising administering the said dosage form.
DETAILED DESCRIPTION
In one general embodiment, the present invention provides prolonged release dosage form of levosulpiride, more particularly a bilayer tablet of levosulpiride which comprises of: a) Immediate release blend and b) Prolonged release blend.
4

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, monolithic 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. The immediate release blend can be manufactured by any method known to a person of ordinary skill, preferably by dry granulation process or by wet granulation process. The most 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 polymer/s and pharmaceutically 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
5

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. 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.
According to instant invention, the desired release profile of Levosulpride is as below:
1 hour - Not more than 45%
4 hour - Not more than 75%
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 "levosulpiride or active agent" as used herein is to encompass free base, metabolites or pharmaceutically acceptable acid addition salts of levosulpiride or mixtures thereof. It is also intended to include various polymorphic forms of levosulpiride or its pharmaceutically acceptable acid addition salt.
The particle size of 90% particles of levosulpride is less than 200 microns; preferably particle size of 90% particles of levosulpride is less than 150 microns; more preferably particle size of 90% particles of levosulpride is less than 120 microns.
6

According to instant invention, the most preferred particle size of levosulpride is as follows:
A Particle size of 90% particles of levosulpride is less than 120 microns.
A Particle size of 50% particles of levosulpride is less than 30 microns.
The excipients that can be used as the release controlling agent either within the granule(s) and/or 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, known to the person skilled in art.
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, a hydroxy propyl cellulose, a hydroxy ethyl cellulose, a methyl cellulose, a xantham gum or a 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 agents of the present invention is hydroxy propyl methyl cellulose.
A dosage form as described herein may comprise one or more pharmaceutically
7

acceptable excipients, during granulation, compression or coating, and may be selected from diluent/filler, glidant, disintegrant, binder, lubricant, release controlling agent, plasticizef, opacifier, stabilizer, anti-tacking agent, surfactant, solvent, 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 90 % by weight of the composition.
Examples of "binders" include but not limited to polyvinylpyrrolidone (povidone), copovidone, cellulose derivatives, shellac, zein, gelatin, polymethacrylates, starch, 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, Sodium stearyl fumarate, Zinc stearate, Talc or Silica, Hydrogenated castor oil or mixtures thereof. The lubricant may be present in an amount ranging from 0.1 % to 5 % by weight of the composition.
8

Plasticizer may be used in a film coating 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.
As used herein, the term "solvent" comprises without limitation water, isopropyl alcohol, methanol, acetone, dichloromethane (DCM), etc and mixtures thereof
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 or dry granulation, extrusion spheronization or any other possible methods. Preferably wet granulation method is applied.
In 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 Levosulpride 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.
9

The second part is prolonged release part which is manufactured by mixing Levosulpride 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 levosulpride 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.
In another embodiment, the immediate release pharmaceutical composition of levosulpride is coated over prolonged release pharmaceutical composition of levosulpride.
In another embodiment, the immediate release pharmaceutical composition of levosulpride and prolonged release pharmaceutical composition of levosulpride is filled into capsules in the form of granules, beads, pellets and the like, .
In another embodiment, prolonged release oral dosage of Levosulpride is manufactured by mixing Levosulpride 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.
10

The invention will be further illustrated by the following Examples, however, without restricting its scope to these embodiments.
EXAMPLE-1
Table 1

Sr.No Ingredients Mg/Tab
Immediate release (IR) Part
Dry mix
1 Levosulpiride 50.00
2 Lactose Monohydrate 63.40
3 Microcrystalline Cellulose 37.30
4 Sodium Starch Glycolate 3.60
Granulation
1 PVP K 30 5.40
2 Purified water* _q.s.
Blending
1 Sodium Starch Glycol ate 27.60
2 Microcrystalline cellulose (PH 200) 9.00
3 Iron Oxide Red 1.00
4 Magnesium Steatate 2.70
Prolonged release Part
Dry Mix
1 Levosulpiride 150.00
2 Lactose Monohydrate 18.35
3 Microcrystalline Cellulose 13.00
4 Hydroxy Propyl Methyl Cellulose (K 100LV) 79.00
5 Crospovidone XL 12.65
Granulation
1 Povidone (PVP K-30) 22.00
2 IPA* q.s
3 Water* q.s
Blending
1 Microcrystalline Cellulose (PH 200) 25.00
2 Magnesium Stearate 5.00
Compression
1 Immediate Release (IR) Part / Blend 200.00
2 Prolonged Release Part / Blend 325.00
Total weight 525.00
* Removed during manufacturing process, except in traces.
11

Manufacturing Process:
1) Preparation of Immediate Release (IR) Part / Blend:
1. Levosulpiride, Lactose Monohydrate, Microcrystalline Cellulose, Iron oxide red and Sodium Starch Glycolate were sifted through appropriate sieves and mixed.
2. PVP K 30 was dissolved in purified water with stirring.
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 (PH 200), and Iron oxide red 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 Part / Blend:
1. Levosulpiride, Lactose Monohydrate, Microcrystalline Cellulose, Hydroxy Propyl Methyl Cellulose (K100LV) and Crospovidone XL were sifted through appropriate sieves and mixed.
2. PVP K 30 was dissolved in solution mixtures of IPA and purified water with stirring.
3. Materials of Step No-1 was loaded in a RMG and granulated with the binder solution of Step No-2.
12

4. Wet mass of Step No-3 was dried and sieved through appropriate sieve.
5. Microcrystalline Cellulose (PH 200) was 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.
8. Blend obtained from Step No-7 was lubricated with Magnesium Stearate of Step No-6.
Compression:
1. The IR blend and the prolonged release blend were compressed to tablets using suitable punches and compression machine.
EXAMPLE-2
Table 2

Ingredient Mg / Tablet
Dry Mix
Levosulpiride 200.00
Mannitol 123.75
Microcrystalline Cellulose 139.00
Granulation
Ethylcellulose 20cps 15.00
DCM: Acetone (1:1)* q.s
Blending
Microcrystalline Cellulose 26.25
Talc 11.50
Magnesium Stearate 9.50
Total weight of Core Tablet 525.00
Removed during manufacturing process: except in traces.
13

Manufacturing Steps:
1. Sift Levosulpiride, Mannitol and Microcrystalline Cellulose through appropriate sieve and Mix.
2. Dissolve Ethylcellulose in mixture of Dichloromethane and Acetone (1:1) with stirrer.
3. Load the material of step-1 in RMG and granulate with the binder solution of step-2.
4. Dry the wet mass of step-3 and size through appropriate sieve.
5. Sift Microcrystalline Cellulose and Talc through appropriate sieve.
6. Sift Magnesium Stearate through appropriate sieve.
7. Blend the granules of step-4 alongwith Ingredients of step-5 in a blender.
8. Lubricate the blend of step-7 with material of step-6 in a blender.
9. Compress the blend from step-8 to tablets using suitable punches & compression machine.
Dated this 18th day of August, 2008

Praveen Chand Gandhi,
Torrent Pharmaceuticals Limited,
Torrent Research Centre
P.O. Bhat - 382428, Gandhinagar
Gujarat, India
14