FIELD OF INVENTION

The present invention relates to the stable pharmaceutical composition comprising levodopa, carbidopa and entacapone, or a pharmaceutically acceptable salt or hydrate thereof and a stabilizer. The invention also relates to the process for preparing such stable pharmaceutical composition.

BACK GROUND OF THE INVENTION

Levodopa, an aromatic amino acid, is a white, crystalline compound, slightly soluble in water, with a molecular weight of 197.2. It is designated chemically as (-)-L-a-amino-P(3,4-dihydroxybenzene) propanoic acid. Its empirical formula is C9HnN04, and its structural formula is

Carbidopa, an inhibitor of aromatic amino acid decarboxylation, is a white, crystalline compound, slightly soluble in water, with a molecular weight of 244.3. It is designated chemically as (-)-L-(α-hydrazino-(a-methyl-P-(3,4-dihydroxybenzene) propanoic acid monohydrate. Its empirical formula is C10HI4N2O4XH2O, and its structural formula is

Levodopa and carbidopa are most commonly used drugs in the treatment of the Parkinson's disease. Levodopa and carbidopa are commercially available as a combination with the trade name SINMET in the dosage form of tablets and marketed by Merck Sharp & Dohme limited in UK.

Entacapone, an inhibitor of catechol-O-methyltransferase (COMT), is a nitro-catechol-structured compound with a molecular weight of 305.3. The chemical name of entacapone is (E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide. Its empirical formula is C14H15N3O5 and its structural formula is

Entacapone is described in the European patent EP0444899 BI as a catechol-0-methyl- transferase (COMT) inhibitor. The publication further discloses that for the treatment of the Parkinson's disease, entacapone is given with levodopa, in each of its own composition or combined in one composition. The European patent EP1 112065 B1 describes an oral compacted composition comprising a pharmaceutically effective amount of entacapone or a pharmaceutically acceptable salt thereof and a croslinked cellulose derivative. Entacapone is commercially available with the trade name COMTESS in the dosage form of film coated tablets and marketed by Orion Corporation in UK.

In the treatment regimen of Parkinsonism, medicament needs to be taken several times a day to the keep the patient without symptoms. In the regimen where two separate tablets i.e. one containing levodopa and carbidopa, and the other containing entacapone, is problematic for many patients, such as those with tremor and old age. The patient compliance has been improved by combining these three active ingredients i.e. levodopa, carbidopa and entacapone. Entacapone in combination with carbidopa and levodopa is commercially available with the trade name STALEVO in the dosage form of film coated tablets and marketed by Orion Corporation in UK.

European Patent EP 1189608 BI discloses an oral solid pharmaceutical composition comprising levodopa, carbidopa and entacapone and a pharmaceutically acceptable excipient wherein the carbidopa is separated from entacapone and levodopa. In that way the bioavailability of carbidopa was reported to be increase. It further states that bioavailability of carbidopa is significantly affected by the method of preparing the composition. It is further reported that many commonly used excipients and not suitable for the solid composition comprising levodopa, carbidopa and entacapone. Most of the levodopa and carbidopa formulations available in the market contain microcrystalline cellulose as a carrier. The inventors of the Patent EP1189608B1 found that microcrystalline cellulose destabilized the formulation on a long term storage, wherein said three active ingredients are combined together.

WO patent application WO2007113371A1 describes the oral pharmaceutical compositions of levodopa, carbidopa and entacapone with microcrystalline cellulose and starch by simultaneous mixing of all three active ingredients. The composition is prepared by compaction granulation. The application describes the disadvantages

associated with the wet granulation technique which includes destabilization of composition due to use of water in the wet granulation method.

WO2008053297 A2 describes the single oral composition comprising levodopa, carbidopa and entacapone or pharmaceutically acceptable salts thereof, where in substantial portion of entacapone or a pharmaceutically acceptable salt or hydrate thereof is separated from the mixture of levodopa and carbidopa or pharmaceutically acceptable salts or hydrates thereof. It further discloses the pharmaceutical composition comprising levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof and microcrystalline cellulose.

Therefore there is a need to develop a stable pharmaceutical composition comprising the levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof. The Present invention addresses and encounters the commonly encountered problems described in the prior art.

SUMMARY OF THE INVENTION

In the general aspect the present invention describes the stable pharmaceutical composition comprising levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof and a stabilizer.
In further embodiment the stable pharmaceutical composition may further include one or more pharmaceutically acceptable excipients selected from fillers, lubricants, disintegrants and glidants.

The further embodiment describes the process for preparation of stable pharmaceutical composition comprising levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof and a stabilizer by

a) simultaneous mixing of pharmaceutically effective amounts of levodopa, carbidopa and entacapone together with atleast one acidic stabilizer or alkaline stabilizer or mixtures thereof, atleast one filler such as microcrystalline cellulose, atleast one
binder such as hydroxy propyl methyl cellulose, atleast one disintegrant such as
crospovidone

b) Granulating the first mixture to obtain granules

c) adding atleast one filler, atleast one lubricant, and/or atleast one disintegrant to the granules of step b) to obtain the second mixture

d) formulating the second composition into an oral solid composition and
e) if desired coating the composition obtained in step d.

DETAILED DESCRIPTION OF THE INVENTION

The present inventors have now found that a pharmaceutical composition comprising levodopa, carbidopa and entacapone or pharmaceutically acceptable salt or hydrates thereof and a stabilizer poses no stability problems and the desired therapeutic effect is achieved. The inventors also have discovered that when the pharmaceutically acceptable excipient like microcrystalline cellulose is used in a triple combination comprising levodopa, carbidopa, and entacapone or the pharmaceutically acceptable salts or hydrates thereof and a stabilizer poses no stability problems on long term storage. The process for preparation of stable pharmaceutical composition comprising levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof and a stabilizer by a) simultaneous mixing of pharmaceutically effective amounts of levodopa, carbidopa and entacapone together with atleast one acidic stabilizer or alkaline stabilizer or mixtures thereof, atleast one filler such as microcrystalline cellulose, atleast one binder such as hydroxy propyl methyl cellulose, and/or atleast one disintegrant such as crospovidone, b) granulating the first mixture to obtain granules, c) adding atleast one lubricant, and/or atleast one disintegrant to the granules of step b) to obtain the second mixture, d) formulating the second composition into an oral solid composition and , e) if desired coating the composition obtained in step d.

Thus the present invention relates to the stable pharmaceutical composition comprising levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof and a stabilizer. The stabilizer useful in the pharmaceutical composition of the present invention is acidic substance or alkaline substance or mixtures thereof.

The acidic substances used as the stabilizers in the stable pharmaceutical composition comprising levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof is selected from the group consisting of citric acid, tartaric acid, malie acid and mixtures thereof. Out of these citric acid is most preferred acidic substance used as a stabilizer.

The alkaline substances used as the stabilizers the stable pharmaceutical composition comprising levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof is selected from the group consisting of sodium carbonate, ammonium carbonate, anhydrous sodium carbonate, sodium carbonate monohydrate, sodium tartrate, sodium potassium tartrate, sodium citrate, sodium hydroxide, calcium acetate, sodium acetate, dibasic sodium phosphate, anhydrous dibasic sodium phosphate, di ammonium hydrogen phosphate, sodium pyrophosphate and mixtures thereof. Out of these alkaline substances di basic sodium phosphate, sodium citrate, ammonium carbonate and the mixtures thereof are most preferred alkaline substances used as a stabilizer.

The stable pharmaceutical composition comprising levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof preferably contains the stabilizer from 0.5% to 10% by weight of the total solid dosage form. Most preferably, the composition contains the stabilizer from 1 to 5% by weight of the total solid dosage form (e.g. 1 to 5% of the total tablet weight).

The stable pharmaceutical composition as described herein may include other pharmaceutically acceptable excipients. Excipient of the pharmaceutically acceptable excipients used herein includes fillers, binders, lubricants, disintegrants, glidants and the like.

Suitable fillers may include one or more of the microcrystalline cellulose and dibasic calcium phosphate. The filler used in the stable pharmaceutical composition of levodopa, carbidopa, and entacapone or pharmaceutically acceptable salts or hydrates thereof is microcrystalline cellulose. The microcrystalline cellulose is present in the range from about 5% to 50% w/w of the total pharmaceutical composition. Most preferably the microcrystalline cellulose may be present in the range from about 10% to 30% w/w of the total pharmaceutical composition.

Suitable binders may include one or more of povidone, starch, stearic acid, gums, hydroxy propyl methyl cellulose and the like.

Suitable lubricants may include one or more of magnesium stearate, zinc stearate, calcium stearate, stearic acid, sodium stearyl fumarate, hydrogenated vegetable oil and the like.

Suitable disintegrants may include one or more of crospovidone, sodium starch glycolate and Amberlite IRP-88.

The Present invention describes the process for preparation of the stable pharmaceutical composition comprising levodopa, carbidopa and entacapone or pharmaceutically acceptable salts or hydrates thereof and a stabilizer by

a) simultaneous mixing of pharmaceutically effective amounts of levodopa, carbidopa and entacapone together with atleast one acidic stabilizer or alkaline stabilizer or mixtures thereof, atleast one fïller such as microcrystalline cellulose, atleast one binder such as hydroxy propyl methyl cellulose, atleast one disintegrant such as crospovidone

b) granulating the first mixture to obtain granules

c) adding atleast one lubricant, atleast one disintegrant, atleast one filler to the granules of step b) to obtain the second mixture

d) Formulating the second composition into an oral solid composition and

e) if desired coating the composition obtained in step d.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Procedure: The Pharmaceutical composition is prepared by mixing levodopa, carbidopa monohydrate, entacapone, microcrystalline cellulose, sodium starch glycolate, hydroxy propyl methyl cellulose, dibasic sodium phosphate, citric acid, in a double cone blender. The mixture is dry granulated foliowed by milling to form granules. The granules are mixed with Amberlite-IRP88 in a double cone blender and lubricated with Sodium stearyl fumarate and talc. Further the above mixture is compressed into the tablets by the punches and film coated with the film coating solution.

Procedure: The Pharmaceutical composition is prepared by mixing levodopa, carbidopa monohydrate, entacapone, microcrystalline cellulose, sodium starch glycolate, dibasic sodium phosphate, citric acid, in a double cone blender. The mixture is dry granulated, foliowed by milling to form the granules. The granules are mixed with extra granular portion comprising microcrystalline cellulose, sodium starch glycolate, sodium stearyl fumarate and talc. Further the above mixture is compressed into the tablets by the punches and film coated with the film coating solution.

Procedure: The Pharmaceutical composition is prepared by mixing levodopa, carbidopa monohydrate, entacapone, microcrystalline cellulose, crospovidone, hydroxy propyl methyl cellulose, microcrystalline cellulose, citric acid and lubricated with magnesium stearate. The mixture is dry granulated foliowed by milling to form the granules. The granules are mixed with extra granular portion comprising crospovidone, magnesium stearate, and aerosil. Further the above mixture is compressed into the tablets by the punches and film coated with Opadry brown coating solution.

We claim:

1. A stable pharmaceutical composition comprising levodopa, carbidopa and entacapone, or a pharmaceutically acceptable salt or hydrate thereof and a stabilizer.

2. A stable pharmaceutical composition of claim 1 wherein the stabilizer is acidic or alkaline or the mixtures thereof.

3. A stable pharmaceutical composition of claim 2 wherein the acidic stabilizer is citric acid, tartaric acid, malic acid and mixtures thereof.

4. A stable pharmaceutical composition of claim 2 wherein the alkaline stabilizer is sodium citrate, sodium hydroxide, calcium acetate, sodium acetate, dibasic sodium phosphate, anhydrous dibasic sodium phosphate, di ammonium hydrogen phosphate, sodium pyrophosphate and mixtures thereof.

5. A stable pharmaceutical composition of claim 1 wherein the composition further comprises one or more pharmaceutically acceptable excipients comprising fillers, binders, lubricants, disintegrants and glidants.

6. A stable pharmaceutical composition of claim 5 wherein the filler is microcrystalline cellulose.

7. The process for preparation of the stable pharmaceutical composition of claim 1 as

a) simultaneous mixing of pharmaceutically effective amounts of levodopa, carbidopa and entacapone together with atleast one

acidic stabilizer or alkaline stabilizer or mixtures thereof, atleast one filler, atleast one binder,, atleast one disintegrant.

b) granulating the first mixture to obtain granules

c) adding atleast one filler, atleast one lubricant, and/or atleast one disintegrant, to the granules of step b) to obtain the second mixture

d) formulating the second composition into an oral solid composition and

e) if desired coating the composition obtained in step d.