Title of Invention

A SUSTAINED RELEASE ANTIMALARIAL TABLET COMPOSITION COMPRISING PRIMAQUINE PHOSPHATE AND A PROCESS FOR PREPARING THE SAME

Abstract

This invention relates to sustained release anti-malarial formulation of Primaquine or its pharmaceutically acceptable salt with reduced side effects typically associated with the dosing of primaquine and method for preparing the same. The preparation of formulation involves use of a hydrophilic polymer such as, hydroxypropyl methyl cellulose K15 M for sustained release of drug over specific period of time.

Full Text

FORM 2 THE PATENTS ACT 1970 (39 of 1970) & The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10 and rule 13) 1. TITLE OF THE INVENTION: "A Process for preparation of stable sustained release antimalarial formulation" 2. APPLICANT (S) (a) NAME: IPCA LABORATORIES LIMITED (b) NATIONALITY: INDIAN (c) ADDRESS: 48, Kandivli Industrial Estate, Mumbai - 400 067, Maharashtra, India 3. PREAMBLE TO THE DESCRIPTION The following specification particularly describes the invention and its use thereof. Technical Field: This invention relates to sustained release antimalarial formulation comprising Primaquine or its pharmaceutically acceptable salt which has reduced side effects typically associated with the dosing of primaquine and method for preparing the same. Background and Prior Art: Malaria is one of the most serious protozoal infections in man. According to estimation made in the 90's, about 300 to 500 million people develop clinical infection and one million die of severe infection every year. India is also among the countries to have endemic regions of the disease. It is, therefore, of prime concern and requirement to have therapeutically safe agents for multiple use, especially those that block transmission of malaria through the individuals visiting endemic regions [The Lancet, 350, 717(1997)]. Malaria is caused by infection with any one of the four species of Plasmodia. The transmission of malaria, is through the injection of sporozoites by the bite of mosquitoes. These sporozoites develop in the mosquito feeding on an individual carrying mature gametocytes. Primaquine, over the years, has been the clinical drug of choice with widespread use in the treatment of relapsing Plasmodium vivax and P. ovale malaria [Drugs, 39, 160(1990) D. M. Panisko et al. ibid 39, 337(1990) J. S Keystone]. Primaquine has no sporontocidal activity when provided directly to the insects but has strong gametocytocidal activity and even stops transmission of resistant isolates when mosquitoes are fed on infected blood from primaquine treated animals. Thus, primaquine is also a strong transmission blocking agent. However, primaquine even being associated with radical curative and gametocytocidal activities is not in use as a prophylactic agent. Primaquine, used clinically as phosphate salt. Primaquine phosphate is a synthetic 8-aminoquinoline derivative. After oral administration, the drug is usually well absorbed, reaching peak plasma levels in 1-2 hours, and then is almost completely metabolized and excreted in the urine. The problems associated with use of 8-aminoquinolines are mainly related to their toxicity because of prolonged use. Primaquine is known to induce hemolytic lesions in patients suffering from a deficiency in glucose-6-phosphate-dehydrogenase (G-6PD). Anemia is a common complication of hemolysis. Primaquine produces metabolites like o-quinone and p-quinomine functionalities, which because of their oxidative nature, oxidise unsaturated fatty acid of erythrocytes causing red blood cell (RBC) lysis. Primaquine is absorbed and metabolized very fast and as a consequence, oxidative burst ocuurs very fast. Therefore, its controlled delivery may result in less toxicity. In clinical practice normally the toxicity of primaquine precludes administration of a single curative dose for humans. Thus, to achieve a radical cure of P. vivax in humans, the dose is ordinarily given in divided doses over 14 to 21 days. This is accompanied with a three-day course of chloroquine, a suppressive drug to clear the blood of schizonts which may "leak" from the tissue cycle of parasite development. In addition to therapeutic activity against the parasitic infections, primaquine in combination with clindamycin has been successfully used for the treatment as well as prophylaxis of Pneumocystis carinii pneumonia in AIDS patients [South. Med. J., 83, 403(1990) R. Kay et al.; Lancet i, 1046(1989) E. Toma et al.; Clin. Infect. Dis., 14: 183(1992) G. S. Noskinm et al.]. Over the years, several attempts have been made to improve the therapeutic index of primaquine against malaria and Leishmania through modification of its chemical structure. Introduction of 4-methyl and 5-phenoxy [J. Med. Chem. 25, 1094(1982) M. P. LaMontagne et al.; ibid, 25, 1097(1982) E. A. Nodiff et al.] or alkoxy groups [J. Med. Chem. 30, 1193(1987) E. H. Chen et al.] have produced analogs with much superior tissue and blood schizonticidal activity. US 7,183,291 B2 and EP1055427 Al discloses a method of treatment of malaria by the use of primaquine derivative N1- (3 - ethylidinotetrahydrofuran - 2 - one) - N4- (6 - methoxy - 8 - quinolinyl) - 1,4 -pentanediamine as a gametocytocidal agent. PCT/US00/09091 or US 6413993 relates to combination of atovaquone {2 - [4 - (4 -chlorophenyl) cyclohexyl] - 3-hydroxy - 1, 4 - naphthoquinone}, proguanil {l-(4-chlorophenyl)-5-isopropylbiguanide hydrochloride} and primaquine {(RS)-8-(4-amino-l-methylbutylamino)-6-methoxyquinoline diphosphate} which have antimalarial activity. More specifically, the invention is concerned with the use of such combinations in the treatment and prophylaxis of Plasmodium vivax malaria. EP 1702616 Al disclosed medicament for the treatment of malaria, in particular to a combination comprising artemisinin with primaquine and other having high and rapid therapeutic effect. US 6,376,511 B2 relates to the use of enantiomers of 8-aminoquinoline compounds for the treatment of Pneumocystis carinii, pneumonia (PCP), toxoplasmosis, malaria, trypanosomaiasis, and leishmaniasis in mammals and the prevention of PCP and malaria in mammals. US 4,980,360 pertains to 5-phenylalkoxy (5-ORR') primaquine compounds and pharmaceutically acceptable acid addition salts thereof and the use of such compounds to treat both blood and tissue schizonticidal malarial forms. Surprisingly, such compounds demonstrate efficacy that is at least comparable to the well-known 5-alkoxy (5-OR) primaquine analogues as per US 4,554,279 (Saggiomo et al) with the added benefit that the compounds of the this invention are less toxic than the '279 compounds at the upper end of normal dosage ranges. In US 5104885 a first aspect of the invention pertains to 5-phenylalkoxy (5-ORR') primaquine compounds and pharmaceutically acceptable acid addition salts thereof and the use thereof to treat both blood and tissue schizonticidal malarial forms. Similarly, 4-methyl-5-(unsubstituted and substituted phenoxy)-6-methoxy-8-(aminoalkylamino) quinolines are reported in US Patent 4,431,807 (Strube et al) as being effective antimalarial agents demonstrating both tissue schizonticidal (radical curative) and blood schizonticidal (suppressive) activity. In CN1371689, Primaquine Phosphate relates to a new use of primaquine phosphate for the treatment of piroplasmosis, toxoplasma disease and other diseases of animals and fowl with good efficacy. US 4617394 discolses compound of the class including 4-methyl-5-(unsubstituted and substituted phenoxy)-2,6-dimethoxy-8-(aminoalkylamino)quinolines as the free bases and pharmaceutically acceptable acid amine salts. The compounds are highly effective antimalarial agents. In addition, these drugs exhibit significantly better therapeutic indices than primaquine. US 20060263427 disclosed herein are controlled-release quinine formulations, methods of preparing the same and methods of preventing or treating malaria by administering the same. The controlled-release quinine formulations may help to reduce or eliminate adverse side effects typically associated with the dosing of quinine. The dosage formulation in the form of sutstain-release tablets are ofetnly be taken less frequently than instant release formulations and that they keep the drug levels steady in the bloodstream. In sustained release tablets formulation, the active ingredient is embedded in the matrix of insoluble substance and it dissolvs through the holes in the matrix. Thus, there is a need of sustained release pharmaceutical composition with reduced dosage frequency, with enhanced therapeutic effectiveness, minimized side effects and better patient compliances. The object of the present invention is to prepare a sustained release pharmaceutical formulation of Pramiquine or pharmaceutically acceptable salts thereof for the treatment of malaria and methods of preparing the same. Summary Of The Invention: The invention discloses a monolithic matrix with dosage form that improves patient compliance and reduces the dosage frequency to once daily for the treatment of malaria. The invention further discloses a dosage form of primaquine that sustained the release of primaquine in such a manner that an effective concentration in blood can be maintained over a longer period of time to improve therapeutic efficacy and minimize the side effects. Detailed Description; According to the present invention, the preferred embodiment is that, antimalarial sustained release pharmaceutical composition comprising pharmaceutically acceptable hydrophilic polymer i.e. hydroxypropyl methyl cellulose along with Primaquine or its pharmaceutically acceptable salts as active ingredient. The present pharmaceutical composition comprises Primaquine or it's pharmaceutically acceptable salt and pharmaceutically acceptable excipients selected from hydrophilic polymer, diluents, binders, preservatives, pH adjuster, alkalizing agent, disintegrating agents, film formers, lubricants, plastisizers and/or glidants. The term Primaquine used herein is intended to include Primaquine salt selected from phosphate or diphosphate, preferably phosphate in an amount of 15 to 30mg, preferably 7.5 to 15 mg. The composition involves use of a hydrophilic polymer such as, hydroxypropyl methyl cellulose K15 M which is incorporated to extend release of drug over specific period of time and is present in an amount of 0.45% to 1.0% of w/w tablet. The said diluents are microcrystalline cellulose and are used in the range of 2 to 95% of tablet weight. The said binders are selected from the group consisting of corn starch pregelatinized, microcrystalline cellulose and polyvinylpyrrolidone preferably polyvinylpyrrolidone present in an amount of 3 to 15%. The Lubricants are selected from the group consisting of magnesium stearate and zinc stearate preferably magnesium stearate in the range of 0.25% to 5.0%. The Glidants are selected from the group consisting of purified talc in the range of 0.1% to 2%. The Plasticizers are selected from the group consisting of polyethylene glycol of molecular weight 6000 in the range of 5%-15%. The film formers are selected from the group of polymers such as starch, natural gums and modified celluloses preferably hydroxypropyl methyl cellulose E 5. The Opacifiers are selected from the group consisting of titanium dioxide in range of 0.1% to 2.7%. The Solvents are selected from isopropyl alcohol and methylene chloride in the range of 0.5 to 2%. The Color used is iron red oxide in the range of 0.1 to 5%. Other miscellaneous auxiliaries required for processing the product and maintaining stability. The preferred embodiment of the present invention relates to a process for preparation of a stable sustained release pharmaceutical composition comprising a Primaquine or it's pharmaceutically active salt and pharmaceutically acceptable excipients. The tablet may be obtained by conventional manufacturing techniques, e.g. by mixing ingredients together and compressing into tablet cores or by dry compacting (slugging or roller compaction) a part of excipients, adding the remaining excipients and compressing the material into tablet cores. The process can be illustrated as follows: i) sifting Primaquine phosphate, microcrystalline cellulose, hydroxy propyl methyl cellulose K 15 M and mixing to form a blend; ii) granulating the blend with mixture of polyvinylpyrrolidone 90 and isopropyl alcohol using non-aqueous wet granulation; iii) milling the wet granules through mesh and air-dried and then at 60°C in FBD until it reach 2-3% LOD at 105°C; iv) lubricating the dried granules with hydroxy propyl methyl cellulose K 15 M and talc and sifting; v) lubricating the blend with magnesium stearate for 2 minutes; vi) making the tablets using direct compression method. The said pharmaceutical composition of primaquine phosphate according to the invention is preferably in the solid dosage form, such as tablets, pills, granules, capsules or sachets, preferably tablets particularly film coated. The composition can be administered orally in a single dosage form daily. The said tablet may be coated with hydroxy propyl methyl cellulose, talc, titanium dioxide, polyethylene glycol 6000 and the said composition of primaquine phosphate is physically and chemically stable over its shelf life period. The stable sustained release composition exhibits the following dissolution profile when tested in a USP type 2 apparatus at 100 rpm in 900 ml of simulated intestinal fluid (pH 7.4 phosphate buffer) and at 37°C: after 2 hour not more than 60% of the drug is released; after 4 hours 45%-75% of the drug is released; after 12 hours not less than 75% of the drug is released. The following examples illustrate various aspects of the present invention: Example 1 Primaquine phosphate granules: Contains 30mg Primaquine phosphate equivalent to 30mg Primaquine along with the following excipients. Sr. No. Ingredient Qty % w/w of total weight 1 Primaquine phosphate 23.09% 2 Microcrystalline cellulose 55.17% 3 Hydroxypropyl methyl cellulose K15M 13.04% 4 Polyvinylpyrrolidone K30 6.52% 5 Magnesium stearate 1.09% 6 Isopropyl alcohol Qs 7 Talc 1.09% Preparation of primaquine granules: Primaquine phosphate, microcrystalline cellulose, hydroxy propyl methyl cellulose K 15 M sifted through mesh #40 and all were mixed geometrically for 10 minuets in RMG. This blend was granulated with mixture of polyvinylpyrrolidone 90 and isopropyl alcohol using non-aqueous wet granulation. The wet granules were milled through mesh #14. Granules are initially air-dried and then at 60°C in FBD until it reach 2-3% LOD at 105°C. Dried granules were lubricated with hydroxy propyl methyl cellulose K 15 M and talc and then sifted through mesh #40. Finally this bend lubricated with magnesium stearate for 2 minutes. The sustained release tablets were prepared using direct compression with 9 mm punch size known in art. The coating solution to be coated on the tablets has the following composition: Sr. No. Ingredient Qty % w/w of total weight 1 Hydroxypropyl methyl cellulose E5 80% 2 Polyethylene glycol 6000 8% 3 Talc 4% 4 Titanium dioxide 4% 5 Iron oxide red 4% 6 Methylene chloride qs 7 Isopropyl alcohol qs There is a 3% weight gain by coating. Take isopropyl alcohol in suitable stainless steel container and disperse Hydroxypropyl methyl cellulose E5 under constant stirring for approximately 10 minutes. Then add titanium dioxide, purified talc again under stirring for approximately 10 minutes. Now add methylene chloride and polyethylene glycol 6000 and iron oxide red under stirring for 10 minutes. Continue stirring for 30 minutes and pass the suspension through a bolting cloth, homogenized by passing through a homogenizer. This solution is used to coat tablet with conventional coater/auto-coater. Example 2 Primaquine phosphate granules: Contains 15mg Primaquine phosphate equivalent to 15mg Primaquine along with the following excipients. Sr. No. Ingredient Qty % w/w of total weight 1 Primaquine phosphate 17.7% 2 Microcrystalline cellulose 62.3% 3 Hydroxypropyl methyl cellulose K15M 13% 4 Polyvinylpyrrolidone K30 5% 5 Magnesium stearate 1% 6 Isopropyl alcohol Qs 7 Talc 1% Preparation of primaquine granules: Primaquine phosphate, microcrystalline cellulose, hydroxy propyl methyl cellulose K 15 M sifted through mesh #40 and all were mixed geometrically for 10 minuets in RMG. This blend was granulated with mixture of polyvinylpyrrolidone 90 and isopropyl alcohol using non-aqueous wet granulation. The wet granules were milled through mesh #14. Granules are initially air-dried and then at 60°C in FBD until it reach 2-3% LOD at 105°C. Dried granules were lubricated with hydroxy propyl methyl cellulose K 15 M and talc and then sifted through mesh #40. Finally this bend lubricated with magnesium stearate for 2 minutes. The sustained release tablets were prepared using direct compression with 7.5 mm punch size known in art. The coating solution to be coated on the tablets has the following composition: Sr. No. Ingredient Qty % w/w of total weight 1 Hydroxypropyl methyl cellulose E5 26.67% 2 Polyethylene glycol 6000 2.67% 3 Talc 1.33% 4 Titanium dioxide 1.33% 5 Iron oxide red 1.33% 6 Methylene chloride Qs 7 Isopropyl alcohol Qs There is a 3% weight gain by coating. Take isopropyl alcohol in suitable stainless steel container and disperse Hydroxypropyl methyl cellulose E5 under constant stirring for approximately 10 minutes. Then add titanium dioxide, purified talc again under stirring for approximately 10 minutes. Now add methylene chloride and polyethylene glycol 6000 and iron oxide red under stirring for 10 minutes. Continue stirring for 30 minutes and pass the suspension through a bolting cloth, homogenized by passing through a homogenizer. This solution is used to coat tablet with conventional coater/auto-coater. Example 3 Primaquine phosphate granules: Contains 30mg Primaquine phosphate equivalent to 30mg Primaquine along with the following excipients. Sr. No. Ingredient Qty % w/w of total weight 1 Primaquine phosphate 23.09% 2 Microcrystalline cellulose 57.35% 3 Hydroxypropyl methyl cellulose K15 M 10.86% 4 Polyvinylpyrrolidone K30 6.52% 5 Magnesium stearate 1.09% 6 Isopropyl alcohol Qs 7 Talc 1.09% Preparation of primaquine granules: Primaquine phosphate, microcrystalline cellulose, hydroxy propyl methyl cellulose K 15 M sifted through mesh #40 and all were mixed geometrically for 10 minuets in RMG. This blend was granulated with mixture of polyvinylpyrrolidone 90 and isopropyl alcohol using non-aqueous wet granulation. The wet granules were milled through mesh #14. Granules are initially air-dried and then at 60°C in FBD until it reach 2-3% LOD at 105°C. Dried granules were lubricated with hydroxy propyl methyl cellulose K 15 M and talc and then sifted through mesh #40. Finally this bend lubricated with magnesium stearate for 2 minutes. The sustained release tablets were prepared using direct compression with 9.5 mm punch size known in art. The coating solution to be coated on the tablets has the following composition: Sr. No. Ingredient Qty % w/w of total weight 1 Hydroxypropyl methyl cellulose E5 33.45% 2 Polyethylene glycol 6000 3.35% 3 Talc 1.64% 4 Titanium dioxide 1.64% 5 Iron oxide red 1.64% 6 Methylene chloride Qs 7 Isopropyl alcohol Qs There is a 3% weight gain by coating. Take isopropyl alcohol in suitable stainless steel container and disperse Hydroxypropyl methyl cellulose E5 under constant stirring for approximately 10 minutes. Then add titanium dioxide, purified talc again under stirring for approximately 10 minutes. Now add methylene chloride and polyethylene glycol 6000 and iron oxide red under stirring for 10 minutes. Continue stirring for 30 minutes and pass the suspension through a bolting cloth, homogenized by passing through a homogenizer. This solution is used to coat tablet with conventional coater/auto-coater. Example 4 Primaquine phosphate granules: Contains 30mg Primaquine phosphate equivalent to 30mg Primaquine along with the following excipients. Sr. No. Ingredient Qty % w/w of total weight 1 Primaquine phosphate 23.09% 2 Microcrystalline cellulose 59.52% 3 Hydroxypropyl methyl cellulose K15 M 10.86% 4 Polyvinylpyrrolidone K30 6.52% 5 Magnesium stearate 1.09% 6 Isopropyl alcohol Qs 7 Talc 1.09% Preparation of primaquine granules: Primaquine phosphate, microcrystalline cellulose, hydroxy propyl methyl cellulose K 15 M sifted through mesh #40 and all were mixed geometrically for 10 minuets in RMG. This blend was granulated with mixture of polyvinylpyrrolidone 90 and isopropyl alcohol using non-aqueous wet granulation. The wet granules were milled through mesh #14. Granules are initially air-dried and then at 60°C in FBD until it reach 2-3% LOD at 105°C. Dried granules were lubricated with hydroxy propyl methyl cellulose K 15 M and talc and then sifted through mesh #40. Finally this bend lubricated with magnesium stearate for 2 minutes. The sustained release tablets were prepared using direct compression with 9.5 mm punch size known in art. The coating solution to be coated on the tablets has the following composition: Sr. No. Ingredient Qty % w/w of total weight 1 Hydroxypropyl methyl cellulose E5 33.45% 2 Polyethylene glycol 6000 3.35% 3 Talc 1.67% 4 Titanium dioxide 1.67% 5 Iron oxide red 1.67% 6 Methylene chloride Qs 7 Isopropyl alcohol Qs There is a 3% weight gain by coating. Take isopropyl alcohol in suitable stainless steel container and disperse Hydroxypropyl methyl cellulose E5 under constant stirring for approximately 10 minutes. Then add titanium dioxide, purified talc again under stirring for approximately 10 minutes. Now add methylene chloride and polyethylene glycol 6000 and iron oxide red under stirring for 10 minutes. Continue stirring for 30 minutes and pass the suspension through a bolting cloth, homogenized by passing through a homogenizer. This solution is used to coat tablet with conventional coater/auto-coater. The dissolution profile of the modified release composition is studied and shown as follows: Dissolution profile: For 15mg Hrs. Limits Results 2 NMT 60% 44.05%-49.72% 4 45%-75% 63.63%-69.21% 8 Data collection 84.09%-94.08% 12 NLT 75% 94.26%-98.45% The pharmaceutical composition of is physically and chemically stable over its shelf life period. The stability data for 15mg tablet is as follows: Test Specification Hrs. Initial After 03 months Appearance white / yellow coloured, bilayered, oval, biconvex, plain tablets Complies Complies Dissolution 25±2°C & 60±5%Rh NMT 60% 45%-75% Data collection NLT 75% 4 63.63%-69.21% 65.27%-68.32% 8 84.09%-94.08% 87.54%-93.17% 12 94.26%-98.45% 96.39%-101.45% 40±2°C & 75±5%Rh NMT 60% 45%-75% Data collection NLT 75% 2 44.05%-49.72% 45.37%-47.40% 4 63.63%-69.21% 64.08%-66.91% 8 84.09%-94.08% 86.88%-91.93% 12 94.26%-98.45% 91.06%-96.86% Assay 25±2°C & 60±5%Rh 90%-110% 101.70% 97.18% 40±2°C & 75±5%Rh NLT 90% 101.70% 97.87% The dissolution profile of the modified release composition is studied and shown as follows: Dissolution profile: For 30mg Hrs. Limits Results 2 NMT 60% 43.93%-47.40% 4 45%-75% 61.90%-64.07% 8 Data collection 80.22%-86.28% 12 NLT 75% 93.22%-96.84% The pharmaceutical composition of is physically and chemically stable over its shelf life period. The stability data for 30mg is as follows: Test Specification Hrs. Initial After 03 months Appearance white / yellow coloured, bilayered, oval, biconvex, plain tablets Complies Complies Dissolution 25±2°C & 60±5%Rh NMT 60% 45%-75% Data collection NLT 75% 2 43.93%-47.40% 47.02%-58.58% 4 61.90%-64.07% 63.56%-73.36% 8 80.22%-86.28% 83.75%-96.08% 12 93.22%-96.84% 95.02%-99.41% 40±2°C & 75±5%Rh NMT 60% 45%-75% Data collection NLT 75% 2 43.93%-47.40% 41.51%-54.96% 4 61.90%-64.07% 59.77%-71.66% 8 80.22%-86.28% 80.33%-96.29% 12 93.22%-96.84% 89.42%-99.78% Assay 25±2°C & 60±5%Rh 90%-110% 100.12% 99.90% 40±2°C & 75±5%Rh NLT 90% 100.12% 100.77% It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. We claim: 1. A sustained release anti-malarial pharmaceutical composition comprising Primaquine or pharmaceutical^ acceptable salts thereof as an active ingredient in an amount of 15 - 30 mg, a release controlling polymer and pharmaceutically acceptable excipients. 2. The sustained release pharmaceutical composition as claimed in claim 1, wherein the pharmaceutically acceptable salts of Primaquine are phosphate or diphosphate preferably phosphate and is present in an amount of 15 - 30 mg preferably 7.5 to 15 mg. 3. The sustained release pharmaceutical composition as claimed in claim 1, wherein the release controlling polymer is hydrophilic polymer selected from hydroxy propyl methyl cellulose, ethyl cellulose, or their modified forms. 4. The sustained release pharmaceutical composition as claimed in claim 3, wherein the hydrophilic polymer is preferably hydroxy propyl methyl cellulose K 15 M or hydroxy propyl methyl cellulose E5 and is present in the range of 0.45% to 1.0% of w/w tablet. 5. The stable sustained release composition as claimed in claim 1, wherein said pharmaceutically acceptable excipients are selected from diluents, binders, lubricants, glidants, film formers and plasticizers either alone or combinations thereof. 6. The stable controlled release composition as claimed in claim 1 , wherein the diluent is microcrystalline cellulose in the range of 2 - 95 % of w/w tablet. 7. The stable controlled release composition as claimed in claim 1 and 5, wherein the binder is polyvinylpyrrolidone and is present in the range of 5-10% of w/w tablet. 8. The stable sustained release composition as claimed in claim 1, wherein the lubricant is magnesium stearate and is present in the range of 0.25% to 5.0% of w/w tablet. 9. The stable sustained release composition as claimed in claim 1, wherein the film formers are selected from the group of polymers such hydroxypropyl methyl cellulose E 5. 10. The stable controlled release composition as claimed in claim 1, wherein plasticizers are selected from the family of glycols such as polyethylene glycol 6000 in the range of 5%-15%. 11. The stable sustained release composition as claimed in claiml, wherein said composition is in the form of film-coated or uncoated tablets. 12. The stable controlled release composition as claimed in claim 1, wherein the tablet is film coated by alcoholic or aqueous coating. 13. The process for preparation of the sustained release antimalarial pharmaceutical composition as claimed in claim 1 comprising: i) sifting Primaquine phosphate, microcrystalline cellulose, hydroxy propyl methyl cellulose K 15 M and mixing to form a blend; ii) granulating the blend with mixture of polyvinylpyrrolidone 90 and isopropyl alcohol using non-aqueous wet granulation; iii) milling the wet granules through mesh and air-dried and then at 60°C in FBD until it reach 2-3% LOD at 105°C; iv) lubricating the dried granules with hydroxy propyl methyl cellulose K 15 M and talc and sifting; v) lubricating the blend with magnesium stearate for 2 minutes; vi) making the tablets using direct compression method. Dated this 12th day of July 2007 DR. GOPAKUMAR G. NAIR Agent for the Applicant GOPAKUMAR NAIR ASSOCIATES 19 Abstract: This invention relates to sustained release anti-malarial formulation of Primaquine or its pharmaceutical^ acceptable salt with reduced side effects typically associated with the dosing of primaquine and method for preparing the same. The preparation of formulation involves use of a hydrophilic polymer such as, hydroxypropyl methyl cellulose K15 M for sustained release of drug over specific period of time.

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