Title of Invention	PROCESS FOR PREPARATION OF A STABLE SOLID ORAL COMPOSITION COMPRISING OF A BIGUANIDE AND AN INSULIN ENHANCER IN COMBINATION
Abstract	The present invention provides a process for preparation of single-dose per day stable solid oral pharmaceutical composition comprising of metformin hydrochloride and nateglinide in the weight ratio of 8:1 and 4:1. Further invention provides a process for preparation of a stable, synergistic pharmaceutical composition comprising of a combination of metformin and nateglinide and its formulation thereof. The pharmaceutical combination contains therapeutically effective amounts of metformin hydrochloride and nateglinide. This combination drug product is intended for oral use and is useful for the treatment of type II diabetes, hyperglycemia and related metabolic disorders.

Title of Invention

PROCESS FOR PREPARATION OF A STABLE SOLID ORAL COMPOSITION COMPRISING OF A BIGUANIDE AND AN INSULIN ENHANCER IN COMBINATION

Abstract

The present invention provides a process for preparation of single-dose per day stable solid oral pharmaceutical composition comprising of metformin hydrochloride and nateglinide in the weight ratio of 8:1 and 4:1. Further invention provides a process for preparation of a stable, synergistic pharmaceutical composition comprising of a combination of metformin and nateglinide and its formulation thereof. The pharmaceutical combination contains therapeutically effective amounts of metformin hydrochloride and nateglinide. This combination drug product is intended for oral use and is useful for the treatment of type II diabetes, hyperglycemia and related metabolic disorders.

Full Text	FORM 2 THE PATENTS ACT, 1970 (39 of 1970) COMPLETE SPECIFICATION [See section 10, rule 39] Process for preparation of a stable solid oral composition comprising of a biguanide and an insulin enhancer in combination. (a) IPCA LABORATORIES LTD. (b) 48, Kandivli Industrial Estate, Mumbai - 400 067, Maharashtra, India (c) Indian Company incorporated under the Companies Act 1956 The following specification describes the nature of this invention and the manner in which it is to be performed: ORIGINAL 737/MUM/2003 GRANTED 10-11-2004 Technical Field of Invention This invention relates to a process for preparation of a new stable oral combination of metformin hydrochloride and nateglinide. The combination in particular, relates to the formulation of metformin hydrochloride 500mg with nateglinide 60 and 120 mg in a stable solid oral dosage form. A method of pharmaceutical preparation comprising of the two-drug combination is described. Background and Prior Art Metformin is a dimethyl biguanide, an orally-administered antihyperglycemic agent, used in the management of non-insulin-dependent diabetes mellitus. It is typically used clinically as a pharmaceutically acceptable salt, preferably the hydrochloride salt. Nateglinide is an orally-administrable insulin sensitizer that stimulates insulin secretion from the pancreas and strengthens insulin action to lower blood sugar in diabetic patients. Type II diabetes is characterized by both increased peripheral insulin resistance and abnormal insulin secretion. At least two abnormalities of insulin secretion are recognized: in the first phase insulin is both delayed and inadequate in the face of elevated circulating glucose levels and in the second phase insulin secretion is lost. Several metabolic, hormonal, and pharmacological entities are known to stimulate insulin secretion including glucose, amino-acids and gastrointestinal peptides. The present invention relates to a process for preparation of stable solid oral pharmaceutical composition which comprises of metformin and nateglinide as the dual active agents in the composition and pharmaceutically acceptable dosage forms of two strengths of nateglinide with metformin in the combination. Examples of prior art references which relate to a biguanide and /or an insulin sensitizer are mentioned below. European Patent No. 1258249 (N. Nobutaka et al.) describes an oral preparation containing the active ingredient nateglinide which directly decreases both of the post prandial blood glucose level and the fasting blood glucose level close to normal levels by release-sustaining a drug, nateglinide, capable of decreasing the post prandial blood glucose level of diabetic patients close to the normal level, or mixing a controlled release drug, nateglinide, capable of decreasing the post prandial blood glucose level close to the normal level with an immediate release drug. US Patent No. 6,437,147 (Andersen et al.) describes a novel class of imidazol heterocyclic compounds are administered with metformin and nateglinide. These compounds are claimed to be useful for the treatment and/or prevention of diseases and disorders in which an interaction with the histamine H3 receptor is beneficial. Patent No.WO0234254 (N. Nobutaka et. al.) describe single drug preparations containing nateglinide as the active ingredient which are quick release preparations useful as drugs for diabetes, wherein the nateglinide is in the amorphous state. US Patent No. 2003104049 (S.B.Charles) describes the preparation and composition of single ingredient metformin hydrochloride tablets of relatively small size and good hardness by a dry-mix process using methylcellulose as a dry-mix binder, provided that no stearate is added, or alternatively the amount of stearate that is added is under 0.6% by weight. United States Patent No. 6,559,188 by Gatlin, et al., refers to, in an abstract thereof a combination of nateglinide or repaglinide with at least one other antidiabetic compound selected from the group consisting of thiazolidinedione derivatives (glitazones), sulfonyl urea derivatives and metformin. However, surprisingly neither in the description or in the claim or anywhere else in the entire specification refers to a combination. The claims in this patent refer to a single ingredient formulation of nateglinide or pharmaceutically acceptable salts thereof. Patent application number WO02094285 fundamentally discloses oral galenic forms such as capsules which are associated with a biguanide, preferably metformin and at least another anti-hyperglycemic active principle B selected from Glibenclamide, pioglitazone hydrochloride, rosiglitazone maleate, nateglinide, glipezide, glimeperide. This further describes a capsule consisting of a core of metformin coated with a film to enable a prolonged release of metformin in vivo. Optionally the capsule have been coated with active principle B to enable prolonged release of active principle B. The delayed release of active principle A and B ensure a once-a-day single dosage form of the invention. The description and examples of this patent illustrates only combination of metformin with glibenclamide as the active principle B. Composition or combination of mateformin and nateglinide or its strength is not even mentioned in the description, examples and claims. While our invention specifically relates to only a two-drug combined pharmaceutical preparation of metformin with nateglinide to render a therapeutic effective once-a-day tablet dosage form. Our invention further relates to immediate release tablet form of both metformin and nateglinide in the combination and not the prolonged release of either of the two actives. Further our invention relates to immediate release once-a-day dosage form for a combination of metformin 500 mg with nateglinide 60 and 120 mg are effective lower than when two drugs are administered separately. More specifically our invention relates to a therapeutically effective combined preparation of metformin of strength 500 mg with nateglinide of strength 60 and 120 mg and detailed composition of the combined preparation of the solid dosage form is described. Other patent application number WO 0121159 describes combined preparation or pharmaceutical composition which comprises nateglinide or rapeglinide and at least one other antidiabetic compound selected from group consisting of thiozolidone derivatives (glitazone), sulfonyl urea derivatives and metformin for simultaneous, separate, sequential use in the prevention, delay of progression or treatment of disease, especially metabolic disorders and in particular type 2 diabetes and diseases and conditions associates with diabetes. Eventhough abstract makes a geenralised mention of combinations of nateglinide or rapeglinide with thiozolidone derivatives, sulfonyl urea derivatives or metformin for treatment of metabolic disorders related with diabetes, there is no combination or composition claimed or reported in the patent. Further this patent describes administration of independent dosage forms 60 and 120 mg Nateglinide and 250 and 1000 mg Metformin. These individual dosage forms of metformin and nateglinide can be used concomitantly for prevention and treatment of diabetes. Other than this no oral dosage forms and pharmaceutical compositions of the combination drug are mentioned or described in detail description, examples and claims in the patent. There is a generalized mentioned of the possibility of favourable results from the combined effect of metformin and nateglinide, this patent clearly emphasizes and relates to a method of treatment / prevention of diabetes in warm blooded animals with the combined use (not combination) of drags mentioned. The example of this patent specifies a pharmaceutical tablet composition of 60 and 120 mg Nateglinide alone (SINGLE INGREDIENT DRUG). The composition of a combined preparation of two drugs or even metformin alone is not described. While our invention specifically relates to a two-drug combined pharmaceutical preparation of metformin with nateglinide to render a once-a-day tablet dosage form. Further it edcsribes the novel pharmaceutical combination of metformin with nateglinide in a single dosage form wherein the selected strength of metformin 500 mg with nateglinide 60 and 120 mg are effectively lower than when two drugs are administered separately. The stable pharmaceutical composition of the tablet form of this two drug combination is exemplified in detail. This invention more particularly relates to first time combination of metformin with nateglinide in a single tablet form and the pharmaceutical composition thereof. In our invention therapeutically effective combined preparation of metformin of strength 500 mg with nateglinide strength 60 and 120 mg is developed. Further aspect to the present invention the detailed composition of the combined preparation of the solid dosage form is described in detail. None of the above prior art references as discussed above claims pharmaceutical combinations of metformin or a pharmaceutical acceptable salt thereof with nateglinide and the pharmaceutical composition related to the same. Objectives The objective of the present invention is to provide a process for preparation of stable formulation of a metformin and nateglinide in the form of coated tablets. It is an object of the present invention to provide a process for preparation of an improved pharmaceutical composition, in particular for the treatment of diabetic complaints. Summary A process for preparation of a new stable oral combination of metformin hydrochloride and nateglinide is disclosed. The combination in particular, relates to the formulation of metformin hydrochloride 500mg with nateglinide 60 and 120 mg in a stable solid oral dosage form. A method of pharmaceutical preparation comprising of the two-drug combination is described. A process for preparation of single-dose per day stable pharmaceutical composition comprising of metformin hydrochloride and nateglinide in the weight ratio of 8:1 and 4:1 wherein the said process comprises wet granulating the two active ingredients jointly after prior mixing or separately single ingredientwise granulation and blending them prior to compression; compressing the granules into tablets with hardness varying from 90 newtons to 140 newtons; and film coating the tablets with alcohol coating using red ferric oxide and yellow ferric oxide in the film coating in the weight percentage of 0.01 and 0.03 weight percent respectively to provide yellow or brown colour respectively to the tablets depending on the strength of the combination. More specifically it describes the process fro preparation of tablet of the combination of metformin hydrochloride and nateglinide along with the pharmaceutically acceptable excipients used as binders, disintegrants, glidants and lubricants. Further it includes the film-coating of the tablet core and its requisite composition. Detailed Description of the Invention As a result of various studies of medicinal properties of metformin and nateglinide such as for diabetes and related disorders, the present inventors combined an insulin sensitizer nateglinide with a biguanide metformin hydrochloride in a single dosage form, and found, for the first time, that such combination unexpectedly provided quite excellent properties as a medicine such as an excellent blood sugar lowering effect. The clinical research data from the journal references and US Patent No. 6,559,188 cited in the prior art showed no apparent detection of side effects for the single dosage forms, etc. Based on this finding, the present inventors have completed the present invention. This invention intends to use this combination for the preparation of a pharmaceutically acceptable solid oral dosage form for the two combination drugs for diabetes and the use of such combination for the control of obesity by enhancing the loss of excess body weight. The present invention relates to a pharmaceutical composition comprising metformin and nateglinide as the dual active agents in the composition and pharmaceutically acceptable dosage forms of two strengths of nateglinide with metformin in the combination and to a process of making such a stable pharmaceutical composition. This invention intends to provide a pharmaceutically acceptable combination for oral use that is a stable preparation of the combination of metformin hydrochloride and nateglinide. Namely, the present invention relates to a pharmaceutical combination of the two active compounds which is especially effective in the treatment of diabetes and diabetes related disorders and complications. Further aspects of this invention suggest that the pharmaceutical combination of the present invention possesses an enhanced blood sugar lowering action and therefore, the amount of drugs used can be reduced as compared with monotherapy with an insulin sensitizer or biguanide alone. Metformin is a typical biguanide (i. e. drugs having actions of stimulation of anaerobic glycolysis) used clinically as in the pharmaceutically acceptable salt of hydrochloride. Nateglinide is a non-sulfonylurea insulin enhancer. Experimental results suggest that the combined administration of nateglinide with metformin or a pharmaceutical acceptable salt thereof results in a more beneficial and synergistic therapeutic effect than monotherapy with either one of the active compounds alone. The therapeutic effect of the combination results in a more effective prevention or preferably treatment of the metabolic disorder of diabetes especially type 2 diabetes mellitus, and diseases and conditions associated with it. The compounds of the present invention can also be used as anti-obesity drugs alone or can be administered with other anti-obesity drugs. For a warm-blooded animal which is a human being of about 70 kg body weight, nateglinide is preferably administered in a dosage in the range of about 5 to 1200mg/day, more preferably 10 to lOOOmg/day and most preferably 25 to 800 mg/day. Metformin is preferably administered in a dosage range of about 250 mg/day to 2250mg/day. But the therapeutic combination of the above would ideally suffice to have a dosage range of 60mg Nateglinide with 500 mg metformin to 120mg nateglinide with 500mg metformin. This combination not only is less cumbersome than taking two different dosages of both drugs separately but also is effective in a lesser strength than any of the drugs taken individually. As a further aspect of the invention, the pharmaceutially acceptable excipients such as binders, disintegrants and lubricants required in the formulation of the drug combination are described along with a hydro-alcoholic film coating for the tablet core. Tablets of this invention are granulated by means of wet granulation techniques as defined. The formulation details of the pharmaceutical composition used in the combinations are disclosed herein. Metformin hydrochloride and nateglinide are active ingredients which do not have good binding properties. Hence the direct compression method for tabletting is ruled out. For the purpose of wet granulation, metformin and nateglinide are separately granulated and then mixed, lubricated and compressed. Out of the commonly used wet-granulation binders, a povidone (PVP K-30) is used. In this approach, the binder is activated in a solvent (purified water) and is used to granulate the active drugs as well as the inactive excipients. The tablets made by this approach using povidone as the binder, and magnesium stearate as lubricant. This approach enables tablets of adequate hardness with minimum weight and size. The particle size specification for nateglinide was not less than 100% of particles are Metformin hydrochloride and nateglinide have a pronounced bitter taste and accordingly, the tablets are film coated in order to mask any unpleasant taste. Further the present composition comprising of the formulation and the process for the preparation of coated tablets of the said formulation. According to the present invention, there is provided a single dose tablet -form satble solid pharmaceutical composition for oral administration comprising : (i) a biguanide, metformin hydrochloride; (ii) a non-sulfonylurea insulin enhancer, nateglinide; in the weight ratio within the range of 8:1 to 4:1; (iii) excipients comprising, binder,disintegrant, lubricant and glidant; and (iv) a film coating. A pharmaceutically acceptable binder, povidone is used in the range of 4.0 to 4.7% by weight on a dry weight basis, based on the weight of the formulation. Pharmaceutically acceptable disintegrants such as microcrystalline cellulose, cross caramellose sodium and sodium starch glycollate are used in the range of 17.5% to 19.9% by weight on a dry weight basis, based on the weight of the formulation. A pharmaceutically acceptable lubricant, magnesium stearate is used in the range of 0.9 to 1% by weight on a dry weight basis, based on the weight of the formulation. A pharmaceutically acceptable glidant, colloidal silicon dioxide is used in the range of 0.88 to 0.95% by weight on a dry weight basis, based on the weight of the formulation. Also provided in accordance with the invention is a process for the preparation an oral pharmaceutical composition, the composition comprising metformin hydrochloride and nateglilnide in the weight ratio of 8:1 and 4 : 1, the composition further comprising excipients including one or more of the following excipients : binder, disintegrants such as sodium starch glycolate, lubricant, glidant and a film coating, the process comprising the following steps: a) wet granulating the two active ingredients jointly after prior mixing or separately ingle ingredient wise granulation and blending them prior to compression; b) compressing the granules inot tablets with hardness varying from 90 newtons to 140 newtons and c) film coating the tablets with alcohol coating using red ferric oxide and yellow ferric oxide the film coating in the weight percentage of 0.01 and 0.03 weight percent respectively to provide yellow or brown colour respectively to the tablets depending on the strength of the combination. This invention will be further exemplified in the following examples: EXAMPLE 1 The manufacturing process for clinical products proceeded as follows: Sodium starch glycollate and metformin are blended together. The resultant dry mix is granulated with an aqueous povidone solution and the solvent is evaporated from the granulate by drying in a fluid bed dryer at approximately 60°C to achieve a specified moisture content, determined by loss on drying. The dried granulation is reduced with a screening mill. Nateglinide is similarly granulated separately. This is followed by blending the metformin and nateglinide granules along with colloidal silicon dioxide, microcrystalline cellulose (Avicel pH 102) and cross carmellose sodium (Ac-di-Sol). Among the stearates, magnesium stearate is incorporated as a lubricant to produce the final compression blend. The function of the magnesium stearate in the core tablet is to act as a lubricant to prevent sticking to the tooling (punches and dies) in the tabletting process. In order to achieve the desired tablet hardness with the requisite friability, magnesium stearate is used at about 0.9% of the weight of the tablet. The function of the povidone is to act as a binder to cause the metformin hydrochloride and nateglinide to bind into a sufficiently hard tablet under compression in the tabletting process. The resultant blend was compressed into tablets, to a desired target on a suitable tablet press. The theoretical tablet weight (based on formula composition with no adjustment for moisture content) was 850 mg for the 500 mg/120 mg strength and 735 mg for the 500/60 mg strength products. TABLE 1 : Tablet comprising metformin hydrochloride and nateglilnide in the weight ratio of 4 : 1 Ingredients Parts by weight of tablet Metformin hydrochloride 58.82% Sodium starch glycollate 3.53% PVP K-30 3.53% Purified water qs Nateglinide 14.12%% Microcrystalline cellulose 7.06% Cross caramellose sodium (Ac -di-Sol) 1.76% PVP K-30 1.17% Purified water qs Sodium starch glycollate 2.94% Cross caramellose sodium (Ac-Di-Sol) 1.76% Colloidal silicon dioxide (Aerosil) 0.88% Cellulose, microcrystalline (Avicel pH 2.94% 102) Magnesium stearate 0.94% Similarly, Tablets containing metformin hydrochloride 500mg with nateglinide 60 mg (ie. 8 :1 ratio) are prepared. Tablets that were prepared by conventional procedures of aqueous granulation by mixing both the drugs together and granulating failed in the disintegration test as per United States Pharmacopoeia standards. Further trials with similar approaches using decreased quantity of binder and increased quantity of disintegrant also did not have any significant effect on improving the disintegration of the tablets. On the contrary less binder let to higher friability and the tablets failed in friability test. The method of separately granulating metformin and nateglinide and then mixing the dried granules prior to compression of tablets gave excellent results which are as follows; Approaches Hardness Friability Disintegration time I Aqueous granulation with both metformin and nateglinide mixed and granulated together. 100 Newton 0.2% More than 45 minutes II Aqueous granulation with decreased binder and increased disintegrant where metformin and nateglinide were mixed and granulated together. 100 Newton 0.5% More than 30 minutes III Separate granulation of metformin and nateglinide, followed by mixing of dried granules prior to tabletting. 100 Newton Nil 2 minutes 30 seconds STABILITY DATA FOR (METFORMIN + NATEGLINIDE) TABLETS At accelerated conditions of stability, the formulation for the combined preparation was found to be stable for the studied period. The assay for metformin and nateglinide was within limits during the period of study. The dissolution results were also in compliance with the standards. TESTS SPECIFICATION INITIAL 25°C/60% RH 40°C/75%RH 3 months 1 month 2 months 3 months DESCRIPTION Light yellow capsule shaped tablets Complies Complies Complies Complies Complies IDENTIFICATION Retention time of metformin and Complies Complies Complies Complies Complies nateglinide in sample solution is concordant with standard in assay preparation DISSOLUTION Medium: 1% SLS buffer Apparatus: Paddle RPM: 100 Time: 45 minutes Temperature: 37°C Metformin- not less than 70% in 45 minutes 104.3-106.9 105.2-107.1 103.3-108.5 100.9-105.2 102.3-106.7 Nateglinide- not less than 70% in 45 minutes 99.2-106.4 92.0- 94.3 91.7-99.2 87.3-91.5 91.4-94.3 ASSAY Metformin- 90-110% 97.4 103.2 104.9 102.3 103.5 Nateglinide- 90-110% 104.6 101.2 102.2 100.9 104.3 EXAMPLE 2 Tablets manufactured for clinical use were film-coated in a coating pan with an appropriate non-aqueous/alcoholic hydroxypropyl methylcellulose (HPMC) based film coat. The film coat was designed to mask any unpleasant taste of the tablet and was also applied for aesthetic purposes. The typical level of film coat applied to the tablets was 2% w/w. Film coating of uncoated tablets made in Example I was performed with the following coating solution: TABLE 2 Ingredients Parts by weight of tablet Hydroxypropyl methyl cellulose 1.194% Talc 0.482% Titanium dioxide 0.207% Yellow Ferric oxide 0.029% Polyethylene glycol 6000 0.087% Isopropyl alcohol qs Methylene chloride qs Tablets of example 1 were coated with 2% of this solution per tablet weight using a film coating device to obtain the tablets of the present invention. Similarly Tablets containing metformin hydrochloride 500mg and nateglinide 60 mg are film coated using red ferric oxide. During manufacture, the tablets were monitored for weight, hardness, thickness and friability. The hardness was adjusted to between 90 and 140N, preferably between 100 and 120 N. The tablet thickness ranged from 5.3mm to about 6.1mm. Friability was maintained below 1%. TABLE 3 Hardness (in L Newton) Disintegration (in Friability (%) n = 20 n=10 minutes) n = 3 Time=4 minutes=100 rotations 90±10 1 0.05 100dzl0 2 0.1 120±10 3 0.1 140±10 3 Nil Industrial Applicability This invention intends to provide a pharmaceutical^ acceptable combination for oral use that is a stable preparation of the combination of metformin hydrochloride and nateglinide. Namely, the present invention relates to the process for preparation of a stable solid oral pharmaceutical combination of the two active compounds which is especially effective in the treatment of diabetes and diabetes related disorders and complications. Further aspects of this invention suggest that the pharmaceutical combination of the present invention obtained by the process as claimed possesses an enhanced blood sugar lowering action, and therefore, the amount of drugs used can be reduced as compared with monotherapy with an insulin sensitizer or biguanide alone. We claim, 1. A process for preparation of single-dose per day stable solid oral pharmaceutical composition comprising of a biguanide, metformin hydrochloride and a non- sulfonyl urea, nateglinide in the weight ratio of 8:1 and 4:1 alongwith excipients comprising of binder, disintegrants such as sodium starch glycolate, lubricant and glidant wherein the said process comprises a) wet granulating the two active ingredients such as a biguanide, metformin hydrochloride and a sulfonyl urea, nateglinide jointly after prior mixing or separately single ingredientwise granulation and blending them prior to compression; b) compressing the granules into tablets with hardness varying from 90 newtons to 140 newtons; and c) film coating the tablets with alcohol coating using red ferric oxide and yellow ferric oxide in the film coating in the weight percentage of 0.01 and 0.03 weight percent respectively, to provide yellow or brown colour respectively to the tablets depending on the strength of the combination. 2. The process as claimed in claim 1, wherein the amount of metformin hydrochloride in the composition is 500 mg. 3. The process as claimed in claim 1, wherein the nateglinide in the composition is 60 mg and 120 mg in respective dosage form. 4. The process as claimed in claim 1, wherein after granulation the composition contains less than 20 % by weight of granules having size of 850 urn or more. 5. The process as claimed in claim 1, wherein a pharmaceutically acceptable binder, povidone is used in the range of 4.0 to 4.7% by weight on a dry weight basis, based on the weight of the formulation. 6. The process as claimed in claim 1, wherein pharmaceutically acceptable disintegrants such as microcrystalline cellulose, cross caramellose sodium and sodium starch glycollate are used in the range of 17.5% to 19.9% by weight on a dry weight basis, based on the weight of the formulation. 7. The process as claimed in claim 1, wherein the disintegrant is selected from microcrystalline cellulose, cross caramellose sodium and sodium starch glycolate either alone or in combination. 8. The process as claimed in claim 1, wherein disintegrant, sodium starch glycollate is used intra-granularly or extra-granularly. 9. The process as claimed in claim 1, wherein a pharmaceutically acceptable lubricant, magnesium stearate is used about 0.9 to 1% by weight on a dry weight basis, based on the weight of the formulation. 10. The process as claimed in claim 1, wherein a pharmaceutically acceptable glidant, colloidal silicon dioxide is used in the range of 0.88 to 0.95% by weight on a dry weight basis, based on the weight of the formulation. 11. The process as claimed in claim 1 wherein the film coating is an alcohol coating using red and / or yellow ferric oxide in the film. 12. The process as claimed in claim 1 wherein the film coating comprises hydroxypropyl methyl cellulose, Talc, Titanium dioxide, Polyethylene glycol 6000, Isopropyl alcohol and methylene chloride. 13. The process as claimed in claim 1, wherein the said single dose tablet-form stable pharmaceutical composition for oral administration are caplet shaped 14. A process for preparation of single-dose per day stable pharmaceutical composition comprising of metformin hydrochloride and nateglinide as substantially described herein with reference to the foregoing examples 1 to 3. Dated this the 23rd day of July 2003 Dr. Gopakumar G. Nair Agent for the Applicant

Full Text

FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
COMPLETE SPECIFICATION
[See section 10, rule 39]
Process for preparation of a stable solid oral composition comprising of a biguanide
and an insulin enhancer in combination.
(a) IPCA LABORATORIES LTD.
(b) 48, Kandivli Industrial Estate, Mumbai - 400 067, Maharashtra, India
(c) Indian Company incorporated under the Companies Act 1956
The following specification describes the nature of this invention and the manner in which it is to be performed:

ORIGINAL
737/MUM/2003

GRANTED

10-11-2004

Technical Field of Invention
This invention relates to a process for preparation of a new stable oral combination of metformin hydrochloride and nateglinide. The combination in particular, relates to the formulation of metformin hydrochloride 500mg with nateglinide 60 and 120 mg in a stable solid oral dosage form. A method of pharmaceutical preparation comprising of the two-drug combination is described.
Background and Prior Art
Metformin is a dimethyl biguanide, an orally-administered antihyperglycemic agent, used in the management of non-insulin-dependent diabetes mellitus. It is typically used clinically as a pharmaceutically acceptable salt, preferably the hydrochloride salt.
Nateglinide is an orally-administrable insulin sensitizer that stimulates insulin secretion from the pancreas and strengthens insulin action to lower blood sugar in diabetic patients.
Type II diabetes is characterized by both increased peripheral insulin resistance and abnormal insulin secretion. At least two abnormalities of insulin secretion are recognized: in the first phase insulin is both delayed and inadequate in the face of elevated circulating glucose levels and in the second phase insulin secretion is lost. Several metabolic, hormonal, and pharmacological entities are known to stimulate insulin secretion including glucose, amino-acids and gastrointestinal peptides.
The present invention relates to a process for preparation of stable solid oral pharmaceutical composition which comprises of metformin and nateglinide as the dual active agents in the composition and pharmaceutically acceptable dosage forms of two strengths of nateglinide with metformin in the combination.

Examples of prior art references which relate to a biguanide and /or an insulin sensitizer are mentioned below.
European Patent No. 1258249 (N. Nobutaka et al.) describes an oral preparation containing the active ingredient nateglinide which directly decreases both of the post prandial blood glucose level and the fasting blood glucose level close to normal levels by release-sustaining a drug, nateglinide, capable of decreasing the post prandial blood glucose level of diabetic patients close to the normal level, or mixing a controlled release drug, nateglinide, capable of decreasing the post prandial blood glucose level close to the normal level with an immediate release drug.
US Patent No. 6,437,147 (Andersen et al.) describes a novel class of imidazol heterocyclic compounds are administered with metformin and nateglinide. These compounds are claimed to be useful for the treatment and/or prevention of diseases and disorders in which an interaction with the histamine H3 receptor is beneficial.
Patent No.WO0234254 (N. Nobutaka et. al.) describe single drug preparations containing nateglinide as the active ingredient which are quick release preparations useful as drugs for diabetes, wherein the nateglinide is in the amorphous state.
US Patent No. 2003104049 (S.B.Charles) describes the preparation and composition of single ingredient metformin hydrochloride tablets of relatively small size and good hardness by a dry-mix process using methylcellulose as a dry-mix binder, provided that no stearate is added, or alternatively the amount of stearate that is added is under 0.6% by weight.
United States Patent No. 6,559,188 by Gatlin, et al., refers to, in an abstract thereof a combination of nateglinide or repaglinide with at least one other antidiabetic compound selected from the group consisting of thiazolidinedione derivatives (glitazones), sulfonyl

urea derivatives and metformin. However, surprisingly neither in the description or in the claim or anywhere else in the entire specification refers to a combination. The claims in this patent refer to a single ingredient formulation of nateglinide or pharmaceutically acceptable salts thereof.
Patent application number WO02094285 fundamentally discloses oral galenic forms such as capsules which are associated with a biguanide, preferably metformin and at least another anti-hyperglycemic active principle B selected from Glibenclamide, pioglitazone hydrochloride, rosiglitazone maleate, nateglinide, glipezide, glimeperide. This further describes a capsule consisting of a core of metformin coated with a film to enable a prolonged release of metformin in vivo. Optionally the capsule have been coated with active principle B to enable prolonged release of active principle B. The delayed release of active principle A and B ensure a once-a-day single dosage form of the invention. The description and examples of this patent illustrates only combination of metformin with glibenclamide as the active principle B. Composition or combination of mateformin and nateglinide or its strength is not even mentioned in the description, examples and claims. While our invention specifically relates to only a two-drug combined pharmaceutical preparation of metformin with nateglinide to render a therapeutic effective once-a-day tablet dosage form. Our invention further relates to immediate release tablet form of both metformin and nateglinide in the combination and not the prolonged release of either of the two actives. Further our invention relates to immediate release once-a-day dosage form for a combination of metformin 500 mg with nateglinide 60 and 120 mg are effective lower than when two drugs are administered separately. More specifically our invention relates to a therapeutically effective combined preparation of metformin of strength 500 mg with nateglinide of strength 60 and 120 mg and detailed composition of the combined preparation of the solid dosage form is described.
Other patent application number WO 0121159 describes combined preparation or pharmaceutical composition which comprises nateglinide or rapeglinide and at least one

other antidiabetic compound selected from group consisting of thiozolidone derivatives (glitazone), sulfonyl urea derivatives and metformin for simultaneous, separate, sequential use in the prevention, delay of progression or treatment of disease, especially metabolic disorders and in particular type 2 diabetes and diseases and conditions associates with diabetes. Eventhough abstract makes a geenralised mention of combinations of nateglinide or rapeglinide with thiozolidone derivatives, sulfonyl urea derivatives or metformin for treatment of metabolic disorders related with diabetes, there is no combination or composition claimed or reported in the patent. Further this patent describes administration of independent dosage forms 60 and 120 mg Nateglinide and 250 and 1000 mg Metformin. These individual dosage forms of metformin and nateglinide can be used concomitantly for prevention and treatment of diabetes. Other than this no oral dosage forms and pharmaceutical compositions of the combination drug are mentioned or described in detail description, examples and claims in the patent. There is a generalized mentioned of the possibility of favourable results from the combined effect of metformin and nateglinide, this patent clearly emphasizes and relates to a method of treatment / prevention of diabetes in warm blooded animals with the combined use (not combination) of drags mentioned. The example of this patent specifies a pharmaceutical tablet composition of 60 and 120 mg Nateglinide alone (SINGLE INGREDIENT DRUG). The composition of a combined preparation of two drugs or even metformin alone is not described.
While our invention specifically relates to a two-drug combined pharmaceutical preparation of metformin with nateglinide to render a once-a-day tablet dosage form. Further it edcsribes the novel pharmaceutical combination of metformin with nateglinide in a single dosage form wherein the selected strength of metformin 500 mg with nateglinide 60 and 120 mg are effectively lower than when two drugs are administered separately. The stable pharmaceutical composition of the tablet form of this two drug combination is exemplified in detail. This invention more particularly relates to first time combination of metformin with nateglinide in a single tablet form and the pharmaceutical

composition thereof. In our invention therapeutically effective combined preparation of metformin of strength 500 mg with nateglinide strength 60 and 120 mg is developed. Further aspect to the present invention the detailed composition of the combined preparation of the solid dosage form is described in detail.
None of the above prior art references as discussed above claims pharmaceutical combinations of metformin or a pharmaceutical acceptable salt thereof with nateglinide and the pharmaceutical composition related to the same.
Objectives
The objective of the present invention is to provide a process for preparation of stable formulation of a metformin and nateglinide in the form of coated tablets.
It is an object of the present invention to provide a process for preparation of an improved pharmaceutical composition, in particular for the treatment of diabetic complaints.
Summary
A process for preparation of a new stable oral combination of metformin hydrochloride and nateglinide is disclosed. The combination in particular, relates to the formulation of metformin hydrochloride 500mg with nateglinide 60 and 120 mg in a stable solid oral dosage form. A method of pharmaceutical preparation comprising of the two-drug combination is described.
A process for preparation of single-dose per day stable pharmaceutical composition comprising of metformin hydrochloride and nateglinide in the weight ratio of 8:1 and 4:1 wherein the said process comprises wet granulating the two active ingredients jointly after prior mixing or separately single ingredientwise granulation and blending them prior to compression; compressing the granules into tablets with hardness varying from 90 newtons to 140 newtons; and film coating the tablets with alcohol coating using red

ferric oxide and yellow ferric oxide in the film coating in the weight percentage of 0.01 and 0.03 weight percent respectively to provide yellow or brown colour respectively to the tablets depending on the strength of the combination.
More specifically it describes the process fro preparation of tablet of the combination of metformin hydrochloride and nateglinide along with the pharmaceutically acceptable excipients used as binders, disintegrants, glidants and lubricants. Further it includes the film-coating of the tablet core and its requisite composition.
Detailed Description of the Invention
As a result of various studies of medicinal properties of metformin and nateglinide such as for diabetes and related disorders, the present inventors combined an insulin sensitizer nateglinide with a biguanide metformin hydrochloride in a single dosage form, and found, for the first time, that such combination unexpectedly provided quite excellent properties as a medicine such as an excellent blood sugar lowering effect. The clinical research data from the journal references and US Patent No. 6,559,188 cited in the prior art showed no apparent detection of side effects for the single dosage forms, etc. Based on this finding, the present inventors have completed the present invention.
This invention intends to use this combination for the preparation of a pharmaceutically acceptable solid oral dosage form for the two combination drugs for diabetes and the use of such combination for the control of obesity by enhancing the loss of excess body weight. The present invention relates to a pharmaceutical composition comprising metformin and nateglinide as the dual active agents in the composition and pharmaceutically acceptable dosage forms of two strengths of nateglinide with metformin in the combination and to a process of making such a stable pharmaceutical composition.

This invention intends to provide a pharmaceutically acceptable combination for oral use that is a stable preparation of the combination of metformin hydrochloride and nateglinide.
Namely, the present invention relates to a pharmaceutical combination of the two active compounds which is especially effective in the treatment of diabetes and diabetes related disorders and complications.
Further aspects of this invention suggest that the pharmaceutical combination of the present invention possesses an enhanced blood sugar lowering action and therefore, the amount of drugs used can be reduced as compared with monotherapy with an insulin sensitizer or biguanide alone.
Metformin is a typical biguanide (i. e. drugs having actions of stimulation of anaerobic glycolysis) used clinically as in the pharmaceutically acceptable salt of hydrochloride. Nateglinide is a non-sulfonylurea insulin enhancer. Experimental results suggest that the combined administration of nateglinide with metformin or a pharmaceutical acceptable salt thereof results in a more beneficial and synergistic therapeutic effect than monotherapy with either one of the active compounds alone. The therapeutic effect of the combination results in a more effective prevention or preferably treatment of the metabolic disorder of diabetes especially type 2 diabetes mellitus, and diseases and conditions associated with it. The compounds of the present invention can also be used as anti-obesity drugs alone or can be administered with other anti-obesity drugs.
For a warm-blooded animal which is a human being of about 70 kg body weight, nateglinide is preferably administered in a dosage in the range of about 5 to 1200mg/day, more preferably 10 to lOOOmg/day and most preferably 25 to 800 mg/day. Metformin is preferably administered in a dosage range of about 250 mg/day to 2250mg/day. But the therapeutic combination of the above would ideally suffice to have a dosage range of

60mg Nateglinide with 500 mg metformin to 120mg nateglinide with 500mg metformin. This combination not only is less cumbersome than taking two different dosages of both drugs separately but also is effective in a lesser strength than any of the drugs taken individually.
As a further aspect of the invention, the pharmaceutially acceptable excipients such as binders, disintegrants and lubricants required in the formulation of the drug combination are described along with a hydro-alcoholic film coating for the tablet core. Tablets of this invention are granulated by means of wet granulation techniques as defined. The formulation details of the pharmaceutical composition used in the combinations are disclosed herein.
Metformin hydrochloride and nateglinide are active ingredients which do not have good binding properties. Hence the direct compression method for tabletting is ruled out. For the purpose of wet granulation, metformin and nateglinide are separately granulated and then mixed, lubricated and compressed. Out of the commonly used wet-granulation binders, a povidone (PVP K-30) is used. In this approach, the binder is activated in a solvent (purified water) and is used to granulate the active drugs as well as the inactive excipients. The tablets made by this approach using povidone as the binder, and magnesium stearate as lubricant. This approach enables tablets of adequate hardness with minimum weight and size. The particle size specification for nateglinide was not less than 100% of particles are Metformin hydrochloride and nateglinide have a pronounced bitter taste and accordingly, the tablets are film coated in order to mask any unpleasant taste.
Further the present composition comprising of the formulation and the process for the preparation of coated tablets of the said formulation.

According to the present invention, there is provided a single dose tablet -form satble solid pharmaceutical composition for oral administration comprising :
(i) a biguanide, metformin hydrochloride;
(ii) a non-sulfonylurea insulin enhancer, nateglinide;
in the weight ratio within the range of 8:1 to 4:1;
(iii) excipients comprising, binder,disintegrant, lubricant and glidant; and
(iv) a film coating.
A pharmaceutically acceptable binder, povidone is used in the range of 4.0 to 4.7% by
weight on a dry weight basis, based on the weight of the formulation.
Pharmaceutically acceptable disintegrants such as microcrystalline cellulose, cross
caramellose sodium and sodium starch glycollate are used in the range of 17.5% to
19.9% by weight on a dry weight basis, based on the weight of the formulation.
A pharmaceutically acceptable lubricant, magnesium stearate is used in the range of 0.9
to 1% by weight on a dry weight basis, based on the weight of the formulation.
A pharmaceutically acceptable glidant, colloidal silicon dioxide is used in the range of
0.88 to 0.95% by weight on a dry weight basis, based on the weight of the formulation.
Also provided in accordance with the invention is a process for the preparation an oral pharmaceutical composition, the composition comprising metformin hydrochloride and nateglilnide in the weight ratio of 8:1 and 4 : 1, the composition further comprising excipients including one or more of the following excipients : binder, disintegrants such as sodium starch glycolate, lubricant, glidant and a film coating, the process comprising the following steps:
a) wet granulating the two active ingredients jointly after prior mixing or
separately ingle ingredient wise granulation and blending them prior to
compression;

b) compressing the granules inot tablets with hardness varying from 90 newtons to 140 newtons and
c) film coating the tablets with alcohol coating using red ferric oxide and yellow ferric oxide the film coating in the weight percentage of 0.01 and 0.03 weight percent respectively to provide yellow or brown colour respectively to the tablets depending on the strength of the combination.
This invention will be further exemplified in the following examples:
EXAMPLE 1
The manufacturing process for clinical products proceeded as follows: Sodium starch glycollate and metformin are blended together. The resultant dry mix is granulated with an aqueous povidone solution and the solvent is evaporated from the granulate by drying in a fluid bed dryer at approximately 60°C to achieve a specified moisture content, determined by loss on drying. The dried granulation is reduced with a screening mill. Nateglinide is similarly granulated separately. This is followed by blending the metformin and nateglinide granules along with colloidal silicon dioxide, microcrystalline cellulose (Avicel pH 102) and cross carmellose sodium (Ac-di-Sol). Among the stearates, magnesium stearate is incorporated as a lubricant to produce the final compression blend. The function of the magnesium stearate in the core tablet is to act as a lubricant to prevent sticking to the tooling (punches and dies) in the tabletting process. In order to achieve the desired tablet hardness with the requisite friability, magnesium stearate is used at about 0.9% of the weight of the tablet. The function of the povidone is to act as a binder to cause the metformin hydrochloride and nateglinide to bind into a sufficiently hard tablet under compression in the tabletting process.
The resultant blend was compressed into tablets, to a desired target on a suitable tablet press. The theoretical tablet weight (based on formula composition with no adjustment

for moisture content) was 850 mg for the 500 mg/120 mg strength and 735 mg for the 500/60 mg strength products.
TABLE 1 : Tablet comprising metformin hydrochloride and nateglilnide in the weight ratio of 4 : 1

Ingredients

Parts by weight of tablet

Metformin hydrochloride 58.82%
Sodium starch glycollate 3.53%
PVP K-30 3.53%
Purified water qs
Nateglinide 14.12%%
Microcrystalline cellulose 7.06%
Cross caramellose sodium (Ac -di-Sol) 1.76%
PVP K-30 1.17%
Purified water qs
Sodium starch glycollate 2.94%
Cross caramellose sodium (Ac-Di-Sol) 1.76%
Colloidal silicon dioxide (Aerosil) 0.88%
Cellulose, microcrystalline (Avicel pH 2.94%
102)
Magnesium stearate 0.94%
Similarly, Tablets containing metformin hydrochloride 500mg with nateglinide 60 mg (ie. 8 :1 ratio) are prepared.
Tablets that were prepared by conventional procedures of aqueous granulation by mixing both the drugs together and granulating failed in the disintegration test as per United States Pharmacopoeia standards. Further trials with similar approaches using decreased

quantity of binder and increased quantity of disintegrant also did not have any significant effect on improving the disintegration of the tablets. On the contrary less binder let to higher friability and the tablets failed in friability test. The method of separately granulating metformin and nateglinide and then mixing the dried granules prior to compression of tablets gave excellent results which are as follows;

Approaches Hardness Friability Disintegration time
I Aqueous granulation with both metformin and nateglinide mixed and granulated together. 100 Newton 0.2% More than 45 minutes
II Aqueous granulation with decreased binder and increased disintegrant where metformin and nateglinide were mixed and granulated together. 100 Newton 0.5% More than 30 minutes
III Separate granulation of metformin and nateglinide, followed by mixing of dried granules prior to tabletting. 100 Newton Nil 2 minutes 30 seconds
STABILITY DATA FOR (METFORMIN + NATEGLINIDE) TABLETS
At accelerated conditions of stability, the formulation for the combined preparation was found to be stable for the studied period. The assay for metformin and nateglinide was within limits during the period of study. The dissolution results were also in compliance with the standards.

TESTS SPECIFICATION INITIAL 25°C/60% RH 40°C/75%RH

3 months 1 month 2 months 3 months
DESCRIPTION Light yellow capsule shaped tablets Complies Complies Complies Complies Complies
IDENTIFICATION Retention time of metformin and Complies Complies Complies Complies Complies

nateglinide in sample solution is concordant with standard in assay preparation
DISSOLUTION Medium: 1% SLS buffer
Apparatus: Paddle RPM: 100 Time: 45 minutes Temperature: 37°C Metformin- not less than 70% in 45 minutes 104.3-106.9 105.2-107.1 103.3-108.5 100.9-105.2 102.3-106.7

Nateglinide- not less than 70% in 45 minutes 99.2-106.4 92.0- 94.3 91.7-99.2 87.3-91.5 91.4-94.3
ASSAY Metformin- 90-110% 97.4 103.2 104.9 102.3 103.5

Nateglinide- 90-110% 104.6 101.2 102.2 100.9 104.3
EXAMPLE 2
Tablets manufactured for clinical use were film-coated in a coating pan with an appropriate non-aqueous/alcoholic hydroxypropyl methylcellulose (HPMC) based film coat. The film coat was designed to mask any unpleasant taste of the tablet and was also applied for aesthetic purposes. The typical level of film coat applied to the tablets was 2%
w/w.
Film coating of uncoated tablets made in Example I was performed with the following coating solution:

TABLE 2

Ingredients

Parts by weight of tablet

Hydroxypropyl methyl cellulose 1.194%
Talc 0.482%
Titanium dioxide 0.207%
Yellow Ferric oxide 0.029%
Polyethylene glycol 6000 0.087%
Isopropyl alcohol qs
Methylene chloride qs
Tablets of example 1 were coated with 2% of this solution per tablet weight using a film coating device to obtain the tablets of the present invention.
Similarly Tablets containing metformin hydrochloride 500mg and nateglinide 60 mg are film coated using red ferric oxide.
During manufacture, the tablets were monitored for weight, hardness, thickness and friability. The hardness was adjusted to between 90 and 140N, preferably between 100 and 120 N. The tablet thickness ranged from 5.3mm to about 6.1mm. Friability was maintained below 1%. TABLE 3

Hardness (in L Newton) Disintegration (in Friability (%) n = 20
n=10 minutes) n = 3 Time=4 minutes=100 rotations
90±10 1 0.05
100dzl0 2 0.1
120±10 3 0.1
140±10 3 Nil

Industrial Applicability
This invention intends to provide a pharmaceutical^ acceptable combination for oral use that is a stable preparation of the combination of metformin hydrochloride and nateglinide.
Namely, the present invention relates to the process for preparation of a stable solid oral pharmaceutical combination of the two active compounds which is especially effective in the treatment of diabetes and diabetes related disorders and complications.
Further aspects of this invention suggest that the pharmaceutical combination of the present invention obtained by the process as claimed possesses an enhanced blood sugar lowering action, and therefore, the amount of drugs used can be reduced as compared with monotherapy with an insulin sensitizer or biguanide alone.

We claim,
1. A process for preparation of single-dose per day stable solid oral pharmaceutical
composition comprising of a biguanide, metformin hydrochloride and a non-
sulfonyl urea, nateglinide in the weight ratio of 8:1 and 4:1 alongwith excipients
comprising of binder, disintegrants such as sodium starch glycolate, lubricant and
glidant wherein the said process comprises
a) wet granulating the two active ingredients such as a biguanide, metformin hydrochloride and a sulfonyl urea, nateglinide jointly after prior mixing or separately single ingredientwise granulation and blending them prior to compression;
b) compressing the granules into tablets with hardness varying from 90 newtons to 140 newtons; and
c) film coating the tablets with alcohol coating using red ferric oxide and yellow ferric oxide in the film coating in the weight percentage of 0.01 and 0.03 weight percent respectively, to provide yellow or brown colour respectively to the tablets depending on the strength of the combination.

2. The process as claimed in claim 1, wherein the amount of metformin hydrochloride in the composition is 500 mg.
3. The process as claimed in claim 1, wherein the nateglinide in the composition is 60 mg and 120 mg in respective dosage form.
4. The process as claimed in claim 1, wherein after granulation the composition contains less than 20 % by weight of granules having size of 850 urn or more.

5. The process as claimed in claim 1, wherein a pharmaceutically acceptable binder, povidone is used in the range of 4.0 to 4.7% by weight on a dry weight basis, based on the weight of the formulation.
6. The process as claimed in claim 1, wherein pharmaceutically acceptable disintegrants such as microcrystalline cellulose, cross caramellose sodium and sodium starch glycollate are used in the range of 17.5% to 19.9% by weight on a dry weight basis, based on the weight of the formulation.
7. The process as claimed in claim 1, wherein the disintegrant is selected from microcrystalline cellulose, cross caramellose sodium and sodium starch glycolate either alone or in combination.
8. The process as claimed in claim 1, wherein disintegrant, sodium starch glycollate is used intra-granularly or extra-granularly.
9. The process as claimed in claim 1, wherein a pharmaceutically acceptable lubricant, magnesium stearate is used about 0.9 to 1% by weight on a dry weight basis, based on the weight of the formulation.
10. The process as claimed in claim 1, wherein a pharmaceutically acceptable glidant, colloidal silicon dioxide is used in the range of 0.88 to 0.95% by weight on a dry weight basis, based on the weight of the formulation.
11. The process as claimed in claim 1 wherein the film coating is an alcohol coating using red and / or yellow ferric oxide in the film.

12. The process as claimed in claim 1 wherein the film coating comprises hydroxypropyl methyl cellulose, Talc, Titanium dioxide, Polyethylene glycol 6000, Isopropyl alcohol and methylene chloride.
13. The process as claimed in claim 1, wherein the said single dose tablet-form stable pharmaceutical composition for oral administration are caplet shaped
14. A process for preparation of single-dose per day stable pharmaceutical composition comprising of metformin hydrochloride and nateglinide as substantially described herein with reference to the foregoing examples 1 to 3.
Dated this the 23rd day of July 2003
Dr. Gopakumar G. Nair
Agent for the Applicant

Documents:

737-mum-2003-abstract(10-11-2004).doc

737-mum-2003-abstract(10-11-2004).pdf

737-mum-2003-cancelled pages(10-11-2004).pdf

737-mum-2003-claims(granted)-(10-11-2004).doc

737-mum-2003-claims(granted)-(10-11-2004).pdf

737-mum-2003-correspondence(1-4-2007).pdf

737-mum-2003-correspondence(ipo)-(19-9-2006).pdf

737-mum-2003-form 1(23-7-2003).pdf

737-mum-2003-form 1(5-4-2004).pdf

737-mum-2003-form 19(21-8-2003).pdf

737-mum-2003-form 2(granted)-(10-11-2004).doc

737-mum-2003-form 2(granted)-(10-11-2004).pdf

737-mum-2003-form 26(23-7-2003).pdf

737-mum-2003-form 3(23-7-2003).pdf

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Patent Number

202752

Indian Patent Application Number

737/MUM/2003

PG Journal Number

43/2008

Publication Date

24-Oct-2008

Grant Date

19-Sep-2006

Date of Filing

23-Jul-2003

Name of Patentee

M/S. IPCA LABORATORIES LIMITED

Applicant Address

48, KANDIVALI INDUSTRIAL ESTATE MUMBAI - 400 067. MAHARASHTA, INDIA.

Inventors:

#	Inventor's Name	Inventor's Address
1	THEMBALATH, RAMACHANDRAN	1)6/35, PRAKASH CO. HOUSING SOCIETY, RELIEF ROAD, SANTACRUZ (WEST), MUMKBAI - 400 054. MAHARASHTRA, INDIA.

PCT International Classification Number

N/A

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA