Title of Invention	STABLE PHARMACEUTICAL COMPOSITION COMPRISING OF AN ANGIOTENSIN II RECEPTOR ANTAGONIST AND A DIURETIC
Abstract	The present invention discloses a stabilized pharmaceutical composition comprising of a combination of an angiotensin II receptor antagonist such as losartan potassium and a diuretic such as chlorthalidone and its formulation thereof. This combination drug product is useful in the treatment of hypertension and such other related diseases.

Full Text

FORM 2 THE PATENTS ACT, 1970 (39 of 1970) COMPLETE SPECIFICATION [See section 10; rule 13] "STABLE PHARMACEUTICAL COMPOSITION COMPRISING OF AN ANGIOTENSIN II RECEPTOR ANTAGONIST AND A DIURETIC" (a) M/S. 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 particularly describes the nature of this invention and the manner in which it is to be performed. TECHNICAL FIELD The present invention relates to a pharmaceutical composition of a new, oral therapeutically active, hitherto unexploited combination of an angiotensin II receptor antagonist such as losartan potassium and a diuretic such as chlorthalidone. More specifically, the invention relates to use of such a drug combination to treat hypertension, heart failure and other such related diseases. BACKGROUND AND PRIOR ART Angiotensin II is a potent vasoconstrictor. Its generation in the renin angiotensin cascade results from the enzymatic action of rennin on a blood plasma a2-globulin, angiotensinogen, to produce angiotensin I. Angiotensin I is then converted to octapeptide hormone angiotensin II by angiotensin converting enzyme (ACE). Angiotensin II has been implicated as a causative agent in hypertension as it leads to vasoconstriction on binding with AT1 receptor. Thus AT1 receptor antagonists that inhibit the pharmacological action of angiotensin II, no matter the pathway of biosynthesis, are useful in the treatment of hypertension. Losartan potassium represents the first antihypertensive in the class of AT1 receptor antagonists which is disclosed in the US patent 5,l38, 069 issued on august 11, 1992 and which is assigned to E. I. du pont de Nemours. Losartan potassium has been demonstrated to be a potent orally active angiotensin II antagonist, selective for AT] receptor subtype, useful in the treatment of hypertension. Diuretics, sometimes commonly referred as "water pills", are drugs that increase the rate of urine flow. Diuretics cause sodium to be lost in the urine thus decreasing the volume of extracellular fluid, as sodium is the main determinant of water present in extracellular space. Diseases associated with excess fluid accumulation include congestive heart failure, pulmonary edema and liver cirrhosis to name a few. Ability of diuretics to reduce the blood pressure is known since decades. Initially the diuretic lowers the blood pressure 2 by causing a decrease in the extracellular fluid volume and decreased cardiac output. The long term effect is due to the reduction in the resistance of vessels to blood flow which results in lower blood pressure. Diuretic treatment converts the non-rennin dependent state in regulating blood pressure to a rennin dependent state. Patent no. W0974932 has reported that about 40% of hypertensive patients are non responsive to angiotensin converting enzyme inhibitors (ACEI). But when a diuretic is given together with an ACEI the blood pressure of most hypertensive patients is effectively normalized. Sulfonamide diuretics, such as chlorthalidone are commonly used in the initial treatment of high blood pressure. They are also used in the treatment of conditions associated with excess fluid accumulation including congestive heart failure. Chlorthalidone is a well known diuretic agent which has been widely marketed since the early 1960's. Patent number WO0241890 (Mizuno Makoto et. al.) describes Medicinal compositions comprising of angiotensin II receptor antagonist and one or more diuretics. Because of having an excellent hypotensive effect and little toxicity, these medicinal compositions are useful as preventives or remedies for hypertension or heart diseases. Patent number W09749392 (Sweet Charles S. et. al.) describes the combination of losartan potassium and enalapril for use in the treatment of hypertension and heart failure. This patent also mentions that diuretic treatment converts the non-rennin dependent state in regulating blood pressure to a rennin dependent state, thus providing a strong rationale for the combination of angiotensin II receptor antagonist and a diuretic. Patent number US2003158244 (Devane John et. al.) describes gastric retained dosage form of losartan potassium for the treatment of hypertension and other disease states. Gastric retained dosage forms help in better absorption of losartan potassium and in upper gastrointestinal tract, increases the tmax of losartan potassium allowing a smoother and prolonged antihypertensive effects and reduces the cmax, thereby reducing the incidence of losartan potassium 's major side effect of dizziness. 3 Patent number W09533454 (Ahmed Asif Syed et. al.) describes the combination of angiotensin converting enzyme inhibitor, angiotensin II receptor antagonist, and renin inhibitor for the treatment of uterine fibroids. Since angiotensin II is the implicated in the myometrial cell proliferation causing uterine fibroids, methods of inhibiting its production provide a valuable alternative treatment to hormone based therapy and surgery. Patent number ES8602633 (Boehringer Ingelheim Ltd., US) describes the process of solid state dispersion of chlorthalidone in order to increase the dissolution rate of chlorthalidone and thereby increasing its bioavailability. Other diuretic compounds viz., sulfonamide compounds such as acetazolamide, methazolamide, ethoxzolamide, clofenamide, dichlorphenamide, disulfamide, mefruside, chlorthalidone, quinethazone, furosemide, clopamide, tripamide, indapamide, chlorexolone, metolazone, xipamide, bumetanide, piretanide and X-54; thiazide compounds such as hydrochlorothiazide, methylclothiazide, benzylhydrochlorothiazide, trichloromethiazide, cyclopenthiazide, polythiazide, ethiazide, cyclothiazide, bendroflumethiazide, and hydroflumethiazide; phenoxyacetic acid compounds such as ethacrynic acid, tienilic acid, indacrinone and quincarbate; triamterene; amiloride; spironolactone; potassium canrenoate; torasemide; MK-447; and traxanox sodium. These single diuretic active ingredients are disclosed in US patent number 2,554,816, US patent number 2,980,679, US patent number 2,783,241, GB 795,174, J. Chem. Soc, 1125 (1928), US patent number 2,835,702, GB 851,287, US patent number 3,356,692, US patent number 3,055,904, US patent number 2,976,289, US patent number 3,058,882, Helv. Chim. Acta, 45, 2316 (1962), Pharmacometrics, 21, 607 (1982), US patent number 3,183,243, US patent number 3,360,518, US patent number 3,567,777, US patent number 3,634,583, US patent number 3,025,292, J. Am. Chem. Soc, 82, 1132 (1960), US patent number 3,108,097, Experientia, 16, 113 (1960), J. Org. Chem., 26, 2814 (1961), US patent number 3,009,911, US patent number 3,265,573, US patent number 3,254,076, US 4 patent number 3,255,241, US patent number 3,758,506, BE 639,386 and US patent number 3,163,645. None of the above listed inventions mentions. about the formulation of combination comprising of losartan potassium and chlorthalidone. According to the literature survey done, no one has used the technologies of protecting the hygroscopic losartan potassium from absorbing atmospheric moisture by granulating it with polyvinylpyrrollidone (PVP) starch paste. Also the present study reveals the process of direct compression under controlled conditions of temperature and relative humidity and usage of such excipients which prevented the absorption of moisture. SUMMARY OF THE INVENTION • The present invention relates to the use of a combination of drugs for the treatment of hypertension and/or cardiac failure comprising administering a therapeutically effective dosage of hitherto unexploited combination of losartan potassium and chlorthalidone in a stable oral dosage form to patients in need of such treatment. • The present invention addresses a major medical need by providing an effective, safe, simple and convenient way to reduce the risk of hypertension in patients suffering from hypertension and/or cardiac failure, which has high probability for patient compliance. • Losartan potassium has a quicker onset of action (1 hour) and short plasma half life (6-9 hours); whereas chlorthalidone has a delayed onset of action (2.6 hours) but longer plasma half life (40-60 hours). Thus this combination provides a sustained pharmacological effect. • Tablets formulated with wet granulation approach, were granulated with polyvinylpyrrolidone-starch paste that formed a protective layer around the losartan potassium molecule preventing moisture absorption. • The tablets formulated with direct compression approach were prepared in controlled conditions of temperature and relative humidity. During formulating losartan potassium and chlorthalidone into a tablet dosage form the excipient were selected 5 such that they prevent the absorption of moisture by losartan potassium, which is highly hygroscopic in nature. OBJECTIVE OF THE PRESENT INVENTION The objective of the present investigation is to provide a stabilized pharmaceutical composition of losartan potassium and chlorthalidone tablets. DETAILED DESCRIPTION OF THE INVENTION Losartan potassium represents the first antihypertensive in the class of AT1 receptor antagonists. It is a potent orally active angiotensin II antagonist, selective for AT1 receptor subtype. Angiotensin II, generated in the rennin angiotensin cascade, has been implicated as a causative agent in hypertension as it leads to vasoconstriction on binding with AT1 receptor. Thus AT1 receptor antagonists that inhibit the pharmacological action of angiotensin II are useful in the treatment of hypertension. Diuretics cause sodium to be lost in the urine thus decreasing the volume of extracellular fluid, as sodium is the main determinant of water present in extracellular space. Initially the diuretic lowers the blood pressure by causing a decrease in the extracellular fluid volume and decreased cardiac output. The long-term effect is due to the reduction in the resistance of vessels to blood flow, which results in lower blood pressure. Chlorthalidone is a well-known diuretic agent that has been widely marketed since the early 1960's. It is well known that co-administration of an angiotensin II receptor antagonist and a diuretic is an effective therapy for the prevention or treatment of hypertension (particularly treatment). Patent number WO0241890 describes that angiotensin II receptor antagonist and diuretic exerts better therapeutic efficacy by combined administration rather when used separately. Since it is clinically convenient if these two agents are administered at the same time, efforts were made in the present invention to 6 formulate a stable oral dosage form containing a combination of angiotensin II receptor antagonist and diuretic. The present invention provides a pharmaceutical composition containing a specific angiotensin II receptor antagonist and a diuretic as the active ingredients (particularly pharmaceutical compositions for preventing or treating hypertension), the use of a specific angiotensin II receptor antagonist and a diuretic for manufacturing the pharmaceutical compositions (particularly pharmaceutical compositions for preventing or treating hypertension), and a pharmaceutical composition for administering simultaneously a specific angiotensin II receptor antagonist and a diuretic for preventing or treating hypertension. One of the active ingredients of the pharmaceutical composition of this invention is angiotensin II receptor antagonist, most preferably losartan potassium. Another active ingredient in pharmaceutical composition of this invention is diuretic viz., sulfonamide compounds such as acetazolamide, methazolamide, ethoxzolamide, clofenamide, dichlorphenamide, disulfamide, mefruside, chlorthalidone, quinethazone, furosemide, clopamide, tripamide, indapamide, chlorexolone, metolazone, xipamide, bumetanide, piretanide and X-54; thiazide compounds such as hydrochlorothiazide, methylclothiazide, benzylhydrochlorothiazide, trichloromethiazide, cyclopenthiazide, polythiazide, ethiazide, cyclothiazide, bendroflumethiazide, and hydroflumethiazide; phenoxyacetic acid compounds such as ethacrynic acid, tienilic acid, indacrinone and quincarbate; triamterene; amiloride; spironolactone; potassium canrenoate; torasemide; MK-447; and traxanox sodium. The preferred diuretic is a sulfonamide compound and the most preferred one is chlorthalidone. . Since it is clinically convenient if the two active pharmaceutical ingredients are administered at the same time, the specific angiotensin II receptor antagonist, preferably 7 losartan potassium, and a diuretic, preferably chlorthalidone, is formulated as a single pharmaceutical composition that can be administered with advantage and convenience as a single dose. The administration route of specific angiotensin II receptor antagonists, such as losartan potassium and diuretic such as chlorthalidone is generally oral. Thus these 2 groups of compounds can be prepared as separate single formulations of each or as a single formulation, preferably single formulation. Administration formulations are, for instance, powder, granules, tablets, capsules, etc. Most preferred oral dosage form is tablet. The free compounds or pharmacologically acceptable salts or esters thereof are mixed with constituents, diluents, etc., and prepared according to conventional preparation techniques as described below. Namely, preparations as described above are manufactured by conventionally known methods using additives such as diluents (for instance, organic diluents including sugar derivatives such as lactose, sucrose, glucose, mannitol, sorbitol; starch derivatives such as cornstarch, potatostarch, alpha -starch, and dextrin; cellulose derivatives such as crystalline cellulose; gum arabic; dextran; pullulan; and inorganic diluents including silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, magnesium aluminometasilicate; phosphate derivatives such as calcium hydrogenphosphate; carbonates such as calcium carbonate; and sulfate derivatives such as calcium sulfate), lubricants (for instance, metallic salts of stearic acid such as stearic acid, calcium stearate, magnesium stearate; talc; waxes such as beeswax, spermaceti; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL-leucine; laurylsulphates such as sodium lauryl sulfate, magnesium lauryl sulfate; silicates such as anhydrous silicic acid, silicic acid hydrates; and starch derivatives described above can be listed), binders (for instance, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, and similar diluents described above), disintegrators (for instance, cellulose derivatives such as low- substituted hydroxypropylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, and internally bridged-sodium carboxymethylcellulose; 8 chemically modified starch/cellulose derivatives such as carboxymethylstarch, sodium carboxymethylstarch, bridged polyvinylpyrrolidone; and starch derivatives described above), Tablets containing losartan potassium and chlorthalidone can be prepared either by wet granulation method or by direct compression. In the wet granulation method losartan potassium and chlorthalidone are granulated separately. Out of the various ingredients available di-calcium phosphate anhydrous is used as a diluent for maintaining hardness of the tablet during its shelf-life. Polyvinylpyrrolidone (PVP) and starch were used to provide a protective layer to reduce hygroscopicity. Cross carmellose sodium and sodium starch glycolate are used as a disintegrants. Colloidal silicon dioxide is used as a preferred lubricant and/or disintegrant. Magnesium stearate is used as an anti adherent. The tablet formulated by this approach gives required hardness, friability, disintegration time and dissolution rate. Out of the various ingredients available for direct compression, starch 1500 and microcrystalline cellulose is used to increase the compressibility of the blend for direct compression. Losartan potassium has a pronounced bitter taste and is hygroscopic. Hence the tablets are film coated to mask unpleasant taste and enhance stability. The dose and rate of administration of the specific angiotensin II receptor antagonist, such as losartan potassium, and diuretic like chlorthalidone depend upon various factors such as the drugs' activities, symptoms, age, and body weight of the patients. However, generally speaking, the adult dosage (mg dose/time) of losartan potassium and chlorthalidone is 0.5 to 1,000 mg (preferably 1 to 100 mg) and approximately 0.05 to 9 1,500 mg (preferably 5 to 300 mg), respectively. Compounds are administered once or several times per day, depending upon the symptoms of the patients. Dosing ratios of the drugs may also be varied. However, generally speaking, the rates of losartan potassium and chlorthalidone are 1:1 to 10:1, preferably 2:1 to 4:1 as their weight ratios. In the present invention, losartan potassium and chlorthalidone are simultaneously administered at the doses described above in the dosage form of a composition formulated as described herein. The present invention is described in more detail by way of the following Examples. However, the present invention is not limited to these examples. EXAMPLE 1 Formulation of tablets by wet granulation method Losartan potassium and chlorthalidone are granulated separately using Polyvinylpyrrolidone (PVP) - starch paste that gives a moisture protective layer thereby reducing hygroscopicity. Losartan potassium and chlorthalidone are granulated separately in order to prevent direct contact between losartan potassium and chlorthalidone under normal atmospheric conditions that otherwise would have effected have the physical parameters of the finished product. Detailed manufacturing procedure is described below in the following four steps: 10 Step I: Granulation of Losartan potassium: Losartan potassium, di-calcium phosphate anhydrous and pregelatinised starch were mixed in geometric proportion and the blend is granulated with polyvinylpyrrolidone - starch paste. Polyvinylpyrrolidone and starch paste forms a protecting layer on losartan potassium there by reducing its hygroscopicity. Granules were rasped through 8# sieve and dried at 50-60 °C. Dried granules were rasped through 20# sieve. Step II Granulation of Chlorthalidone: Chlorthalidone, di-calcium phosphate anhydrous, cross carmellose sodium and sodium starch glycolate are mixed in geometric proportions and granulated with Polyvinylpyrrolidone-starch paste. Granules were rasped through 8# sieve and dried at 50-60 °C. Dried granules were passed through 20# sieve. Step III Lubrication: Both losartan potassium and- chlorthalidone granules were mixed together. These granules were lubricated with sodium starch glycolate, dried starch and colloidal silicon dioxide. Magnesium stearate is added at the final stage, resulting in blend ready for compression Step IV: Compression: The resultant blend is compressed into tablets of required thickness, hardness, and disintegration time, on a suitable tablet press. The theoretical tablet weight (based on formula composition with no adjustment for moisture content) is 350 mg for 50 mg losartan potassium and 12.5 mg chlorthalidone and 325 mg for 25 mg losartan potassium and 12.5 mg chlorthalidone strength products. During manufacture, the tablets were monitored for weight, hardness, thickness and friability. The hardness is adjusted between 30 and 145 newton preferably 40-120 newton. The tablet thickness ranged from 3.5 to 5.2 mm. Friability is maintained below 1%. The pharmaceutical compositions of the tablets are given in table 1. 11 Table 1: Pharmaceutical composition of tablets containing losartan potassium 50 and chlorthalidone 12.5 mg prepared by wet granulation method mg Ingredients Parts by weight of tablet LOSARTAN POTASSIUM GRANULATION Losartan potassium 14.29 Di-calcium phosphate anhydrous 20.57 Pregelatinised starch 8.57 Starch 2.86 Polyvinylpyrrolidone 2.29 Purified water q.s. CHLORTHALIDONE GRANULATION Chlorthalidone 3.57 Di-calcium phosphate anhydrous 15.56 Cross carmellose sodium 0.86 Sodium starch glycolate 0.29 Starch 10.0 Polyvinylpyrrolidone 1.43 Purified water q.s. LUBRICATION AND BLENDING Sodium starch glycolate ' 5.71 Starch 12.00 Colloidal silicon dioxide 1.43 Magnesium stearate 0.57 Tablets containing losartan potassium 25 mg and chlorthalidone 12.5 mg are similarly prepared by wet granulation method. EXAMPLE 2 Formulation by direct compression: All excipients except magnesium stearate are mixed with active drug in a geometric proportion to ensure uniform mixing.. Magnesium stearate is added at last stage. The resultant blend is compressed into tablets of required thickness, hardness, disintegration time, on a suitable tablet press. During formulation controlled conditions of temperature and relative humidity were found to be crucial. A very high percentage of relative humidity resulted in the absorption of moisture by losartan potassium, as it is a hygroscopic drug, whereas very low percentage of relative humidity resulted in low compressibility of the blend. The pharmaceutical compositions of the tablets are given in table 2. Table 2: Pharmaceutical composition of tablets containing losartan potassium 50 mg and chlorthalidone 12.5 mg prepared by direct compression method. Ingredients Parts by weight of tablet Losartan potassium 17.75 Chlorthalidone 4.6 Starch 1500 18.51 Microcrystalline cellulose 52.63 13 Colloidal silicon dioxide 2.11 Crosspovidone 1.75 Sodium starch glycolate 1.05 Talc 0.70 Magnesium stearate 0.88 1 ablets containing losartan potassium 25 mg and chlorthalidone 12.5 mg are similarly prepared by direct compression method. EXAMPLE 3: Film coating: Tablets formulated were film coated in a coating pan using HPMC solution prepared using non-aqueous solvents. The film coating was provided to prevent moisture absorption and thus enhancing the stability of the product, as losartan potassium is hygroscopic and also to mask any unpleasant taste. Coating solution for tablets mentioned in examples land 2 are shown in table 3. Table 3: Composition of coating solution Ingredients Parts by weight of tablet HPMC15cps 0.925-1.099 PEG-6000 0.074-0.088 Titanium dioxide 0.140-0.166 Purified Talc 0.052-0.062 Methylene chloride q.s. 2-propanolol q.s. Tablets of example 1 and 2 were coated with 2% of this solution using a film coating device to obtain the tablet of the present invention. Tablets containing losartan potassium 25 mg and chlorthalidone 12.5 mg were coated similarly. 14 EXAMPLE 4 Stability data: The tablets thus manufactured were subjected to accelerated stability tests. The stability data of losartan potassium and chlorthalidone after three months in 40°C temperature and 75% relative humidity shows that the formulation is stabled. The tablets when prepared using unprotected moisture layer of PVP-starch paste becomes soften (hardness decreased) on exposure to stress conditions. Since the physical parameters were not within the limits the, no further study is carried out. Stability data of tablets prepared using moisture protected granules of higher strength (Losartan potassium 50mg and chlorthalidone 12.5 mg) are shown in table 4. Table 4: Stability Data of Losartan potassium 50mg and chlorthalidone 12.5 mg Losartan potassium Chlorthalidone Assay (average of 3 batches) 99.063 % 102.80 % Dissolution rate 94.88-103.93 %i 95.64-104.56% I I i Stability data of tablets prepared using moisture protected granules of strength (Losartan potassium 25mg and chlorthalidone 12.5 mg) are shown in table 5. 15 Table 5: Stability Data of Losartan potassium 25mg and chlorthalidone 12.5 mg Losartan potassium Chlorthalidone Assay (average of 3 batches) 99.23 % 103.80 % Dissolution rate 93.88-98.93 % 98.23-104.87% While the present invention is described above in connection with preferred or illustrative embodiments, these embodiments are not intended to be exhaustive or limiting of the invention. Rather, the invention is intended to cover all alternatives, modifications and equivalents included within its spirit and scope, as defined by the appended claims. 16 We Claim 1. A stable pharmaceutical composition comprising of angiotensin II receptor antagonist such as losartan potassium (which is highly hygroscopic) and a diuretic such as chlorthalidone in the ratios of 2:1 and 4:1 wherein the said composition comprises, losartan potassium; chlorthalidone; diluents such as organic diluents including sugar derivatives such as lactose, sucrose, glucose, mannitol, sorbitol; starch derivatives such as cornstarch, potatostarch, alpha - starch, and dextrin; cellulose derivatives such as crystalline cellulose; gum arabic; dextran; pullulan; and inorganic diluents including silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, magnesium aluminometasilicate; phosphate derivatives such as calcium hydrogenphosphate; carbonates such as calcium carbonate; and sulfate derivatives such as calcium sulfate and di-calcium phosphate anhydrous; binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, and similar diluents; moisture barriers such as polyvinylpyrrolidone (PVP)-starch paste; disintegrants such as cellulose derivatives such as low-substituted hydroxypropylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, and internally bridged-sodium carboxymethylcellulose; chemically modified starch/cellulose derivatives such as carboxymethylstarch, sodium carboxymethylstarch, bridged polyvinylpyrrolidone; and starch derivatives crosscarmellose sodium and sodium starch glycolate; lubricants such as metallic salts of stearic acid such as stearic acid, calcium stearate, magnesium stearate; talc; waxes such as beeswax, spermaceti; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL-leucine; laurylsulphates such as sodium lauryl sulfate, magnesium lauryl sulfate; silicates such as anhydrous silicic acid, silicic acid hydrates; and starch derivatives and colloidal silicon dioxide; and 17 anti adherent or glidant such as magnesium steararte; wherein the said composition is prepared by wet granulation and direct compression methods; wherein, a) wet granulation comprises of, granulating losartan potassium; granulating chlorthalidone; mixing both the granules together; lubricating the granules; b) adding magnesium stearate and compressing the blend to tablet form. c) direct compression comprises mixing of all excipients except magnesium stearate with active ingradients in geometric proportion; adding magnesium stearate; compressing the blend into tablets. 2. A stable pharmaceutical composition as claimed in claim 1 (a) wherein, the said diluent for maintaining the hardness of the tablet re di-calcium phosphate anhydrous. 3. A stable pharmaceutical composition as claimed in claim 1 (a) wherein the said disintegrants are cross carmellose sodium and sodium starch glycolate. 4. A stable pharmaceutical composition as claimed in claim 1 (a) wherein the said lubricant is colloidal silicon dioxide. 5. A stable pharmaceutical composition as claimed in claim 1 (b) wherein the said lubricants is purified talc. 6. A stable pharmaceutical composition as claimed in claim 1 (b) wherein, the said diluents are starch 1500 and micro crystalline cellulose. 7. A stable pharmaceutical composition as claimed in claim 1 (b) wherein, the said excipients are microcrystalline cellulose (Grade Avicel PH 200) and colloidal silicon dioxide. 8. A stable pharmaceutical composition as claimed in claim 1 (a) wherein, the said binder and disintegrant is pregelatinised starch. 9. A stable pharmaceutical composition as claimed in claim 1 wherein the said tablets are film coated. 10. A stable pharmaceutical composition as claimed in claims 1 and 9 wherein the said tablets are coated with polymer such as hydroxy propyl methyl cellulose in quantity of 2 to 3 mg per tablet. 11. A stable pharmaceutical composition as claimed in claims 1, 9 and 10 wherein, the coating solution contains plasticizer such as poly ethylene glycol in quantity of 0.2 to 0.3 mg per tablet. 18 12. A stable pharmaceutical composition as claimed in claim 1, and 9 to 11 wherein the said coating solution contains opacifier such as titanium dioxide in a quantity of 0.3 to 0.5 mg per tablet. 13. A stable pharmaceutical composition as claimed in claims land 9 to 12 wherein the said coating solution is prepared in 2-propanol and methylene chloride. 14. A stable pharmaceutical composition as claimed in claim 1 wherein the amount of losartan potassium is 50 mg and 25 mg and chlorthalidone is 12.5 mg. 15. A stable pharmaceutical composition as claimed in claim 1 wherein the hardness of the said tablet is between 30 to 145 newtons. 16. A stable pharmaceutical composition as claimed in claims 1 to 15 as substantially described herein with reference to the foregoing examples 1-4. 19 8. Following are the attachment with the application: (d) Complete specification (2 copies) (e) Statement and Undertaking on Form 3 (f) copy Form 26 (Original Power of Attorney in our favour has been submitted with application number 150/MUM/2003) (g) Fee Rs.3000/- in cheque bearing No. 663665 dated 13th Feb, 2004 on Global Trust Bank Limited, Mumbai. We request that a patent may be granted to us for the said invention. Dated this the 13th day of Feb 2004 Dr. Gopakumar G. Nair Agent for the Applicant Gopakumar Nair Associates Nair Baug, Akurli Road, Kandivli (East), Mumbai - 400 101, Maharashtra, India To The Controller of Patents The Patent Office, At Mumbai. ABSTRACT The present invention discloses a stabilized pharmaceutical composition comprising of a combination of an angiotensin II receptor antagonist such as losartan potassium and a diuretic such as chlorthalidone and its formulation thereof. This combination drug product is useful in the treatment of hypertension and such other related diseases.

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