FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
COMPLETE SPECIFICATION
[See section 10; rule 13]

"PROCESS FOR PREPARATION OF A STABLE COMPOSITION COMPRISING 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 process for preparation of stable pharmaceutical composition of a new, oral therapeutically active, hitherto unexploited combination of 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. lts generation in the renin angiotensin cascade results from the enzymatic action of rennin on a blood plasma a2-globulin, angiotensinogen, to produce angiotensin L 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 5,138,069 issued on august 11, 1992 and which is assigned to E. L du pont de Nemours. Losartan potassium has been demonstrated to be a potent orally active angiotensin II antagonist, selective for ATi 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 mus 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
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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. WO974932 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 W00241890 (Mizuno Makoto et. al.) destribes 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 h^art diseases.
Patent number WO9749392 (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-renin 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 hyperterision 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 jjotassium allowing a smoother and prolonged antihypertensive effects and reduces the cmax, thereby reducing the incidence of losartan potassium 's major side effect of dizziness.
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Patent number WO9533454 (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 fïbroids, 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 chlorthaïidone 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, bendroflurnethiazide, 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
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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 chiorthalidone. 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 poly vinyl pyrrollidone (PVP) - starch paste. Also the present stüdy 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
chiorthalidone in a stable oral dosage form to patients in need of such treatment.
• The present invention addresses a major rnedical need by providing an effective, safe,
simple and convenient way to reduce the risk of hypertension in patients suffering
trom hypertension and/or cardiac failure, which has high probability for patiënt
compliance.

• Losartan potassium has a quicker onset of action (l hour) and short plasma half life
(6-9 hours); whereas chiorthalidone has a delayed onset of action (2.6 hours) but
longer plasma half life (40-60 hours). Thus mis 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 chiorthalidone into a tablet dosage form the excipient were selected
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such that they prevent the absorption of moisture by losartan potassium, which is highly hygroscopic in nature.
OBJECTIVE OF THE INVENTION:
The objective of the present investigation is to provide a process for stabilized pharmaceutical composition of losartan potassium and chlorthalidone tablets.
DETAILED DESCRIPTION OF THE INVENTION
Losartan potassium represents the fïrst antihypertensive in the class of AT] receptor antagonists. It is a potent orally active angiotensin II antagonist, selective for AT1 receptor subtype. Angiotensin II, generaled in the renin angiotensin cascade, has been implicated as a causative agent in hypertension as it leads to vasoconstriction on binding with AT1 receptor. Thus AT] 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 mam 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 reductioh 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 W00241890 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 formulate a stable oral dosage form containing a combination of angiotensin II receptor antagonist and diuretic.
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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 ingrediënt in pharmaceutical composition of this invention is diuretic viz., sulfonamide compounds such as acetazolamide, methazolamide, ethoxzolamide, clofenamide, dichJorphenamide, 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 hydrofïumethiazide; phenoxyacetic acid compounds such as ethacrynic acid, tienilic acid, indacrinone and quincarbate; triamterene; amiloride; spironolactone; potassium canrenoate; torasemide; MK-447; and rraxanox sodium.
The preferred diuretic is a sulfonamide compound and the most preferred one is chiorthalidone. .
Since it is clinically convenient if the two active pharmaceutical ingredients are administered at the same time, the specific angiotensin II receptor antagonist, preferably 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.
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The administration route of specifïc 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 formuJations 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; staren derivatives such as
cornstarch, potato starch, aipha -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 so.dium sulfate; glycol; fbmaric 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, hydroxypropy l cellulose,
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; chemically modified starch/cellulose derivatives such as carboxymethy l starch, sodium carboxy methyl starch, bridged polyvinylpyrrolidone; and starch derivatives described above),
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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
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chlorthalidone is 0.5 to 1,000 mg (preferably l to 100 mg) and approximately 0.05 to 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 l
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 the physical parameters of the fmished
product.
Detailed manufacturing procedure is described below in the following four steps:
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Step I: Granulation of Losartan potassium
Losartan potassium, di-calcium phosphate anhydrous and pregelatinised starch were
mixed in geometrie 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 geometrie 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.
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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 is ranged from 3.5 to 5.2 mm. Friability is maintained below 1%. Pharmaceutical composition of the tablets prepared by wet granulation is given in the followingtable-1.
Table 1: Pharmaceutical composition of tablets containing losartan potassium 50 mg and chlorthalidone 12.5 mg prepared by wet granulation method

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.
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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 excepients except magnesium stearate are mixed with active drug in a geometrie 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. Pharmaceutical composition of the tablets prepared by direct compression is given in the foliowing table-2.
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Table 2: Pharmaceutical composition of tablets containing losartan potassi u m 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
Staren 1500 18.51
Microcrystalline cellulose 52.63
Colloidal silicon dioxide 2.11
Crosspovidone 1.75
Sodium starch glycolate 1.05
Talc 0.70
Magnesium stearate 0.88
Tablets 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 is 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.
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TabJe3; Composition of coating solution

Tablets of example l 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.
EXAMPLE 4 Stability data:
The tablets thus manufactured were subjected to accelerated stability tests. The stability data of losartan and chlorthalidone after three months in 40°C temperature and 75% relative humidity shows that the formulation was 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 was carried out.
Stability data of tablets prepared using moisture protected granules of higher strength (Losartan potassium 50mg and chlorthaüdone 12.5 mg) are shown in table 4.
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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 %
Dissnlution rate 94.88-103.93% 95.64-104.56%
Stability data of tablets prepared using moisture protected granules of strength (Losartan potassium 25mg and chlorthalidone 12.5 mg) are shown in table 5.
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 scope, as defined by the appended claims.
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We Claim
1. A process for preparation of a stable pharmaceutical tablet 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 wet granulation process comprises;
mixing losartan potassium, di-calcium phosphate anhydrous and pregelatinised starch in
geometrie proportion;
stabilizing the composition by providing a moisture banier layer by adding
polyvinylpyrrolidone (PVP)-starch paste into above blend of losartan potassium;
granulating the above blend to obtain losartan potassium granules;
drying the granules at 50-60°C and rasping dried granules through 20# sieve;
mixing chlorthalidone, di-calcium phosphate anhydrous. cross carmellose sodium and
sodium starch glycolate in geometrie proportion;
providing a moisture barrier layer by adding polyvinylpyrrolidone (PVP)-starch paste
into above blend of chlorthalidone;
granulating the above blend to obtain chlorthalidone granules;
drying the granules at 50-60°C and rasping dried granules through 20# sieve;
mixing the moisture protected granules of losartan potassium and chlorthalidone with
lubricants such as sodium starch glycolate, dried starch and colloidal silicon dioxide.
adding glidant such as magnesium stearate ;
compressing the granules into tablets with hardness varying from 30 to 145 newton
having thickness between 3.5-5.2 mm and
film coating the tablets with hydroxy propyl methyl cellulose.
2. A process for preparation of a stable pharmaceutical tablet 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 direct compression process comprises of.
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blending the active ingredients along with excipients such as microcrystalline cellulose (Grade Avicel PH 200) and colloidal silicon dioxide that prevented moisture absorption by losartan potassium under controlled conditions of temperature and relative humidity; adding gfidant such as magnessium stearate;
compressing the blend into tablets with hardness varying from 30 to 145 newton and film coating the tablets with hydroxy propyl methyl cellulose.
3. A process for preparation of a stable pharmaceutical tablet composition as claimed in
claim l; wherein the said granulation is aqueous or hydroalcoholic.
4. A process for preparation of a stable pharmaceutical tablet composition as claimed in
claim l ;wherein the said binder and disintegrant for wet granulation is
pregelatinized starch.
5. A process for preparation of a stable pharmaceutical tablet composition as claimed in
claim 2, wherein the lubricant for direct compression is purified talc.
6. A process for preparation of a stable pharmaceutical tablet composition as claimed in
claims l to 5 wherein the said composition comprises the amount of losartan
potassium is 25 mg and 50 mg and chlorthalidone 12.5 mg.
7. A process for preparation of a stable pharmaceutical tablet composition as claimed in
claims l to 6 wherein the said the tablets are coated with a polymer such as hydroxy
propyl methyl cellulose in a quantity of 2 to 3 mg per tablet.
8. A process for preparation of a stable pharmaceutical tablet composition as claimed in
claim l to 7, wherein the said coating solution contains plasticizer such as polyethylene
glycol in a quantity of 0.2 mg to 0.3 mg per tablet.
9. A process for preparation of a stable pharmaceutical tablet composition as claimed in
claims l to 8 . wherein the said coating solution contains opacifier such as titanium
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dioxide in a quantity of 0.3 mg to 0.5mg per tablet.
10. A process for preparation of a stable pharmaceutical tablet composition as claimed in
claims l to 9 wherein the said coating solution is prepared in 2-propanol and
methylene chloride.
11, A process for preparation of a stable pharmaceutical tablet composition as claimed in
claims l to 10 substantially as described herein with reference to the foregoing examples 1-4.
Dated this 13th day of Feb, 2004

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