Form 2 THE PATENTS ACT, 1970(39 of 1970) & THE PATENTS RULE 2003 PROVISIONAL SPECIFICATION[See section 10 and rule 13]
1. TITLE OF THE INVENTION “Stable pharmaceutical compositions for treatment of hypertension and process of preparation thereof”
2. APPLICANT(a) NAME: USV LIMITED(b) NATIONALITY: Indian Company incorporated under the Companies ACT 1956
(c) ADDRESS: B.S.D. Marg, Govandi, Mumbai 400 088, Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION
The following specification describes the invention.

Technical field of the invention:
The present invention relates to stable pharmaceutical compositions used for the treatment of hypertension comprising about 0.1% to about 5.0% by weight of an HMG CoA reductase inhibitor, about 0.2% to about 6.0% by weight of an ACE inhibitor, about 10.0% to about 40.0% by weight of a Nonsteroidal antiinflammatory drug (NSAIDs) together with other pharmaceutically acceptable excipients wherein said compositions are stabilized with about 1.0% to about 6.0% by weight of a stabilizer selected from either tris(hydroxymethyl) amino methane or N-methyl glucamine. Particularly, the invention relates to compositions where the HMG CoA reductase inhibitor is Atorvastatin, ACE inhibitor is Ramipril and the Nonsteroidal anti-inflammatory drug is Aspirin. Further, the invention relates to a process for preparation of said stable compositions.
Background and Prior art:
Cardiovascular diseases (CVD) cause millions of death around the world. Major risk factors associated with CVD include high blood pressure, high blood cholesterol, tobacco smoking, myocardial infarction, systemic lupus erythematosus, hemodialysis, congestive cardiac failure, Insulin resistance Diabetes mellitus, Obesity, hyperhomocysteine levels, physical inactivity/ Sedentary lifestyle, stress, strokes and others. In 2003, the global death due to CVD was 16.7 million. In India the Cardiovascular diseases are rapidly increasing. According to a report, in India the mortality from cardiovascular disease among people aged 35-64 years of age is found to be one and a half to two times as high as that of the United States.
Hypertension means high blood pressure in the arteries, which carry blood from heart to all the tissues and organs of the body. Hypertension may be associated with various vascular pathologies such as ventricular hypertrophy, atherosclerosis,
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arteriolar sclerosis and necrosis, heart failure, renal ischemia, intracranial hemorrhage and encephalopathy. It has been well established that higher the levels of either systolic or diastolic blood pressure greater is the risk of death due to cardiovascular diseases. Early treatment of hypertension can reduce the risk of morbidity and mortality due to cardiovascular diseases.
Various treatments are available for hypertension. HMG-CoA reductase inhibitors or Statins are drugs which lower the cholesterol levels in people at risk of cardiovascular diseases. They lower cholesterol by inhibiting the enzyme HMG-CoA reductase, which is the rate-limiting enzyme of the mevalonate pathway of cholesterol synthesis. Inhibition of this enzyme in the liver stimulates LDL receptors, resulting in an increased clearance of low-density lipoprotein (LDL) from the bloodstream and a decrease in blood cholesterol levels. Commonly used statins include Simvastatin, pravastatin, atorvastatin, lovastatin, fluvastatin.
Angiotensin converting enzyme inhibitors (ACE inhibitors) are drugs which inhibit the activity of angiotensin converting enzyme which inturn decreases the production of angiotensin II resulting in blood vessel, dilation to reduce the blood pressure. ACE inhibitors are used for controlling blood pressure, treating heart failure and preventing kidney damage in people with hypertension or diabetes.
Aspirin, which is a cyclooxygenase inhibitor is administered in low doses over a period of time to prevent myocardial infarction and strokes due to thrombosis. Aspirin or acetylsalicylic acid is a salicylate used as an analgesic, antipyretic and as an anti-inflammatory. Aspirin also has an antiplatelet effect.
There are several marketed preparations containing Atorvastatin alone or in combination with other drugs such as Aspirin, Amlodipine besylate, etc. Lipitor® tablets which contain Atorvastatin is marketed by Pfizer and is available in strengths of 10mg, 20mg, 40mg or 80mg. Caduet® is another marketed
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preparation containing Atorvastatin and Amlodipine besylate. Ramipril is marketed as Tritace® or Altace®. Altace® is supplied as hard shell capsules in doses of 1.25mg, 2.5mg, 5mg, and l0mg of Ramipril and the inactive ingredients include pregelatinized starch NF, gelatin, and titanium dioxide.
CN1785196 discloses a medicine in the form of an enteric tablet for preventing and treating atherosclerosis, hyperlipemia, hypertension, coronary heart disease, cerebral apoplexy and diabetes is prepared from Aspirin, Folic acid, Simvastatin, Ramipril and excipient.
US6235311 discloses a pharmaceutical composition for cholesterol lowering and reducing the risk of a myocardial infarction, containing a statin, such as Pravastatin, Lovastatin, Simvastatin, Atorvastatin, Cerivastatin or Fluvastatin, in combination with Aspirin, in a manner to minimize interaction of Aspirin with the statin and minimize side effects of aspirin. However, there is no mention of an ace-inhibitor in this patent.
US6669955 discloses an orally administrable pharmaceutical formulation containing a cholesterol-lowering agent, an inhibitor of the renin-angiotensin system, aspirin, and optionally at least one of vitamin B6, B12, and folate.
WO2005/011586 discloses a pharmaceutical dosage form for treating or preventing cardiovascular events containing a beta-adrenergic receptor antagonist, a diuretic, or both; a cholesterol-lowering agent; an inhibitor of the renin-angiotensin system; and aspirin.
US5151433 discloses compositions containing Ramipril in the form of agglomerate stabilized using 3 to 25% of polymeric protective coating. However, the invention makes no mention of any other actives such as Statins or Aspirin.
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US2007021491 discloses use of an inhibitor of the renin-angiotensin system optionally together with another antihypertensive, a cholesterol lowering agent, a diuretic or aspirin.
Several single ingredient compositions or stand alone products are commercially available and are specially used for flexibility in dose titration. Major drawbacks associated with such compositions include patient non-compliance due to multiple dosing and missing of dose of a particular drug which might in turn put the patient at high health risk.
Although there are various combinations available for treatment of hypertension, it is found that long term stability of such combinations may not be guaranteed.
Compositions containing Ramipril undergo slow degradation by virtue of unstable nature of Ramipril. The physical stress associated with the formulating processes increases the rate of decomposition of Ramipril. In Ramipril degradation occurs via two pathways: (i) hydrolysis to Ramipril-diacid; and (ii) cyclization or condensation to Ramipril-diketopiperazine. The main product of decomposition is diketopiperazine compound. Factors that influence the stability of Ramipril formulations are mechanical stress, compression, manufacturing processes, excipients, storage conditions, heat, air and moisture or combination of all the factors.
In view of the aforementioned drawbacks associated with prior art compositions it is apparent that there still exists a need for stable compositions which possess good shelf life stability and do not degrade on long term storage.
The inventors of the present invention have developed compositions which overcome the disadvantages of instability of the prior art compositions.
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Object of the Invention:
The main object of the invention is to provide stable pharmaceutical compositions for the treatment of hypertension comprising an HMG Co A reductase inhibitor, an ACE inhibitor and a non steroidal anti inflammatory drug.
Another object of the invention is to provide compositions which are used in the treatment of hypertensive-obese subjects.
Another object of the invention is to provide fixed dose combinations containing Atorvastatin, Ramipril and Aspirin.
Yet another object of the invention is to provide a process for preparation of stable compositions wherein the compositions are stabilized with about 1.0% to about 6.0% by weight of a stabilizer selected from either tris(hydroxymethyl) amino methane or N-methyl glucamine.
Still another object of the invention is to provide compositions which exhibit an improved stability of the medicament Ramipril in combination with Aspirin and Atorvastatin.
Yet another object of the invention is to provide compositions of Atorvastatin, Ramipril and Aspirin as a unit dosage form for ease of administration and better patient compliance.
Further object of the invention is to provide compositions comprising Atorvastatin, Ramipril and Aspirin incorporated in hard gelatin capsules or hard cellulose capsules; wherein Atorvastatin is formulated into granules, Ramipril is formulated into premix and Aspirin is formulated into delayed release tablets.
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Still further object of the invention is to provide a cold formed blister pack for the compositions which acts as an excellent moisture barrier with negligible moisture vapour transmission rates.
Summary of the invention:
The present invention discloses stable pharmaceutical compositions used for the treatment of hypertension comprising about 0.1% to about 5.0% by weight of an HMG CoA reductase inhibitor, about 0.2% to about 6.0% by weight of an ACE inhibitor, about 10.0% to about 40.0% by weight of a Nonsteroidal antiinflammatory drug (NSAIDs) together with other pharmaceutically acceptable excipients wherein said compositions are stabilized with about 1.0% to about 6.0% by weight of a stabilizer selected from either tris(hydroxymethyl) amino methane or N-methyl glucamine. Particularly, the invention discloses compositions where the HMG CoA reductase inhibitor is Atorvastatin, ACE inhibitor is Ramipril and the Nonsteroidal anti-inflammatory drug is Aspirin.
The invention further discloses a process for preparation of said stable pharmaceutical compositions, the process comprising the steps of:
(i) preparing granules of Atorvastatin calcium using suitable pharmaceutical
excipients;
(ii) preparing premix of Ramipril with an alkalizing agent and suitable
pharmaceutical excipients;
(iii) preparing a blend of Atorvastatin calcium granules from step (i), Ramipril
premix from step
(ii) and suitable pharmaceutical excipients;
(iv) preparing Aspirin delayed-release tablets using suitable pharmaceutical
excipients;
(v) filling the Aspirin delayed-release tablets of step(iv) and blend of step (iii)
into hard gelatin or hard cellulose capsules.
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Detailed Description:
The present invention describes stable pharmaceutical compositions used for the treatment of hypertension comprising about 0.1% to about 5.0% by weight of an HMG CoA reductase inhibitor, about 0.2% to about 6.0% by weight of an ACE inhibitor, about 10.0% to about 40.0% by weight of a Nonsteroidal antiinflammatory drug (NSAIDs) together with other pharmaceutically acceptable excipients wherein said compositions are stabilized with about 1.0% to about 6.0% by weight of a stabilizer selected from either tris(hydroxymethyl) amino methane or N-methyl glucamine.
According to one aspect, the invention describes pharmaceutical compositions comprising ACE inhibitor in combination with HMG CoA reductase inhibitor and NSAID wherein the ACE inhibitor is stabilized against degradation by use of an alkalizing agent.
According to the invention HMG CoA reductase inhibitors which can be used include Atorvastatin, Pravastatin, Fluvastatin, Simvastatin, Lovastatin and pharmaceutically acceptable salts thereof; ACE inhibitors which can be used include Trandolapril, Ramipril, Lisinopril.
According to another aspect of the invention the HMG CoA reductase inhibitor is Atorvastatin Calcium, ACE inhibitor is Ramipril and the non steroidal anti inflammatory drug is Aspirin.
Particularly, said compositions are in the form of solid dosage forms such as hard gelatin capsules or hard cellulose capsules which are formulated and developed using pharmaceutically acceptable excipients wherein the Atorvastatin is formulated into granules, Ramipril is formulated into premix and Aspirin is formulated into delayed release tablets.
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Atorvastatin is chemically [R-(R*, R*)]-2-(4-fluorophenyl)-p\ 8 -dihydroxy-5- (1-methylethyl)-3-phenyl-4-[(phenylamino) carbonyl]-1 H-pyrrole-1 -heptanoic acid. Empirical formula of Atorvastatin is (C33H34 FN2O5) and its molecular weight
is 558.64. Atorvastatin calcium is [R-(R*, R*)]-2-(4-fluorophenyl)-b, d -dihydroxy-5- (l-methylethyl)-3-phenyl-4-[(phenylamino) carbonyl]-lH-pyrrole-1-heptanoic acid, calcium salt (2:1) trihydrate. The empirical formula of atorvastatin calcium is (C33H34 FN205)2Ca*3H2O and its molecular weight is 1209.42. Calcium salt of Atorvastatin is a white to off-white crystalline powder that is insoluble in aqueous solutions of pH 4 and below. Atorvastatin calcium is very slightly soluble in distilled water, pH 7.4 phosphate buffer, and acetonitrile, slightly soluble in ethanol, and freely soluble in methanol.
Ramipril is chemically [2S,3aS,6aS]-l-[((2S)-2-[[(lS)-l-(Ethoxycarbonyl)-3-phenylpropyl]amino]-l-oxopropyl]octahydrocyclopental[b]pyrrole-2-carboxylic acid. Ramipril is a white, crystalline substance soluble in polar organic solvents and buffered aqueous solutions.
Compositions containing Ramipril undergo slow degradation. Factors that influence the stability of Ramipril formulations are mechanical stress, compression, manufacturing processes, excipients, storage conditions, heat, air and moisture or combination of all the factors. Physical stress associated with the formulating processes increases the rate of decomposition of Ramipril. Degradation of Ramipril occurs via two pathways: (i) hydrolysis to Ramipril-diacid; and (ii) cyclization or condensation to Ramipril-diketopiperazine. Main product of decomposition is diketopiperazine compound.
Compositions containing Atorvastatin, Ramipril and Aspirin in a unit dosage form pose several formulation challenges due to chemical interactions of actives in presence of each other and under influence of moisture leading to destabilization
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of formulation.
Inventors of the present invention have developed a process to prepare stable pharmaceutical compositions comprising combination of Atorvastatin, Ramipril and Aspirin. Stable compositions of present invention are not prone to degradation or discoloration and exhibit an extended shelf life under normal storage conditions. Compositions of the present invention are stable both physically as well as chemically. Compositions, more particularly the capsule dosage form so prepared is stable at accelerated conditions of temperature and humidity.
Ramipril is unstable in the presence of acidic environment and Aspirin is acidic in nature. Further, Ramipril is prone towards destabilization upon compression. Hence the present invention avoids the compressed form of Ramipril. Aspirin on the other hand is sensitive towards moisture leading to degradation and formation of Free Salicylic Acid (FSA). This tendency of Aspirin is arrested with the use of enteric coating where the enteric coat serves the dual purpose of avoiding gastric irritation and acts as a moisture barrier.
Suitable pharmaceutically acceptable excipients that can be used according to the present invention include, but are not limited to diluents/fillers, binders, disintegrating agents, wetting agents, glidants, lubricants, solvents, antiadherants and the like.
Another aspect of the invention provides fixed dose combinations for treatment of hypertension comprising HMG CoA reductase inhibitor, ACE inhibitor and non steroidal anti-inflammatory agent in a solid dosage form such as hard gelatin capsule or hard cellulose capsule.
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According to a preferred aspect, the fixed dose combinations for treatment of hypertension comprises of Atorvastatin, Ramipril and Aspirin formulated in a solid unit dosage form such as hard gelatin capsule or hard cellulose capsule.
Fixed dose combinations of the present invention are particularly in the form of solid dosage forms such as hard gelatin capsules or hard cellulose capsules wherein the Atorvastatin is in the form of granules, Ramipril is in the form of premix and Aspirin is the form of a delayed release tablet.
According to one aspect, Atorvastatin is present in the composition preferably in an amount from 5 mg to 20mg; more preferably as 5mg and lOmg dose.
According to another aspect, Ramipril is present in the composition preferably in an amount from 1.5 mg to 5mg; more preferably as 2.5mg and 5mg dose.
According to yet another aspect, Aspirin is present in the composition preferably in an amount from 50mg to 150mg; more preferably as 75mg and 150mg dose. Composition containing 150mg Aspirin contains two delayed release tablets each containing 75mg Aspirin.
According to a preferred aspect of the present invention, the fixed dose combination contains lOmg of Atorvastatin, 2.5 mg of Ramipril and 75mg of Aspirin.
According to another preferred aspect, the fixed dose combination contains lOmg of Atorvastatin, 5 mg of Ramipril and 75mg of Aspirin.
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According to the invention, the compositions comprising HMG CoA reductase inhibitor, ACE inhibitor and Nonsteroidal anti-inflammatory agent are used in the treatment of hypertensive-obese subjects. Solid unit dosage form provides ease of administration and thereby better patient compliance.
The invention further describes a process for preparation of stable pharmaceutical compositions, the process comprising the steps of:
(i) preparing granules of Atorvastatin calcium using suitable pharmaceutical
excipients;
(ii) preparing premix of Ramipril with an alkalizing agent and suitable
pharmaceutical excipients;
(iii) preparing a blend of Atorvastatin calcium granules from step (i), Ramipril
premix from step (ii) and suitable pharmaceutical excipients;
(iv) preparing Aspirin delayed-release tablets using suitable pharmaceutical
excipients;
(v) filling the Aspirin delayed-release tablets of step(iv) and blend of step (iii)
into hard gelatin or hard cellulose capsules.
According to one embodiment of present invention, there is provided a process for preparation of granules of Atorvastatin calcium comprising the steps of:
(1) co-sifting Atorvastatin calcium with disintegrants and precipitated calcium carbonate through 40# on a vibratory sifter;
(2) sifting separately the diluents through 40# on a vibratory sifter;
(3) mixing sifted Atorvastatin calcium with diluents, disintegrants and precipitated calcium carbonate for about 10 minutes;
(4) granulating the blend of step (3) with a binder solution prepared by dissolving the binder in a suitable solvent, to form a wet mass;
(5) drying the wet mass of step(4) in a suitable equipment at 60-65 °C for sufficient time till loss on drying is not more than 3.0%,
(6) sizing the dried mass of step (5) through 30# sieve on a vibratory sifter and
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further milling the over sized granules through 1.0 mm screen on the multi-mill and then sifting through 30 # on Vibratory sifter.
According to the invention, Atorvastatin is present in an amount from 0.1% to about 5.0 % by weight of total composition.
Diluents which can be used for preparation of Atorvastatin granules as per the invention include, but are not limited to maize starch, lactose anhydrous, microcrystalline cellulose, dibasic calcium phosphate anhydrous or mixtures thereof in an amount from 2% to 60% by weight of the total composition. Lactose anhydrous is the preferred diluent used in an amount from 5% to 40% by weight of the total composition, preferably from 2% to 15% by weight of the total composition.
Calcium carbonate precipitated can be used as a stabilizer for Atorvastatin, preferably in an amount from 5% to 10% by weight of the total composition.
Binders which can be used for preparation of Atorvastatin granules as per the invention include, but are not limited to povidone, ethylcellulose, hydroxy propyl cellulose, hydroxy ethyl cellulose, hydroxy propyl methyl cellulose, pregelatinised starch and the like or mixtures thereof in an amount from 2% to 6% by weight of the total composition. Preferred binder being hydroxy propyl cellulose used in an amount from 2% to 6% by weight of the total composition; preferably from 3% to 5% by weight of the total composition.
Solvents which can be used include isopropyl alcohol, water or mixtures thereof.
Disintegrants which can be used for preparation of Atorvastatin granules as per the invention include, but are not limited to croscarmellose sodium, sodium starch glycolate, dried maize starch, microcrystalline cellulose, crospovidone and the
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like or mixtures thereof in an amount from 0.5% to 5.0% by weight of the total composition. Preferred disintegrant is croscarmellose sodium preferably in an amount from 1% to 4% by weight of the total composition.
Mixing and granulation can be carried out in a conventional rapid mixer granulator and the wet granules can be further dried using fluid bed drier. However, in a conventional fluid bed processor both the steps of granulation and drying can be carried out in the same equipment thereby simplifying the process and saving the processing time.
According to another embodiment of the present invention, there is provided a process for preparation of premix of Ramipril comprising the steps of:
(1) sifting separately alkalizing agent and diluents through 40 # on a vibratory sifter;
(2) co-sifting Ramipril with pre-sifted alkalizing agent through 40 # on Vibratory sifter;
(3) mixing the sifted materials of step (2) in geometric progression with the sifted diluent of step (1) in a suitable equipment to form a blend.
According to the invention, Ramipril is present in an amount from 0.2% to about 6.0 % by weight of total composition.
Alkalizing agents are ingredients which are used to stabilize the compositions. Suitable alkalizing agents which can be used for preparation of Ramipril premix include tris(hydroxymethyl) amino methane or N-methyl glucamine; preferably in an amount from 1% to 6% by weight of the total composition.
Tris(hydroxymethyl) amino methane, also known as tromethamine is a white crystalline powder having the formula (HOCH2)3CNH2 and molecular weight of 121.14. Tromethamine is readily soluble in water.
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N-methyl glucamine, also known as Meglumine is a derivative of sorbitol in which the hydroxyl group in position 1 is replaced by a methylamino group. Meglumine is a white crystalline powder; having melting point of 130°C.
Diluents which can be used for preparation of Ramipril premix as per the invention include, but are not limited to dried maize starch, lactose anhydrous, microcrystalline cellulose, dibasic calcium phosphate anhydrous, pregelatinised starch or mixtures thereof and is used in an amount from about 2% to about 80% by weight of the total composition. Preferred diluent is pregelatinised starch and is used in an amount from 5% to 75% by weight of the total composition, preferably from 25% to 75% by weight of the total composition.
A process for preparation of Aspirin delayed-release tablet USP as an enteric coated tablet comprises of the following steps:
(i) blending Aspirin with suitable pharmaceutical excipients having low
moisture content;
(ii) compression of the blend into tablets of suitable size using conventional
compression machine;
(iii) coating the compressed tablets with delayed release coating polymer.
According to the invention, Aspirin is present in an amount from 10.0 % to about 40.0 % by weight of total composition; preferably in an amount from 23% to 46% by weight of the total composition.
Suitable pharmaceutical excipients used in preparation of Aspirin delayed release tablets include diluents, lubricants, glidants and the like.
Diluents which can be used for preparation of Aspirin delayed release tablets include, but are not limited to maize starch, microcrystalline cellulose,
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pregelatinised starch, coprocessed cellulose, lactose and the like.
Lubricants which can be used for preparation of Aspirin delayed release tablets include, but are not limited to sodium stearyl fumarate, stearic acid and the like. Glidants which can be used include colloidal silicon dioxide, talc and the like.
Enteric coating Polymers which can be used for preparation of Aspirin delayed release tablets include, but are not limited to methacrylic acid copolymer, cellulose acetate phthalate and the like.
According to another embodiment, there is provided a process for preparation of capsule dosage form comprising the steps of:
(a) blending Atorvastatin granules and Ramipril premix in a suitable equipment;
(b) sifting lubricants through 60# on a vibratory sifter;
(c) mixing the sifted lubricants with blend of step(a) for a suitable period of time;
(d) filling the delayed release Aspirin tablet, followed by blend of step(c) into empty hard gelatin capsule or empty hard cellulose capsule using suitable capsule filling machine equipped with suitable change parts for filling of tablet in capsule.
Lubricants which can be used include sodium stearyl fumarate, magnesium stearate, calcium stearate and the like. Preferred lubricant is sodium stearyl fumarate and is used in an amount from 0.25% to 2.0% by weight of the total composition, preferably 0.5% to 1.5% by weight of the total composition.
According to one embodiment, Aspirin may be formulated in the form of enteric coated pellets; Atorvastatin may be in the form of immediate release pellets and Ramipril in the form of pre-mix; filled into hard gelatin or hard cellulose capsule.
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According to another embodiment, Aspirin may be in the form of enteric coated tablet, Atorvastatin may be in the form of a film coated tablet and Ramipril in the form of pre-mix; all filled into hard gelatin or hard cellulose capsule.
According to yet another embodiment, Aspirin may be in the form of enteric coated tablet, Atorvastatin may be in the form of a granular blend, Ramipril in the form of pre-mix filled in size 4 capsule and finally all the three filled into hard gelatin or hard cellulose capsule.
Process of preparation according to the present invention provides compositions which exhibit an improved stability of the medicament Ramipril in combination with Aspirin and Atorvastatin.
Empty hard gelatin capsule or empty hard cellulose capsule can be used in the size from '0' to '00'; preferred being size '0'.
Compositions may be packed in aluminium strips or by cold formed blister pack which is a cold process of blister packing which acts as an excellent moisture barrier with negligible moisture vapour transmission rate and provides protection from external environment.
The present invention is further illustrated by reference to the following examples which does not limit the scope of the invention in any way. It will be apparent to those skilled in the art that many modifications, both to the materials and methods, can be practiced without departing from the purpose and scope of the disclosure.
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Examples
Example 1
Step I: Mix Atorvastatin (114.2 gm) with croscarmellose sodium (60gm), calcium carbonate (300 gm) and lactose monohydrate (85) gm to form a blend. Prepare binder solution by dissolving hydroxy propyl cellulose (3.0 gm) in 300ml of purified water. Granulate the blend with binder solution to form a cohesive wet mass. Dry the wet mass in Glatt drier at inlet temperature 60°C for sufficient time till loss on drying is not more than 2.0%. Size the dried granules.
Step II: Mix Ramipril (3.5 gm) with pregelatinised starch (173 gm) and tromethamine (10.5) gm in a suitable blender for 5 minutes. Mix these materials with dried and sized Atorvastatin granules of Step I in a cone blender or conta blender. Add the lubricant sodium stearyl fumarate (2.1) gm to it and mix.
Step III: Mix Aspirin (375gm) with pregelatinised starch (75 gm), colloidal silicon dioxide (7.5 gm) and stearic acid (5.0 gm) in a blender of suitable capacity. Compress the blend into tablets of suitable size. Coat the tablets using enteric coating polymer cellulose acetate phthalate to achieve 8-12% weight gain.
Step IV: Fill the lubricated blend of Step II and Aspirin delayed release tablets 75mg of step III into hard gelatin capsules of suitable size.
Example 2
Step I: Mix Atorvastatin (114.2 gm) with croscarmellose sodium (60gm), calcium carbonate (300 gm), lactose monohydrate (85 gm) and hydroxy propyl cellulose (3.0gm) to form a blend. Granulate the blend with 300ml purified water to form a cohesive wet mass. Dry the wet mass in Glatt drier at inlet temperature 60°C for sufficient time till loss on drying is not more than 2.0%. Size the dried granules.
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Step II: Mix Ramipril (3.5 gm) with pregelatinised starch (173 gm) and tromethamine (10.5 gm) in a suitable blender for 5 minutes. Mix these materials with dried and sized Atorvastatin granules of Step I in a cone blender or conta blender. Add the lubricant sodium stearyl fumarate (2.1 gm) to it and mix.
Step III: Mix Aspirin (375gm) with pregelatinised starch (75 gm), colloidal silicon dioxide (7.5 gm) and stearic acid (5.0 gm) in a blender of suitable capacity. Compress the blend into tablets of suitable size. Coat the tablets using enteric coating polymer cellulose acetate phthalate to achieve 8-12% weight gain.
Step IV: Fill the lubricated blend of Step II and Aspirin delayed release tablets 75mg of step III into hard gelatin capsules of suitable size.
Example 3
Step I: Mix Atorvastatin (114.2 gm) with croscarmellose sodium (60gm), calcium carbonate (300 gm), lactose monohydrate (85 gm) and hydroxy propyl cellulose (3.0 gm) to form a blend. Prepare binder solution by dissolving (3.5 gm) Polysorbate 80 in 300ml of warm water. Granulate the blend with binder solution to form a cohesive wet mass. Dry the wet mass in Glatt drier at inlet temperature 60°C for sufficient time till loss on drying is not more than 2.0%. Size the dried granules.
Step II: Mix Ramipril (3.5 gm) with pregelatinised starch (173 gm) and tromethamine (10.5 gm) in a suitable blender for 5 minutes. Mix these materials with dried and sized Atorvastatin granules of Step I in a cone blender or conta blender. Add the lubricant sodium stearyl fumarate (2.1 gm) to it and mix.
Step III: Mix Aspirin (375gm) with pregelatinised starch (75 gm), colloidal silicon
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dioxide (7.5 gm) and stearic acid (5.0 gm) in a blender of suitable capacity. Compress the blend into tablets of suitable size. Coat the tablets using enteric coating polymer cellulose acetate phthalate to achieve 8-12% weight gain.
Step IV: Fill the lubricated blend of Step II and Aspirin delayed release tablets 75mg of step III into hard gelatin capsules of suitable size.
Example 4
Step I: Mix Atorvastatin (114.2 gm) with croscarmellose sodium (60gm), calcium carbonate (300 gm), lactose monohydrate (85 gm) and and hydroxy propyl cellulose (3.0 gm) to form a blend. Prepare binder solution by dissolving (3.5 gm) Polysorbate 80 in 300ml of warm water. Granulate the blend with binder solution to form a cohesive wet mass. Dry the wet mass in Glatt drier at inlet temperature 60°C for sufficient time till loss on drying is not more than 2.0%. Size the dried granules.
Step II: Mix Ramipril (3.5 gm) with pregelatinised starch (173 gm) and pre-sifted tromethamine (10.5 gm) [initially sifted through 80# and then through 40#] in a suitable blender for 5 minutes. Mix these materials with dried and sized Atorvastatin granules of Step I in a cone blender or conta blender. Add the lubricant sodium stearyl fumarate (2.1 gm) to it and mix.
Step III: Mix Aspirin (375gm) with pregelatinised starch (75 gm), colloidal silicon dioxide (7.5 gm) and stearic acid (5.0 gm) in a blender of suitable capacity. Compress the blend into tablets of suitable size. Coat the tablets using enteric coating polymer cellulose acetate phthalate to achieve 8-12% weight gain.
Step IV: Fill the lubricated blend of Step II and Aspirin delayed release tablets 75mg of step III into hard gelatin capsules of suitable size.
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Example 5
Step I: Mix Atorvastatin (114.2) gm with croscarmellose sodium (60gm), calcium carbonate (300 gm) and lactose monohydrate (85 gm) to form a blend. Prepare binder solution by dissolving (3.0 gm) hydroxy propyl cellulose in 300ml of water. Granulate the blend with binder solution to form a cohesive wet mass. Dry the wet mass in Glatt drier at inlet temperature 60°C for sufficient time till loss on drying is not more than 2.0%. Size the dried granules.
Step II: Mix Ramipril (3.5 gm) with pregelatinised starch (173 gm) and Meglumine (10.5 gm) in a suitable blender for 5 minutes. Mix these materials with dried and sized Atorvastatin granules of Step I in a cone blender or conta blender. Add the lubricant sodium stearyl fumarate (2.1 gm) to it and mix.
Step III: Mix Aspirin (375gm) with pregelatinised starch (75 gm), colloidal silicon dioxide (7.5 gm) and stearic acid (5.0 gm) in a blender of suitable capacity. Compress the blend into tablets of suitable size. Coat the tablets using enteric coating polymer cellulose acetate phthalate to achieve 8-12% weight gain.
Step IV: Fill the lubricated blend of Step II and Aspirin delayed release tablets 75mg of step III into hard gelatin capsules of suitable size.
Example 6
Step I: Mix Atorvastatin (114.2 gm) with croscarmellose sodium (60gm), calcium carbonate (300 gm), lactose monohydrate (85 gm) and hydroxy propyl cellulose (3.0gm) to form a blend. Granulate the blend with 300ml of water to form a cohesive wet mass. Dry the wet mass in Glatt drier at inlet temperature 60°C for sufficient time till loss on drying is not more than 2.0%. Size the dried granules.
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Step II: Mix Ramipril (3.5 gm) with pregelatinised starch (173 gm) and Meglumine (10.5 gm) in a suitable blender for 5 minutes. Mix these materials with dried and sized Atorvastatin granules of Step I in a cone blender or conta blender. Add the lubricant sodium stearyl fumarate (2.1 gm) to it and mix.
Step III: Mix Aspirin (375gm) with pregelatinised starch (75 gm), colloidal silicon dioxide (7.5 gm) and stearic acid (5.0 gm) in a blender of suitable capacity. Compress the blend into tablets of suitable size. Coat the tablets using enteric coating polymer cellulose acetate phthalate to achieve 8-12% weight gain.
Step IV: Fill the lubricated blend of Step II and Aspirin delayed release tablets 75mg of step III into hard gelatin capsules of suitable size.
Example 7
Step I: Mix Atorvastatin (114.2 gm) with croscarmellose sodium (60gm), calcium carbonate (300 gm), lactose monohydrate (85 gm) and hydroxy propyl cellulose (3.0 gm) to form a blend. Prepare binder solution by dissolving (3.5 gm) Polysorbate 80 in 300ml of warm water. Granulate the blend with binder solution to form a cohesive wet mass. Dry the wet mass in Glatt drier at inlet temperature 60°C for sufficient time till loss on drying is not more than 2.0%. Size the dried granules.
Step II: Mix Ramipril (3.5 gm) with pregelatinised starch (173 gm) and Meglumine (10.5 gm) in a suitable blender for 5 minutes. Mix these materials with dried and sized Atorvastatin granules of Step I in a cone blender or conta blender. Add the lubricant sodium stearyl fumarate (2.1 gm) to it and mix.
Step III: Mix Aspirin (375gm) with pregelatinised starch (75 gm), colloidal silicon dioxide (7.5 gm) and stearic acid (5.0 gm) in a blender of suitable capacity.
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Compress the blend into tablets of suitable size. Coat the tablets using enteric coating polymer cellulose acetate phthalate to achieve 8-12% weight gain.
Step IV: Fill the lubricated blend of Step II and Aspirin delayed release tablets 75mg of step III into hard gelatin capsules of suitable size.
Example 8
Step I: Mix Atorvastatin (114.2 gm) with croscarmellose sodium (60gm), calcium carbonate (300 gm), lactose monohydrate (85 gm) and hydroxy propyl cellulose (3.0 gm) to form a blend. Prepare the binder solution by dissolving (3.5 gm) Polysorbate 80 in 300ml of warm water. Granulate the blend with binder solution to form a cohesive wet mass. Dry the wet mass in Glatt drier at inlet temperature 60°C for sufficient time till loss on drying is not more than 2.0%. Size the dried granules.
Step II: Mix Ramipril (3.5 gm) with pregelatinised starch (173 gm) and pre-sifted Meglumine (10.5 gm) [initially sifted through 80# and then through 40#] in a suitable blender for 5 minutes. Mix these materials with dried and sized Atorvastatin granules of Step I in a cone blender or conta blender. Add the lubricant sodium stearyl fumarate (2.1 gm) to it and mix.
Step III: Mix Aspirin (375gm) with pregelatinised starch (75 gm), colloidal silicon dioxide (7.5 gm) and stearic acid (5.0 gm) in a blender of suitable capacity. Compress the blend into tablets of suitable size. Coat the tablets using enteric coating polymer cellulose acetate phthalate to achieve 8-12% weight gain.
Step IV: Fill the lubricated blend of Step II and Aspirin delayed release tablets 75mg of step III into hard gelatin capsules of suitable size.
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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.
Dated this the 07th day of August 2007
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