This invention relates to pharmaceutical composition comprising ramipril and pharmaceutical^ acceptable salts thereof, and atorvastatin and pharmaceutical^ acceptable salts thereof, and a process for the preparation of the same, as well as methods of using such compositions to treat subjects suffering from hypertension and hypercholesterolemia.
Atherosclerotic cardiovascular disease and its complications are a major health problem in most countries of the world and continue to rank among the leading causes of mortality and morbidity. They result in huge health care expenditures and economic losses and are a source of great suffering for those affected and their families. Atherosclerotic disease is on the increase in many countries undergoing rapid industrialization and lifestyle changes as in India.
Hypertension and hyperlipidemia are independent risk factors for atherosclerotic cardiovascular disease. Hypertension commonly co-exists with hypercholesterolaemia (Goode GK et al, Hyperlipidaemia, hypertension, and coronary heart disease. Lancet. 1995, 345:362-4). The concomitant occurrence of these factors leads to a cumulative increase in the risk of congenital heart disease (Assmann G and Schulte H, The Prospective Cardiovascular Munster (PROCAM) study: prevalence of hyperlipidemia in persons with hypertension and/or diabetes mellitus and the relationship to coronary heart disease. Am Heart J. 1988, 116: 1713-24).
Clinical trials have demonstrated that effective control of blood pressure in hypertensive patients reduces mortality and morbidity associated with atherosclerotic cardiovascular disease.
ACE inhibitors are effective antihypertensive agents that are also approved for the treatment of congestive heart failure and heart failure following myocardial infarction (Ml); and for reducing the risk of myocardial infarction, stroke or cardiovascular death. Cholesterol lowering therapy using HMG-CoA reductase inhibitors (statins) has been shown to significantly reduce cardiovascular events (Shepherd J et al Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med. 1995, 16; 333(20): 1301-7)
Hypertension and hypercholesterolemia are the most important modifiable risk factors of cardiovascular diseases (Amarenco P et al. Statins and stroke prevention. Cerebrovasc Dis.; 2004, 17 Suppl 1: 81-8). A concomitant management of hypertension and hypercholesterolemia has been suggested to significantly reduce the extent of
cardiovascular complications (Borghi C, Interactions between hypercholesterolemia and hypertension: implications for therapy. CurrOpin Nephrol Hypertens. 2002, 11(5); 489-96).
Considering the above, combined use of statins and ACE inhibitors might be beneficial in controlling hypertension and hypercholesterolemia simultaneously and this could have a better effect in preventing cardiovascular complications. Further, a fixed combination of a statin with an ACE inhibitor in one presentation form has the advantage that patient compliance is greater than in the case of separate administration. It lowers the number of preparations per administration time-point and has greater reliability of administration. A fixed combination accordingly improves the safety and reliability of a therapy.
WO 99/11260 relates to the combination of atorvastatin with blood-pressure-lowering agents, inter alia ACE inhibitors.
US 2004/0137054 relates pharmaceutical formulation having a content of at least one statin and at least one ACE inhibitor, wherein the at least one statin and the at least one ACE inhibitor are separated by a physiologically acceptable inert material. It explicitly discloses a three layer tablet comprising simvastatin and ramipril wherein simvastatin and ramipril layers are separated by inert layer of microcrystalline cellulose.
Inventors have now found out that it is advantageous to combine atorvastatin and ramipril in a single dosage form as both ramipril and atorvastatin can be dosed once daily,, both can be dosed at any time of the day without regard to the timing of meals and there are no studies reported on any interaction between ramipril and atorvastatin.
The inventors have developed a once a day capsule comprising atorvastatin and ramipril wherein atorvastatin component is in tablet form and ramipril component is in granule or powder blend form or vice versa. The present invention thus provides an alternate composition which involves less number of production steps, hence is more cost effective.
Atorvastatin, which is an inhibitor of the enzyme 3-hydroxy-3-methyl glutaryl coenzyme A
reductase (HMG-CoA reductase), is commercially available for the treatment of primary
hypercholesterolemia, dysbetalipoproteinemia and homozygous familial
hypercholesterolemia.
Although cholesterol is an indispensable component of all cell membranes as well as a precursor of a variety of steroid hormones and bile acids, excessively high levels of blood
cholesterol and lipids increase the risk of the onset of atherosclerosis and coronary heart disease. The blood cholesterol pool is generally dependent upon dietary uptake of cholesterol and the biosynthesis of cholesterol. HMG-CoA reductase enzyme inhibitors, such as atorvastatin, bring about a reduction in the levels of blood cholesterol, especially the low-density lipoproteins, by inhibiting the synthesis of cholesterol. They are therefore excellent candidates for controlling blood cholesterol levels.
Ramipril is a 2-aza-bicyclo [3.3.0]-octane-3-carboxylic acid derivative. Ramiprilat, the diacid metabolite of ramipril, is a non-sulfhydryl angiotensin converting enzyme inhibitor. Ramipril is converted to ramiprilat by hepatic cleavage of the ester group. Ramipril and ramiprilat are angiotensin-converting enzyme (ACE) inhibitors. Ramipril is indicated for the treatment of hypertension and in stable patients who have demonstrated clinical signs of congestive heart failure within the first few days after sustaining acute myocardial infarction. The preparation and pharmaceutical use of ramipril, and its salts are described in EP 79,022 B1.
According to one of the aspect, there is provided a once day capsule composition comprising atorvastatin and ramipril or pharmaceutically acceptable salts thereof wherein atorvastatin component is in tablet form and ramipril component is in granule or powder blend form.
According to another aspect, there is provided a once day capsule composition comprising atorvastatin and ramipril or pharmaceutically acceptable salts thereof wherein ramipril component is in tablet form and atorvastatin component is in granule or powder blend form.
According to another aspect, there is provided a once day capsule composition comprising atorvastatin and ramipril or pharmaceutically acceptable salts thereof wherein both atorvastatin and ramipril component are in tablet form.
According to another aspect, there is provided a process for the preparation of a once a day capsule composition comprising atorvastatin and ramipril or pharmaceutically acceptable salts thereof comprising the steps of:
a) preparing atorvastatin tablet
b) preparing ramipril powder blend/granule
c) filing atorvastatin tablet and ramipril powder blend/granule into capsules.
According to another aspect, there is provided a process for the preparation of a once a day capsule composition comprising atorvastatin and ramipril or pharmaceutical^ acceptable salts thereof comprising the steps of:
a) preparing ramipril tablet
b) preparing atorvastatin powder blend/granule
c) filing ramipril tablet and atorvastatin powder blend/granule into capsules.
According to another aspect, there is provided a process for the preparation of a once a day capsule composition comprising atorvastatin and ramipril or pharmaceutical^ acceptable salts thereof comprising the steps of:
a) preparing ramipril tablet
b) preparing atorvastatin tablet
c) filing ramipril and atorvastatin tablet into capsules.
According to another there is provided a method of treating cardiovascular disorders such as hypertension and hypercholesterolemia by administering to said patient a once day capsule composition comprising therapeutically effective amount atorvastatin and ramipril or pharmaceutically acceptable salts thereof wherein atorvastatin component is in tablet form and ramipril component is in granule or powder blend form.
According to another there is provided a method of treating cardiovascular disorders such as hypertension and hypercholesterolemia by administering to said patient a once day capsule composition comprising therapeutically effective amount atorvastatin and ramipril or pharmaceutically acceptable salts thereof wherein atorvastatin component is in granule or powder blend form and ramipril component is in tablet form.
According to another there is provided a method of treating cardiovascular disorders such as hypertension and hypercholesterolemia by administering to said patient a once day capsule composition comprising therapeutically effective amount atorvastatin and ramipril or pharmaceutically acceptable salts thereof wherein both atorvastatin component and ramipril component are in tablet form.
Tablet as used herein includes minitablet or pills as well.
The details of one or more aspects of the invention are set forth in the description below. Other features and advantages of the invention will be apparent from the description and the claims.
As used herein the term "atorvastatin" refers to atorvastatin calcium, atorvastatin magnesium, atorvastatin aluminum, atorvastatin iron, atorvastatin zinc, and other suitable salts of atorvastatin or an adjunct salt of atorvastatin & ramipril. Atorvastatin may exist in any of the solid state forms available such as amorphous, crystalline or any other polymorphic form.
The ACE inhibitors have a tendency to undergo decomposition reactions such as hydrolysis, cyclization or oxidation (cf., EP 280,999 B1). They may be stabilized using buffer substances such as sodium dihydrogen phosphate, sodium citrate, sodium or magnesium carbonate, sodium hydrogen carbonate or tris(hydroxymethyl)aminomethane, magnesium oxide and/or by addition of saccharides; cf., EP 317,878 B1.
Therapeutically effective amount of atorvastatin or pharmaceutically acceptable salt thereof ranges from 10-80 mg equivalent to atorvastatin. Therapeutically effective amount of ramipril or pharmaceutically acceptable salt thereof ranges from 2.5-20 mg equivalent to ramipril. The combination may comprise strengths such as atorvastatin and ramipril - 10 and 2.5 mg; 10 and 5 mg; and 10 and 10 mg, respectively.
The particle size of atorvastatin may be used with d90 of less than approximately 200 µm. These size may be obtained either directly by the synthesis or by using conventional milling techniques, such as air jet milling, ball milling, cad milling, multi milling and other suitable size reduction techniques.
In an acidic environment atorvastatin degrades into corresponding lactone. It is further destabilized on contact with excipients, such as binders, diluents, and surfactants, when formulated in the form of tablets, powders or other dosage forms. So, the atorvastatin component may comprise stabilizing alkali metal salt additive selected from amongst one or more of sodium carbonate, sodium hydroxide, sodium silicate, disodium hydrogen orthophosphate, sodium aluminate and other suitable alkali metal salts. In particular, the stabilizing alkali metal salt additive may be selected from amongst sodium carbonate and disodium hydrogen orthophosphate, although the other alkali metal salt additives may also be selected. The alkali metal salt additive is present at a concentration of between approximately 1.2 % to less than about 5% by weight of the composition. Suitable alkaline metal salt additives such as calcium carbonate, calcium hydroxide, magnesium carbonate, magnesium hydroxide, magnesium silicate, magnesium aluminate, and aluminum magnesium hydroxide may also be used.
The term "pharmaceutically inert excipient" as used herein includes substances known in the art as diluents, binders, disintegrants, coloring agents, flavoring agents, stabilizers, surfactants, lubricants/glidants, plasticizers and preservatives for pharmaceutical compositions. The excipients are selected based on the desired physical aspects of the final composition; e.g., obtaining a tablet with desired hardness and friability, being rapidly dispersible and easily swallowed, etc.
Examples of disintegrants include sodium starch glycolate, croscarmellose sodium, crospovidone, low substituted hydroxypropyl cellulose, and the like.
Examples of binders include methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, and the like.
Examples of diluents include cellulose powdered, microcrystalline cellulose, dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, starch pregelatinized, sucrose, sugar compressible, sugar confectioners, and the like.
Examples of lubricants and glidants include magnesium stearate, sodium stearyl fumarate, colloidal anhydrous silica, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, and the like.
Examples of surfactants include both non-ionic and ionic (Cationic, Anionic and Zwitterionic) surfactants suitable for use in pharmaceutical compositions. These include polyethoxylated fatty acids and its derivatives, for example polyethylene glycol 400 distearate, polyethylene glycol - 20 dioleate, polyethylene glycol 4 -150 mono dilaurate, polyethylene glycol -20 glyceryl stearate; alcohol - oil transesterification products, for example polyethylene glycol -6 corn oil; polyglycerized fatty acids, for example polyglyceryl - 6 pentaoleate; propylene glycol fatty acid esters, for example propylene glycol monocaprylate; mono and diglycerides, for example glyceryl ricinoleate; sterol and sterol derivatives, for example sitosterol; sorbitan fatty acid esters and its derivatives, for example polyethylene glycol - 20 sorbitan monooleate, sorbitan monolaurate; polyethylene glycol 8 alkyl ether or phenols, for example polyethylene glycol - 20 cetyl ether, polyethylene glycol 10 - 100 nonyl phenol; sugar esters, for example sucrose monopalmitate; polyoxyethylene polyoxypropylene block copolymers known as "poloxamer"; ionic surfactants, for example sodium caproate, sodium glycocholate,
soy lecithin, sodium stearyl fumarate, propylene glycol alginate, octyl sulfosuccinate disodium, palmitoyl carnitine; and the like.
Examples of plasticizers include polyethylene glycol, triethyl citrate, triacetin, diethyl plithalate, dibutyl sebacate and the like.
Examples of stabilizers include antioxidants, buffers, alkalizers, chelating agents and the like.
The pharmaceutically acceptable antioxidants may be selected from amongst one or more of those suitable antioxidants known in the art. Examples of suitable pharmaceutically acceptable antioxidants include, but are not limited to, butylated hydroxyanisole (BHA), sodium ascorbate, butylated hydroxytoluene (BHT), sodium sulfite, citric acid, malic acid, and ascorbic acid.
The chelating agents may be selected from amongst one or more of those suitable chelating agents known in the art. Examples of suitable chelating agent includes, but is not limited to disodium edetate (EDTA). The chelating agents are present at a concentration of up to approximately 5% by weight of the formulations.
The pharmaceutical composition may be provided in the form of capsules wherein atorvastatin composition in the form of tablets, minitablets, or pills and ramipril in the form of the powder or granules or vice versa.
In another embodiment, there is provided a process for the preparation of a capsule composition comprising atorvastatin and ramipril or pharmaceutically acceptable salts thereof comprising the steps of
a) blending atorvastatin, with one or more pharmaceutically inert excipients;
b) optionally granulating the blend of step a,
c) lubricating the blend or granules of step b,
d) compressing the lubricated blend of step c into suitable size tablet,
e) blending ramipril and one or more pharmaceutically inert excipients;
f) filling the atorvastatin tablet and ramipril powder blend into a capsule.
The granulation could be carried out by wet or dry granulation. The tablets may also be prepared by direct compression process.
The tablets as described above may have an additional non-functional coating such as polyethylene glycol or Opadry or opadry AMB (aqueous moisture barrier).
Examples of coloring agents include any FDA approved colors for oral use.
Coating may be performed by applying one or more film forming polymers, with or without other pharmaceutically inert excipients, as a solution/suspension using any conventional coating technique known in the art, such as spray coating in a conventional coating pan or fluidized bed processor; or dip coating.
The following examples illustrate the invention but should not be construed as limiting the scope of the invention.
EXAMPLE 1

(TABLE REMOVED)
ATORVASTATIN TABLETS
1. Sift Atorvastatin Calcium, part of Croscarmellose Sodium & colloidal anhydrous silica, part of microcrystalline cellulose, sodium lauryl sulphate & Hydroxypropyl cellulose- L were sifted.
2. Sodium carbonate & the remaining quantity of microcrystalline cellulose were milled together.
3. Butylated hydroxyanisole & Butylated hydroxytoluene was dissolved in Isopropyl alcohol & filter through nylon cloth.
4. A part of lactose was sifted and granulated with solution of step 3. The granules were then dried.
5. Remaining quantity of Croscarmellose sodium & Colloidal anhydrous silica were sifted with remaining quantity of lactose.
6. The material of step 1 & step 2 was blended and added to the material of step 4 & step 5 & again mixed.
7. Magnesium Stearate was sifted and added to the material of step 6 & mixed.
8. The blend of step 7 was compressed into tablets.
9. The tablets were film coated with aqueous dispersion of Opadry.
RAMIPRIL BLEND
1. Ramipril and pregelatinized starch were mixed together.
CAPSULE FILLING
Each capsule was filled with a tablet of Atorvastatin 10 mg along with 160 mg of the Ramipril blend.
In vitro dissolution study
In vitro release of atorvastatin and ramipril capsules as per composition of example 1 was done in 900 ml phosphate buffer (pH 6.8) in USP type I apparatus at a basket speed of 100 rpm. The results are shown in table 1.
Table 1: Drug release profile of Atorvastatin and ramipril capsules.
(TABLE REMOVED)

WE CLAIM:
1. A once day capsule composition comprising atorvastatin and ramipril or pharmaceutically acceptable salts thereof wherein atorvastatin component is in tablet form and ramipril component is in granule or powder blend form.
2. A once day capsule composition comprising atorvastatin and ramipril or pharmaceutically acceptable salts thereof wherein atorvastatin component is in granule or powder blend form and ramipril component is in tablet form.
3. A once day capsule composition comprising atorvastatin and ramipril or pharmaceutically acceptable salts thereof wherein atorvastatin component and ramipril component are in tablet form.
4. The composition according to claim 1-3 wherein tablet includes tablet, minitablet, or pills.
5. The composition according to claim 4 wherein tablet is film coated.
6. The composition according to claims 1-3 wherein pharmaceutically acceptable salts of atorvastatin include atorvastatin calcium, atorvastatin magnesium, atorvastatin aluminum, atorvastatin iron, and atorvastatin zinc or an adjunct salt of atorvastatin & ramipril.
7. The composition according to claims 1-3 wherein atorvastatin may exist in any of the solid state forms selected from the group consisting of amorphous, crystalline and any polymorphic form.
8. The composition according to claims 1-3 wherein atorvastatin or pharmaceutically acceptable salt thereof is present in dosage range of 10-80 mg equivalent to atorvastatin and ramipril or pharmaceutically acceptable salt thereof ranges from 2.5-20 mg equivalent to ramipril.
9. The composition according to claims 1-3 wherein composition further comprises one or more pharmaceutically acceptable excipients selected from the group comprising metal salt additive, buffers, diluents, surfactants, antioxidants, disintegrants, binders, lubricants, glidants and chelating agents.
10. The composition according to claims 9 wherein atorvastatin component comprises metal salt additive, surfactant and antioxidant.
11. The composition according to claim 10 wherein metal salt additive is selected from alkali or alkaline metal salt additive selected from the group consisting sodium carbonate, sodium hydroxide, sodium silicate, disodium hydrogen orthophosphate, sodium aluminate; and calcium carbonate, calcium hydroxide, magnesium carbonate,
magnesium hydroxide, magnesium silicate, magnesium aluminate, and aluminum magnesium hydroxide, respectively.
12. The composition according to claim 9 wherein ramipril component comprises buffers.
13. The composition according to claim 1 wherein the composition is prepared by the process comprising the steps of:

a) preparing atorvastatin tablet
b) preparing ramipril powder blend/granule
c) filing atorvastatin tablet and ramipril powder blend/granule into capsules.
14. The composition according to claim 2 wherein the composition is prepared by the
process comprising the steps of:
a) preparing atorvastatin powder blend/granule
b) preparing ramipril tablet
c) filing atorvastatin powder blend/granule and ramipril tablet into capsules.
15. The composition according to claim 3 wherein the composition is prepared by the
process comprising the steps of:
a) preparing atorvastatin tablet
b) preparing ramipril tablet
c) filing atorvastatin and ramipril tablet into capsules.

16. The composition according to claim 13-15 wherein the tablet is prepared by direct compression, wet or dry granulation.
17. The composition according to claim 13-15 wherein the granules are prepared by wet or dry granulation.
18. Use of capsule composition as defined in any of the preceding claims for the treatment of cardiovascular disorders such as hypertension and hypercholesterolemia
19. A once a day capsule composition comprising atorvastatin and ramipril as herein described.