EP2588102A1

EP2588102A1 - New dosage forms for treatment of cardiovascular diseases

Info

Publication number: EP2588102A1
Application number: EP11746335.6A
Authority: EP
Inventors: Mahmut Bilgic
Original assignee: Individual
Current assignee: Individual
Priority date: 2010-06-30
Filing date: 2011-06-29
Publication date: 2013-05-08
Also published as: WO2012002920A1; EP2588103A1; WO2012011882A1; TR201005325A2; WO2012002919A1

Abstract

The present invention relates to dosage forms comprising effective amounts of aspirin and atorvastatin or their pharmaceutically acceptable salts, hydrates, enantiomers, racemates, organic salts, inorganic salts, esters, polymorphs, crystal forms and amorphous forms and/or combinations thereof; and to dosage forms comprising combinations thereof.

Description

NEW DOSAGE FORMS FOR TREATMENT OF CARDIOVASCULAR DISEASES

The present invention relates to dosage forms comprising effective amounts of aspirin and atorvastatin or their pharmaceutically acceptable salts, hydrates, enantiomers, racemates, organic salts, inorganic salts, esters, polymorphs, crystal forms and amorphous forms and/or combinations thereof.

The Prior Art

Cardiovascular disease is one of the leading causes of death in the world and one of the most significant factors for these diseases is total/high density lipoprotein (HDL) cholesterol level. However, recent developments have indicated that only taking the cholesterol level under control is not sufficient for cardiovascular treatment. In line with this need, researchers have found that use of some active agents in combination provides a more effective treatment method.

In the prior art, it is disclosed that cardiovascular diseases such as atherosclerosis, heart attack, angina pectoris arise from increase in lipid levels in blood; however, another factor called "thrombosis" plays an important role in nervous system diseases accompanying these such as stroke, paralysis. Thrombosis means obstruction of blood vessels in consequence of formation of a blood clot in the blood vessels. This obstruction may occur in any part of the body. Due to the obstruction, blood flow through the target organ gets slower and it may completely stop in advanced stages. Rarely, this clot obstructs brain vessels and causes brain hemorrhage or obstruction of heart veins, in other terms coronary infarction. Formation of thrombosis in brain or blood veins going to the brain generally leads to fatal results.

To this respect, it is important to eliminate thrombosis and the factors leading to thrombosis in addition to lowering cholesterol level in blood in the effective treatment of cardiac diseases.

One of the drugs commonly used in the treatment and prevention of thrombosis is aspirin. Although aspirin, chemical name of which is 2-(acetyloxy)benzoic acid, has been used as an analgesic and antipyretic drug for more than 100 years, it has been pointed out in recent years that use of aspirin in low doses reduces platelet formation and therefore prevents thrombosis. It is known that use of 20-40 mg aspirin once a day prevents formation of thrombosis.

This anti-platelet effect of aspirin enables it to take part in the treatment and prevention of most cardiac diseases. Atorvastatin is a hypolipidemic drug used as a HMG-CoA reductase enzyme inhibitor as the other statins. Distinctly from other drugs in this group, it is the only drug having the indication of lowering both the increased LDL cholesterol and triglyceride levels in patients with hypercholesterolemia. In various publications, it is suggested that atorvastatin is more effective than other HMG CoA reductase enzyme inhibitors when used in recommended doses:

- Nawrocki JW, Weiss SR, Davidson MH et al. Reduction of LDL cholesterol by 25% to 60% in patients with primary hypercholesterolemia by atorvastatin, a new HMG- CoA reductase inhibitor. Arterioscler Thromb Vase Biol 1995 ; 15: 678-82.

- Bakker- Arkema RG, Davidson MH, Goldstein RJ et al. Efficacy and safety of a new HMG-CoA Reductase inhibitor, atorvastatin, in patients with hypertriglyceridemia. JAMA 1996; 257:128-33.

Atorvastatin lowers LDL cholesterol levels by 60%; when administered in low doses, such as 2.5 mg/day, it displays activity at recommended routine level of other HMG CoA reductase enzyme inhibitors. While atorvastatin lowers the triglyceride levels in patients with hypercholesterolemia by 45%, it may raise HDL cholesterol level at 12%. It was disclosed in the tricentric double-blind study conducted with patients having hypercholesterolemia that atorvastatin lowers total cholesterol, LDL cholesterol, apolipoprotein B and triglyceride levels compared with lolvastatin, pravastatin and simvastatin.

It is well known that aspirin use reduces the risk of contracting cardiovascular diseases such as myocardial infarction and similarly, statin group active agents are effective in prevention and treatment of cardiovascular, cerebrovascular diseases (Ridker PM, Cushman M, Stampfer MJ et al. Inflammation, aspirin, and the risk of cardiovaskuler disease apparently healthy in men. NengJMed 1997; 336:973-9).

Use of aspirin and statin group active agents in combination is known to decrease mortality rates of cardiovascular diseases. Hennekens et. al. attested that aspirin reduces the risk of contracting cardiovascular diseases by 24% averagely in comparison with statin treatment only. In parallel with this, statin treatment alone reduces the same risk by 13% in comparison with aspirin treatment (Hennekens CH, Sacks FM, Tonkin A, Jukema JW, Byington RP, Pitt B, Berry DA, Berry SM, Ford NF, Walker AJ, Natarajan K, Sheng-Lin C, Fiedorek FT, Belder R: Additive benefits of pravastatin and aspirin to decrease risks of cardiovascular disease: randomized and observational comparisons of secondary prevention trials and their metaanalyses. Arch Intern Med 164:40-44, 2004).

However, many problems are encountered in formulation of aspirin and statin group active agents together, the most important ones of which are low bioavailability and chemical degradation. As it is known, aspirin is an active agent with weak acidic features while most of the statins are basic active agents used in their salt forms. Therefore, formulation of the two active agents together causes the statins to be degraded and their bioavailability to decrease.

In the prior art, there exist various approaches for formulation of the two active agents together.

In the patent numbered US 6235311, pharmaceutical formulations comprising a statin group active agent and aspirin are disclosed. In the treatment proposed in the patent, the active agents are formulated as bilayer tablets. However, combination products produced in bilayer dosage forms carry the risk of failure to prevent interaction of the active agents with each other. In this case, the product may be disintegrated during its shelf life and the patient may not realize that. This may result in serious complications in the patient. To this end, the dosage form disclosed in the patent is not a good choice for products having high potential to interact such as atorvastatin and aspirin.

The application numbered EP 1581194 relates to multilayer tablet dosage form comprising pravastatin and aspirin as the active agents. In said application, the layers comprising the active agents are separated by a barrier layer in order to impede their interaction. However, it is quite inconvenient to produce this type of tablet formulations and it is not certainly known if the barrier layer would maintain its effect during the shelf life of the tablet dosage form.

As can be seen in the examples above; stable and user friendly formulations of atorvastatin and aspirin which are formulated so as to provide sufficient active agent stability and impede the interaction of the active agents completely; and have long shelf life have not been referred in the prior art. Detailed Description of the Invention

The present invention relates to dosage forms comprising effective amounts of atorvastatin and aspirin or their pharmaceutically acceptable salts, hydrates, enantiomers, racemates, organic salts, inorganic salts, esters, polymorphs, crystalline or amorphous forms and/or combinations thereof.

The dosage forms according to the present invention are obtained by formulating the two active agents separately and then combining them in a compact dosage form. Multiple dosage forms which are prepared by combining separate dosage forms in a single, compact dosage form has reduced the interaction of the two active agents both with each other and with other pharmaceutically acceptable excipients. Hence, the problems of the active agent have been efficiently solved and the efficiency of the combined drug has been improved.

In general, multiple dosage forms are more advantageous compared to single dosage forms such as pellets, micro tablets, granules, coated tablets. Multiple dosage forms are dispersed in gastrointestinal tract homogeneously and transmitted from the stomach to the intestines. Both the effective dispersion of the active agents in the stomach is ensured and the bioavailability is improved this way. Multiple dosage forms are also advantageous as they can be formulated such that they enable different release characteristics of the two active agents.

Multiple dosage forms of the present invention are composed by combining one or more unit dosage forms preferably in a capsule. These unit dosage forms can be in granule, powder, pellet, tablet, mini tablet, micro tablet, capsule, micro capsule form and/or combinations thereof.

The multiple dosage form preferred according to the present invention is obtained by combining micro tablet, granule, powder and/or pellet formulations comprising atorvastatin calcium with tablet formulations comprising aspirin in a capsule preferably made of soft gelatin. Tablet formulations of aspirin of the present invention are preferably enterically coated.

However, during the stability studies of the multiple dosage form comprising atorvastatin and aspirin that he developed, the inventor has found that the dosage form incurs chemical degradation which becomes apparent with yellowing. The reason for degradation of the dosage form is that the enteric coating layer reacts with the layer comprising the active agents in aspirin tablet formulations which are enterically coated as aspirin causes stomach problems.

As a result of the reaction between the enteric coating layer and aspirin, acetic acid is produced. With this undesired reaction, acetic acid produced also reacts with the atorvastatin formulation in the multiple dosage form and hence the stability of these formulations decrease in addition that the amount of aspirin in the dosage is reduced.

In consequence of the stability studies conducted, it has been concluded that triethyl citrate comprised in the enteric coating material reacts with aspirin and as a result, the dosage form incurs chemical degradation which becomes apparent with yellowing.

Consequently, sufficient stability of the combined product cannot be ensured during its shelf life.

As a solution to this problem, the inventor has coated the tablet formulations comprising aspirin with a sub-coating before the enteric coating layer. The tablet formulations of aspirin of the present invention are composed of an active agent layer comprising an effective amount of aspirin, a pharmaceutically acceptable filling material, a binder, a disintegrant and at least one lubricant; a sub-coating layer on said active agent layer; and finally an enteric coating layer.

A characteristic feature of said sub-coating layer is that the coating material comprises a cellulose derivative coating agent and talc.

Another characteristic feature of said sub-coating layer is that the coating material comprises at least 70%, preferably in the range of 70-90% of a cellulose derivative coating agent by weight; and at least 10%, preferably in the range of 10-30% talc by weight.

Another characteristic feature of said sub-coating layer is that the ratio of the cellulose derivative coating material to talc by weight is in the range of 1 to 30; preferably in the range of 1 to 25, more preferably in the range of 1 to 20, even more preferably in the range of 1 to 15. They have found that the sub-coating obtained by using the sub-coating agents in the amounts specified above ensures both the rubbing away of the tablets at the minimum level during enteric coating and hence providing tablet stability; and improving the release characteristics.

The cellulose derivative coating material comprised in the sub-coating of the present invention is selected from a group comprising hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, hydroxypropyl methyl cellulose phthalate or combinations thereof.

Content of enteric coating material plays a role in providing sufficient stability of formulations of the present invention. To this end, enteric coating material has been chosen carefully in order to hinder the potential interaction of the enteric coating material with the sub-coating material in the multiple dosage forms produced in scope of the present invention.

The enteric coating material of the present invention comprises at least one release rate determinant polymer, at least one plasticizer agent and at least one other pharmaceutically acceptable excipient. The release rate determinant polymers used in the enteric coating material of formulations of the present invention can be selected from methacrylic copolymers, for instance methacrylic acid/methyl methacrylate, methacrylic acid/ethyl acrylate copolymers, methacrylic acid/methyl acrylate/methyl methacrylate copolymers, shellac, hydroxypropyl methylcellulose phthalate, hydroxyl propyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose trimellitate, cellulose acetate phthalates, polyvinyl acetate phthalates or combinations thereof. The release rate determinant polymer is comprised in the range of 1- 30%, preferably in the range of 1-20%, more preferably in the range of 1-15% of the total weight of the unit dose.

The plasticizer agent used in the enteric coating material of the present invention is triacetyl citrate and it is in the range of 0.1-5%, preferably in the range of 0.1-3%, more preferably in the range of 0.1-1% by weight in proportion to the total weight of the unit dose.

The enteric coating material of the present invention comprises at least one other pharmaceutically acceptable excipient in addition to the ones listed above. Said excipients can be opacifying agents (for instance, titanium dioxide), anti-adhesive substances (for instance talc), filling materials, lubricants etc. The amount of aspirin used in the formulations of the present invention is approximately in the range of 1-500 mg., preferably approximately in the range of 1-300 mg., more preferably approximately in the range of 1-150 mg. per unit dosage form.

Atorvastatin formulations of the present invention are in the form of micro tablet, granule, powder and/or pellet form and they comprise an effective amount of atorvastatin calcium, at least one pharmaceutically acceptable filling material, at least one binder, at least one disintegrant, at least one diluent, at least one surfactant, at least one buffer substance and at least one other excipient.

"Atorvastatin" used in the formulations of the present invention is preferably atorvastatin calcium and it is preferably in crystalline form polymorphically.

One feature of the multiple dosage forms of the present invention is that said forms comprise atorvastatin calcium in micro tablet, granule, powder and/or pellet form; and aspirin in tablet form.

Another feature of the multiple dosage forms of the present invention is that aspirin tablet formulations are enterically coated and there is a sub-coating between the enteric coating and the active agent layer comprising aspirin.

Pharmaceutically acceptable excipients used in the atorvastatin and aspirin formulations of the present invention are selected from binders, disintegrants, viscosity enhancing components, filling materials, drying agents, lubricants, buffer substances, diluents, binders, glidants, wetting agents, coating agents designed so as to provide various release characteristics, anti-adhesive agents, solvents, sweeteners or combinations thereof.

The buffer substances of the present invention are either water-soluble or water-insoluble and selected from a group comprising meglumine, tromethamol, sodium bicarbonate, sodium carbonate, sodium citrate, calcium gluconate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium tartrate, sodium acetate, calcium glycerophosphate, tromethamine, magnesium oxide, magnesium hydroxide, aluminum hydroxide, dihydroxy aluminum, sodium carbonate, calcium carbonate, aluminum carbonate, dihydroxy aluminum amino acetate, diethanolamine, triethanolamine, N-methyl-glucamine, glucosamine, ethylenediamine, triethyleneamine, isopropylamine, di-isopropyl amine or combinations thereof. The filling agents used in the present invention comprise one or more components selected from the group comprising lactose, sugar, starch, modified starch, corn starch, mannitol, sorbitol, inorganic salts, microcrystalline cellulose, cellulose, calcium sulfate, xylitol and lactitol and/or pharmaceutically acceptable hydrates thereof.

The filling material used in the atorvastatin formulations is preferably lactose and/or a pharmaceutically hydrate or anhydrate thereof. The disintegrant used in the present invention enables the dosage form to disperse in water easily and rapidly, and it is significant from this aspect. The disintegrants can be selected from a group comprising polymers having high dispersing characteristics such as cross-linked hydroxypropyl cellulose, polyvinylpyrrolidone, high molecular weight polymers, microcrystalline cellulose, sodium starch glycolate, croscarmellose sodium, povidone; the products known under the trademarks Crospovidone®, Polyplasdone® or colloidal silicon dioxide, alginic acid, sodium alginate, corn starch.

The surfactants used in the present invention are selected from a group comprising hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, vinyl acetate, sodium lauryl sulfate, dioctyl sulfosuccinate, gelatin, casein, lecithin, dextran, sorbitan esters, polyoxy ethylene alkyl ethers, polyethylene glycols, polyethylene stearates, collodial silicon dioxide, phosphates, carboxymethyl cellulose calcium, carboxy methyl cellulose sodium, triethanolamine, polyvinyl alcohol, hydroxy propyl methyl cellulose phthalate.

The anti-adhesive agents of the present invention are used in order to prevent the mixture comprising active agents to adhere onto device and machine surfaces and create rough surfaces. The substances used for this purpose comprise one or more components selected from a group comprising talc, colloidal silicone dioxide (Aerosil, Syloid, Cab-OSil), magnesium stearate and corn starch.

The binders used in the present invention comprise one or more components selected from a group comprising potato, wheat or corn starch; microcrystalline cellulose, for instance Avicel®, Filtrak®, Heweten® or Pharmacel®; hydroxypropyl cellulose, hydroxyethyl cellulose; hydroxypropylmethyl cellulose, for instance hydroxypropylmethyl cellulose-type 2910 USP; hypromellose and polyvinylpyrrolidone, for instance Povidone® K30(BASF), lactose, guar gum, pectin, gelatin, sodium alginate. The lubricants used in the present invention comprise one or more components selected from a group comprising metallic stearates (such as magnesium stearate, calcium stearate, aluminum stearate), fatty acid esters (such as sodium stearyl fumarate), fatty acids (such as stearic acid), fatty alcohol, glyceryl behenate, mineral oil, paraffins, hydrogenated vegetable oil, leucine, polyethylene glycols (PEG), metallic lauryl sulfate (such as sodium lauryl sulfate, magnesium lauryl sulfate), sodium chloride, sodium benzoate, sodium acetate, talc, siliconized talc and/or hydrates thereof.

The diluents used in the present invention comprise one or more components selected from a group comprising alkali metal carbonates, cellulose derivatives (microcrystalline cellulose, cellulose acetate, etc.), dextrin, fructose, dextrose, glyceryl palmitostearate, lactitol, lactose, direct compression lactose, maltose, mannitol, simethicone, sorbitol, starch, talc, xylitol and/or hydrates thereof and/or derivatives thereof.

Pharmaceutically acceptable carriers of the present invention can be selected from a group comprising polyether glycols, polypropylenes, xylitol, sorbitol, potassium sodium tartrate, sucrose tribehenate, glucose, lactitol, behenic acid, hydroquinone, monomethyl ether, sodium acetate, ethyl fumarate, myristic acid, citryl acid, saturated hydrocarbons, paraffins, sorbitan esters, fats, waxes, polyvinylpyrrolidone polymers, acrylic polymers and/or mixtures thereof.

The formulations according to the present invention can optionally be formulated so as to provide different release characteristics. The release rate determinant polymers that can be used in the formulations in order to provide the required release characteristics can be pH- dependant polymers, non pH-dependant polymers, swellable polymers, non-swellable polymers, hydrophilic polymers, hydrophobic polymers and/or one or more hydrophobic substances; ionic polymers such as sodium alginate, carbomer, calcium carboxy methyl cellulose or carboxy methyl cellulose; non-ionic polymers such as hydroxy propyl methyl cellulose; natural or/synthetic polysaccharides such as alkyl celluloses, hydroxyl alkyl celluloses, cellulose ethers, nitrocellulose, dextrin, agar, carrageenan, pectin, starch and starch derivatives or mixtures thereof; cellulosic polymers; methacrylate polymers, methacrylate copolymers, polyvinylpyrrolidone, polyvinylpyrrolidone-polyvinyl acetate copolymer, ethyl cellulose, cellulose acetate, cellulose propionate (high, medium and low molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, polyvinyl acetate, polyvinyl chloride. The solvents used in preparation of the formulations of the present invention comprise one or more components selected from a group comprising water, toluene, benzene, acetone, methyl acetate, tetrahydrofurane, heptane, hexane, acetonitrile; alcohol, for instance ethanol, methanole, isopropyl alcohol, butanol; and/or alcohol mixtures.

Atorvastatin and aspirin formulations of the present invention can be prepared by any one of the methods existing in the prior art such as wet granulation, dry granulation, dry blending. The tablet formulations of aspirin of the present invention are preferably prepared by the following preparation method:

I. An effective amount of aspirin, at least one pharmaceutically acceptable binder, at least one disintegrant, at least one other excipient are blended dryly. The dry mixture is treated with a pharmaceutically acceptable lubricant and tablets are compressed, II. A cellulose derivative coating agent and talc are dissolved in deionized water for preparation of sub-coating solution. The aspirin tablets obtained in the first step are coated with this sub-coating solution,

III. The tablets obtained in the second step are coated with enteric coating and the dosage form is finalized. Enterically coated tablet formulations prepared this way are combined with atorvastatin calcium formulations produced according to one of the unit dosage forms given in scope of the present invention in a capsule preferably made of soft gelatin.

Examples belonging to the formulations of the present invention are given below. Formulations of the present invention are not limited to these examples.

EXAMPLES

1. Multiple dosage form composed of powder formulation of atorvastatin and enterically coated tablet formulation of aspirin

Multiple dosage form composed of pellet formulation of atorvastatin and enterically coated tablet formulation of aspirin

Claims

1. A multiple dosage form comprising atorvastatin calcium in micro tablet, granule powder or pellet form and aspirin in tablet form characterized in that aspirin tablets are enterically coated and there is a sub-coating layer between the enteric coating and the layer comprising aspirin as the active agent.

2. The tablet formulation comprising aspirin as the active agent according to claim 1 characterized in that said formulation is composed of an active agent layer comprising an effective amount of aspirin, a pharmaceutically acceptable filling material, a binder, a disintegrant and at least one lubricant; a sub-coating on the active agent layer; and finally an enteric coating layer.

3. The tablet formulation comprising aspirin according to claim 1 characterized in that the coating material constituting the sub-coating layer comprises a cellulose derivative coating agent and talc.

4. The tablet formulation comprising aspirin according to claim 3 characterized in that the coating material constituting the sub-coating layer comprises at least 70%, preferably in the range of 70-90% of a cellulose derivative coating agent by weight.

5. The tablet formulation comprising aspirin according to claim 4 characterized in that the cellulose derivative coating agent is selected from a group comprising hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, hydroxypropyl methyl cellulose phthalate or combinations thereof.

6. The tablet formulation comprising aspirin according to claim 3 characterized in that the coating material constituting the sub-coating material comprises at least 10%, preferably 10-30% talc by weight.

7. The tablet formulation comprising aspirin according to claim 3 characterized in that the ratio of the cellulose derivative coating agent to talc is in the range of 1 to 30 by weight.

8. The tablet formulation comprising aspirin according to claim 7 characterized in that the ratio of the cellulose derivative coating agent to talc is in the range of 1 to 25 by weight.

9. The tablet formulation comprising aspirin according to claim 8 characterized in that the ratio of the cellulose derivative coating agent to talc is in the range of 1 to 15 by weight.

10. The tablet formulation comprising aspirin according to claim 1 characterized in that the enteric coating material comprises at least one release rate determinant polymer, at least one plasticizer agent and at least one other pharmaceutically acceptable excipient.

11. The tablet formulation comprising aspirin according to claim 1 characterized in that the release rate determinant polymer in the enteric coating material is selected from a group comprising methacrylic acid/methyl methacrylate, methacrylic acid/ethyl acrylate copolymers, methacrylic acid/methyl acrylate/methyl methacrylate copolymers, shellac, hydroxypropyl methylcellulose phthalate, hydroxyl propyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose trimellitate, hydroxylpropyl methyl cellulose phthalate, cellulose acetate phthalates, polyvinyl acetate phthalates or combinations thereof.

12. The tablet formulation comprising aspirin according to claim 10 characterized in that the plasticizer agent existing in the enteric coating material is triethyl citrate.

13. The tablet formulation comprising aspirin according to claim 12 characterized in that the enteric coating material comprises triethyl citrate in the range of 0.1-5% in proportion to the weight of unit dosage form.

14. The tablet formulation comprising aspirin according to claim 13 characterized in that the enteric coating material comprises triethyl citrate in the range of 0.1-3% in proportion to the weight of unit dosage form.

15. The tablet formulation comprising aspirin according to claim 14 characterized in that the enteric coating material comprises triethyl citrate in the range of 0.1-1% in proportion to the weight of unit dosage form.

16. The method for preparation of the tablet formulation comprising aspirin according to claim 1 characterized in that said method comprises the steps that;

I. An effective amount of aspirin, at least one pharmaceutically acceptable binder, at least one disintegrant, at least one other excipient are blended dryly. The dry mixture is treated with a pharmaceutically acceptable lubricant and tablets are compressed;

II. A cellulose derivative coating agent and talc are dissolved in deionized water for preparation of sub-coating solution. The aspirin tablets obtained in the first step are coated with this sub-coating solution,

III. The tablets obtained in the second step are coated with enteric coating and the dosage form is finalized.

17. The formulations comprising atorvastatin calcium in micro tablet, granule, powder and or pellet form according to claim 1 characterized in that said formulations comprise an effective amount of atorvastatin calcium, at least one pharmaceutically acceptable filling material, at least one binder, at least one disintegrant, at least one diluent, at least one surfactant, at least one buffer substance and at least one other excipient.

18. The multiple dosage form according to claim 1 characterized in that said dosage form is obtained by combining atorvastatin calcium formulations in micro tablet, granule, powder and or pellet form and aspirin formulations in tablet form in a capsule preferably made of soft gelatin.