(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date . 5 January 2012 (05.01.2012) WO 2012/002919 Al

(51) International Patent Classification: AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, A61K 31/40 (2006.01) A61P 3/06 (2006.01) CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, A61K 31/60 (2006.01) A61P 9/10 (2006.01) DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, (21) International Application Number: KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, PCT/TR201 1/000161 ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, (22) International Filing Date: NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, 29 June 201 1 (29.06.201 1) SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every (26) Publication Language: English kind of regional protection available): ARIPO (BW, GH, (30) Priority Data: GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, 2010/05325 30 June 2010 (30.06.2010) TR ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (72) Inventor; and EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, (71) Applicant : BILGIC, Mahmut [TR/TR]; Tozkoparan LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, Mah. General Ali Riza Gurcan Cad. Merter Is, Merkezi SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, Bagimsiz Bolum No: 2/13 Merter/Istanbul, 34173 (TR). GW, ML, MR, NE, SN, TD, TG).

(74) Agent: ISCANI, Burcu; Tozkoparan Mah. General Ali Published: Riza Gurcan Cad. Merter Is, Merkezi Bagimsiz Bolum — with international search report (Art. 21(3)) No: 2/13, 34173 Merter/Istanbul (TR). (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM,

©o o- (54) Title: PHARMACEUTICAL FORMULATIONS COMPRISING ATORVASTATIN AND ASPIRIN (57) Abstract: The present invention relates to pharmaceutical compositions comprising aspirin and atorvastatin and/or pharma- ceutically acceptable salts, hydrates, enantiomers, racemates, organic salts, inorganic salts, esters, polymorphs, crystal forms and ¾ amorphous forms thereof and/or their combinations in order to be used in the treatment and prophylaxis of cardiovascular dis- eases. PHARMACEUTICAL FORMULATIONS COMPRISING ATORVASTATIN AND ASPIRIN

The present invention relates to pharmaceutical compositions comprising aspirin and atorvastatin and/or pharmaceutically acceptable salts, hydrates, enantiomers, racemates, organic salts, inorganic salts, esters, polymorphs, crystal forms and amorphous forms thereof and/or their combinations in order to be used in the treatment and prophylaxis of cardiovascular diseases.

The characteristic feature of the formulations of the patent is that said formulations are formulized and produced such that they provide to effectively solve the problems resulting from the interaction of the active agent with each other.

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 as well as 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 R 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. N eng J Med 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 meta¬ analyses. Arch Intern Med 164:40-44, 2004).

However, many problems are encountered when aspirin and statin group active agents are formulated 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 addition, another problem is that statin group active agents are susceptible to external factors such as humidity, light and they disintegrate easily. This poses serious obstacles in development of stable pharmaceutical formulations and combinations. Particularly, atorvastatin is transformed into lactone as a result of "intramolecular esterification" reaction which occurs between carboxylic acid in its structure and hydroxyl groups on β and δ carbons of this carboxylic acid. These reactions take place in acidic environment and basic agents cause the reaction to be reversed. Major degradation products (3R, 5S) produced as a result of disintegration of statins are lactones and oxidation products. This feature reduces the stability of atorvastatin and therefore shortens its shelf life.

Thus, this problem also needs to be resolved in order to obtain products which have sufficient stability and shelf life during preparation of formulations comprising aspirin which is a weak acid and atorvastatin which has disintegration potential in acidic environment.

In the prior art, there exist various documents on combined use of aspirin and statin group HMG-Co A reductase inhibitors. Some examples of these documents are as follows:

In the patent numbered US 623531 1, pharmaceutical formulations comprising a statin group active agent and aspirin are disclosed. In the treatment proposed in the patent, the active agents are formulized 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, insufficient dose intake or prolonged treatment. 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.

In the application numbered WO03020243, on the other hand, at least one cholesterol- lowering agent, at least one rennin-angiotensin converting enzyme inhibitor and aspirin combinations are disclosed.

The application numbered EP158 1194 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.

Description of the Invention

The present invention relates to pharmaceutical dosage forms comprising effective amounts of atorvastatin and aspirin and/or their pharmaceutically acceptable salts, hydrates, solvates, esters, amorphous or crystalline forms and/or mixtures thereof, and preparation of said dosage forms so as to be used in the treatment/prophylaxis of cardiovascular diseases.

The term "cardiovascular diseases" used here refers to hypercholesterolemia, atherosclerosis, coronary and cerebral diseases, for instance myocardial infarction, secondary myocardial infarction, myocardial ischemia, angina pectoris, congestive heart diseases, cerebral infarction, cerebral thrombosis, cerebral ischemia and temporary ischemic attacks.

The active agents in the formulations of the present invention are formulated separately and the unit dosage forms prepared with these formulations are presented as combined in a multi dosage form in order to eliminate interaction. It has been found that bioavailability of the formulations prepared as described is higher than the formulations and dosage forms in the prior art; atorvastatin that is one of the active agents of the formulations is chemically degraded less; therefore the final product has longer shelf life.

The formulations prepared according to the present invention comprise atorvastatin and aspirin in separate dosage forms. Unit dosage forms comprising atorvastatin and aspirin are combined in a single dosage form, preferably in a capsule and multi dosage forms of the present invention are obtained.

Preparation of the active agents separately as unit dosage forms with different physical features and contents reduced the interaction of said active agents both with each other and with other pharmaceutically acceptable excipients. Thus, problems of the active agents have been solved effectively and efficiency of the combined drug has been improved.

At the same time, complicated process steps that combining two active agents known in the prior art in a single dosage form brings about, for instance use of barrier layer, feeding the formulations to tablet compression machines form different feeding units, have been overcome with the use of multiple dosage forms.

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. 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.

Unit dosage forms of the present invention are preferably in tablet, micro tablet, granule, powder and/or pellet form and they have pharmaceutically similar contents as known tablet and capsule dosage forms. Unit dosage forms can be coated with protective coating, enteric coating, film coating and/or coatings that can enable different release characteristics afterwards. The invention further comprises various coating materials and pharmaceutically acceptable excipients in addition to effective amounts of atorvastatin and aspirin in the form of tablet, micro tablet, granule, powder and/or pellet contained in gelatin capsules.

Multiple dosage form of the present invention is preferably composed of micro tablet and pellet or micro tablet and powder or tablet and powder formulations.

Micro tablet or tablets comprise effective amounts of aspirin, at least one pharmaceutically acceptable filling material, binder, disintegrant, coating material and at least one other excipient; powder or pellets comprise effective amounts of atorvastatin calcium, at least one pharmaceutically acceptable filling material, binder, disintegrant, diluent, surfactant, buffer substance and at one other excipient.

The term "micro tablet" used throughout the text refers to tablets, round ones of which have a radius smaller than 10 mm or the longest one of which is smaller than 10 mm.

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

The amount of aspirin used in the formulations of the present invention is approximately in the range of 1-500 mg, preferably in the range of 1-300 mg, more preferably in the range of 1- 150 mg per dose.

The amount of atorvastatin used in the formulations of the present invention is approximately in the range of 1-200 mg, preferably in the range of 1-150 mg, more preferably in the range of 1-100 mg per dose.

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

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, 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 buffer substance used in the formulations is preferably a water-soluble amine group substance, preferably tromethamol or meglumine.

During the development of said formulations, the inventors have found that stability of the formulation is increased in the case that a water-soluble amine group substance is used in the atorvastatin formulation as the buffer substance. The amount of the buffer substance preferred in the formulations of the present invention is in the range of 0.1% to 80%, preferably in the range of 0.1% to 50%, more preferably in the range of 0.1% to 25% by weight.

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 acceptable hydrate, for instance monohydrate form 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.

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. It has been observed that impurities resulting from chemical degradation of atorvastatin are lower when a surfactant is used in the atorvastatin formulation in the formulations of the present invention.

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.

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.

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.

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. Release rate determinant polymers that can be used in the formulations of the present invention 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.

Film coating material of the present invention can be following components and/or combinations thereof: lactose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, triacetine, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate phthalate, polyvinyl acetate phthalate, diethyl phthalate, sugar derivatives, polyvinyl derivatives, waxes, fats and gelatins, triethyl citrate, glyceride, titanium oxide, talc, sodium alginate, stearic acid, lecithin.

Solvents used in the present invention comprise one or more components selected from a group comprising toluene, benzene, acetone, methyl acetate, tetrahydrofurane, heptanes, hexane, acetonitrile, alcohol and/or alcohol mixtures.

Aspirin used in the formulations of the present invention is mostly formulated as enteric coated since it leads to stomach diseases in long-term use due to its acidic chemical structure. Enteric coating does not dissolve in acidic environment; it generally dissolves in 5-7.5 pH. Enteric coated dosage forms administered to the patient are transmitted to the intestines without dissolving in the stomach; dissolve in the intestines and release the active agent there.

Optionally only one or both of the unit dosage forms comprising the formulations of the present invention can be coated with enteric coating.

Coating materials that can be used in enteric coating of said dosage forms 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.

Enteric coating material is preferably 1-30% of total weight of unit dosage form.

Formulations of the present invention can optionally be coated with a sub-coating before being coated with enteric coating. Sub-coating materials can be selected from lactose, microcrystalline cellulose, hydroxypropyl methyl cellulose, starch, calcium phosphate, calcium carbonate, talc, lecithine, titanium dioxide, croscarmellose sodium, crospovidone or combinations thereof.

Sub-coating material is preferably in the range of 0.1-20% of total weight of unit dosage form.

Formulations of the present invention can be prepared by any one of the methods of dry blending, wet granulation, dry granulation in the prior art.

According to the proposed production method, aspirin micro tablets and atorvastatin pellets are prepared according to wet granulation method.

According to another proposed method, on the other hand, aspirin tablet and atorvastatin powder formulations are prepared by dry blending method and aspirin tablets are coated with enteric coating.

Unit dosage forms prepared this way are preferably presented as combined in a capsule made of soft gelatin.

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

Example 1.

Micro tablet and pellet formulations prepared according to prescription of the formulation given above are filled into a capsule made of soft gelatin. Example 2.

Tablet and powder formulations prepared according to prescription of the formulation given above are filled into a capsule made of soft gelatin. Example 3.

Tablet and powder formulations prepared according to prescription of the formulation given above are filled into a capsule made of soft gelatin. CLAIMS

1. A pharmaceutical formulation comprising atorvastatin and aspirin or salts, hydrates, enantiomers, racemates, organic salts, inorganic salts, esters, polymorphs, crystal forms and amorphous forms and/or combinations thereof as the active agents characterized in that said formulation is produced in multiple dosage form. 2. The formulation according to claim 1 characterized in that the multiple dosage form is composed of unit dosage forms such as capsule, tablet, mini tablet, micro tablet, micro capsule, granule, pellet and/or powder. 3. The formulation according to claim 2 characterized in that the unit dosage forms are composed of micro tablet and pellet forms. 4. The formulation according to claim 2 characterized in that the unit dosage forms are composed of micro tablet and powder forms. 5. The formulation according to claim 2 characterized in that the unit dosage forms are composed of tablet and powder forms. 6. The formulation according to claims 2-5 characterized in that tablet or micro tablet formulations comprise effective amounts of aspirin, at least one pharmaceutically acceptable filling material, binder, disintegrant, coating material and at least one other excipient. 7. The formulation according to claim 6 characterized in that the amount of aspirin that said formulation comprises is in the range of 1-500 mg, preferably 1-300 mg, more preferably 1-150 mg per dose. 8. The formulation according to claim 7 characterized in that the dosage forms are enteric-coated. 9. The formulation according to claims 2-5 characterized in that pellet or powder formulations comprise effective amounts of atorvastatin calcium, at least one pharmaceutically acceptable filling material, binder, surfactant, disintegrant, diluent, buffer substance and at least one other excipient. 10. The formulation according to claim 9 characterized in that the amount of atorvastatin that said formulation comprises is in the range of 1-200 mg, preferably 1-150 mg, more preferably 1-100 mg per dose. 11. The formulation according to claim 9 characterized in that the buffer substance that said formulation comprises is an amine group substance. 1 . The buffer substance according to claim 11 characterized in that said buffer substance is in the range of 0.1-80%, preferably in the range of 0.1-50%, more preferably in the range of 0.1-25% by weight in the formulations. 13. The formulation according to claims 11-12 characterized in that the amine group buffer substance is tromethamol or meglumine. 14. The pellet formulation according to claim 9 characterized in that said formulation comprises lactose, sugar, starch, modified starch, corn starch, mannitol, sorbitol, inorganic salts, microcrystalline cellulose, cellulose, calcium sulfate, xylitol and/or lactitol as the filling material. 15. The filling material according to claim 14 characterized in that said filling material is preferably lactose and/or a pharmaceutically acceptable hydrate thereof. 16. The formulation according to claims 2-5 characterized in that unit dosage forms are placed in capsules preferably made of soft gelatin. 17. The method to be used in preparation of the formulation according to claim 1 characterized in that dry blending, wet granulation and/or dry granulation methods are used. 18. The formulation according to claim 1 characterized in that said formulation is used in the treatment/prophylaxis of hypercholesterolemia, atherosclerosis, coronary and cerebral diseases, for instance myocardial infarction, secondary myocardial infarction, myocardial ischemia, angina pectoris, congestive heart diseases, cerebral infarction, cerebral thrombosis, cerebral ischemia and temporary ischemic attacks. INTERNATIONAL SEARCH REPORT International application No PCT/TR201 1/0OQ 161

A . CLASSIFICATION O F SUBJECT MATTER I NV . A61 K3 1/40 A6 1K3 1/60 A61 P3/06 A6 1P9/ 10 ADD .

According to International Patent Classification (IPC) or to both national classification and IPC

B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) A6 1K A61 P

Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched

Electronic data base consulted during the international search (name of data base and, where practical, search terms used)

EPO- I nternal , BI OS I S, EMBASE , WPI Data

C . DOCUMENTS CONSIDERED TO BE RELEVANT

Category* Citation of document, with Indication, where appropriate, of the relevant passages Relevant to claim No.

X WO 2009/02282 1 A2 ( HANALL PHARMAC EUT I CAL 1- 18 CO [KR] ; KI M SUNG WU K [KR] ; J UN SUNG S00 [KR] ; J ) 19 February 2 9 (2009 -02 - 19 ) c l a i ms ; examp l e s 25 , 38 , 40

X W0 2004/080488 A2 ( BAYER HEA LTHCARE AG 1- 18 [DE] ; WAG EN ER GI LBERT [ DE] ; ELMAHD I KHAI RY [DE] ) 23 September 2004 ( 2004 -09 -23 ) page 8 ; c l a i ms ; examp l e s 1 , 2

X W0 99/47 123 Al ( SQU I BB BRI STO L MY ERS CO 1- 18 [US] ) 23 September 1999 ( 1999 -09 -23 ) page s 4 , 7 ; c l a i ms

E W0 20 11/096665 A2 ( HANM I HO LD I NGS CO LTD 1- 18 [KR] ; WOO JONG S00 [KR] ; PARK JAE HYUN [KR] ; KI M) 11 August 201 1 (20 11-08- 11) c l a i ms ; examp l e s

-/--

Further documents are listed in the continuation of Box C . See patent family annex.

* Special categories of cited documents : "T" later document published after the international filing date or priority date and not in conflict with the application but "A" document defining the general state of the art which is not cited to understand the principle or theory underlying the considered to be of particular relevance invention "E" earlier document but published on or after the international "X" document of particular relevance; the claimed invention filing date cannot be considered novel or cannot be considered to "L" document which may throw doubts on priority claim(s) or involve an inventive step when the document is taken alone which is cited to establish the publication date of another " document of particular relevance; the claimed invention citation or other special reason (as specified) cannot be considered to involve an inventive step when the "O" document referring to a n oral disclosure, use, exhibition or document is combined with one or more other such docu¬ other means ments, such combination being obvious to a person skilled in the art. "P" document published prior to the international filing date but later than the priority date claimed "&" document member of the same patent family

Date of the actual completion of the international search Date of mailing of the international search report

8 September 201 1 16/09/201 1

Name and mailing address of the ISA/ Authorized officer European Patent Office, P.B. 5818 Patentlaan 2 NL - 2280 HV Rijswijk Tel. (+31-70) 340-2040, Fax: (+31-70) 340-3016 Zi mmer Barbara INTERNATIONAL SEARCH REPORT International application No PCT/TR201 1/0OQ 161

C(Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT

Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No.

X , P WO 2 0 10/092450 A l ( KHAMAR BA L UKESH 1 - 10 , MAFAT LAL [ I N] ; PADHEE KUMUD KUMAR [ I N] ; 14 - 18 PATE L NI LAMKUM) 19 August 20 10 (2010 -08- 19 ) examp l e I B INTERNATIONAL SEARCH REPORT International application No Information on patent family members PCT/TR2011/0OQ161

Patent document Publication Patent family Publication cited in search report date member(s) date

O 2009022821 A2 19 -02- -2009 EP 2180891 A2 05-05-2010 KR ;20090017423 A 18-02-2009

o 2004080488 A2 23 -09- -2004 UY 28221 Al 08-11-2004 wo 9947123 Al 23 -09- -1999 AT 300284 T 15-08-2005 AU 760520 B2 15-05-2003 AU 2901599 A 11-10-1999 B R 9908690 A 05-12-2000 CA 2324283 Al 23-09-1999 DE 69926351 Dl 01-09-2005 DE 69926351 T2 20-04-2006 EP 1071403 Al 31-01-2001 ES 2245092 T3 16-12-2005 P 4541543 B2 08-09-2010 P 2002506809 A 05-03-2002 US 6235311 Bl 22-05-2001 US 2002034546 Al 21-03-2002 wo 2011096665 A2 11 -08- -2011 NONE wo 2010092450 Al 19 -08- -2010 NONE