WO2010021609A1

WO2010021609A1 - Solubility and stability enhancing pharmaceutical formulation

Info

Publication number: WO2010021609A1
Application number: PCT/TR2009/000109
Authority: WO
Inventors: Mahmut Bilgic
Original assignee: Mahmut Bilgic
Priority date: 2008-08-22
Filing date: 2009-08-24
Publication date: 2010-02-25
Also published as: TR200806302A2

Abstract

The present invention relates to the pharmaceutical formulations comprising a therapeutically active substance which has a stability problem in combination with another therapeutically active substance which has a solubility problem, and the methods for the preparation thereof, and the use thereof.

Description

SOLUBILITY AND STABILITY ENHANCING PHARMACEUTICAL FORMULATION

Field of the invention The present invention relates to the pharmaceutical formulations comprising a therapeutically active substance which has a stability problem in combination with another therapeutically active substance which has a solubility problem, and the methods for the preparation thereof, and the use thereof.

Background of the invention

The present invention provides a combination effective in reducing elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), and triglycerides (TG)₅ and in increasing high-density lipoprotein cholesterol (HDL-C) in patients with mixed hyperlipidemia or primary hypercholesterolemia (heterozygous familial and non- familial hypercholesterolemia); in reducing elevated total-C and LDL-C in patients with homozygous familial hypercholesterolemia (HoFH); and in reducing elevated sitosterol and campesterol levels in patients with homozygous familial sitosterolemia. This effect which is provided by the combination according to the present invention is hereinafter referred as "the desirable effect". The mentioned combination comprises ezetimibe as a cholesterol absorption inhibitor and simvastatin as an HMG-CoA reductase inhibitor.

Ezetimibe is a cholesterol absorption inhibitor with a chemical name of (3i?,45) -1- (4- fluorophenyl) -3- [(3iS)-3-(4-fluorophenyl)-3-hydroxypropyl] -4- (4-hydroxyphenyl) -2- azetidinone (Formula I).

Ezetimibe is disclosed for the first time in the patent numbered US5631365 A (USRE37721E, US5767115 A, US5846966 A₅ WO9508532 Al and EP0720599 B1 are in the same patent family). Processes for preparing ezetimibe, pharmaceutical compositions comprising ezetimibe and the use of ezetimibe as a hypocholesterolemic agent are also disclosed in the same prior art. Also disclosed is that the use of ezetimibe in combination with HMG-CoA reductase inhibitors such as lovastatin, pravastatin, fmvastatin, simvastatin and atorvastatin is effective in reducing the plasma cholesterol levels and in the treatment of atherosclerosis.

Ezetimibe is an anti-hyperlipidemic medication suitable for oral use. It lowers serum cholesterol concentration by selectively inhibiting the absorption of cholesterol and phytosterols structurally similar to cholesterol in the intestine. Its mechanism of action is complementary to HMG-CoA reductase inhibitors. So, when ezetimibe and HMG-CoA reductase inhibitors are co-administered, the cholesterol lowering effect increases synergistically.

Simvastatin is an HMG-CoA reductase inhibitor with a chemical name of 2,2-dimethyl butanoic acid (IS,3RJS,SSMR) -1,2,3,7,8,8a- hexahydro -3,7-dimethyl -8- [2-[(2R,4R)- tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl]ethyl]-l-naphtalenyl ester (Formula II).

Simvastatin is disclosed for the first time in the patent numbered US4444784 A (EP0033538 Bl₅ US4293496 A and US4450171 A are in the same patent family). Processes for preparing simvastatin and the use of simvastatin as a cholesterol biosynthesis inhibitor are also disclosed in the same prior art.

Simvastatin is an antilipemic prodrug which inhibits hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase, such as the other drugs in the same class. It has a very high affinity to this enzyme. Simvastatin increases HDL cholesterol while reducing LDL cholesterol, total cholesterol, triglycerides and apolipoprotein B.

Synergistically increasing cholesterol lowering effect of ezetimibe and HMG-CoA reductase inhibitors was proven by the various clinical trials:

• Davis HR, PuIa KK, Alton KB, Burner RE & Watkins RW. The Synergistic Hypocholesterolemic Activity of the Potent Cholesterol Absorption Inhibitor, Ezetimibe, in Combination With 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors in Dogs. Metabolism 2001; 50(10):1234-1241 • Sudhop T, Von Bergmann K. Cholesterol absorption inhibitors for the treatment of hypercholesterolaemia. Drugs 2002; 62(16):2333-47

• Gagne C, MD; Gaudet D, MD PhD; Bruckert E, MD PhD. Efficacy and Safety of Ezetimibe Coadministered With Atorvastatin or Simvastatin in Patients With Homozygous Familial Hypercholesterolemia. Circulation 2002; 105; 2469-2475 • Davidson M.H., Ballantyne CM., Kerzner B., Melani L., Sager P.T., Lipka L., Strony

J., Suresh R., Veltri E., For Ezetimibe Study Group. Efficacy and safety of ezetimibe coadministered with statins: randomised, placebo-controlled, blinded experience in 2382 patients with primary hypercholesterolemia. Journal of Clinical Practice, August 2004, 58(8): 746-755 • Gagne C; Bays H.E.; Weiss S.R.; Mata P.; Quinto K.; Melino M.; Cho M.; Musliner

T. A.; Gumbiner B.I; Ezetimibe Study Group. Efficacy and safety of ezetimibe added to ongoing statin therapy for treatment of patients with primary hypercholesterolemia. Am J Cardiol 2002; 90: 1084-1091

• Christie M. Ballantyne, John Houri, Alberto Notarbartolo, Lorenzo Melani, Leslie J. Lipka, Ramachandran Suresh, Steven Sun, Alexandre P. LeBeaut, Philip T. Sager ve

Enrico P. Veltri. Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial. Circulation 2003; 107; 2490-2415

• Lipka L.J.. Ezetimibe: a first-in-class, novel cholesterol absorption inhibitor. Cardiovascular Drug Reviews, 21 (4); 293 -312

• Kosoglu T, Meyer I, Veltri EP, et al. Pharmacodynamic interaction between the new selective cholesterol absorption inhibitor ezetimibe and simvastatin. Br J Clin Pharmacol. 2002 The present invention is directed to obtain a combination of ezetimibe as an effective hypocholesterolemic agent and simvastatin as a potent antilipemic agent, which provides the desirable effect, depending on synergistically increasing cholesterol lowering effect of ezetimibe and HMG-CoA reductase inhibitors.

The object of the invention is to provide a dosage form such as tablet by combining pharmaceutically acceptable, non-toxic and therapeutically effective amount of ezetimibe and simvastatin in a manner so as to obtain the desirable effect.

When the solid dosage forms, such as tablets, are taken orally, in many cases, the drug must first dissolve in aqueous gastrointestinal fluids before exhibiting its effect. But, because many drugs such as ezetimibe are small organic molecules with low solubility, dissolution problems arise. And having low dissolution rates limit their bioavailability.

One of the known techniques applied to address the solubility problem of poorly soluble drugs is particle size reduction. Because the dissolution rate of a particulate solid depends on the surface area and the surface area increases as the particle size reduces, reducing particle size may increase dissolution rate.

However, particle size reduction is not always effective at increasing the dissolution rate of a drug. Because, many hydrophobic drugs have a strong tendency to agglomerate while being transformed into larger particles during the dosage form manufacturing process depending on an overall decrease in effective surface area.

Another technique applied to increase the surface area is nanoparticulate technology. But, there are some barriers faced during the processes for obtaining nanoparticles such as technical and mechanical limitation of breaking the drug particles into the size of nano particles and the stabilization of these small drug particles in the dosage form.

So, there is a need for novel methods for overcoming the solubility problem of ezetimibe to be able to combine ezetimibe and the other therapeutical agents such as HMG-CoA reductase inhibitors on which ezetimibe has a synergistic effect. In addition to the solubility problem of a combination of ezetimibe and simvastatin, there is also stability problem. Because, simvastatin is prone to degradation due to oxidation of the diene and oxidation of the hydroxy! group in the simvastatin molecule. This condition brings about the need of choosing the suitable excipient composition to provide the stabilization of simvastatin in the tablet.

Stabilizing agents were used to provide the stabilization of statins such as simvastatin in the tablet according to the prior art. But, which composition of these stabilizing agents should be chosen must be discussed in terms of on the one hand stability and on the other hand therapeutical activity and solubility.

The compounds comprising a first pharmacological moiety covalently linked to a second pharmacological moiety through a physiologically labile linkage are disclosed in the patent application numbered WO2006110882 A2. First pharmacological moiety is selected from HMG-CoA reductase inhibitors and second pharmacological moiety is selected from the group of medicines including cholesterol absorption inhibitors such as ezetimibe. HMG-CoA reductase inhibitors are defined to be atorvastatin, pravastatin, simvastatin, lovastatin, fluvastatin, cerivastatin and rosuvastatin. The mechanism of action of ezetimibe and HMG- CoA reductase inhibitors is complementary according to the patent application. It is also stated in the application that this synergistic effect had been proven by clinical trials. As a result, this invention relates to novel compounds consisting of two pharmacological moieties and the use thereof. The solubility problem of ezetimibe is not mentioned in the application, accordingly there is not any solution for this problem presented in the application.

Stable antihyperlipoproteinemic oral pharmaceutical formulations which comprise ezetimibe, an HMG-CoA reductase inhibitor, disintegrants and glidants are disclosed in the patent application numbered WO2006134604 Al. HMG-CoA reductase inhibitors are defined to be atorvastatin, simvastatin and rosuvastatin. This invention discloses examples of formulations with known excipients. But, the solubility problem of ezetimibe is not mentioned in the application, accordingly there is not any solution for this problem presented in the application.

A method for treating or preventing sitosterolemia comprising administering at least one sterol absorption inhibitor (ezetimibe) optionally in combination with at least one lipid lowering agent is disclosed in the patent application numbered WO02058696 A2. Lipid lowering agent is defined to be an HMG-CoA reductase inhibitor selected from atorvastatin, pravastatin, simvastatin, lovastatin, fluvastatin, pravastatin and rosuvastatin. This invention particularly relates to the medical use of ezetimibe. The solubility problem of ezetimibe is not mentioned in the application, accordingly there is not any solution for this problem presented in the application.

Pharmaceutical compositions comprised of from 1% to 20% by weight of a cholesterol absorption inhibitor, from 1% to 80% by weight of simvastatin, from 0.01% to 2% by weight of at least one stabilizing agent, and citric acid up to a maximum of 10% by weight, provided that the composition is not comprised of ascorbic acid, are disclosed in the patent numbered EPl 531805 Bl. Cholesterol absorption inhibitor is defined to be ezetimibe. This invention only relates to pharmaceutical formulations which are not comprised of ascorbic acid. The solubility problem of ezetimibe is not mentioned in the patent, accordingly there is not any solution for this problem presented in the patent.

Pharmaceutical compositions comprising simvastatin and ezetimibe, wherein the use of stabilizing agents, particularly antioxidants, is omitted, are disclosed in the patent application numbered WO2007003365 Al. This invention only relates to pharmaceutical formulations which are not comprised of stabilizing agents. Due to low solubility of ezetimibe, the micronized form of ezetimibe is preferably used according to the invention. But, this is a known method.

The above-mentioned patents and patent applications are directed to combine ezetimibe and HMG-CoA reductase inhibitors because of their synergistic effect. But, the solubility problem that does not allow such combinations to work efficiently is not mentioned in the patents/patent applications. So, there is still a need for various solutions which allow formulators to combine ezetimibe and HMG-CoA reductase inhibitors so as to achieve the desirable effect.

Summary of the invention

The present invention relates to a process for the preparation of a pharmaceutical composition comprising therapeutically effective amount of ezetimibe or a pharmaceutically acceptable salt thereof and therapeutically effective amount of simvastatin for use in the manufacture of a medicament for the treatment of primary hypercholesterolemia (heterozygous familial and non-familial hypercholesterolemia), mixed hyperlipidemia, homozygous familial hypercholesterolemia and homozygous familial sitosterolemia, characterized in that ezetimibe or a pharmaceutically acceptable salt thereof and simvastatin are preformulated in a series of manufacturing process steps.

According to the present invention, the manufacturing process which provides a formulation so as to obtain the desirable effect is as follows:

- a mixture of ezetimibe or a pharmaceutically acceptable salt thereof, at least one pharmaceutically acceptable diluent and optionally other pharmaceutically acceptable excipients is granulated with a granulation solution comprising a pharmaceutically acceptable surfactant which the surfactant is dissolved in a solvent comprising a cellulose derivative and/or a suitable pure solvent or a solvent mixture;

- the granules obtained in the previous step are dried and sieved, and optionally mixed with other pharmaceutically acceptable excipients to obtain the first mixture; - a mixture of simvastatin, stabilizing agent(s), at least one pharmaceutically acceptable diluent and optionally other pharmaceutically acceptable excipients is granulated with a granulation solution comprising a suitable pure solvent or a solvent mixture and optionally other pharmaceutically acceptable excipients;

- the granules obtained in the previous step are dried and sieved, and optionally mixed with other pharmaceutically acceptable excipients to obtain the second mixture;

- both of the mixtures are optionally mixed to obtain a homogenous tablet, and the final mixture is optionally mixed with the other pharmaceutically acceptable excipients and made ready for tablet press;

- both of the mixtures are optionally fed separately to the tablet press machine to obtain a stratified tablet;

- tablets obtained in the previous step are optionally film-coated.

Detailed description of the invention

The present invention is directed to obtain a combination of ezetimibe and simvastatin, which provides the desirable effect, depending on synergistically increasing cholesterol lowering effect of ezetimibe and HMG-CoA reductase inhibitors. But, as defined before, there is a solubility problem which is faced during the studies. To make sure the combination of ezetimibe and simvastatin provides the desirable effect, on the one hand solubility problem of ezetimibe and stability problem of simvastatin must be overcome, and on the other hand therapeutically effective amounts of the active components and the suitable composition of the excipients must be found.

Surprisingly, it is found that a pharmaceutical composition comprising ezetimibe (or a pharmaceutically acceptable salt thereof), simvastatin, a pharmaceutically acceptable surfactant and at least one pharmaceutically acceptable stabilizing agent, wherein ezetimibe (or a pharmaceutically acceptable salt thereof) and simvastatin are preformulated, has an optimum efficacy in the treatment of the various cardiovascular diseases.

According to another aspect of the invention, a pharmaceutical composition comprising ezetimibe (or a pharmaceutically acceptable salt thereof) in a specific amount, simvastatin in a specific amount, a pharmaceutically acceptable surfactant in an adequate amount, at least one pharmaceutically acceptable stabilizing agent in an adequate amount, at least one pharmaceutically acceptable diluent in an adequate amount and optionally one or more pharmaceutically acceptable excipients selected from the additives such as binders, disintegrants, lubricants and glidants, has an optimum efficacy in the treatment of the various cardiovascular diseases.

Solubility and stability problems are solved by applying a series of manufacturing process steps to ezetimibe and simvastatin due to their specific properties.

- In the first step, a mixture of ezetimibe or a pharmaceutically acceptable salt thereof, at least one pharmaceutically acceptable diluent and optionally other pharmaceutically acceptable excipients is granulated with a granulation solution comprising a pharmaceutically acceptable surfactant used for its solubility enhancing effect which the surfactant is dissolved in a solvent comprising a cellulose derivative and/or a suitable pure solvent or a solvent mixture. The granules obtained in that way and afterwards dried and sieved exhibit more than 90% dissolution in the first 10 minutes in the dissolution medium of ezetimibe, while ezetimibe normally tends to agglomerate. The first mixture is obtained by optionally mixing the granules with the other pharmaceutically acceptable excipients.

- In the second step, a mixture of simvastatin, stabilizing agent(s), at least one pharmaceutically acceptable diluent and optionally other pharmaceutically acceptable excipients is granulated with a granulation solution comprising a suitable pure solvent or a solvent mixture and optionally other pharmaceutically acceptable excipients. The granules obtained in that way are dried and sieved. The second mixture is obtained by optionally mixing the granules with the other pharmaceutically acceptable excipients. - Then, the final mixture obtained by mixing both of the mixtures is optionally mixed with the other pharmaceutically acceptable excipients and made ready for tablet press; or both of the mixtures are fed separately to the tablet press machine to obtain a stratified tablet.

- Finally, tablets obtained in the previous step are optionally film-coated.

The term "the various cardiovascular diseases" as used herein refers to primary hypercholesterolemia (heterozygous familial and non-familial hypercholesterolemia), mixed hyperlipidemia, homozygous familial hypercholesterolemia and homozygous familial sitosterolemia.

The terms "in a specific amount", "in an adequate amount" and "optionally" as used herein refer to ezetimibe (or a pharmaceutically acceptable salt thereof) in an amount of from about 0.1 to 20% by weight, simvastatin in an amount of from about 1 to 40% by weight, a pharmaceutically acceptable surfactant in an amount of from about 0.01 to 5% by weight, at least one pharmaceutically acceptable stabilizing agent in an amount up to about 10% by weight, at least one pharmaceutically acceptable diluent in an amount of more than about 60% by weight and one or more pharmaceutically acceptable excipients selected from the additives such as binders, disintegrants, lubricants and glidants which are used when needed, which all of them are preferred to obtain the desirable effect.

Pharmaceutically acceptable surfactants may be selected from polyoxyethylene-sorbitan-fatty acid esters (polysorbates), sodium lauryl sulfate, polyoxyethylene alkyl ethers, sorbitan fatty acid esters, polyethylene glycols, polyoxyethylene castor oil derivatives, docusate sodium, quaternary ammonium compounds, sugar esters of fatty acids, glycerides of fatty acids, and the like. According to the invention, pharmaceutical composition comprises preferably sodium lauryl sulfate as a surfactant.

Pharmaceutically acceptable stabilizing agents may be selected from antioxidants, chelating agents, alkalinizing agents, photoprotectants, and the like. Pharmaceutically acceptable antioxidants may be selected from butylated hydroxyanisole (BHA), sodium ascorbate, butylated hydroxytoluene (BHT), sodium sulfite, gallates (such as propyl gallate), tocopherol, citric acid, malic acid, ascorbic acid, and the like. BHA and ascorbic acid are preferably used together. These antioxidants prevent the oxidation of simvastatin.

Pharmaceutically acceptable chelating agents may be selected from disodium EDTA, edetic acid, citric acid, sodium citrate, potassium citrate or combinations thereof, and the like. Preferably citric acid is used. Citric acid prevents the oxidation by surrounding the metal ions that may catalyse the oxidation process.

Pharmaceutically acceptable alkalinizing agents may be selected from alkali metal salts or alkaline earth metal salts. Alkali metal salts can be sodium carbonate, sodium hydroxide, sodium silicate, disodium hydrogen orthophosphate, sodium aluminate, and the like; alkaline earth metal salts can be calcium carbonate, calcium hydroxide, tribasic calcium phosphate, calcium acetate, calcium gluconate, calcium glycerophosphate, magnesium carbonate, magnesium hydroxide, magnesium acetate, magnesium silicate, magnesium aluminate, and the like.

Pharmaceutically acceptable photoprotectants may be selected from metal oxides such as titanium oxide, ferric oxide, zinc oxide, and the like.

Pharmaceutically acceptable diluents may be selected from lactose, microcrystalline cellulose, starch, pregelatinized starch, modified starch, calcium phosphate (dibasic and/or tribasic), calcium sulfate trihydrate, calcium sulfate dihydrate, calcium carbonate, kaolin, lactilol, powder cellulose, dextrose, dextrates, dextrin, sucrose, maltose, fructose, mannitol, sorbitol, xylitol, and the like. Preferably lactose and microcrystalline cellulose are used.

Pharmaceutically acceptable binders may be selected from starches (such as potato starch, com starch, wheat starch), sugars such as sucrose, glucose, dextrose, lactose and maltodextrin, natural and synthetic gums (such as acacia), gelatin, cellulose derivatives (such as microcrystalline cellulose, HPC, HEC, HPMC, carboxymethylcellulose, methylcellulose, ethylcellulose), polyvinylpyrrolidone, polyethylene glycol, waxes, calcium carbonate, calcium phosphate, alcohols (such as sorbitol, xylitol, mannitol), water, and the like. Binder is present in an amount within the range of preferably 0 to 10% by weight, more preferably 0.1 to 5% by weight.

Pharmaceutically acceptable disintegrants may be selected from starch (such as potato starch, corn starch), sodium starch glycolate, pregelatinized starch, cellulose derivatives (such as croscarmellose sodium, microcrystalline cellulose), polyvinylpyrrolidone, crospovidone, alginic acid, sodium alginate, clays (such as xanthan gum or Veegum), ion-exchange resins, effervescent systems such as those utilizing food acids and alkaline carbonate components, and the like. Preferably croscarmellose sodium and starch are used. Disintegrant is present in an amount within the range of preferably 0 to 10% by weight, more preferably 1 to 5% by weight.

Pharmaceutically acceptable lubricants may be selected from metallic stearates (such as magnesium stearate, calcium stearate, aluminium stearate), fatty acid esters (such as sodium stearyl fumarate), fatty acids (such as stearic acid), fatty alcohols, glyceryl behenate, mineral oils, paraffins, hydrogenated vegetable oils, leucine, polyethylene glycols, metallic lauryl sulfates (such as sodium lauryl sulfate, magnesium lauryl sulfate), sodium chloride, sodium benzoate, sodium acetate, talk, and the like. Preferably magnesium stearate is used. Lubricant is present in an amount within the range of preferably 0 to 10% by weight, more preferably

0.25 to 5% by weight.

Pharmaceutically acceptable glidants may be selected from silicon dioxide, magnesium trisilicate, powder cellulose, starch, talk, tribasic calcium phosphate, metallic stearates, calcium silicate, metallic lauryl sulfates, and the like. Glidant is present in an amount up to 1% by weight.

In addition, solubility enhancers, electrolytes, sweeteners, colorants, coating agents, and the like may be used in the formulation.

The examples according to the invention are given below. These examples are given to explain the invention, but does not limit the scope of the invention. Examples Exam le 1.

Exam le 3.

Claims

1. A process for the preparation of a pharmaceutical composition comprising therapeutically effective amount of ezetimibe or a pharmaceutically acceptable salt thereof and therapeutically effective amount of simvastatin for use in the manufacture of a medicament for the treatment of primary hypercholesterolemia (heterozygous familial and non-familial hypercholesterolemia), mixed hyperlipidemia, homozygous familial hypercholesterolemia and homozygous familial sitosterolemia, characterized in that ezetimibe or a pharmaceutically acceptable salt thereof and simvastatin are preformulated in a series of manufacturing process steps.

2. The process according to claim 1, characterized in that a mixture of ezetimibe or a pharmaceutically acceptable salt thereof, at least one pharmaceutically acceptable diluent and optionally other pharmaceutically acceptable excipients is granulated with a granulation solution comprising a pharmaceutically acceptable surfactant which the surfactant is dissolved in a solvent comprising a cellulose derivative and/or a suitable pure solvent or a solvent mixture; and the first mixture is obtained by optionally mixing the granules obtained in that way and afterwards dried and sieved, with the other pharmaceutically acceptable excipients.

3. The process according to claim 1, characterized in that a mixture of simvastatin, stabilizing agent(s), at least one pharmaceutically acceptable diluent and optionally other pharmaceutically acceptable excipients is granulated with a granulation solution comprising a suitable pure solvent or a solvent mixture and optionally other pharmaceutically acceptable excipients; and the second mixture is obtained by optionally mixing the granules obtained in that way and afterwards dried and sieved, with the other pharmaceutically acceptable excipients.

4. The process according to claim 1, characterized in that both of the mixtures are optionally mixed to obtain a homogenous tablet, the final mixture is optionally mixed with the other pharmaceutically acceptable excipients and made ready for tablet press; or both of the mixtures are optionally fed separately to the tablet press machine to obtain a stratified tablet.

5. The pharmaceutical composition prepared according to any one of the claims between 1 and 4, characterized in that the pharmaceutical composition comprises, based on the weight of the core tablet,

- ezetimibe or a pharmaceutically acceptable salt thereof in an amount of from about 0.1 to 20% by weight,

- simvastatin in an amount of from about 1 to 40% by weight,

- a pharmaceutically acceptable surfactant in an amount of from about 0.01 to 5% by weight, at least one stabilizing agent in an amount up to 10% by weight, and - optionally one or more pharmaceutically acceptable excipients selected from the additives such as binders, disintegrants, diluents, lubricants and glidants.

6. The pharmaceutical composition prepared according to any one of the claims between 1 and 4, characterized in that the pharmaceutical composition comprises, based on the weight of the core tablet,

- simvastatin in an amount of from about 1 to 40% by weight, a pharmaceutically acceptable surfactant in an amount of from about 0.01 to 5% by weight,

- at least one stabilizing agent in an amount up to 10% by weight,

- at least one pharmaceutically acceptable diluent in an amount of more than about 60% by weight, and optionally one or more pharmaceutically acceptable excipients selected from the additives such as binders, disintegrants, lubricants and glidants.

7. The pharmaceutical composition prepared according to any one of the claims between 1 and 4, characterized in that the pharmaceutical composition comprises preferably sodium lauryl sulfate as surfactant.

8. The pharmaceutical composition prepared according to any one of the claims between 1 and 4, characterized in that the pharmaceutical composition comprises preferably BHA, ascorbic acid or a combination thereof as antioxidant as stabilizing agent.

9. The pharmaceutical composition prepared according to any one of the claims between 1 and 4, characterized in that the pharmaceutical composition comprises preferably citric acid as chelating agent as stabilizing agent.

10. The pharmaceutical composition prepared according to any one of the claims between

1 and 4, characterized in that the pharmaceutical composition comprises preferably lactose, rnicrocrystalline cellulose or a combination thereof as diluent.

11. The pharmaceutical composition prepared according to any one of the claims between 1 and 4, characterized in that the pharmaceutical composition comprises preferably croscarmellose sodium, starch or a combination thereof as disintegrant.

12. The pharmaceutical composition according to claim 11, characterized in that the disintegrant is present in an amount within the range of preferably 0 to 10% by weight, more preferably 1 to 5% by weight.

13. The pharmaceutical composition prepared according to any one of the claims between 1 and 4, characterized in that the pharmaceutical composition comprises preferably magnesium stearate as lubricant.

14. The pharmaceutical composition according to claim 13, characterized in that the lubricant is present in an amount within the range of preferably 0 to 10% by weight, more preferably 0.25 to 5% by weight.

15. The pharmaceutical composition prepared according to any one of the claims between

1 and 4, characterized in that the pharmaceutically acceptable glidant is selected from silicon dioxide, magnesium trisilicate, powder cellulose, starch, talk, tribasic calcium phosphate, metallic stearates, calcium silicate and metallic lauryl sulfates.

16. The pharmaceutical composition according to claim 15, characterized in that the glidant is present in an amount up to 1% by weight.

17. The pharmaceutical composition according to any preceding claim, characterized in that the pharmaceutical composition is in the form of a solid dosage form for oral use.

18. The pharmaceutical composition according to claim 17, characterized in that the pharmaceutical composition is in the form of tablet, preferably film tablet.