WO2011002422A2

WO2011002422A2 - Solubility enhancing pharmaceutical formulation

Info

Publication number: WO2011002422A2
Application number: PCT/TR2010/000123
Authority: WO
Inventors: Bilgic Mahmut
Original assignee: Bilgic Mahmut
Priority date: 2009-07-02
Filing date: 2010-06-25
Publication date: 2011-01-06
Also published as: EP2448564A2; WO2011002422A3

Abstract

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

Description

SOLUBILITY ENHANCING

PHARMACEUTICAL FORMULATION

Field of the invention

Background of 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)₅ and triglyceride (TG) levels, and in increasing high-density lipoprotein cholesterol (HDL-C) levels in patients with mixed hyperlipidemia or primary hypercholesterolemia (heterozygous familial and non-familial hypercholesterolemia); in reducing elevated total-C and LDL-C levels in patients with homozygous familial hypercholesterolemia (HoFH); and in reducing elevated sitosterol and campesterol levels in patients with homozygous familial sitosterolemia. This effect provided by the combination of the present invention is hereinafter referred as "the desired effect". The mentioned combination comprises ezetimibe as a cholesterol absorption inhibitor and atorvastatin as an HMG-CoA reductase inhibitor.

Ezetimibe is a cholesterol absorption inhibitor with the chemical name of (3R,4S) -1- (4- fluorophenyl) -3- [(35)-3-(4-fluorophenyl)-3-hydroxypropyl] -4- (4-hydroxyphenyl) -2- azetidinone (Formula I).

Formula (I)

Ezetimibe is disclosed for the first time in the U.S. patent application of 5631365 A (USRE37721E, US5767115 A, US5846966 A, WO9508532 Al and EP0720599 B1 are also members of the same patent family). Processes for preparation of ezetimibe, pharmaceutical compositions comprising ezetimibe and the use of ezetimibe as a hypocholesterolemic agent are also disclosed in the same prior art. It is also disclosed that use of ezetimibe in combination with HMG-CoA reductase inhibitors, such as lovastatin, pravastatin, fluvastatin, 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 administration. It lowers serum cholesterol concentration by selectively inhibiting the absorption of phytosterols, such as cholesterol and the like, in the intestine. Its mechanism of action is complementary to that of HMG-CoA reductase inhibitors. Therefore, the cholesterol lowering effect of coadministered ezetimibe and HMG-CoA reductase inhibitors increases synergistically.

Atorvastatin is an HMG-CoA reductase inhibitor with a chemical name of (βR, δR)-2-(4- Fluoro-phenyl)- β,δ -dihydroxy-5-(l -methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH^'- pyrrole-1-heptanoic acid (Formula II).

Formula (II)

Atorvastatin is disclosed for the first time in the patent numbered EP409281 Bl (EP1061073 Bl and US5273995 A are in the same patent family). Processes for preparing atorvastatin and the use of atorvastatin as a cholesterol biosynthesis inhibitor are also disclosed in the same prior art._f

Atorvastatin is a hypolipidemic drug which is a selective competitive inhibitor of 3-hydroxy- 3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase. Atorvastatin is the only drug in this class that can reduce both elevated LDL cholesterol and triglycerides in patients with hypercholesterolemia.

The synergistic cholesterol lowering effect of ezetimibe and HMG-CoA reductase inhibitors has been proved by 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 based on the synergistic cholesterol lowering effect of ezetimibe and HMG-CoA reductase inhibitors is directed to obtain a combination of ezetimibe as an effective hypocholesterolemic agent with atorvastatin as a potent hypolipidemic agent that provides the desired effect.

The object of the invention is to provide a formulation of the invention comprising pharmaceutically acceptable, non-toxic and therapeutically effective amount of a combination of ezetimibe and atorvastatin in a dosage form such as a tablet designed to achieve the desired effect.

Usually, when solid dosage forms such as tablets are administered orally, the drug must first dissolve in gastrointestinal fluids before exhibiting its effect. However dissolution problems arise with active agents such as ezetimibe with small particulate sizes. Low dissolution rates of these active agents affect their bioavailability adversely.

One of the known techniques applied to overcome the solubility problem of poorly soluble drugs is particle size reduction. Since the dissolution rate depends on the surface area of the particle directly, decreasing the size of the particles increases the total surface area, hence the dissolution rate.

However, particle size reduction might not be always effective in increasing the dissolution rate of a drug, because as the particles get bigger during the manufacturing process of the pharmaceutical dosage form, increase in the particle size results in the agglomeration of particles.

Another technique applied to increase the surface area is nanoparticulate technology. However some problems are faced during the nanoparticulate formation, such as technical and mechanical limitations that prevent the reduction of particle size to nanoparticulate measures, and stability issues of these small sized active agent particles.

Thus, there is a need for novel methods to overcome the solubility problem arisen from the combination of ezetimibe with other therapeutical agents, such as HMG-CoA reductase, which combination results in a synergistic effect.

In the International Patent Application with publication number WO 2006/110882, compounds comprising a first pharmacological moiety covalently connected to a second pharmacological moiety through a physiologically labile linker are described. First pharmacological moiety is selected from HMG-CoA reductase inhibitors and second pharmacological moiety is selected from the group of active agents including cholesterol absorption inhibitors such as ezetimibe. HMG-CoA reductase inhibitors are defined as atorvastatin, pravastatin, simvastatin, lovastatin, fluvastatin, cerivastatin and rosuvastatin. The mechanism of action of ezetimibe and HMG-CoA reductase inhibitors are indicated as complementary in this patent application. It is also stated that this synergistic effect has been proven by clinical trials. So, this invention relates to novel compounds consisting of two pharmacological moieties and the use thereof. The solubility problem of ezetimibe is not mentioned here, hence no solution for this problem was presented by this application. Stable antihyperlipoproteinemic oral pharmaceutical formulations which comprise ezetimibe, an HMG-CoA reductase inhibitor, disintegrants and glidants are disclosed in the International Patent Application with publication number 2006/134604. HMG-CoA reductase inhibitors are defined to be atorvastatin, simvastatin and rosuvastatin. TMs invention provides examples of formulations with known excipients. However, the solubility problem of ezetimibe is not mentioned here, hence no solution for this problem was presented by this 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 International Patent Application with publication number 2002/058696. Lipid lowering agent is defined to be an HMG-CoA reductase inhibitor selected from atorvastatin, pravastatin, simvastatin, lovastatin, fluvastatin, pitavastatin and rosuvastatin. This invention particularly relates to the medical use of ezetimibe. The solubility problem of ezetimibe is not mentioned here, hence no solution for this problem was presented by this application.

The above-mentioned patent applications are directed to the combination of ezetimibe and HMG-CoA reductase inhibitors because of their synergistic effect. However, the solubility problem that inhibits efficient work on this combination is not mentioned in these patents or patent applications. So, there is still need for various solutions which would allow formulators to combine ezetimibe and HMG-CoA reductase inhibitors to achieve the desired 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 a therapeutically effective amount of atorvastatin or a pharmaceutically acceptable salt thereof 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 atorvastatin or a pharmaceutically acceptable salt thereof are preformulated in a series of manufacturing process steps.

The manufacturing process of the present invention, which provides a formulation so as to obtain the desired effect is as follows: atorvastatin or a pharmaceutically acceptable salt thereof, at least one pharmaceutically acceptable diluent and optionally other pharmaceutically acceptable excipients, preferably a disintegrant and a glidant, are mixed and afterwards sieved to obtain the first mixture;

- Ezetimibe or a pharmaceutically acceptable salt is dissolved in 1-propanol, 2- propanol, acetone or a mixture of these to obtain a granulation solution;

a pharmaceutically acceptable diluent is granulated by spraying the granulation solution;

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

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

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

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

Detailed Description of the Invention

The present invention based on the synergistic cholesterol lowering effect of ezetimibe and HMG-CoA reductase inhibitors is directed to obtain a combination of ezetimibe and atorvastatin to provide the desired effect. However, as mentioned before, a solubility problem is encountered in these attempts. To achieve the desired effect from the combination of ezetimibe and atorvastatin, there is the need to overcome the solubility problem of ezetimibe and to find the appropriate amounts of active agents and excipients of the composition.

Surprisingly, it was found that pharmaceutical compositions comprising ezetimibe (or a pharmaceutically acceptable salt) and atorvastatin (or a pharmaceutically acceptable salt), which are preformulated in a series of manufacturing steps, show the optimum efficiency in the treatment of various cardiovascular diseases.

As another embodiment of the invention, it was found that pharmaceutical compositions comprising specific amounts of ezetimibe (or a pharmaceutically acceptable salt) and atorvastatin (or a pharmaceutically acceptable salt) and at least one diluent in an high amount and, optionally, at least one pharmaceutically acceptable excipient selected from the group of binders, disintegrants, lubricants and glidants, show the optimum efficiency in the treatment of various cardiovascular diseases.

The problem of solubility has been solved by applying a series of manufacturing steps to ezetimibe and atorvastatin according to their solubility characteristics.

- atorvastatin or a pharmaceutically acceptable salt thereof, at least one pharmaceutically acceptable diluent and optionally other pharmaceutically acceptable excipients, preferably a disintegrant and a glidant, were mixed and afterwards sieved to obtain the first mixture;

- Then, ezetimibe or a pharmaceutically acceptable salt was dissolved in a granulation solution comprising 1-propanol, 2-propanol, acetone or a mixture of these. Although ezetimibe usually tends to agglomerate, the granules obtained by spraying the granulation solution comprising ezetimibe onto a pharmaceutically acceptable diluent and after being dried and sieved, exhibited a dissolution rate greater than 90% in the first 10 minutes in the dissolution medium of ezetimibe. The second mixture was obtained by optionally mixing these granules with other pharmaceutically acceptable excipients, preferably a disintegrant.

Both of the mixtures were mixed together and this final mixture was optionally mixed with other pharmaceutically acceptable excipients, preferably a lubricant, and was finalized for tablet press or to obtain a layered tablet both of the mixtures were fed separately to the tablet press machine.

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

The term "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 high amount" and "optionally" as used herein refer to ezetimibe (or a pharmaceutically acceptable salt thereof) in an amount of 0.1 to 20% by weight, atorvastatin (or a pharmaceutically acceptable salt thereof) in an amount of 1 to 40% by weight, at least one pharmaceutically acceptable diluent in an amount of at least 60% by weight, preferably at least 70%, more preferably at least 80% by weight and if needed at least one pharmaceutically acceptable excipient selected from excipients such as binders, disintegrants, lubricants and glidants, which all of them are preferred to obtain the desired effect.

"Pharmaceutically acceptable salt of atorvastatin" may be derived from inorganic bases selected from the group of alkali metals such as sodium, lithium and potassium, earth alkali metals such as calcium and magnesium, and other inorganic bases such as aluminium, zinc, ammonium or organic bases selected from the group of arginine, betaine, caffeine, . choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N- ethylpiperidine, glucamine, glucosamine, histidine, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, basic ion-exchange resins such as triethylamine, trimethylamine, tripropylamine, cyclic amines, substituted amines, primary, secondary, tertiary amines, and preferably calcium salt.

The pharmaceutically acceptable diluents may be selected from the group of 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. The pharmaceutical composition of the invention comprises preferably lactose as diluent. Lactose may be selected from the different forms of lactose such as lactose DC, lactose monohydrate, lactose anhydrous, and the like. Besides the lactose another diluent selected from the group listed above can also be added to the composition.

The pharmaceutically acceptable binders can be selected from the group of starch (e.g. potato starch, cornstarch or wheat starch), sucrose, glucose, dextrose, lactose, sugars like maltodexrin, natural and synthetic gums (e.g. acacia tree), gelatin, cellulose derivatives (e.g. microcrystalline cellulose, HPC, HEC, HPMC₅ carboxymethylcellulose, methylcellulose, ethylcellulose), polyvinylpyrrolidone, polyethylene glycol, waxes, calcium carbonate, calcium phosphate, alcohols (e.g. sorbitol, xylitol and mannitol) and water. The binder is present in the formulation preferably in a range of 0-10% by weight, more preferably in a range of 0.1-5% by weight.

The pharmaceutically acceptable disintegrants may be selected from the group of starch (e.g. potato starch, corn starch), sodium starch glycolate, pregelatinized starch, cellulose derivatives (e.g. croscarmellose sodium, microcrystalline cellulose), polyvinylpyrrolidone, crospovidone, alginic acid, sodium alginate, clays (e.g. 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 is used. Disintegrant is present in the formulation preferably in a range of 0-10% by weight, more preferably in a range of 1-5% by weight.

The pharmaceutically acceptable glidants can be selected from the group of silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, tribasic calcium phosphate, metallic stearates, calcium silicate and metallic lauryl sulfate. Preferably silicon dioxide is used. The weight % of the glidant in the formulation is lower than 1%.

The pharmaceutically acceptable lubricants can be selected from the group of metallic stearates (e.g. magnesium stearate, calcium stearate, aluminum stearate), fatty acid esters (e.g. sodium stearyl fumarate), fatty acids (e.g. stearic acid), fatty alcohols, glyceryl behenate, mineral oils, paraffins, hydrogenated vegetable oils, leucine, polyethylene glycols (PEG), metallic lauryl sulfates (e.g. sodium lauryl sulfate, magnesium lauryl sulfate), sodium chloride, sodium benzoate, sodium acetate and talk. Lubricant is present in the formulation preferably in a range of 0-10% by weight, more preferably in a range of 0.25-5% by weight. In addition, antioxidants, protectors, stabilizers, solubility enhancers, electrolytes, sweeteners, colorants, coating agents can be used as other pharmaceutically acceptable excipients in the formulation.

The formulation examples of the invention are given below. These examples are given only to explain the invention and the scope of the invention is not limited to these examples.

EXAMPLES

Example 1.

* Equivalent of 10 mg of atorvastatin

Example 2.

* Equivalent of 20 mg of atorvastatin Example 3.

* Equivalent of 40 mg of atorvastatin

Example 4.

* Equivalent of 80 mg of atorvastatin

Claims

CLAIMS A process for the preparation of a pharmaceutical composition comprising therapeutically effective amount of ezetimibe or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of atorvastatin or a pharmaceutically acceptable salt thereof 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 atorvastatin or a pharmaceutically acceptable salt thereof are preformulated in a series of manufacturing process steps.

1. The process according to claim 1, characterized in that atorvastatin or a pharmaceutically acceptable salt thereof, at least one pharmaceutically acceptable diluent and optionally other pharmaceutically acceptable excipients, preferably a disintegrant and a glidant, are mixed and afterwards sieved to obtain the first mixture.

2. The process according to claim 1, characterized in that ezetimibe or a pharmaceutically acceptable salt is dissolved in solution comprising 1-propanol, 2- propanol, acetone or a mixture of these to obtain a granulation solution; granulation is achieved by spraying the granulation solution onto a pharmaceutically acceptable diluent and after the granules are dried and sieved, they are optionally mixed with other pharmaceutically acceptable excipients, preferably a disintegrant, to obtain the second mixture.

3. The process according to claim 1, characterized in that both of the mixtures are optionally mixed together and this final mixture is optionally mixed with other pharmaceutically acceptable excipients, preferably a lubricant, and finalized for tablet press or to obtain a layered tablet optionally both of the mixtures are fed separately to the tablet press machine.

4. 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 0.1 to

20% by weight,

- atorvastatin a pharmaceutically acceptable salt thereof in an amount of 1 to 40% by weight,

- at least one pharmaceutically acceptable excipient selected from excipients such as binders, disintegrants, diluents, lubricants and glidants.

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 0.1 to

20% by weight,

- rosuvastatin a pharmaceutically acceptable salt thereof in an amount of 1 to

40% by weight,

at least one pharmaceutically acceptable diluent in an amount of at least 60% by weight, preferably at least 70%, more preferably at least 80% by weight, and,

at least one pharmaceutically acceptable excipient selected from excipients 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 atorvastatin calcium as the pharmaceutically acceptable salt.

7. The pharmaceutical composition prepared according to any one of the claims between 1 and 4, characterized in that the pharmaceutical composition comprises a diluent, preferably lactose.

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

1 and 4, characterized in that the pharmaceutical composition comprises a disintegrant, preferably croscarmellose sodium.

9. The pharmaceutical composition according to claim 9 characterized in that the disintegrant is present in the formulation preferably in a range of 0-10% by weight, more preferably in a range of 1-5% by weight.

10. The pharmaceutical composition prepared according to any one of the claims between 1 and 4, characterized in that the pharmaceutical composition comprises a glidant, preferably silicon dioxide.

11. The pharmaceutical composition according to claim 11 characterized in that the weight % of the glidant in the formulation is lower than 1%.

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

1 and 4, characterized in that the pharmaceutical composition preferably comprises a lubricant, preferably magnesium stearate.

13. The pharmaceutical composition according to claim 13 characterized in that the lubricant is present in the formulation preferably in a range of 0-10% by weight, more preferably in a range of 0.25-5% by weight.

14. The pharmaceutical composition according to any one of the previous claims, characterized in that the pharmaceutical composition is in solid dosage form for oral administration.

15. The pharmaceutical composition according to claim 15, characterized in that the solid dosage form is a tablet, preferably a film tablet.