WO2010021608A1 - Solubility enhancing pharmaceutical formulation - Google Patents
Solubility enhancing pharmaceutical formulation Download PDFInfo
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- WO2010021608A1 WO2010021608A1 PCT/TR2009/000108 TR2009000108W WO2010021608A1 WO 2010021608 A1 WO2010021608 A1 WO 2010021608A1 TR 2009000108 W TR2009000108 W TR 2009000108W WO 2010021608 A1 WO2010021608 A1 WO 2010021608A1
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- pharmaceutically acceptable
- pharmaceutical composition
- weight
- acceptable salt
- ezetimibe
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
Abstract
The present invention relates to the pharmaceutical formulations comprising a therapeutically active substance which has a 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
The present invention relates to the pharmaceutical formulations comprising a therapeutically active substance which has a solubility problem in combination with other therapeutically active substances, 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), 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 atorvastatin as an HMG-CoA reductase inhibitor.
Ezetimibe is a cholesterol absorption inhibitor with a chemical name of (3R,4S) -1- (4- fluorophenyl) -3- [(3S)-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 A, 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, 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 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.
Atorvastatin is an HMG-CoA reductase inhibitor with a chemical name of (βR, δR)-2-(4- Fluoro-phenyl)- β,δ -dihydroxy-5-( 1 -methylethyl)-3 -phenyl-4- [(phenylamino)carbonyl] - 1 H- pyrrole- 1-heptanoic acid (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.
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.
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 hypercholesterolemia. 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 LJ.. 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 atorvastatin as a potent hypolipidemic 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 atorvastatin 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.
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, pitavastatin 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.
The above-mentioned 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 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.
According to the present invention, the manufacturing process which provides a formulation so as to obtain the desirable effect is as follows:
- atorvastatin or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable diluent and optionally other pharmaceutically acceptable excipients are mixed and afterwards sieved to obtain the first mixture;
- ezetimibe or a pharmaceutically acceptable salt thereof is dissolved by the addition thereof into 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; a pharmaceutically acceptable diluent is granulated with a granulation solution;
- 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 atorvastatin, 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 atorvastatin provides the desirable effect, on the one hand solubility problem of ezetimibe 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), atorvastatin (or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable surfactant, wherein ezetimibe (or a pharmaceutically acceptable salt thereof) and atorvastatin (or a pharmaceutically acceptable salt thereof) 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, atorvastatin (or a pharmaceutically acceptable salt thereof) in a specific amount, a pharmaceutically acceptable surfactant 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, glidants and lubricants, has an optimum efficacy in the treatment of the various cardiovascular diseases.
Solubility problem is solved by applying a series of manufacturing process steps to ezetimibe and atorvastatin due to their specific properties.
- In the first step, atorvastatin or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable diluent and optionally other pharmaceutically acceptable excipients are mixed together and the first mixture is obtained.
- In the second step, granulation solution is obtained by dissolving a pharmaceutically acceptable surfactant in a solvent containing a cellulose derivative and/or a suitable pure solvent or a solvent mixture. Ezetimibe or a pharmaceutically acceptable salt thereof is dissolved by the addition thereof into a granulation solution comprising a pharmaceutically acceptable surfactant used for its solubility enhancing effect. The granules obtained by spraying the granulation solution comprising ezetimibe onto a
pharmaceutically acceptable diluent 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 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, atorvastatin (or a pharmaceutically acceptable salt thereof) 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 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, glidants and lubricants which are used when needed, which all of them are preferred to obtain the desirable effect.
"Pharmaceutically acceptable salt of atorvastatin" may be derived from inorganic bases selected from alkali metals such as sodium, lithium and potassium, alkaline earth metals such as calcium and magnesium, and aluminium, zinc, ammonium, and the like; or organic bases selected from 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, triethylamine, trimethylamine, basic ion-exchange resins such as tripropylamine, cyclic amines, substituted amines, primary, secondary, tertiary amines, and the like; and is preferably calcium salt.
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 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. 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 one more diluent selected from the group listed above can also be added to the composition when needed.
Pharmaceutically acceptable binders may be selected from starches (such as potato starch, corn 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 is 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 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. Preferably silicon dioxide is used. Glidant is present in an amount up to 1% 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.
In addition, antioxidants, protecting agents, stabilizing agents, 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
Example 1.
Equivalent to 10 mg of atorvastatin
Example 2.
Equivalent to 20 mg of atorvastatin
Example 3.
Equivalent to 40 mg of atorvastatin
Example 4.
Equivalent to 80 mg of atorvastatin
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 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.
2. The process according to claim 1, characterized in that the first mixture is obtained by mixing and afterwards sieving atorvastatin or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable diluent and optionally other pharmaceutically acceptable excipients together.
3. The process according to claim 1, characterized in that the granulation solution is obtained by dissolving ezetimibe or a pharmaceutically acceptable salt thereof by the addition thereof into a 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; a pharmaceutically acceptable diluent is granulated with a granulation solution 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, atorvastatin or a pharmaceutically acceptable salt thereof 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, and - optionally one or more pharmaceutically acceptable excipients selected from the additives such as binders, disintegrants, diluents, glidants and lubricants.
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, ezetimibe or a pharmaceutically acceptable salt thereof in an amount of from about 0.1 to 20% by weight,
- atorvastatin or a pharmaceutically acceptable salt thereof 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 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, glidants and lubricants.
7. The pharmaceutical composition prepared according to any one of the claims between 1 and 4, characterized in that the pharmaceutical composition comprises calcium salt of atorvastatin as a pharmaceutically acceptable salt of atorvastatin.
8. 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.
9. The pharmaceutical composition prepared according to any one of the claims between 1 and 4, characterized in that the pharmaceutical composition comprises preferably lactose as diluent.
10. 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 as disintegrant.
11. The pharmaceutical composition according to claim 10, 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.
12. The pharmaceutical composition prepared according to any one of the claims between 1 and 4, characterized in that the pharmaceutical composition comprises preferably silicon dioxide as glidant.
13. The pharmaceutical composition according to claim 12, characterized in that the glidant is present in an amount up to 1% by weight.
14. 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.
15. The pharmaceutical composition according to claim 14, 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.
16. 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.
17. The pharmaceutical composition according to claim 16, characterized in that the pharmaceutical composition is in the form of tablet, preferably film tablet.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP09741481A EP2328563B1 (en) | 2008-08-22 | 2009-08-24 | Solubility enhancing pharmaceutical formulation |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR2008/06300 | 2008-08-22 | ||
| TR2008/06300A TR200806300A2 (en) | 2008-08-22 | 2008-08-22 | Solubility enhancing pharmaceutical formulation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2010021608A1 true WO2010021608A1 (en) | 2010-02-25 |
Family
ID=41396144
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/TR2009/000108 WO2010021608A1 (en) | 2008-08-22 | 2009-08-24 | Solubility enhancing pharmaceutical formulation |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP2328563B1 (en) |
| TR (1) | TR200806300A2 (en) |
| WO (1) | WO2010021608A1 (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011002422A3 (en) * | 2009-07-02 | 2011-04-28 | Bilgic Mahmut | Solubility enhancing pharmaceutical formulation |
| EP2368543A1 (en) | 2010-03-25 | 2011-09-28 | KRKA, tovarna zdravil, d.d., Novo mesto | Method of preparing a granulated pharmaceutical composition comprising simvastatin and/or ezetimibe |
| CN103784436A (en) * | 2014-02-27 | 2014-05-14 | 安徽联创药物化学有限公司 | Lipid-lowering compound preparation and preparation method thereof |
| WO2015093859A1 (en) * | 2013-12-18 | 2015-06-25 | (주) 드림파마 | Pharmaceutical combined preparation containing hmg-coa reductase inhibitor and cholesterol absorption inhibitor |
| EP2844233A4 (en) * | 2012-05-01 | 2015-12-30 | Althera Life Sciences Llc | Oral tablet formulation consisting of fixed combination of rosuvastatin and ezetimibe for treatment of hyperlipidemia and cardiovascular diseases |
| US10376470B2 (en) | 2012-05-01 | 2019-08-13 | Althera Life Sciences, Llc | Oral tablet formulation consisting of fixed combination of rosuvastatin and ezetimibe for treatment of hyperlipidemia and cardiovascular diseases |
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| WO2002058696A2 (en) * | 2001-01-26 | 2002-08-01 | Schering Corporation | The use of substituted azetidinone compounds for the treatment of sitosterolemia |
| WO2005011638A2 (en) * | 2003-08-05 | 2005-02-10 | Zentiva, A. S. | Methods for the stabilization of atorvastatin |
| WO2006134604A1 (en) * | 2005-06-15 | 2006-12-21 | Hetero Drugs Limited | Combination composition of cholesterol absorption inhibitor and 3-hydroxy-3-methylglutaryl-coenzyme a (hmg-coa) reductase inhibitor |
| EP1741427A1 (en) * | 2005-07-06 | 2007-01-10 | KRKA, D.D., Novo Mesto | Pharmaceutical composition comprising simvastatin and ezetimibe |
| WO2008101723A2 (en) * | 2007-02-23 | 2008-08-28 | Krka | Pharmaceutical composition containing a cholesterol absorption inhibitor |
-
2008
- 2008-08-22 TR TR2008/06300A patent/TR200806300A2/en unknown
-
2009
- 2009-08-24 WO PCT/TR2009/000108 patent/WO2010021608A1/en active Application Filing
- 2009-08-24 EP EP09741481A patent/EP2328563B1/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002058696A2 (en) * | 2001-01-26 | 2002-08-01 | Schering Corporation | The use of substituted azetidinone compounds for the treatment of sitosterolemia |
| WO2005011638A2 (en) * | 2003-08-05 | 2005-02-10 | Zentiva, A. S. | Methods for the stabilization of atorvastatin |
| WO2006134604A1 (en) * | 2005-06-15 | 2006-12-21 | Hetero Drugs Limited | Combination composition of cholesterol absorption inhibitor and 3-hydroxy-3-methylglutaryl-coenzyme a (hmg-coa) reductase inhibitor |
| EP1741427A1 (en) * | 2005-07-06 | 2007-01-10 | KRKA, D.D., Novo Mesto | Pharmaceutical composition comprising simvastatin and ezetimibe |
| WO2008101723A2 (en) * | 2007-02-23 | 2008-08-28 | Krka | Pharmaceutical composition containing a cholesterol absorption inhibitor |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011002422A3 (en) * | 2009-07-02 | 2011-04-28 | Bilgic Mahmut | Solubility enhancing pharmaceutical formulation |
| EP2368543A1 (en) | 2010-03-25 | 2011-09-28 | KRKA, tovarna zdravil, d.d., Novo mesto | Method of preparing a granulated pharmaceutical composition comprising simvastatin and/or ezetimibe |
| WO2011116973A1 (en) | 2010-03-25 | 2011-09-29 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Method of preparing a granulated pharmaceutical composition comprising simvastatin and/or ezetimibe |
| EP2844233A4 (en) * | 2012-05-01 | 2015-12-30 | Althera Life Sciences Llc | Oral tablet formulation consisting of fixed combination of rosuvastatin and ezetimibe for treatment of hyperlipidemia and cardiovascular diseases |
| US9763885B2 (en) | 2012-05-01 | 2017-09-19 | Althera Laboratories Ltd. | Oral tablet formulation consisting of fixed combination of rosuvastatin and ezetimibe for treatment of hyperlipidemia and cardiovascular diseases |
| US10376470B2 (en) | 2012-05-01 | 2019-08-13 | Althera Life Sciences, Llc | Oral tablet formulation consisting of fixed combination of rosuvastatin and ezetimibe for treatment of hyperlipidemia and cardiovascular diseases |
| WO2015093859A1 (en) * | 2013-12-18 | 2015-06-25 | (주) 드림파마 | Pharmaceutical combined preparation containing hmg-coa reductase inhibitor and cholesterol absorption inhibitor |
| CN103784436A (en) * | 2014-02-27 | 2014-05-14 | 安徽联创药物化学有限公司 | Lipid-lowering compound preparation and preparation method thereof |
| CN103784436B (en) * | 2014-02-27 | 2016-06-01 | 安徽联创生物医药股份有限公司 | A kind of blood fat-decreasing compound preparation and its preparation method |
Also Published As
| Publication number | Publication date |
|---|---|
| EP2328563B1 (en) | 2013-03-20 |
| EP2328563A1 (en) | 2011-06-08 |
| TR200806300A2 (en) | 2010-03-22 |
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