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WO2010021609A1 - Préparation pharmaceutique améliorant la solubilité et la stabilité - Google Patents

Préparation pharmaceutique améliorant la solubilité et la stabilité Download PDF

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Publication number
WO2010021609A1
WO2010021609A1 PCT/TR2009/000109 TR2009000109W WO2010021609A1 WO 2010021609 A1 WO2010021609 A1 WO 2010021609A1 TR 2009000109 W TR2009000109 W TR 2009000109W WO 2010021609 A1 WO2010021609 A1 WO 2010021609A1
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Prior art keywords
pharmaceutically acceptable
pharmaceutical composition
weight
amount
ezetimibe
Prior art date
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Ceased
Application number
PCT/TR2009/000109
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English (en)
Inventor
Mahmut Bilgic
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Publication of WO2010021609A1 publication Critical patent/WO2010021609A1/fr
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Classifications

    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • 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
    • 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
    • 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
    • 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
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin

Definitions

  • 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.
  • 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 A 5 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.
  • 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 Bl 5 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.
  • HMG-CoA hydroxymethylglutaryl-coenzyme A reductase
  • 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.
  • the drug 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.
  • particle size reduction 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.
  • 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.
  • nanoparticulate technology 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 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.
  • primary hypercholesterolemia heterozygous familial and non-familial hypercholesterolemia
  • mixed hyperlipidemia homozygous familial hypercholesterolemia and homozygous familial sitosterolemia
  • ezetimibe or a pharmaceutically acceptable salt thereof and simvastatin are preformulated in a series of manufacturing process steps.
  • 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;
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • tablets obtained in the previous step are optionally film-coated.
  • cardiovascular diseases refers to primary hypercholesterolemia (heterozygous familial and non-familial hypercholesterolemia), mixed hyperlipidemia, homozygous familial hypercholesterolemia and homozygous familial sitosterolemia.
  • 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.
  • compositions 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.
  • 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.
  • 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.
  • 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.
  • lactose and microcrystalline cellulose are used.
  • 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.
  • 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.
  • 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.
  • magnesium stearate is used.
  • Lubricant is present in an amount within the range of preferably 0 to 10% by weight, more preferably
  • 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.
  • solubility enhancers may be used in the formulation.
  • electrolytes sweeteners, colorants, coating agents, and the like may be used in the formulation.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne des préparations pharmaceutiques qui comprennent une substance thérapeutiquement active qui présente une problème de stabilité lorsqu'elle est utilisée en combinaison avec une autre substance thérapeutiquement active qui présente une problème de solubilité, ainsi que leurs procédés de préparation et leur utilisation.
PCT/TR2009/000109 2008-08-22 2009-08-24 Préparation pharmaceutique améliorant la solubilité et la stabilité Ceased WO2010021609A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2008/06302 2008-08-22
TR2008/06302A TR200806302A2 (tr) 2008-08-22 2008-08-22 Çözünürlük ve stabilite artırıcı farmasötik formülasyon.

Publications (1)

Publication Number Publication Date
WO2010021609A1 true WO2010021609A1 (fr) 2010-02-25

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WO (1) WO2010021609A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011002424A3 (fr) * 2009-07-02 2011-04-28 Bilgic Mahmut Préparation pharmaceutique améliorant la solubilité et la stabilité

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004010993A1 (fr) * 2002-07-26 2004-02-05 Merck Sharp & Dohme Limited Compositions comprenant un inhibiteur de l'absorption du cholesterol, un inhibiteur de la hmg-coa reductase et un stabilisateur
WO2006134604A1 (fr) * 2005-06-15 2006-12-21 Hetero Drugs Limited Composition combinant un inhibiteur d’absorption du cholestérol et un inhibiteur de la 3-hydroxy-3-méthylglutaryl-coenzyme a (hmg-coa) réductase
WO2007003365A1 (fr) * 2005-07-06 2007-01-11 Krka Composition pharmaceutique comprenant de la simvastatine et de l'ézétimibe
US20070202159A1 (en) * 2006-02-02 2007-08-30 Mathur Rajeev S Pharmaceutical composition comprising stabilized statin particles
WO2008101723A2 (fr) * 2007-02-23 2008-08-28 Krka Composition pharmaceutique comprenant un inhibiteur d'absorption du cholestérol

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004010993A1 (fr) * 2002-07-26 2004-02-05 Merck Sharp & Dohme Limited Compositions comprenant un inhibiteur de l'absorption du cholesterol, un inhibiteur de la hmg-coa reductase et un stabilisateur
WO2006134604A1 (fr) * 2005-06-15 2006-12-21 Hetero Drugs Limited Composition combinant un inhibiteur d’absorption du cholestérol et un inhibiteur de la 3-hydroxy-3-méthylglutaryl-coenzyme a (hmg-coa) réductase
WO2007003365A1 (fr) * 2005-07-06 2007-01-11 Krka Composition pharmaceutique comprenant de la simvastatine et de l'ézétimibe
US20070202159A1 (en) * 2006-02-02 2007-08-30 Mathur Rajeev S Pharmaceutical composition comprising stabilized statin particles
WO2008101723A2 (fr) * 2007-02-23 2008-08-28 Krka Composition pharmaceutique comprenant un inhibiteur d'absorption du cholestérol

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DAVIDSON M H ET AL: "Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia", JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, ELSEVIER, NEW YORK, NY, US, vol. 40, no. 12, 18 December 2002 (2002-12-18), pages 2125 - 2134, XP001155704, ISSN: 0735-1097 *
GAGNE C ET AL: "EFFICACY AND SAFETY OF EZETIMIBE COADMINISTERED WITH ATORVASTATIN OR SIMVASTATIN IN PATIENTS WITH HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA", CIRCULATION, LIPPINCOTT WILLIAMS & WILKINS, US, vol. 105, no. 21, 28 May 2002 (2002-05-28), pages 2469 - 2475, XP001132086, ISSN: 0009-7322 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011002424A3 (fr) * 2009-07-02 2011-04-28 Bilgic Mahmut Préparation pharmaceutique améliorant la solubilité et la stabilité

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TR200806302A2 (tr) 2010-03-22

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