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WO2011019326A2 - Formulation pharmaceutique permettant d'augmenter la solubilité et la stabilité - Google Patents

Formulation pharmaceutique permettant d'augmenter la solubilité et la stabilité Download PDF

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Publication number
WO2011019326A2
WO2011019326A2 PCT/TR2010/000127 TR2010000127W WO2011019326A2 WO 2011019326 A2 WO2011019326 A2 WO 2011019326A2 TR 2010000127 W TR2010000127 W TR 2010000127W WO 2011019326 A2 WO2011019326 A2 WO 2011019326A2
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
pharmaceutically acceptable
weight
ezetimibe
acceptable salt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/TR2010/000127
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English (en)
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WO2011019326A3 (fr
Inventor
Mahmut Bilgic
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Individual
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Individual
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Priority to EP10782065A priority Critical patent/EP2448919A2/fr
Publication of WO2011019326A2 publication Critical patent/WO2011019326A2/fr
Publication of WO2011019326A3 publication Critical patent/WO2011019326A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K9/2022—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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • 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
    • 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
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer

Definitions

  • the present invention relates to pharmaceutical formulations comprising a therapeutically active agent with solubility problem in combination with a therapeutic agent with stability problem, and preparation methods thereof and medical uses 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 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 rosuvastatin as an HMG-CoA reductase inhibitor.
  • Ezetimibe is a cholesterol absorption inhibitor with the chemical name of (3i?,4S) -1- (4- fluorophenyl) -3- [(3 ⁇ S)-3-(4-fluorophenyl)-3-hydroxypropyl] -4- (4-hydroxyphenyl) -2- azetidinone (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.
  • 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.
  • HMG-CoA reductase inhibitors such as lovastatin, pravastatin, fluvastatin, simvastatin and atorvastatin
  • Ezetimibe is an antilipemic 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 co-administered ezetimibe and HMG-CoA reductase inhibitors increases synergistically.
  • Rosuvastatin is an HMG-CoA reductase inhibitor with the chemical name of (3R,5S,6E)-7-[4- (4-fluorophenyl)-6-( 1 -methylethyl)-2- [methyl(methylsulfonyl)amino] -5 -pyrimidinyl] -3,5- dihydroxy-6-heptenoic acid (Formula II).
  • Rosuvastatin is disclosed for the first time in the European Patent No. 0521471 (US5260440 A and USRE37314 El are also members of the same patent family). Processes for preparation of rosuvastatin and its use as a cholesterol biosynthesis inhibitor are disclosed in this patent.
  • Rosuvastatin being one of the inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-1)
  • CoA reductase enzyme is an antilipemic prodrug. Rosuvastatin increases HDL levels as it reduces LDL, triglyceride and apolipoprotein B levels. Due to the structure of its binding sites and its relatively high hydrophilicity it penetrates hepatocytes more efficiently and binds to the HMG-CoA reductase enzyme with an improved affinity as compared with other statins. Therefore, it is more effective in reducing LDL-cholesterol levels as compared with other statins.
  • HMG-CoA reductase inhibitors HMG-CoA reductase inhibitors.
  • Ezetimibe a first-in-class, novel cholesterol absorption inhibitor.
  • HMG-CoA reductase inhibitors is directed to obtain a combination of ezetimibe as an effective hypocholesterolemic agent with rosuvastatin as a potent antilipemic 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 rosuvastatin in a dosage form such as a tablet designed to achieve the desired effect.
  • 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.
  • nanoparticulate technology Another technique applied to increase the surface area is nanoparticulate technology.
  • 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.
  • Stable antihyperlipoproteineniic 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.
  • This invention provides examples of formulations with known excipients.
  • 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 present invention relates to a process for the preparation of a pharmaceutical composition
  • a pharmaceutical composition comprising therapeutically effective amount of ezetimibe or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of rosuvastatin 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 rosuvastatin or a pharmaceutically acceptable salt thereof 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
  • the manufacturing process of the present invention which provides a formulation so as to obtain the desired effect is as follows:
  • 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;
  • a stabilizer and/or stabilizers with at least one diluent is granulated by a granulation solution comprising an appropriate pure solvent or solvent mixture and optionally other pharmaceutically acceptable excipients, preferably a stabilizer and a diluents.
  • 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 second mixture;
  • 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;
  • both of the mixtures are fed separately to the tablet press machine to obtain a layered tablet;
  • tablets obtained in the previous step are film-coated.
  • 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 rosuvastatin to provide the desired effect.
  • a solubility problem is encountered in these attempts.
  • To achieve the desired effect from the combination of ezetimibe and rosuvastatin there is the need to overcome the solubility problem of ezetimibe and stability problem of rosuvastatin, and also the need to find the appropriate amounts of active agents and excipients of the composition.
  • compositions comprising ezetimibe (or a pharmaceutically acceptable salt) and rosuvastatin (or a pharmaceutically acceptable salt), which are preformulated in a series of manufacturing steps, and at least one stabilizer, show the optimum efficiency in the treatment of various cardiovascular diseases.
  • compositions comprising specific amounts of ezetimibe (or a pharmaceutically acceptable salt) and rosuvastatin (or a pharmaceutically acceptable salt), at least one stabilizer in a sufficient amount, 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.
  • ezetimibe or a pharmaceutically acceptable salt was dissolved in a granulation solution comprising 1-propanol, 2-propanol, acetone or a mixture of these.
  • 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 first mixture was obtained by optionally mixing the granules with other pharmaceutically acceptable excipients, preferably a disintegrant.
  • rosuvastatin or a pharmaceutically acceptable salt and the mixture of a stabilizer and/or stabilizers with at least one diluent were granulated by a granulation solution comprising an appropriate pure solvent or solvent mixture and, optionally, other pharmaceutically acceptable excipients, preferably a stabilizer and a diluent.
  • the granules obtained after being dried and sieved were optionally mixed with other pharmaceutically acceptable excipients, preferably a disintegrant, and the second mixture was obtained.
  • tablets obtained in the previous step were optionally film-coated.
  • variable 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
  • rosuvastatin or a pharmaceutically acceptable salt thereof
  • a pharmaceutically acceptable stabilizer 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 diluent 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 rosuvastatin” 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,
  • Stabilizer and/or stabilizers can be selected from the group of antioxidants, chelating agents, alkalizing agents and photoprotectors.
  • the antioxidants can be selected from the group of butylated hydroxyanisole (BHA), sodium ascorbate, butylated hydroxytoluene (BHT), sodium sulphite, gallates (e.g. propyl gallate), tocopherol, citric acid, malic acid and ascorbic acid.
  • BHA butylated hydroxyanisole
  • BHT butylated hydroxytoluene
  • gallates e.g. propyl gallate
  • tocopherol citric acid, malic acid and ascorbic acid.
  • BHA e.g. propyl gallate
  • the chelating agents can be selected from the group of disodium EDTA, edetic acid, citric acid, sodium citrate, potassium citrate and combinations. Preferably citric acid is used.
  • the alkalizing agents can be selected from the group of alkali metal salts like sodium carbonate, sodium hydroxide, sodium silicate, disodium hydrogen orthophosphate, sodium aluminate; and earth alkali metal salts like calcium carbonate, calcium hydroxide, tribasic calcium phosphate, calcium acetate, calcium gluconate, calcium glycerophosphate, magnesium carbonate, magnesium hydroxide, magnesium acetate, magnesium silicate and magnesium aluminate.
  • alkali metal salts like sodium carbonate, sodium hydroxide, sodium silicate, disodium hydrogen orthophosphate, sodium aluminate
  • earth alkali metal salts like calcium carbonate, calcium hydroxide, tribasic calcium phosphate, calcium acetate, calcium gluconate, calcium glycerophosphate, magnesium carbonate, magnesium hydroxide, magnesium acetate, magnesium silicate and magnesium aluminate.
  • the photoprotectors can be selected from metal oxides such as titanium oxide, iron oxide and zinc. Preferably iron oxide is used.
  • the pharmaceutically acceptable diluents can be selected from the group of lactose, microcrystalline cellulose, starch, pregelatinized starch, modified starch, calcium phosphate (dibasic and/or tribasic), calcium sulphate trihydrate, calcium sulphate dihydrate, calcium carbonate, kaolin, lactitol, powdered cellulose, dextrose, dextrates, dextrin, sucrose, maltose, fructose, mannitol, sorbitol and xylitol.
  • lactose or microcrystalline cellulose is used.
  • 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, HPMC, 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.
  • croscarmellose sodium and starch 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 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.
  • 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 e.g. glyceryl behenate
  • mineral oils
  • 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.
  • 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.
  • silicon dioxide is used.
  • the weight % of the glidant in the formulation is lower than 1%.
  • solubility enhancers can be used as other pharmaceutically acceptable excipients in the formulation.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Veterinary Medicine (AREA)
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  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Emergency Medicine (AREA)
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  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

L'invention concerne des formulations pharmaceutiques comprenant l'association d'un agent thérapeutique présentant un problème de solubilité et d'un agent thérapeutique présentant un problème de stabilité. L'invention concerne également des méthodes de préparation de ces formulations, et l'utilisation de telles formulations.
PCT/TR2010/000127 2009-07-02 2010-06-25 Formulation pharmaceutique permettant d'augmenter la solubilité et la stabilité Ceased WO2011019326A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP10782065A EP2448919A2 (fr) 2009-07-02 2010-06-25 Formulation pharmaceutique permettant d'augmenter la solubilité et la stabilité

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2009/5148 2009-07-02
TR200905148 2009-07-02

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Publication Number Publication Date
WO2011019326A2 true WO2011019326A2 (fr) 2011-02-17
WO2011019326A3 WO2011019326A3 (fr) 2011-04-28

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011139256A3 (fr) * 2010-05-04 2012-05-18 Bilgic Mahmut Formulations stables de rosuvastatine
WO2013166117A1 (fr) * 2012-05-01 2013-11-07 Althera Life Sciences, Llc Formulation de comprimé oral constituée d'une combinaison fixe de rosuvastatine et d'ézétimibe pour le traitement de l'hyperlipidémie et de maladies cardiovasculaires
WO2015044698A3 (fr) * 2013-09-30 2015-05-14 Egis Gyógyszergyár Zrt. Composition médicale contenant un inhibiteur de l'absorption du cholestérol et un inhibiteur de la biosynthèse du cholestérol
WO2015199356A1 (fr) * 2014-06-25 2015-12-30 Hanmi Pharm. Co., Ltd. Formulation composite pour administration par voie orale comprenant de l'ézétimibe et de la rosuvastatine et procédé de préparation associé
EP3085364A4 (fr) * 2013-12-18 2017-08-23 Alvogen Korea Co., Ltd. Préparation pharmaceutique combinée contenant un inhibiteur de hmg-coa réductase et un inhibiteur de l'absorption du cholestérol
EP3243506A1 (fr) * 2016-05-09 2017-11-15 Adamed sp. z o.o. Composition pharmaceutique
WO2018041281A1 (fr) 2016-09-05 2018-03-08 Zentiva, K.S. Composition pharmaceutique comprenant de la rosuvastatine et de l'ézétimibe et son procédé de préparation
WO2018041282A1 (fr) 2016-09-05 2018-03-08 Zentiva, K.S. Composition pharmaceutique comprenant de la rosuvastatine et de l'ézétimibe et son procédé de préparation
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
US10434067B2 (en) 2013-12-30 2019-10-08 Hanmi Pharm. Co., Ltd. Composite formulation for oral administration comprising ezetimibe and rosuvastatin
GR1009727B (el) * 2018-11-28 2020-04-14 Elpen Αε Φαρμακευτικη Βιομηχανια Μονολιθικη σταθερη φαρμακοτεχνικη μορφη ταχειας αποδεσμευσης εζετιμιμπης και ροσουβαστατινης
CN117137876A (zh) * 2023-08-07 2023-12-01 福建东瑞制药有限公司 瑞舒伐他汀钙片及其制备方法

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WO1995008532A1 (fr) 1993-09-21 1995-03-30 Schering Corporation Composes d'azetidinone hydroxy-substitues efficaces en tant qu'agents hypocholesterolemiques
WO2002058696A2 (fr) 2001-01-26 2002-08-01 Schering Corporation Utilisation de composes d'azetidinone substituee pour le traitement de la sitosterolemie
WO2006110882A2 (fr) 2005-04-12 2006-10-19 Psivida Inc. Combinaisons d'inhibiteurs de hmgcoa reductases et leurs utilisations
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

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AR040588A1 (es) * 2002-07-26 2005-04-13 Schering Corp Formulacion farmaceutica que comprende un inhibidor de la absorcion del colesterol y un inhibidor de una hmg- co a reductasa
EP1741427A1 (fr) * 2005-07-06 2007-01-10 KRKA, D.D., Novo Mesto Composition pharmaceutique comprenant la simvastatin et l'ezetimibe
EP2120882A2 (fr) * 2007-02-23 2009-11-25 Krka Composition pharmaceutique comprenant un inhibiteur d'absorption du cholestérol
WO2009024889A2 (fr) * 2007-08-21 2009-02-26 Ranbaxy Laboratories Limited Composition pharmaceutique comprenant un inhibiteur de réductase hmg-coa et un ézétimibe

Patent Citations (11)

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Publication number Priority date Publication date Assignee Title
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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
WO2013166117A1 (fr) * 2012-05-01 2013-11-07 Althera Life Sciences, Llc Formulation de comprimé oral constituée d'une combinaison fixe de rosuvastatine et d'ézétimibe pour le traitement de l'hyperlipidémie et de maladies cardiovasculaires
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
WO2015044698A3 (fr) * 2013-09-30 2015-05-14 Egis Gyógyszergyár Zrt. Composition médicale contenant un inhibiteur de l'absorption du cholestérol et un inhibiteur de la biosynthèse du cholestérol
CN114796148A (zh) * 2013-09-30 2022-07-29 埃吉斯药物私人有限公司 含有胆固醇吸收抑制剂和胆固醇生物合成抑制剂的药物组合物
EA034711B1 (ru) * 2013-09-30 2020-03-12 Эгиш Дьёдьсердьяр Зрт. Лекарственная композиция, содержащая ингибитор всасывания холестерина и ингибитор биосинтеза холестерина
EP3085364A4 (fr) * 2013-12-18 2017-08-23 Alvogen Korea Co., Ltd. Préparation pharmaceutique combinée contenant un inhibiteur de hmg-coa réductase et un inhibiteur de l'absorption du cholestérol
RU2649811C2 (ru) * 2013-12-18 2018-04-04 Алвоген Кореа Ко, Лтд. ФАРМАЦЕВТИЧЕСКИЙ КОМБИНИРОВАННЫЙ ПРЕПАРАТ, СОДЕРЖАЩИЙ ИНГИБИТОР HMG-СоА РЕДУКТАЗЫ И ИНГИБИТОР АБСОРБЦИИ ХОЛЕСТЕРИНА
CN113069456A (zh) * 2013-12-18 2021-07-06 艾威群韩国株式会社 含有HMG-CoA还原酶抑制剂和胆固醇吸收抑制剂的药物组合制剂
US10434067B2 (en) 2013-12-30 2019-10-08 Hanmi Pharm. Co., Ltd. Composite formulation for oral administration comprising ezetimibe and rosuvastatin
WO2015199356A1 (fr) * 2014-06-25 2015-12-30 Hanmi Pharm. Co., Ltd. Formulation composite pour administration par voie orale comprenant de l'ézétimibe et de la rosuvastatine et procédé de préparation associé
EP3243506A1 (fr) * 2016-05-09 2017-11-15 Adamed sp. z o.o. Composition pharmaceutique
WO2018041282A1 (fr) 2016-09-05 2018-03-08 Zentiva, K.S. Composition pharmaceutique comprenant de la rosuvastatine et de l'ézétimibe et son procédé de préparation
WO2018041281A1 (fr) 2016-09-05 2018-03-08 Zentiva, K.S. Composition pharmaceutique comprenant de la rosuvastatine et de l'ézétimibe et son procédé de préparation
GR1009727B (el) * 2018-11-28 2020-04-14 Elpen Αε Φαρμακευτικη Βιομηχανια Μονολιθικη σταθερη φαρμακοτεχνικη μορφη ταχειας αποδεσμευσης εζετιμιμπης και ροσουβαστατινης
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