WO2009024889A2 - Composition pharmaceutique comprenant un inhibiteur de réductase hmg-coa et un ézétimibe - Google Patents

Composition pharmaceutique comprenant un inhibiteur de réductase hmg-coa et un ézétimibe Download PDF

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Publication number
WO2009024889A2
WO2009024889A2 PCT/IB2008/053198 IB2008053198W WO2009024889A2 WO 2009024889 A2 WO2009024889 A2 WO 2009024889A2 IB 2008053198 W IB2008053198 W IB 2008053198W WO 2009024889 A2 WO2009024889 A2 WO 2009024889A2
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Prior art keywords
pharmaceutical composition
ezetimibe
hmg
coa reductase
composition according
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PCT/IB2008/053198
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English (en)
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WO2009024889A3 (fr
Inventor
Sumit Madan
Arno Appavoo Enose
Vikas Batra
Anupam Trehan
Vinod Arora
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Ranbaxy Laboratories Limited
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Publication of WO2009024889A2 publication Critical patent/WO2009024889A2/fr
Publication of WO2009024889A3 publication Critical patent/WO2009024889A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K9/2072—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
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • 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
    • A61P3/06—Antihyperlipidemics

Definitions

  • This invention relates to pharmaceutical compositions comprising a HMG-CoA reductase inhibitor and ezetimibe, and processes for the preparation of the same.
  • Ezetimibe chemically, l-(4-fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)- hydroxypropyl]-4(S)-(4-hydroxyphenyl) -2-azetidinone, is a cholesterol absorption inhibitor.
  • the therapeutic uses of ezetimibe and related compounds, and their preparations were disclosed in U.S. Patent No. 5,767,115.
  • Ezetimibe is commercially available as 10 mg tablets. It is sold under the name ZetiaTM.
  • Ezetimibe is available in the U.S. in a combination with simvastatin, sold under the trade name VytorinTM.
  • HMG-CoA reductase inhibitors are currently among the most therapeutically effective drugs available for reducing the level of LDL in the blood stream of a patient at risk for cardiovascular disease.
  • the mechanism of action of HMG-CoA reductase inhibitors has been elucidated in some detail. It is believed that HMG-CoA reductase inhibitors disrupt the biosynthesis of cholesterol and other sterols in the liver by competitively inhibiting the 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase enzyme ("HMG-CoA reductase").
  • HMG-CoA reductase catalyzes the conversion of HMG-CoA to mevalonate, which is the rate determining step in the biosynthesis of cholesterol.
  • the main HMG-CoA reductase inhibitors currently used in therapeutics are: pravastatin, simvastatin, lovastatin, fluvastatin, atorvastatin and cerivastatin.
  • Lovastatin, simvastatin and pravastatin are derived from fungi, whereas fluvastatin and atorvastatin have an entirely synthetic origin.
  • Simvastatin is a chemically modified 2,2-dimethyl- butyrate analogue of lovastatin.
  • Pravastatin is a purified active metabolite of mevastatin with an open hydroxyacid instead of a lactone ring.
  • Pravastatin sodium (sold in the U.S. under the trademark PravacholTM) is sensitive to a low pH environment and will degrade to form its lactone and various isomers.
  • PravacholTM is sensitive to a low pH environment and will degrade to form its lactone and various isomers.
  • Joshi et al. stated in U.S. Patent No. 5,180,589, that in order to stabilize the pharmaceutical composition of pravastatin, it is necessary to add one or more basifying agents to impart a pH of at least 9.
  • Atorvastatin which is an inhibitor of the enzyme 3 -hydroxy- 3 -methyl glutaryl coenzyme A reductase (HMG-CoA reductase), is commercially available for the treatment of primary hypercholesterolemia, dysbetalipoproteinemia and homozygous familial hypercholesterolemia. Atorvastatin is commercially available as 10 mg, 20 mg, 40 mg and 80 mg tablets. It is sold under the name LipitorTM.
  • U.S. Patent Nos. 5,686,104 and 6,126,971 disclose oral pharmaceutical formulations of atorvastatin in which the formulation is described as being stabilized by the addition of a pharmaceutically acceptable alkaline earth metal salt.
  • U.S. Patent Publication No. 2002/0169134 discloses a pharmaceutical composition for the treatment or prevention of sitosterolemia comprising ezetimibe and lipid lowering agents including atorvastatin.
  • U.S. Patent No. 7,229,982 discloses a pharmaceutical composition comprising ezetimibe, simvastatin, BHA, and citric acid, wherein the composition is free of ascorbic acid.
  • PCT Publication WO 2006/134604 discloses a pharmaceutical composition of ezetimibe with various statins such as atorvastatin, simvastatin and rosuvastatin.
  • the pharmaceutical composition discloses a tablet of ezetimibe and statin wherein all the excipients are blended with active ingredients, granulated and compressed into suitable size tablets.
  • Statins can tend to be relatively unstable, and their degradation may be catalyzed by several parameters like oxygen, humidity, acidity and temperature.
  • Alternate compositions are presented herein wherein the atorvastatin component is prepared separately and then blended with ezetimibe granules. Further, ezetimibe is also susceptible to degradation in the presence of alkali metal salts whereas it can be stable in the presence of alkaline earth metal salt additives.
  • Alternate compositions of HMG-CoA reductase inhibitor and ezetimibe have now been developed wherein the composition comprises two components. One component comprises a HMG-CoA reductase inhibitor and the second component comprises granules of ezetimibe.
  • compositions of HMG- CoA reductase inhibitors and ezetimibe for oral administration comprising: a) a first component comprising an HMG-CoA reductase inhibitor or pharmaceutically acceptable salts thereof; and b) a second component comprising granules of ezetimibe.
  • processes for the preparation of pharmaceutical composition of a HMG-CoA reductase inhibitor and ezetimibe for oral administration comprising: combining a first component comprising HMG-CoA reductase inhibitor or pharmaceutically acceptable salts thereof; with a second component comprising granules of ezetimibe.
  • a pharmaceutical composition of HMG-CoA reductase inhibitor and ezetimibe comprising: a) a first component comprising HMG-CoA reductase inhibitor or pharmaceutically acceptable salts thereof; and b) a second component comprising granules of ezetimibe.
  • pharmaceutical compositions for oral administration comprising ezetimibe and at least one alkaline earth metal salt additive.
  • compositions of a HMG-CoA reductase inhibitor and ezetimibe for oral administration comprising a) a first component comprising HMG-CoA reductase inhibitor or pharmaceutically acceptable salts thereof and at least one alkaline earth metal salt additive; and b) a second component comprising granules of ezetimibe.
  • processes for the preparation of pharmaceutical compositions of a HMG-CoA reductase inhibitor and ezetimibe for oral administration comprising: a) combining a first component comprising HMG-CoA reductase inhibitor or pharmaceutically acceptable salts thereof and at least one alkaline earth metal salt additive, with a second component comprising granules of ezetimibe.
  • compositions of a HMG-CoA reductase inhibitor and ezetimibe for oral administration comprising: a) a first component comprising HMG-CoA reductase inhibitor and at least one alkaline earth metal salt additive, and b) a second component comprising granules of ezetimibe.
  • HMG-CoA reductase inhibitor refers to atorvastatin, rosuvastatin, pravastatin, simvastatin, lovastatin, fluvastatin, and cerivastatin.
  • Pharmaceutically acceptable base addition salts of HMG-CoA reductase inhibitors may be formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like.
  • Suitable amines are N, N-1-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine. These may exist in any of the solid state forms available such as amorphous or any other polymorphic form. They can be present in the composition in an amount up to about 50% by weight of the composition.
  • Ezetimibe refers to include any polymorphic form available of ezetimibe such as anhydrous, hydrated or amorphous form. It is present in the composition in an amount 5-20% by weight of HMG-CoA reductase inhibitor component and in an amount 1-10% by weight of total composition.
  • the HMG-CoA reductase inhibitor and ezetimibe combination is indicated as adjunctive therapy to diet for the reduction of elevated total-C, LDL-C, Apo B, TG, and non-HDL-C levels, and to increase HDL-C levels in patients with primary (heterozygous familial and non-familial) hypercholesterolemia or mixed hyperlipidemia. It is also indicated for the reduction of elevated total-C and LDL-C levels in patients with homozygous familial hypercholesterolemia, as an adjunct to other lipid-lowering treatments.
  • HMG-CoA reductase inhibitor or ezetimibe can be milled to obtain a desired particle size.
  • the desired size is obtained either directly through the synthesis or by using conventional milling techniques, such as air-jet milling, ball milling, cad milling, multi milling and other suitable size-reduction techniques.
  • the particle size of the atorvastatin can be reduced to particle size dgo of, for example, less than or equal to about 200 ⁇ m, and more particularly to particle size of between approximately 5 ⁇ m and 50 ⁇ m.
  • the particle size of rosuvastatin used may be dgo less than about 60 ⁇ m, more particularly less than about 20 ⁇ m.
  • Ezetimibe may have a particle size dgo of less than about 10 ⁇ m.
  • the size of the particles may be analyzed using a conventional particle size analyzer (e.g., a Malvern Master Sizer).
  • alkaline earth metal salt additives can include calcium carbonate, calcium hydroxide, calcium phosphate, magnesium carbonate, magnesium hydroxide, magnesium silicate, magnesium aluminate, aluminum magnesium hydroxide or mixtures thereof.
  • the amount of alkaline earth metal salt additives may vary from about 0.1 to about 30% by weight of the HMG-CoA reductase component, or for example, from about 1-10% by weight of the HMG-CoA reductase component.
  • the two components are further processed to obtain the pharmaceutical composition such as a monolayer tablet, bilayer tablet, capsule, pill and the like.
  • the HMG-CoA reductase inhibitor component may be in the form of granules; or may be in the form of blend. Ezetimibe granules may be prepared by granulation using granulating fluid or a binder solution or by dry granulation process such as roller compaction or slugging.
  • the pharmaceutical composition may further comprise pharmaceutically acceptable inert excipients.
  • pharmaceutically acceptable inert excipient includes substances known in the art as diluents, binders, disintegrants, stabilizers, surfactants and lubricants/glidants. The excipients are selected based on the desired physical aspects of the final tablets; e.g., obtaining a tablet with desired hardness and friability, being rapidly dispersible and easily swallowed, etc.
  • antioxidant means an agent that stabilizes the drug, for example, chelating agents, photoprotectants and antioxidants.
  • suitable antioxidants can include, for example, butylated hydroxyanisole (BHA), sodium ascorbate, butylated hydroxytoluene (BHT), sodium sulfite, propyl gallate, tocopherol, citric acid, malic acid, ascorbic acid or mixtures thereof.
  • BHA butylated hydroxyanisole
  • BHT butylated hydroxytoluene
  • the antioxidants can be present at concentrations of, for example, from about 0.01% to about 5% by weight.
  • the antioxidants may be dissolved in organic solvents such as, for example, ethanol, isopropanol, n-propanol, acetone, ethyl acetate or mixtures thereof and sprayed on to pharmaceutically acceptable inert excipients. These antioxidants may be present in either or both the components.
  • chelating agents can include, for example, disodium EDTA, edetic acid, citric acid, and combinations thereof.
  • the chelating agents can be present at a concentration of up to approximately 10% by weight of the composition, for example, from about 0.01 to about 5% by weight.
  • photoprotectant means an agent for the protection from light.
  • examples can include metal oxides such as titanium oxide, ferric oxide or zinc oxide.
  • the photoprotectant can be present at a concentration of up to approximately 10% by weight of the composition, for example, from about 0.01 to about 5% by weight.
  • Suitable binders can include methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth or sodium alginate or mixtures thereof.
  • diluents can include mannitol, pregelatinized starch, lactose, cellulose powdered, microcrystalline cellulose, dextrates, dextrins, dextrose, fructose, kaolin, lactitol, lactose, sorbitol, starch, sucrose, or sugar compressible or mixtures thereof.
  • Suitable disintegrants can include croscarmellose sodium, starch, crospovidone or sodium starch glycolate or mixtures thereof.
  • Suitable surfactants can include polysorbate 80, polyoxyethylene sorbitan, polyoxyethylene -polyoxypropylene copolymer, or sodium lauryl sulphate or mixtures thereof.
  • concentration of surfactant may vary from 1-10% by weight of the composition.
  • lubricants and glidants can include magnesium stearate, sodium stearyl fumarate, colloidal anhydrous silica, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, or mixtures thereof.
  • HMG-CoA reductase inhibitor and ezetimibe may be present in the same matrix or may be separated by one or more pharmaceutically acceptable inert excipients.
  • a pharmaceutical composition in the form of a monolayer tablet comprising: a) a first component comprising HMG-CoA reductase inhibitor and an alkaline earth metal additive; and b) a second component comprising ezetimibe granules.
  • a process for the preparation of a pharmaceutical composition comprising the steps of: i) Preparation of HMG-CoA reductase inhibitor component a) blending HMG-CoA reductase inhibitor, an alkaline earth metal additive and one or more pharmaceutically acceptable inert excipients; b) optionally, granulating the blend of step a); ii) Preparation of ezetimibe component a) blending ezetimibe and one or more pharmaceutically acceptable inert excipients; b) granulating the blend; c) optionally, adding extragranular excipients; iii) Blending the components of step i) and ii); and iv) Lubricating the blend of step iii) and compressing into suitable size tablets.
  • the pharmaceutical composition may be provided in the form of a tablet wherein
  • HMG-CoA reductase inhibitor and ezetimibe are processed to form a bilayer tablet.
  • a pharmaceutical composition in the form of a bilayer tablet wherein a) the first layer comprises HMG-CoA reductase inhibitor and an alkaline earth metal additive; and b) the second layer comprises ezetimibe granules.
  • a process for the preparation of a pharmaceutical composition comprising the steps of: i) Preparation of HMG-CoA reductase inhibitor component a) blending HMG-CoA reductase inhibitor, an alkaline earth metal additive and one or more pharmaceutically acceptable inert excipients; b) optionally granulating the blend; c) lubricating the blend or granules; ii) Preparation of ezetimibe component a) blending ezetimibe and one or more pharmaceutically acceptable inert excipients; b) granulating the blend; c) lubricating the blend or granules; and iii) Compressing the two components of step i) and ii) into a bilayer tablet.
  • the pharmaceutical composition may be provided in the form of a capsule wherein HMG-CoA reductase inhibitor component is in the form of tablet and ezetimibe component is in the form of the granules.
  • a pharmaceutical composition in the form of a capsule comprising: a) a tablet comprising HMG-CoA reductase inhibitor and an alkaline earth metal additive; and b) ezetimibe granules.
  • a process for the preparation of a pharmaceutical composition comprising the steps of: i) Preparation of atorvastatin component a) blending atorvastatin, an alkaline earth metal additive and one or more pharmaceutically acceptable inert excipients; b) optionally granulating the blend; c) lubricating the blend or granules; d) compressing into suitable size tablet; ii) Preparation of ezetimibe component a) blending ezetimibe and one or more pharmaceutically acceptable inert excipients; b) granulating ezetimibe and drying the granules; iii) Filling the atorvastatin tablet of step i) and ezetimibe granule of step ii) into a capsule.
  • a pharmaceutical composition in the form of a capsule comprising: a) a blend of HMG-CoA reductase inhibitor and alkaline earth metal additive; and b) a tablet comprising ezetimibe granules.
  • a process for the preparation of a pharmaceutical composition comprising the steps of: i) Preparation of HMG-CoA reductase inhibitor component a) blending HMG-CoA reductase inhibitor, an alkaline earth metal additive and one or more pharmaceutically acceptable inert excipients; b) optionally granulating the blend; ii) Preparation of ezetimibe component a) blending ezetimibe and one or more pharmaceutically acceptable inert excipients; b) granulating the blend; c) lubricating the blend or granules; and d) compressing into suitable size tablet; iii) Filling the HMG-CoA reductase inhibitor component of step i) and ezetimibe tablet of step ii) into a capsule.
  • a pharmaceutical composition in the form of a capsule comprising: i) a tablet of HMG-CoA reductase inhibitor and alkaline earth metal additive; and ii) a tablet comprising ezetimibe granules.
  • a process for the preparation of a pharmaceutical composition comprising the steps of: i) Preparation of atorvastatin component a) blending atorvastatin and one or more pharmaceutically acceptable inert excipients; b) optionally granulating the blend using roller compactor or slugging; c) compressing the blend or granules into suitable size tablets; ii) Preparation of ezetimibe component a) blending ezetimibe and one or more pharmaceutically acceptable inert excipients; b) granulating the blend; c) lubricating the blend or granules, d) compressing into suitable size tablet, iii) Filling the atorvastatin tablet of step i) and ezetimibe tablet of step ii) into a capsule.
  • the pharmaceutical composition may be further film coated with functional or non functional layer.
  • the coating may be selected from amongst one or more of those suitable coating materials known in the art.
  • the coating material can be Opadry or Opadry AMB (aqueous moisture barrier).
  • coloring agents include any FDA approved colors for oral use.
  • Coating may be performed by applying one or more film forming polymers, with or without other pharmaceutically acceptable inert excipients, as a solution/suspension using any conventional coating technique known in the art, such as spray coating in a conventional coating pan or fluidized bed processor; or dip coating.
  • the pharmaceutical composition may be packaged in unit dosage pack such as blister or into multiunit dosage pack such as bottle.
  • the bottle may be an oxygen permeable container such as HDPE bottle or oxygen impermeable container such as Polyethylene and ethylene vinyl alcohol or glass bottle.
  • the packaging may further comprise oxygen absorbers or desiccants.
  • Ezetimibe was mixed with croscarmellose sodium and lactose and was transferred to rapid mixer granulator and mixed for 15 minutes.
  • step 1 Povidone and sodium lauryl sulfate were dissolved in purified water till clear solution was obtained. 3. Blend of step 1 was granulated with the binder solution of step 2 and the granules so obtained were dried.
  • the ezetimibe blend prepared above was blended with sodium carbonate (6.5 g) and mixed till a uniform blend was obtained.
  • the ezetimibe blend prepared above was blended with calcium carbonate (7.5 g) and mixed till a uniform blend was obtained.
  • Amount equivalent to eight tablets of the ezetimibe blend and sodium carbonate were dispersed in tetrahydrofuran and then acetonitrile was added and filtered. The clear solution was used for HPLC analysis and total impurity was determined. All the samples were analyzed by HPLC method using an Inertsil ODS column.
  • Amount equivalent to eight tablets of the ezetimibe blend and calcium carbonate were dispersed in tetrahydrofuran and then acetonitrile was added and filtered. The clear solution was used for HPLC analysis and total impurity was determined. All the samples were analyzed by HPLC method using Inertsil ODS column and the results are given in Table 1 indicating ezetimibe is stable in the presence of alkaline earth metal salts.
  • Ezetimibe was blended with croscarmellose sodium and lactose, ii) Sodium lauryl sulphate and povidone were dissolved in water. iii) The blend of step i) was granulated with solution of step ii). iv) The granules of step iii) were dried. v) The granules of step iv) were blended with extragranular croscarmellose sodium and microcrystalline cellulose. c) Atorvastatin blend and granules of ezetimibe were blended together and lubricated with magnesium stearate. d) The lubricated blend of step c) was compressed into suitable size tablet. e) The tablet of step d) were coated with a dispersion of Opadry and Sunset Yellow in water.
  • Atorvastatin Component i) Atorvastatin calcium, sodium lauryl sulphate, hydroxypropylcellulose-L, half quantity of croscarmellose sodium and a part of colloidal silicon dioxide and three-fourth quantity of microcrystalline cellulose were blended, ii) Butylated hydroxyanisole and butylated hydroxytoluene were dissolved in isopropyl alcohol. iii) The three fourth quantity of lactose was sifted. iv) The solution of step ii) was added to the bulk of step iii) and mixed. v) The wet mass was dried at 30 C - 40 C in fluidized bed drier and passed through sieve.
  • step i) Calcium carbonate was milled and passed through the sieve. vii)The remaining quantity of microcrystalline cellulose was passed through multimill. viii) The remaining quantity of croscarmellose sodium and remaining part of colloidal silicon dioxide were blended with remaining quantity of lactose, ix) The blends of step i), v)-viii) were mixed together. b) Preparation of Ezetimibe Component i) Ezetimibe was blended with croscarmellose sodium and lactose. ii) Sodium lauryl sulphate and povidone were dissolved in water. iii) The blend of step i) was granulated with solution of step ii).
  • step iv) The granules of step iii) were dried.
  • step v) The granules of step iv) were blended with extragranular croscarmellose sodium and microcrystalline cellulose.
  • Atorvastatin blend and granules of ezetimibe were blended together and lubricated with magnesium stearate.
  • the lubricated blend of step c) was compressed into suitable size tablet.
  • step d) were coated with a dispersion of Opadry and Sunset Yellow in water.
  • Ezetimibe was blended with croscarmellose sodium and lactose, ii) Sodium lauryl sulphate and povidone were dissolved in water, iii) The blend of step i) was granulated with solution of step ii). iv) The granules of step iii) were dried. v) The granules of step iv) were blended with extragranular croscarmellose sodium and microcrystalline cellulose. c) The granules of rosuvastatin and ezetimibe were mixed together. d) Crospovidone, croscarmellose sodium and microcrystalline cellulose were mixed together.
  • step e) The blend of step c) and d) were blended together.
  • step f) The blend of step e) was lubricated using magnesium stearate and compressed into suitable size tablet.
  • Opadry and ferric oxide red were dispersed in water.
  • step f) The tablets of step f) were coated with dispersion of step g).
  • step ii) Blend about 3/4th quantity of microcrystalline cellulose, pregelatinized starch and colloidal silicon dioxide.
  • step iii) Add the solution of step i) to the bulk of step ii and mix.
  • step iii) Dry the wet mass at 40 C - 45 C in a fluidized bed drier and pass through a sieve.
  • atorvastatin calcium, sodium lauryl sulphate and hydroxypropylcellulose through the screen of a quadro comil.
  • step iv) Blend the granules of step iv) with croscarmellose sodium.
  • c) Blend atorvastatin blend and granules of ezetimibe and lubricate with magnesium stearate.
  • d) Compress the lubricated blend of step c) into suitable size monolayer tablet.
  • e) Coat the tablet of step d) with a dispersion of Opadry and Sunset Yellow in water.

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Abstract

La présente invention se rapporte à une composition pharmaceutique d'un inhibiteur de réductase HMG-CoA et d'un ézétimibe adaptée pour une administration orale comprenant un premier composant comprenant un inhibiteur de réductase HMG-CoA ou des sels pharmaceutiquement acceptables de celui-ci et un additif de sel de métal alcalino-terreux ; et un second composant comprenant des granulés d'ézétimibe. En outre, elle se rapporte à une composition pharmaceutique adaptée pour une administration orale comprenant un ézétimibe et un additif de sel de métal alcalino-terreux.
PCT/IB2008/053198 2007-08-21 2008-08-08 Composition pharmaceutique comprenant un inhibiteur de réductase hmg-coa et un ézétimibe WO2009024889A2 (fr)

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Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010063667A2 (fr) * 2008-12-01 2010-06-10 Lek Pharmaceuticals D.D. Composition pharmaceutique contenant de l’ézétimibe et de la simvastatine
WO2011002422A3 (fr) * 2009-07-02 2011-04-28 Bilgic Mahmut Formulation pharmaceutique améliorant la solubilité
WO2011019326A3 (fr) * 2009-07-02 2011-04-28 Mahmut Bilgic Formulation pharmaceutique permettant d'augmenter la solubilité et la stabilité
EP2368543A1 (fr) 2010-03-25 2011-09-28 KRKA, tovarna zdravil, d.d., Novo mesto Procédé de préparation de composition pharmaceutique granulée comprenant de la simvastatine et/ou ézétimibe
WO2011139256A3 (fr) * 2010-05-04 2012-05-18 Bilgic Mahmut Formulations stables de rosuvastatine
WO2012064307A1 (fr) 2010-11-11 2012-05-18 Bilgic Mahmut Compositions pharmaceutiques comprenant la rosuvastatine
WO2013166114A1 (fr) * 2012-05-01 2013-11-07 Althera Life Sciences, Llc Formulation de comprimé oral constituée d'une combinaison fixe d'atorvastatine et d'ézétimibe
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
EP2805714A1 (fr) * 2013-04-25 2014-11-26 Antibiotice S.A. Composition pharmaceutique stable comprenant de la rosuvastatine calcique amorphe
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WO2015102400A1 (fr) * 2013-12-30 2015-07-09 Hanmi Pharm. Co., Ltd. Préparation composite pour une administration orale comportant de l'ézétimibe et de la rosuvastatine
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
US20170354604A1 (en) * 2012-05-01 2017-12-14 Althera Laboratories Ltd Oral Tablet Formulation Consisting Of Fixed Combination Of Rosuvastatin And Ezetimibe For Treatment Of Hyperlipidemia And Cardiovascular Diseases
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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
WO2018101681A1 (fr) * 2016-11-29 2018-06-07 Hanmi Pharm. Co., Ltd. Comprimé composite oral comprenant de l'ézétimibe et de la rosuvastatine
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US20190008779A1 (en) * 2017-05-11 2019-01-10 Gemphire Therapeutics Inc. Gemcabene compositions and methods of use thereof
WO2019182276A1 (fr) * 2018-03-19 2019-09-26 Hanmi Pharm. Co., Ltd. Préparation d'une association de produits pharmaceutiques comprenant de l'ézétimibe et de la rosuvastatine
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WO2020213868A1 (fr) * 2019-04-18 2020-10-22 한미약품 주식회사 Préparation d'une association de produits pharmaceutiques comprenant de l'ézétimibe et du losartan
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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

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