WO2008101723A2 - Pharmaceutical composition containing a cholesterol absorption inhibitor - Google Patents

Pharmaceutical composition containing a cholesterol absorption inhibitor Download PDF

Info

Publication number
WO2008101723A2
WO2008101723A2 PCT/EP2008/001436 EP2008001436W WO2008101723A2 WO 2008101723 A2 WO2008101723 A2 WO 2008101723A2 EP 2008001436 W EP2008001436 W EP 2008001436W WO 2008101723 A2 WO2008101723 A2 WO 2008101723A2
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
cholesterol absorption
absorption inhibitor
hydrophilic polymer
previous
Prior art date
Application number
PCT/EP2008/001436
Other languages
French (fr)
Other versions
WO2008101723A3 (en
Inventor
Vesna Kroselj
Matej Smrkolj
Original Assignee
Krka
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Krka filed Critical Krka
Priority to EP08715987A priority Critical patent/EP2120882A2/en
Publication of WO2008101723A2 publication Critical patent/WO2008101723A2/en
Publication of WO2008101723A3 publication Critical patent/WO2008101723A3/en

Links

Classifications

    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • 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
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • 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
    • A61K9/2013—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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • 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
    • A61K9/2072—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

  • the present invention relates to the field of pharmaceutical technology and particular to the novel pharmaceutical compositions comprising cholesterol absorption inhibitor and pharmaceutically acceptable excipients.
  • (I) is a representative of a class of compounds known as lipid-lowering compounds that selectively inhibits the intestinal absorption of cholesterol and related phytosterols. Its mechanism of action differs from those of other classes of cholesterol lowering compounds, such as HMG-CoA reductase inhibitors. It does not inhibit cholesterol synthesis in the liver or increase bile excretion but inhibits absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver. Such mechanism is complementary to that of HMG-CoA reductase inhibitors.
  • Ezetimibe is marketed under the tradename ZETIA ® or EZETROL ® , which is available as a tablet for oral administration containing 10 mg of ezetimibe and the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, povidone, sodium lauryl sulphate and magnesium stearate.
  • Ezetimibe is practically insoluble in water, which causes it to exhibit a low dissolution rate in aqueous media, e.g. gastrointestinal fluids, which can result in low bioavailability after oral ingestion.
  • Ezetimibe is included in several different pharmaceutical compositions, described for example in EP 720 599 A, wherein the corn starch is present in the pharmaceutical formulation
  • EP 1353696 Bl discloses the formulation containing ezetimibe, lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium, sodium lauryl sulfate and magnesium stearate
  • WO 03/055464 discloses a micronized pharmaceutical powder with immediate release having a grain size distribution of not more than 100 ⁇ m, and comprising of at least an active substance, at least a wetting agent and at least a diluent
  • WO 03/068186 discloses formulation, comprising active ingredients of a great variety and a pharmaceutically acceptable vehicle comprising at least one compound selected from the group consisting of hydrophilic surfactant, a lipophilic surfactant, a triglyceride and a solubilizer
  • WO 2007/011349 discloses a granulate wherein the poorly water
  • ezetimibe and simvastatin stabilized by antioxidant are known, for example the pharmaceutical combination of ezetimibe and simvastatin stabilized by antioxidant is disclosed in WO 2004/010993, WO 2006/134604 discloses the pharmaceutical composition comprising ezetimibe and HMG-CoA reductase inhibitor as active ingredients and disintegrant, glidants and magnesium stearate as pharmaceutical excipients, WO 2007/003365 discloses a pharmaceutical composition comprising simvastatin and ezetimibe wherein the use of antioxidants are omitted.
  • the first embodiment of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one cholesterol absorption inhibitor in amorphous form and at least one hydrophilic polymer, wherein the amorphous cholesterol absorption inhibitor is finely distributed within the hydrophilic polymer.
  • the second embodiment of the present invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one cholesterol absorption inhibitor in amorphous form and at least one hydrophilic polymer, wherein said composition comprises a carrier with finely dispersed at least one cholesterol absorption inhibitor and at least one hydrophilic polymer.
  • Another aspect of the present invention is the process of the production of the pharmaceutical composition according to the present invention.
  • Yet another aspect of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising at least one cholesterol absorption inhibitor in amorphous form and at least one hydrophilic polymer wherein the amorphous form of cholesterol absorption inhibitor is stable throughout the shelflife of the pharmaceutical composition.
  • Yet another aspect of the present invention is the use of a pharmaceutical composition comprising at least one cholesterol absorption inhibitor in amorphous form and at least one hydrophilic polymer for providing amorphous form of cholesterol absorption inhibitor throughout the shelflife of the pharmaceutical composition.
  • Another aspect of the present invention is the method of treating lipid disorders comprising administering a pharmaceutical composition according to the present invention.
  • Fig. 1 shows a comparison of dissolution profiles of Ezetrol 10 mg tablets and Ezetimibe 10 mg tablets of example 4.
  • the first embodiment of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one cholesterol absorption inhibitor in amorphous form and at least one hydrophilic polymer, wherein the amorphous cholesterol absorption inhibitor is finely distributed within the hydrophilic polymer.
  • the second embodiment of the present invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one cholesterol absorption inhibitor in amorphous form and at least one hydrophilic polymer, wherein said composition comprises a carrier with finely dispersed at least one cholesterol absorption inhibitor and at least one hydrophilic polymer.
  • the cholesterol absorption inhibitor is selected from the group consisting of hydroxyl- substituted azetidinones.
  • the cholesterol absorption inhibitor used in the pharmaceutical composition according to the present invention can be in any crystalline or amorphous form with any particle size distribution and/or particle morphology.
  • An example of such cholesterol absorption inhibitor is ezetimibe.
  • Ezetimibe that can be used in the present invention as a cholesterol absorption inhibitor may be prepared by any method known from the literature such as for example EP 0720599, EP 1169468, WO 2004/099132, WO 2005/066120, WO 2006/050634 WO 2006/068990, WO 2006/137080, WO 2007/017705, US 2007/0049748, WO 2007/030721, WO 2007/072088, WO 2007/119106, WO 2007/108007, WO 2007/120824 and PCT/EP2008/000546 and isolated/crystallized or further purified by processes known from the prior art (as for example WO 2004/099132, WO 2005/066120, WO 2006/060808, WO 2005/062897, WO 2005/009955, WO 2006/050634, IPCOM000131677, G.Y.S.K.Swamy at all, Acta Cryst.
  • Ezetimibe exists in different polymorphic and pseudo- polymorphic forms, which are disclosed in for example WO 2005/009955, WO 2005/062897, WO 2006/060808, US 2006/0234996, IPCOMOOOl 31677D, PCT/EP2008/000546.
  • the pharmaceutical composition according to the present invention may comprise from about 1 % to about 50 % by weight of the cholesterol absorption inhibitor, preferably from about 3 % to about 30 %, more preferably from about 5 % to about 20 %.
  • the cholesterol absorption inhibitor present in the pharmaceutical composition according to the present invention is in amorphous form. As the cholesterol absorption inhibitor is dissolved during the process, the amorphous form is formed regardless of the polymorphic form of the starting material. Still more, the amorphous polymorph form is maintained during the shelf life of the product. Moreover, the particle size or shape of the starting material does not affect the dissolution profile of the pharmaceutical composition according to the present invention. This represents a great advantage important particularly for the low-soluble substances incorporated into the final dosage form which generally require careful control of particle size.
  • the hydrophilic polymer used in the pharmaceutical composition according to the present invention may be selected from the group consisting of, but not limited to, povidone, cellulose derivatives (such as for example hydroxypropylcellulose - HPC, hydroxypropylmethylcellulose - HPMC), polyvinyl alcohol, polyethylene glycols (PEG's), poloxamers, gelatin, Eudragits® or other pharmaceutically acceptable hydrophilic polymers.
  • povidone (PVP), hydroxypropylcellulose (HPC) or hydroxypropylmethylcellulose (HPMC) may be used.
  • the pharmaceutical composition according to the present invention may comprise from about 0.1 % to about 50 % by weight of the hydrophilic polymer, preferably from about 0.3 % to about 30 %.
  • Carriers used in the second embodiment of the pharmaceutical compositions according to the second aspect of the present invention may be selected from the group consisting of, but not limited to, lactose monohydrate, anhydrous lactose, starch and starch derivatives, mannitol, xylitol, sorbitol, microcrystalline cellulose, powdered cellulose, magnesium stearate, silica colloidal anhydrous and mixtures thereof.
  • lactose monohydrate, anhydrous lactose, microcrystalline cellulose and/or their mixtures can be used as carriers.
  • the pharmaceutical composition according to the present invention may comprise from about 5 % to about 95 % by weight of the carrier, preferably from about 10 % to about 90 %, more preferably from about 30 % to about 80 %.
  • the pharmaceutical composition according to the present invention may further comprise one or more other active ingredients such as for example other lipid lowering drugs such as for example fenofibrate, bezafibrate, HMG-CoA reductase inhibitors, such as for example representatives of statin group such as simvastatin, atorvastatin, lovastatin, rosuvastatin or salts thereof and any mixtures thereof.
  • active ingredient such as for example other lipid lowering drugs such as for example fenofibrate, bezafibrate, HMG-CoA reductase inhibitors, such as for example representatives of statin group such as simvastatin, atorvastatin, lovastatin, rosuvastatin or salts thereof and any mixtures thereof.
  • statin group such as simvastatin, atorvastatin, lovastatin, rosuvastatin or salts thereof and any mixtures thereof.
  • statin group such as simvastatin, atorvastatin
  • the pharmaceutical composition according to the present invention may further comprise other pharmaceutically acceptable excipients.
  • Suitable excipients include, but are not limited to, surface active agents, diluents, disintegrants, binders, glidants, lubricants and the like, which might be needed for the preparation of final dosage form.
  • the pharmaceutical composition according to the present invention may comprise from about 1 % to about 99 % by weight of other pharmaceutically acceptable excipients, preferably from about 10 % to about 95 %.
  • Surface active agents used in the pharmaceutical composition according to the present invention may include surface active agents such as those commonly known to one skilled in the art.
  • Surface active agents may be selected from the group consisting of, but not limited to, sodium lauryl sulphate, glyceryl esters, polyoxyethylene glycol esters, polyoxyethylene glycol ethers, polyoxyethylene sorbitan fatty acid esters, sulphate containing surfactants, or polyoxyethylene/polyoxypropylene copolymers.
  • Preferred are sodium lauryl sulphate and polysorbate 80.
  • Diluents used in the pharmaceutical composition according to the present invention may include pharmaceutically acceptable fillers selected from the group consisting of, but not limited to, lactose, microcrystalline cellulose, silicified microcrystalline cellulose, powdered cellulose, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, sucrose, glucose, dextrates, dextrins, dextrose, fructose, lactitol, mannitol, sorbitol, starch and/or mixtures of the foregoing.
  • Preferred diluents are microcrystalline cellulose and lactose.
  • Disintegrants used in the pharmaceutical composition according to the present invention may be selected from the group consisting of, but not limited to, croscarmellose sodium, crospovidone, sodium starch glycolate, corn starch, potato starch, maize starch and modified starches, calcium silicates, low substituted hydroxypropylcellulose and the like. Preferred are croscarmellose sodium and crospovidone.
  • Binders used in the pharmaceutical composition according to the present invention may be selected from the group consisting of, but not limited to, povidone, starch grades (pre- gellatinized or plain), cellulose derivatives such as for example hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC) and carboxymethylcellulose (CMC) and their salts and gelatine.
  • HPMC hydroxypropylmethylcellulose
  • HPC hydroxypropylcellulose
  • HPC hydroxypropylcellulose
  • CMC carboxymethylcellulose
  • Glidants used in the pharmaceutical composition according to the present invention may be selected from the group consisting of, but not limited to, silicon dioxide, talc and aluminium silicate.
  • Lubricants used in the pharmaceutical composition according to the present invention may be selected from the group consisting of, but not limited to, magnesium stearate, magnesium lauryl sulphate and sodium stearyl fumarate, sucrose esters or fatty acid, polyethylene glycol, stearic acid and the like. Preferred are magnesium stearate and sodium stearyl fumarate.
  • other pharmaceutically acceptable excipients can be present, as for example stabilizers such as pH modifiers, antioxidants for example sodium hydroxide, calcium phosphate, butylhydroxyanizole, ascorbic acid, coffee acid, gallic acid, quercetine.
  • stabilizers such as pH modifiers, antioxidants for example sodium hydroxide, calcium phosphate, butylhydroxyanizole, ascorbic acid, coffee acid, gallic acid, quercetine.
  • compositions of the present invention may be formulated into variety of compositions for administration to humans and/or animals for treating various diseases through the reduction of cholesterol.
  • the compositions can be used directly for oral administration (filled into sachets) or included into various final dosage forms, such as tablets, powders, granules, capsules, suspensions, suppositories, injection preparations etc.
  • the dosage forms can be optionally packed in inert gas atmosphere (for example nitrogen or argon), under reduced pressure or with oxygen absorbers.
  • compositions according to the present invention are incorporated into tablets.
  • a composition for tabletting can be prepared by commonly used processes, such as wet granulation, dry granulation or direct compression.
  • Another embodiment of the present invention is the preparation of the pharmaceutical compositions according to the present invention.
  • compositions of the present invention can be prepared in a fast, efficient and highly reproducible ways.
  • the pharmaceutical composition according to the first embodiment of the present invention may be prepared by dissolving cholesterol absorption inhibitor and hydrophilic polymer in sufficient amount of organic solvent, followed by drying. Preferably spray-drying is used. The remaining solid matrix has then the drug finely dispersed/dissolved in the hydrophilic polymer. Other pharmaceutically acceptable excipients can be optionally added to the solid matrix. Such matrix can be further milled, sieved, and optionally filled into gelatine capsules or compressed into tablets. In such way, the dissolution of the drug is improved.
  • the pharmaceutical composition according to the second embodiment of the present invention may be prepared by dissolving cholesterol absorption inhibitor and hydrophilic polymer and optionally surfactant, in a sufficient amount of organic solvent, followed by dispersion onto a suitable carrier.
  • Surfactant can be selected from the group of pharmaceutically acceptable ingredients which dissolved in water at room temperature in concentration of more than Ig in 10 ml of water, such as for example sorbitol, polyethylenglycol 4000, mannitol, maltitol.
  • the drug is finely dispersed over the carrier, together with hydrophilic polymer, which acts as a binder and crystallization inhibitor.
  • Other pharmaceutically acceptable excipients can be optionally added to the pharmaceutical composition
  • Such composition can be optionally filled into gelatine capsules or compressed into tablets. In such way, the dissolution of the drug is improved.
  • Organic solvents used in the production of the pharmaceutical composition according to the present invention include pharmaceutically acceptable solvents selected from the group consisting of, but not limited to, methanol, ethanol, acetone and other pharmaceutically acceptable organic solvents, in which cholesterol absorption inhibitor is soluble.
  • pharmaceutically acceptable solvents selected from the group consisting of, but not limited to, methanol, ethanol, acetone and other pharmaceutically acceptable organic solvents, in which cholesterol absorption inhibitor is soluble.
  • methanol or ethanol is used.
  • the amount of organic solvent used is such that the active ingredient or ingredients are dissolved.
  • composition according to the present invention further comprises one or more other active ingredients
  • these ingredients can be added in any step of the manufacturing process as described above.
  • the obtained dosage form can optionally be coated with water soluble coating with decreased permeability for gases such as water vapour and oxygen.
  • the coating is based on polymers such as for example polyvinyl alcohol, low viscosity hypromelose types, aminoalkyl methycrylate sopolymers (Eudragit E PO) with water permeability rate below 300 g/m 2 .d (determined according to DIN 53122), preferably below 200 g/m 2 .d.
  • the final dosage form is packed in primary packaging under inert atmosphere such as for example nitrogen, argon or xenon resulting in decreased concentration of oxygen in the atmosphere surrounding the dosage form in primary packaging such as for example blisters, strips, plastic or glass containers.
  • inert atmosphere such as for example nitrogen, argon or xenon
  • concentration of oxygen means, that the concentration of residual oxygen in the atmosphere surrounding the individual dosage form such as for example tablet or capsule is below 10 vol/vol%, preferably below 7.5 vol/vol%, more preferably below 5 vol/vol% and most preferably below 2.5 vol/vol%.
  • both improvements represent the crucial factor in the designing of an efficient pharmaceutical composition.
  • both pharmaceutical compositions of the present invention can be prepared by melting (fusion) or melting-solvent methods as known in the art.
  • Another aspect of the present invention is the pharmaceutical composition according to the present invention comprising at least one cholesterol absorption inhibitor in amorphous form and at least one hydrophilic polymer wherein the amorphous form of cholesterol absorption inhibitor is stable throughout the shelflife of the pharmaceutical composition.
  • Yet another aspect of the present invention is the use of the pharmaceutical composition according to the rpesent invention comprising at least one cholesterol absorption inhibitor in amorphous form and at least one hydrophilic polymer for providing amorphous form of cholesterol absorption inhibitor throughout the shelflife of the pharmaceutical composition.
  • compositions of the present invention is useful in the treatment of different lipid disorders such as primary hypercholesterolemia (heterozygous familial or non- familial) or homozygous sitosterolemia.
  • Ezetimibe, sodium lauryl sulphate and povidone K 30 were dissolved in ethanol and sprayed onto mixture of lactose monohydrate, microcrystalline cellulose and Vi croscarmellose sodium. After drying and sieving, the remained croscarmellose sodium was added to the obtained granules. After addition of magnesium stearate, mixture was compressed into tablets.
  • Ezetimibe and PEG 4000 were dissolved in ethanol and spray dried. Obtained powder was mixed with lactose tablettose, microcrystalline cellulose, croscarmellose sodium and silica, colloidal anhydrous. After addition of magnesium stearate, mixture was compressed into tablets.
  • Ezetimibe and povidone were dissolved in ethanol and spray dried. Obtained powder was mixed with lactose tablettose, microcrystalline cellulose, croscarmellose sodium and silica, colloidal anhydrous. After addition of magnesium stearate, mixture was compressed into tablets.
  • Example 4
  • Ezetimibe, povidone and sodium lauryl sulphate were dissolved in methanol and sprayed onto mixture of lactose monohydrate, microcrystalline cellulose and 1 A croscarmellose sodium. After drying and sieving, the remained croscarmellose sodium was added to the obtained granules. After addition of magnesium stearate, mixture was compressed into tablets.
  • Ezetimibe, hydroxypropylcellulose and sodium lauryl sulphate were dissolved in methanol and sprayed onto mixture of lactose monohydrate, microcrystalline cellulose and Vi crospovidone. After drying and sieving, the remained crospovidone was added to the obtained granules. After addition of magnesium stearate, mixture was compressed into tablets.
  • Ezetimibe, lactose monohydrate and 1 A croscarmellose sodium were mixed and granulated with solution of hydroxypropylmethylcellulose and sodium lauryl sulphate in purified water. After drying and sieving, microcrystalline cellulose and the remained croscarmelose sodium was added to the obtained granules. After addition of magnesium stearate, mixture was compressed into tablets.
  • Ezetimibe, hydroxypropylcellulose and polysorbate 80 were dissolved in methanol and sprayed onto mixture of lactose monohydrate, microcrystalline cellulose and Vi croscarmellose sodium. After drying and sieving, the remained croscarmellose sodium was added to the obtained granules. After addition of magnesium stearate, mixture was compressed into tablets.
  • Example 10 Ezetimibe, hydroxypropylcellulose and polysorbate 80 were dissolved in methanol and sprayed onto mixture of lactose monohydrate, microcrystalline cellulose and Vi croscarmellose sodium. After drying and sieving, the remained croscarmellose sodium was added to the obtained granules. After addition of magnesium stearate, mixture was compressed into tablets.
  • Ezetimibe, povidone and sodium lauryl sulphate were dissolved in methanol and sprayed onto mixture of manitol, microcrystalline cellulose and 1 A croscarmellose sodium. After drying and sieving, the remained croscarmellose sodium was added to the obtained granules. After addition of magnesium stearate, mixture was compressed into tablets.
  • Ezetimibe, povidone and sodium lauryl sulphate were dissolved in methanol and sprayed onto sorbitol. After drying and sieving, the microcrystalline cellulose was added to the obtained granules. After addition of magnesium stearate, mixture was compressed into tablets.
  • Ezetimibe and Pluronic F 68 (poloxamer) were dissolved in methanol and the clear solution was sprayed onto the mixture of sorbitol and part ('/3) of croscarmellose sodium.
  • the obtained granulate was milled and sieved through the 120 Mesh sieve (apertures of the sieve 0.125mm). Microcrystalline cellulose and the rest of croscarmellose sodium were added to the obtained granules. At the end magnesium stearate was admixed to the obtained mixture and final mixture was compressed into tablets.
  • Ezetimibe granules Ezetimibe, hydroxypropylmethylcellulose and sodium lauryl sulphate were dissolved in methanol and sprayed onto mixture of lactose monohydrate, microcrystalline cellulose and croscarmellose sodium.
  • Simvastatin granules Simvastatin, lactose monohydrate, microcrystalline cellulose and croscarmellose sodium were granulated with hydroxypropylmethylcellulose solution in purified water. The obtained granulate was dried and sieved.
  • Ezetimib granules and simvastatin granules were mixed, magnesium stearate was added and the obtained compression mixture was pressed into tablets.
  • Ezetimibe, atorvastatin calcium and Pluronic F 68 (poloxamer) were dissolved in methanol and the clear solution was sprayed onto the mixture of mannitol, calcium carbonate and part (Vi) of croscarmellose sodium.
  • the obtained granulate was milled and sieved through the 120 Mesh sieve (apertures of the sieve 0.125mm). Microcrystalline cellulose and the rest of croscarmellose sodium were added to the obtained granules.
  • At the end magnesium stearate was admixed to the obtained mixture and final mixture was compressed into tablets, was admixed to the obtained mixture and final mixture was compressed into tablets.
  • Example 15 Example 15:
  • Ezetimibe, atorvastatin calcium, sodium lauryl sulphate, sodium hydroxide and povidone K 30 were dissolved in methanol and sprayed onto mixture of lactose monohydrate, microcrystalline cellulose and Vi croscarmellose sodium. After drying and sieving, the remained croscarmellose sodium was added to the obtained granules. After addition of magnesium stearate, mixture was compressed into tablets.
  • Ezetimibe granules Ezetimibe, hydroxypropylmethylcellulose and sodium lauryl sulphate were dissolved in methanol and sprayed onto mixture of lactose monohydrate, microcrystalline cellulose and croscarmellose sodium.
  • Fenofibrate mixture Fenofibrate, lactose monohydrate, pregelatinised starch and crospovidone were homogenously mixed.
  • Ezetimib granules and fenofibrate mixture were blended together, magnesium stearate was added and the obtained mixture was filled into capsules.
  • Ezetimibe granules Ezetimibe, hydroxypropylmethylcellulose and sodium lauryl sulphate were dissolved in methanol and sprayed onto mixture of lactose monohydrate, microcrystalline cellulose and croscarmellose sodium.
  • Rosuvastatin granules Rosuvastatin calcium, lactose monohydrate, microcrystalline cellulose, calcium phosphate, croscarmellose sodium were granulated with hydroxypropylmethylcellulose solution in purified water. The obtained granulate was dried and sieved.
  • Ezetimib granules and rosuvastatin granules were mixed, magnesium stearate was added and the obtained compression mixture was pressed into tablets.

Abstract

The present invention relates to a pharmaceutical composition comprising at least one cholesterol absorption inhibitor in amorphous form and at least one hydrophilic polymer, wherein the amorphous cholesterol absorption inhibitor is finely distributed within the hydrophilic polymer or at least one amorphous cholesterol absorption inhibitor and at least one hydrophilic polymer are dispersed onto a carrier.

Description

PHARMACEUTICAL COMPOSITION CONTAINING A CHOLESTEROL
ABSORPTION INHIBITOR
FIELD OF THE INVENTION
The present invention relates to the field of pharmaceutical technology and particular to the novel pharmaceutical compositions comprising cholesterol absorption inhibitor and pharmaceutically acceptable excipients.
BACKGROUND OF THE INVENTION
Ezetimibe with chemical name l-(4-fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)- hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone and structural formula (I)
Figure imgf000002_0001
(I) is a representative of a class of compounds known as lipid-lowering compounds that selectively inhibits the intestinal absorption of cholesterol and related phytosterols. Its mechanism of action differs from those of other classes of cholesterol lowering compounds, such as HMG-CoA reductase inhibitors. It does not inhibit cholesterol synthesis in the liver or increase bile excretion but inhibits absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver. Such mechanism is complementary to that of HMG-CoA reductase inhibitors. Ezetimibe is marketed under the tradename ZETIA® or EZETROL®, which is available as a tablet for oral administration containing 10 mg of ezetimibe and the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, povidone, sodium lauryl sulphate and magnesium stearate.
Ezetimibe is practically insoluble in water, which causes it to exhibit a low dissolution rate in aqueous media, e.g. gastrointestinal fluids, which can result in low bioavailability after oral ingestion.
Ezetimibe is included in several different pharmaceutical compositions, described for example in EP 720 599 A, wherein the corn starch is present in the pharmaceutical formulation, EP 1353696 Bl discloses the formulation containing ezetimibe, lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium, sodium lauryl sulfate and magnesium stearate, WO 03/055464 discloses a micronized pharmaceutical powder with immediate release having a grain size distribution of not more than 100 μm, and comprising of at least an active substance, at least a wetting agent and at least a diluent, WO 03/068186 discloses formulation, comprising active ingredients of a great variety and a pharmaceutically acceptable vehicle comprising at least one compound selected from the group consisting of hydrophilic surfactant, a lipophilic surfactant, a triglyceride and a solubilizer, WO 2007/011349 discloses a granulate wherein the poorly water soluble substance is intimately associated with at least one sugar, WO 2007/073389 discloses the pharmaceutical composition wherein the low soluble drug is fixed in a strong matrix comprising amorphous sugar, in WO 2007/103453 ezetimibe is co-milled with hydrophilic excipient and US 2007/0275052 discloses the pharmaceutical composition comprising micronized ezetimibe of which about 90% of the particles are not more than about 25 microns and of which about 50% of the particles are not more than about 4 microns.
Several different combinations of cholesterol absorption inhibitor and other active ingredients are known, for example the pharmaceutical combination of ezetimibe and simvastatin stabilized by antioxidant is disclosed in WO 2004/010993, WO 2006/134604 discloses the pharmaceutical composition comprising ezetimibe and HMG-CoA reductase inhibitor as active ingredients and disintegrant, glidants and magnesium stearate as pharmaceutical excipients, WO 2007/003365 discloses a pharmaceutical composition comprising simvastatin and ezetimibe wherein the use of antioxidants are omitted. As shown above many different approaches how to improve bioavailability of low soluble drugs and how to minimize the side effects of particle size reduction have already been disclosed in the prior art Therefore, there would be a significant contribution to the art to provide a pharmaceutical composition of cholesterol absorption inhibitor such as for example ezetimibe having high bioavailability with improved dissolution rate. The above mentioned problems have been solved by preparing a pharmaceutical composition comprising cholesterol absorption inhibitor in amorphous form.
SUMMARY OF THE INVENTION
The first embodiment of the present invention relates to a pharmaceutical composition comprising at least one cholesterol absorption inhibitor in amorphous form and at least one hydrophilic polymer, wherein the amorphous cholesterol absorption inhibitor is finely distributed within the hydrophilic polymer.
The second embodiment of the present invention is directed to a pharmaceutical composition comprising at least one cholesterol absorption inhibitor in amorphous form and at least one hydrophilic polymer, wherein said composition comprises a carrier with finely dispersed at least one cholesterol absorption inhibitor and at least one hydrophilic polymer.
Another aspect of the present invention is the process of the production of the pharmaceutical composition according to the present invention.
Yet another aspect of the present invention is a pharmaceutical composition comprising at least one cholesterol absorption inhibitor in amorphous form and at least one hydrophilic polymer wherein the amorphous form of cholesterol absorption inhibitor is stable throughout the shelflife of the pharmaceutical composition.
Yet another aspect of the present invention is the use of a pharmaceutical composition comprising at least one cholesterol absorption inhibitor in amorphous form and at least one hydrophilic polymer for providing amorphous form of cholesterol absorption inhibitor throughout the shelflife of the pharmaceutical composition. Another aspect of the present invention is the method of treating lipid disorders comprising administering a pharmaceutical composition according to the present invention.
FIGURES
Fig. 1 shows a comparison of dissolution profiles of Ezetrol 10 mg tablets and Ezetimibe 10 mg tablets of example 4.
DETAILED DESCRIPTION OF THE INVENTION
The first embodiment of the present invention relates to a pharmaceutical composition comprising at least one cholesterol absorption inhibitor in amorphous form and at least one hydrophilic polymer, wherein the amorphous cholesterol absorption inhibitor is finely distributed within the hydrophilic polymer.
The second embodiment of the present invention is directed to a pharmaceutical composition comprising at least one cholesterol absorption inhibitor in amorphous form and at least one hydrophilic polymer, wherein said composition comprises a carrier with finely dispersed at least one cholesterol absorption inhibitor and at least one hydrophilic polymer.
The cholesterol absorption inhibitor is selected from the group consisting of hydroxyl- substituted azetidinones. The cholesterol absorption inhibitor used in the pharmaceutical composition according to the present invention can be in any crystalline or amorphous form with any particle size distribution and/or particle morphology. An example of such cholesterol absorption inhibitor is ezetimibe.
Ezetimibe that can be used in the present invention as a cholesterol absorption inhibitor may be prepared by any method known from the literature such as for example EP 0720599, EP 1169468, WO 2004/099132, WO 2005/066120, WO 2006/050634 WO 2006/068990, WO 2006/137080, WO 2007/017705, US 2007/0049748, WO 2007/030721, WO 2007/072088, WO 2007/119106, WO 2007/108007, WO 2007/120824 and PCT/EP2008/000546 and isolated/crystallized or further purified by processes known from the prior art (as for example WO 2004/099132, WO 2005/066120, WO 2006/060808, WO 2005/062897, WO 2005/009955, WO 2006/050634, IPCOM000131677, G.Y.S.K.Swamy at all, Acta Cryst. (2005). E61, o3608-o3610). Ezetimibe exists in different polymorphic and pseudo- polymorphic forms, which are disclosed in for example WO 2005/009955, WO 2005/062897, WO 2006/060808, US 2006/0234996, IPCOMOOOl 31677D, PCT/EP2008/000546.
The pharmaceutical composition according to the present invention may comprise from about 1 % to about 50 % by weight of the cholesterol absorption inhibitor, preferably from about 3 % to about 30 %, more preferably from about 5 % to about 20 %.
The cholesterol absorption inhibitor present in the pharmaceutical composition according to the present invention is in amorphous form. As the cholesterol absorption inhibitor is dissolved during the process, the amorphous form is formed regardless of the polymorphic form of the starting material. Still more, the amorphous polymorph form is maintained during the shelf life of the product. Moreover, the particle size or shape of the starting material does not affect the dissolution profile of the pharmaceutical composition according to the present invention. This represents a great advantage important particularly for the low-soluble substances incorporated into the final dosage form which generally require careful control of particle size.
The hydrophilic polymer used in the pharmaceutical composition according to the present invention may be selected from the group consisting of, but not limited to, povidone, cellulose derivatives (such as for example hydroxypropylcellulose - HPC, hydroxypropylmethylcellulose - HPMC), polyvinyl alcohol, polyethylene glycols (PEG's), poloxamers, gelatin, Eudragits® or other pharmaceutically acceptable hydrophilic polymers. Preferably, povidone (PVP), hydroxypropylcellulose (HPC) or hydroxypropylmethylcellulose (HPMC) may be used.
The pharmaceutical composition according to the present invention may comprise from about 0.1 % to about 50 % by weight of the hydrophilic polymer, preferably from about 0.3 % to about 30 %.
Carriers used in the second embodiment of the pharmaceutical compositions according to the second aspect of the present invention may be selected from the group consisting of, but not limited to, lactose monohydrate, anhydrous lactose, starch and starch derivatives, mannitol, xylitol, sorbitol, microcrystalline cellulose, powdered cellulose, magnesium stearate, silica colloidal anhydrous and mixtures thereof. Preferably, lactose monohydrate, anhydrous lactose, microcrystalline cellulose and/or their mixtures can be used as carriers.
The pharmaceutical composition according to the present invention may comprise from about 5 % to about 95 % by weight of the carrier, preferably from about 10 % to about 90 %, more preferably from about 30 % to about 80 %.
The pharmaceutical composition according to the present invention may further comprise one or more other active ingredients such as for example other lipid lowering drugs such as for example fenofibrate, bezafibrate, HMG-CoA reductase inhibitors, such as for example representatives of statin group such as simvastatin, atorvastatin, lovastatin, rosuvastatin or salts thereof and any mixtures thereof. One or more other active ingredient can be present in pharmaceutical composition according to the present invention in any crystalline or amorphous form and it can optionally be micronized.
The pharmaceutical composition according to the present invention may further comprise other pharmaceutically acceptable excipients. Suitable excipients include, but are not limited to, surface active agents, diluents, disintegrants, binders, glidants, lubricants and the like, which might be needed for the preparation of final dosage form.
The pharmaceutical composition according to the present invention may comprise from about 1 % to about 99 % by weight of other pharmaceutically acceptable excipients, preferably from about 10 % to about 95 %.
Surface active agents used in the pharmaceutical composition according to the present invention may include surface active agents such as those commonly known to one skilled in the art. Surface active agents may be selected from the group consisting of, but not limited to, sodium lauryl sulphate, glyceryl esters, polyoxyethylene glycol esters, polyoxyethylene glycol ethers, polyoxyethylene sorbitan fatty acid esters, sulphate containing surfactants, or polyoxyethylene/polyoxypropylene copolymers. Preferred are sodium lauryl sulphate and polysorbate 80.
Diluents used in the pharmaceutical composition according to the present invention may include pharmaceutically acceptable fillers selected from the group consisting of, but not limited to, lactose, microcrystalline cellulose, silicified microcrystalline cellulose, powdered cellulose, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, sucrose, glucose, dextrates, dextrins, dextrose, fructose, lactitol, mannitol, sorbitol, starch and/or mixtures of the foregoing. Preferred diluents are microcrystalline cellulose and lactose.
Disintegrants used in the pharmaceutical composition according to the present invention may be selected from the group consisting of, but not limited to, croscarmellose sodium, crospovidone, sodium starch glycolate, corn starch, potato starch, maize starch and modified starches, calcium silicates, low substituted hydroxypropylcellulose and the like. Preferred are croscarmellose sodium and crospovidone.
Binders used in the pharmaceutical composition according to the present invention may be selected from the group consisting of, but not limited to, povidone, starch grades (pre- gellatinized or plain), cellulose derivatives such as for example hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC) and carboxymethylcellulose (CMC) and their salts and gelatine. Preferred binding agent is HPMC.
Glidants used in the pharmaceutical composition according to the present invention may be selected from the group consisting of, but not limited to, silicon dioxide, talc and aluminium silicate.
Lubricants used in the pharmaceutical composition according to the present invention may be selected from the group consisting of, but not limited to, magnesium stearate, magnesium lauryl sulphate and sodium stearyl fumarate, sucrose esters or fatty acid, polyethylene glycol, stearic acid and the like. Preferred are magnesium stearate and sodium stearyl fumarate.
When one or more other active ingredients are present in the pharmaceutical composition according to the present invention other pharmaceutically acceptable excipients can be present, as for example stabilizers such as pH modifiers, antioxidants for example sodium hydroxide, calcium phosphate, butylhydroxyanizole, ascorbic acid, coffee acid, gallic acid, quercetine.
The pharmaceutical compositions of the present invention may be formulated into variety of compositions for administration to humans and/or animals for treating various diseases through the reduction of cholesterol. The compositions can be used directly for oral administration (filled into sachets) or included into various final dosage forms, such as tablets, powders, granules, capsules, suspensions, suppositories, injection preparations etc. The dosage forms can be optionally packed in inert gas atmosphere (for example nitrogen or argon), under reduced pressure or with oxygen absorbers.
Preferably, pharmaceutical compositions according to the present invention are incorporated into tablets. A composition for tabletting can be prepared by commonly used processes, such as wet granulation, dry granulation or direct compression.
Another embodiment of the present invention is the preparation of the pharmaceutical compositions according to the present invention.
The pharmaceutical compositions of the present invention can be prepared in a fast, efficient and highly reproducible ways.
The pharmaceutical composition according to the first embodiment of the present invention may be prepared by dissolving cholesterol absorption inhibitor and hydrophilic polymer in sufficient amount of organic solvent, followed by drying. Preferably spray-drying is used. The remaining solid matrix has then the drug finely dispersed/dissolved in the hydrophilic polymer. Other pharmaceutically acceptable excipients can be optionally added to the solid matrix. Such matrix can be further milled, sieved, and optionally filled into gelatine capsules or compressed into tablets. In such way, the dissolution of the drug is improved.
The pharmaceutical composition according to the second embodiment of the present invention may be prepared by dissolving cholesterol absorption inhibitor and hydrophilic polymer and optionally surfactant, in a sufficient amount of organic solvent, followed by dispersion onto a suitable carrier. Surfactant can be selected from the group of pharmaceutically acceptable ingredients which dissolved in water at room temperature in concentration of more than Ig in 10 ml of water, such as for example sorbitol, polyethylenglycol 4000, mannitol, maltitol. By this process, the drug is finely dispersed over the carrier, together with hydrophilic polymer, which acts as a binder and crystallization inhibitor. Other pharmaceutically acceptable excipients can be optionally added to the pharmaceutical composition Such composition can be optionally filled into gelatine capsules or compressed into tablets. In such way, the dissolution of the drug is improved.
Organic solvents used in the production of the pharmaceutical composition according to the present invention include pharmaceutically acceptable solvents selected from the group consisting of, but not limited to, methanol, ethanol, acetone and other pharmaceutically acceptable organic solvents, in which cholesterol absorption inhibitor is soluble. Preferably, methanol or ethanol is used. The amount of organic solvent used is such that the active ingredient or ingredients are dissolved.
When the pharmaceutical composition according to the present invention further comprises one or more other active ingredients, these ingredients can be added in any step of the manufacturing process as described above.
The obtained dosage form, as for example tablet, can optionally be coated with water soluble coating with decreased permeability for gases such as water vapour and oxygen. The coating is based on polymers such as for example polyvinyl alcohol, low viscosity hypromelose types, aminoalkyl methycrylate sopolymers (Eudragit E PO) with water permeability rate below 300 g/m2.d (determined according to DIN 53122), preferably below 200 g/m2.d.
To avoid the potential oxidative degradation of incorporated active ingredients susceptible to oxidative degradation, the final dosage form is packed in primary packaging under inert atmosphere such as for example nitrogen, argon or xenon resulting in decreased concentration of oxygen in the atmosphere surrounding the dosage form in primary packaging such as for example blisters, strips, plastic or glass containers. Decreased concentration of oxygen means, that the concentration of residual oxygen in the atmosphere surrounding the individual dosage form such as for example tablet or capsule is below 10 vol/vol%, preferably below 7.5 vol/vol%, more preferably below 5 vol/vol% and most preferably below 2.5 vol/vol%. In this manner the amount of degradation products is substantially decreased and the shelf live of the final product is prolonged. Both improvements represent the crucial factor in the designing of an efficient pharmaceutical composition.
Alternatively, both pharmaceutical compositions of the present invention can be prepared by melting (fusion) or melting-solvent methods as known in the art. Another aspect of the present invention is the pharmaceutical composition according to the present invention comprising at least one cholesterol absorption inhibitor in amorphous form and at least one hydrophilic polymer wherein the amorphous form of cholesterol absorption inhibitor is stable throughout the shelflife of the pharmaceutical composition.
Yet another aspect of the present invention is the use of the pharmaceutical composition according to the rpesent invention comprising at least one cholesterol absorption inhibitor in amorphous form and at least one hydrophilic polymer for providing amorphous form of cholesterol absorption inhibitor throughout the shelflife of the pharmaceutical composition.
The pharmaceutical compositions of the present invention is useful in the treatment of different lipid disorders such as primary hypercholesterolemia (heterozygous familial or non- familial) or homozygous sitosterolemia.
EXAMPLES
The invention is illustrated by reference to the following examples. However, the examples are not intended to limit any scope of the claim anyway. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the purpose and interest of this invention.
Example 1:
Ezetimibe 10.0 mg
Sodium lauryl sulphate 2.0 mg
Povidone K30 4.0 mg
Lactose monohydrate 55.0 mg
Microcrystalline cellulose 20.0 mg
Croscarmellose sodium 8.0 mg
Magnesium stearate 1.0 mg
Ethanol qs
Ezetimibe, sodium lauryl sulphate and povidone K 30 were dissolved in ethanol and sprayed onto mixture of lactose monohydrate, microcrystalline cellulose and Vi croscarmellose sodium. After drying and sieving, the remained croscarmellose sodium was added to the obtained granules. After addition of magnesium stearate, mixture was compressed into tablets.
Example 2:
Ezetimib 10.0 mg
PEG 4000 15.0 mg
Lactose Tablettose 46.0 mg
Microcrystalline cellulose 19.7 mg
Croscarmellose sodium 8.0 mg
Silica, colloidal anhydrous 0.3 mg
Magnesium stearate 1.0 mg
Ethanol qs
Ezetimibe and PEG 4000 were dissolved in ethanol and spray dried. Obtained powder was mixed with lactose tablettose, microcrystalline cellulose, croscarmellose sodium and silica, colloidal anhydrous. After addition of magnesium stearate, mixture was compressed into tablets.
Example 3:
Ezetimibe 10.0 mg
Povidone K 30 15.0 mg
Lactose Tablettose 45.7 mg
Microcrystalline cellulose 20.0 mg
Croscarmellose sodium 8.0 mg
Silica, colloidal anhydrous 0.3 mg
Magnesium stearate 1.0 mg
Ethanol qs
Ezetimibe and povidone were dissolved in ethanol and spray dried. Obtained powder was mixed with lactose tablettose, microcrystalline cellulose, croscarmellose sodium and silica, colloidal anhydrous. After addition of magnesium stearate, mixture was compressed into tablets. Example 4:
Ezetimibe 10.0 mg
Povidone K 25 4.0 mg
Sodium lauryl sulphate 3.0 mg
Lactose monohydrate 54.0 mg
Microcrystalline cellulose 20.0 mg
Croscarmellose sodium 8.0 mg
Magnesium stearate 1.0 mg
Methanol qs
Ezetimibe, povidone and sodium lauryl sulphate were dissolved in methanol and sprayed onto mixture of lactose monohydrate, microcrystalline cellulose and 1A croscarmellose sodium. After drying and sieving, the remained croscarmellose sodium was added to the obtained granules. After addition of magnesium stearate, mixture was compressed into tablets.
It can be seen in Figure 1 that the dissolution rate of the tablets, prepared according to the present invention, is faster than Ezetrol in first 10 minutes and comparable after 15 minutes.
Example 5:
Ezetimibe 10.0 mg
Hydroxypropylcellulose 2.0 mg
Sodium lauryl sulphate 2.0 mg
Lactose monohydrate 59.0 mg
Microcrystalline cellulose 20.0 mg
Croscarmellose sodium 6.0 mg
Magnesium stearate 1.0 mg
Methanol qs
Ezetimibe, hydroxypropylcellulose and sodium lauryl sulphate were dissolved in methanol and sprayed onto mixture of lactose monohydrate, microcrystalline cellulose and 1A croscarmellose sodium. After drying and sieving, the remained croscarmellose sodium was added to the obtained granules. After addition of magnesium stearate, mixture was compressed into tablets. Example 6:
Ezetimibe 10.0 mg
Hydroxypropylcellulose 3.0 mg
Sodium lauryl sulphate 2.0 mg
Lactose monohydrate 59.0 mg
Microcrystalline cellulose 20.0 mg
Crospovidone 5.0 mg
Magnesium stearate 1.0 mg
Methanol qs
Ezetimibe, hydroxypropylcellulose and sodium lauryl sulphate were dissolved in methanol and sprayed onto mixture of lactose monohydrate, microcrystalline cellulose and Vi crospovidone. After drying and sieving, the remained crospovidone was added to the obtained granules. After addition of magnesium stearate, mixture was compressed into tablets.
Example 7:
Ezetimibe 10.0 mg Hydroxypropylmethylcellulose 2.0 mg
Sodium lauryl sulphate 2.0 mg
Lactose monohydrate 59.0 mg
Microcrystalline cellulose 20.0 mg
Croscarmellose sodium 5.0 mg
Magnesium stearate 1.0 mg
Methanol qs
Ezetimibe, hydroxypropylmethylcellulose and sodium lauryl sulphate were dissolved in methanol and sprayed onto mixture of lactose monohydrate, microcrystalline cellulose and Vi croscarmellose sodium. After drying and sieving, the remained croscarmellose sodium was added to the obtained granules. After addition of magnesium stearate, mixture was compressed into tablets. Example 8:
Ezetimibe 10.0 mg Hydro xypropylmethylcellulose 2.0 mg
Sodium lauryl sulphate 2.0 mg
Lactose monohydrate 59.0 mg
Microcrystalline cellulose 20.0 mg
Croscarmellose sodium 6.0 mg
Magnesium stearate 1.0 mg
Purified water qs
Ezetimibe, lactose monohydrate and 1A croscarmellose sodium were mixed and granulated with solution of hydroxypropylmethylcellulose and sodium lauryl sulphate in purified water. After drying and sieving, microcrystalline cellulose and the remained croscarmelose sodium was added to the obtained granules. After addition of magnesium stearate, mixture was compressed into tablets.
Example 9:
Ezetimibe 10.0 mg
Hydroxypropylcellulose 3.0 mg
Polysorbate 80 2.0 mg
Lactose monohydrate 58.0 mg
Microcrystalline cellulose 20.0 mg
Croscarmellose sodium 6.0 mg
Magnesium stearate 1.0 mg
Methanol qs
Ezetimibe, hydroxypropylcellulose and polysorbate 80 were dissolved in methanol and sprayed onto mixture of lactose monohydrate, microcrystalline cellulose and Vi croscarmellose sodium. After drying and sieving, the remained croscarmellose sodium was added to the obtained granules. After addition of magnesium stearate, mixture was compressed into tablets. Example 10
Ezetimibe 10.0 mg
Povidone K 25 4.0 mg
Sodium lauryl sulphate 3.0 mg
Manitol 54.0 mg
Microcrystalline cellulose 20.0 mg
Croscarmellose sodium 8.0 mg
Magnesium stearate 1.0 mg
Methanol qs
Ezetimibe, povidone and sodium lauryl sulphate were dissolved in methanol and sprayed onto mixture of manitol, microcrystalline cellulose and 1A croscarmellose sodium. After drying and sieving, the remained croscarmellose sodium was added to the obtained granules. After addition of magnesium stearate, mixture was compressed into tablets.
Example 11
Ezetimibe 10.0 mg
Povidone K 30 4.0 mg
Sodium lauryl sulphate 3.0 mg
Sorbitol 64.0 mg
Microcrystalline cellulose 10.0 mg
Magnesium stearate 1.0 mg
Methanol qs
Ezetimibe, povidone and sodium lauryl sulphate were dissolved in methanol and sprayed onto sorbitol. After drying and sieving, the microcrystalline cellulose was added to the obtained granules. After addition of magnesium stearate, mixture was compressed into tablets. Example 12
Ezetimibe 10.0 mg
Pluronic F 68 20.0 mg
Sorbitol 70.0 mg
Croscarmellose sodium 2.5 mg
Microcrystalline cellulose 20.0 mg
Magnesium stearate 1.0 mg
Methanol qs
Ezetimibe and Pluronic F 68 (poloxamer) were dissolved in methanol and the clear solution was sprayed onto the mixture of sorbitol and part ('/3) of croscarmellose sodium. The obtained granulate was milled and sieved through the 120 Mesh sieve (apertures of the sieve 0.125mm). Microcrystalline cellulose and the rest of croscarmellose sodium were added to the obtained granules. At the end magnesium stearate was admixed to the obtained mixture and final mixture was compressed into tablets.
Example 13:
Ezetimibe 10.0 mg Hydroxypropylmethylcellulose 3.0 mg
Sodium lauryl sulphate 2.0 mg
Lactose monohydrate 58.0 mg
Microcrystalline cellulose 24.0 mg
Croscarmellose sodium 5.0 mg
Methanol qs
Simvastatin 40.0 mg
Lactose monohydrate 160.0 mg
Microcrystalline cellulose 80.0 mg
Hydroxypropylmethylcellulose 6.0 mg
Croscarmellose sodium 12.0 mg
Purified water qs
Magnesium stearate 4.0 mg Ezetimibe granules: Ezetimibe, hydroxypropylmethylcellulose and sodium lauryl sulphate were dissolved in methanol and sprayed onto mixture of lactose monohydrate, microcrystalline cellulose and croscarmellose sodium.
Simvastatin granules: Simvastatin, lactose monohydrate, microcrystalline cellulose and croscarmellose sodium were granulated with hydroxypropylmethylcellulose solution in purified water. The obtained granulate was dried and sieved.
Ezetimib granules and simvastatin granules were mixed, magnesium stearate was added and the obtained compression mixture was pressed into tablets.
Example 14
Ezetimibe 10.0 mg
Atorvastatin calcium 21.69 mg
Pluronic F 68 30.0 mg
Mannitol 100.0 mg
Croscarmellose sodium 3.0 mg
Calcium carbonate 20.0 mg
Microcrystalline cellulose 30.0 mg
Magnesium stearate 1.0 mg
Methanol qs
Ezetimibe, atorvastatin calcium and Pluronic F 68 (poloxamer) were dissolved in methanol and the clear solution was sprayed onto the mixture of mannitol, calcium carbonate and part (Vi) of croscarmellose sodium. The obtained granulate was milled and sieved through the 120 Mesh sieve (apertures of the sieve 0.125mm). Microcrystalline cellulose and the rest of croscarmellose sodium were added to the obtained granules. At the end magnesium stearate was admixed to the obtained mixture and final mixture was compressed into tablets, was admixed to the obtained mixture and final mixture was compressed into tablets. Example 15:
Ezetimibe 10.0 mg
Sodium lauryl sulphate 2.0 mg
Povidone K30 4.0 mg
Atorvastatin calcium 21.69 mg
Sodium hydroxide 1.0 mg
Lactose monohydrate 120.0 mg
Microcrystalline cellulose 34.0 mg
Croscarmellose sodium 8.0 mg
Magnesium stearate 1.0 mg
Methanol qs
Ezetimibe, atorvastatin calcium, sodium lauryl sulphate, sodium hydroxide and povidone K 30 were dissolved in methanol and sprayed onto mixture of lactose monohydrate, microcrystalline cellulose and Vi croscarmellose sodium. After drying and sieving, the remained croscarmellose sodium was added to the obtained granules. After addition of magnesium stearate, mixture was compressed into tablets.
Example 16:
Ezetimibe 10.0 mg
Hydroxypropylmethylcellulose 3.0 mg
Sodium lauryl sulphate 2.0 mg
Lactose monohydrate 58.0 mg
Microcrystalline cellulose 24.0 mg
Croscarmellose sodium 5.0 mg
Methanol qs
Fenofibrate 50.0 mg
Lactose monohydrate 152.0 mg
Pregelatinised starch 80.0 mg
Crospovidone 12.0 mg
Magnesium stearate 4.0 mg Ezetimibe granules: Ezetimibe, hydroxypropylmethylcellulose and sodium lauryl sulphate were dissolved in methanol and sprayed onto mixture of lactose monohydrate, microcrystalline cellulose and croscarmellose sodium.
Fenofibrate mixture: Fenofibrate, lactose monohydrate, pregelatinised starch and crospovidone were homogenously mixed.
Ezetimib granules and fenofibrate mixture were blended together, magnesium stearate was added and the obtained mixture was filled into capsules.
Example 17:
Ezetimibe 10.0 mg Hydroxypropylmethylcellulose 3.0 mg
Sodium lauryl sulphate 2.0 mg
Lactose monohydrate 58.0 mg
Microcrystalline cellulose 24.0 mg
Croscarmellose sodium 5.0 mg
Methanol qs
Rosuvastatin calcium 20.8 mg
Lactose monohydrate 150.0 mg
Microcrystalline cellulose 80.0 mg
Calcium phosphate 6.0 mg Hydroxypropylmethylcellulose 6.0 mg
Croscarmellose sodium 12.0 mg
Purified water qs
Magnesium stearate 4.0 mg
Ezetimibe granules: Ezetimibe, hydroxypropylmethylcellulose and sodium lauryl sulphate were dissolved in methanol and sprayed onto mixture of lactose monohydrate, microcrystalline cellulose and croscarmellose sodium.
Rosuvastatin granules: Rosuvastatin calcium, lactose monohydrate, microcrystalline cellulose, calcium phosphate, croscarmellose sodium were granulated with hydroxypropylmethylcellulose solution in purified water. The obtained granulate was dried and sieved.
Ezetimib granules and rosuvastatin granules were mixed, magnesium stearate was added and the obtained compression mixture was pressed into tablets.

Claims

1. A pharmaceutical composition comprising at least one cholesterol absorption inhibitor in amorphous form and at least one hydrophilic polymer, wherein said amorphous cholesterol absorption inhibitor is finely distributed within the hydrophilic polymer.
2. A pharmaceutical composition comprising at least one cholesterol absorption inhibitor in amorphous form and at least one hydrophilic polymer, wherein said composition comprises a carrier with finely dispersed at least one cholesterol absorption inhibitor and at least one hydrophilic polymer.
3. The pharmaceutical composition of any previous claim wherein the amorphous cholesterol absorption inhibitor is ezetimibe.
4. The pharmaceutical composition of any previous claim wherein the hydrophilic polymer is selected from the group consisting of povidone, cellulose derivatives, polyvinyl alcohol, polyethylene glycols, poloxamers, gelatin, methacrylate polymers.
5. The pharmaceutical composition of any previous claim wherein the hydrophilic polymer is selected from the group consisting of povidone, hydroxypropylcellulose and hydroxypropylmethylcellulose.
6. The pharmaceutical composition of claims 2 to 5 wherein the carrier is selected from the group consisting of lactose monohydrate, anhydrous lactose, starch and starch derivatives, mannitol, xylitol, sorbitol, microcrystalline cellulose, powdered cellulose, magnesium stearate, silica colloidal anhydrous and any mixtures thereof.
7. The pharmaceutical composition of claims 2 to 6 wherein the carrier is selected from the group consisting of lactose monohydrate, anhydrous lactose, microcrystalline cellulose and any mixtures thereof.
8. The pharmaceutical composition of any previous claim optionally further comprising one or more other active ingredient selected from the group consisting of fenofibrate, bezafibrate and HMG-CoA reductase inhibitor.
9. The pharmaceutical composition of claim 8 wherein the other active substance is HMG- CoA reductase inhibitor.
10. The pharmaceutical composition of any previous claim optionally further comprising other pharmaceutically acceptable excipients selected from the group consisting of surface active agents, diluents, disintegrants, binders, glidants, lubricants and stabilizers.
11. The process of the production of the pharmaceutical composition of any previous claim comprising the following steps: a) dissolving cholesterol absorption inhibitor and hydrophilic polymer in organic solvent, b) drying the obtained solution.
12. The process of the production of the pharmaceutical composition of any previous claim comprising the following steps: a) dissolving cholesterol absorption inhibitor and hydrophilic polymer in organic solvent, b) dispersing the obtain solution onto a suitable carrier.
13. A pharmaceutical composition comprising at least one cholesterol absorption inhibitor in amorphous form and at least one hydrophilic polymer wherein the amorphous form of cholesterol absorption inhibitor is stable throughout the shelflife of the pharmaceutical composition.
14. The use of a pharmaceutical composition comprising at least one cholesterol absorption inhibitor in amorphous form and at least one hydrophilic polymer for providing amorphous form of cholesterol absorption inhibitor throughout the shelflife of the pharmaceutical composition.
15. A method of treating lipid disorders comprising administering to a mammal in need the pharmaceutical composition of any previous claim.
16. Use of the pharmaceutical composition of any previous claim for the manufacture of a medicament useful for treating lipid disorders in a mammal in need.
PCT/EP2008/001436 2007-02-23 2008-02-22 Pharmaceutical composition containing a cholesterol absorption inhibitor WO2008101723A2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP08715987A EP2120882A2 (en) 2007-02-23 2008-02-22 Pharmaceutical composition containing a cholesterol absorption inhibitor

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SIP-200700043 2007-02-23
SI200700043 2007-02-23

Publications (2)

Publication Number Publication Date
WO2008101723A2 true WO2008101723A2 (en) 2008-08-28
WO2008101723A3 WO2008101723A3 (en) 2008-11-27

Family

ID=39710560

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2008/001436 WO2008101723A2 (en) 2007-02-23 2008-02-22 Pharmaceutical composition containing a cholesterol absorption inhibitor

Country Status (2)

Country Link
EP (1) EP2120882A2 (en)
WO (1) WO2008101723A2 (en)

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008063766A2 (en) * 2006-10-10 2008-05-29 Isp Investments Inc. Amorphous ezetimibe and the production thereof
WO2010021608A1 (en) * 2008-08-22 2010-02-25 Mahmut Bilgic Solubility enhancing pharmaceutical formulation
WO2010021609A1 (en) * 2008-08-22 2010-02-25 Mahmut Bilgic Solubility and stability enhancing pharmaceutical formulation
EP2216016A1 (en) 2009-02-06 2010-08-11 LEK Pharmaceuticals d.d. Process for the preparation of a pharmaceutical composition comprising ezetimibe
EP2229938A1 (en) 2009-03-13 2010-09-22 Sanovel Ilac Sanayi ve Ticaret A.S. Ezetimibe compositions
WO2010144066A1 (en) 2009-06-10 2010-12-16 Levent Oner Method for the preparation of ezetimib nanocrystals
WO2011002424A3 (en) * 2009-07-02 2011-04-28 Bilgic Mahmut Solubility and stability enchancing pharmaceutical formulation comprising ezetimibe and simvastatin
WO2011019326A3 (en) * 2009-07-02 2011-04-28 Mahmut Bilgic Solubility and stability enchancing pharmaceutical formulation
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
WO2012064307A1 (en) * 2010-11-11 2012-05-18 Bilgic Mahmut Pharmaceutical compositions comprising rosuvastatin
WO2011139256A3 (en) * 2010-05-04 2012-05-18 Bilgic Mahmut Stable rosuvastatin formulations
EP2468258A1 (en) 2010-12-22 2012-06-27 LEK Pharmaceuticals d.d. Process for the preparation of a pharmaceutical composition comprising a low soluble pharmaceutically active ingredient
EP2331074A4 (en) * 2008-09-17 2012-09-19 Mylan Inc Granulates, process for preparing them and pharmaceutical products containing them
WO2015102400A1 (en) * 2013-12-30 2015-07-09 Hanmi Pharm. Co., Ltd. Composite formulation for oral administration comprising ezetimibe and rosuvastatin
CN105213342A (en) * 2015-10-29 2016-01-06 无锡福祈制药有限公司 Ezetimibe sheet
CN105287513A (en) * 2015-10-23 2016-02-03 浙江永宁药业股份有限公司 Ezetimibe medicine composition and preparation method thereof
CN105310993A (en) * 2015-11-17 2016-02-10 深圳信立泰药业股份有限公司 Pharmaceutical composition containing ezetimibe and preparation method of pharmaceutical composition
KR20160105044A (en) 2015-02-27 2016-09-06 한미약품 주식회사 Solid composite formulation for oral administration comprising ezetimibe and rosuvastatin
EP2217214B1 (en) 2007-12-10 2017-07-19 ratiopharm GmbH Pharmaceutical formulation comprising ezetimibe
JP2017210455A (en) * 2016-05-27 2017-11-30 ニプロ株式会社 Ezetimibe-containing pharmaceutical composition
RU2649811C2 (en) * 2013-12-18 2018-04-04 Алвоген Кореа Ко, Лтд. PHARMACEUTICAL COMBINATION PREPARATION CONTAINING THE INHIBITOR OF HMG-CoA REDUCTASE AND INHIBITOR OF CHOLESTEROL ABSORPTION
JP2019006733A (en) * 2017-06-28 2019-01-17 大原薬品工業株式会社 Ezetimibe-containing oral preparation and method for producing the same
CN115252565A (en) * 2022-05-30 2022-11-01 国药集团致君（深圳）制药有限公司 Ezetimibe tablets, preparation process and dissolution evaluation method thereof

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109718215A (en) * 2017-10-30 2019-05-07 海南皇隆制药股份有限公司 A kind of Ezetimibe piece

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
WO2006138163A2 (en) * 2005-06-15 2006-12-28 Merck & Co., Inc. Anti-hypercholesterolemic compounds
EP1741427A1 (en) * 2005-07-06 2007-01-10 KRKA, D.D., Novo Mesto Pharmaceutical composition comprising simvastatin and ezetimibe
WO2008068762A2 (en) * 2006-12-07 2008-06-12 Noah Ben-Shalom Chitosan formulation for cholesterol reduction in humans

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
WO2006138163A2 (en) * 2005-06-15 2006-12-28 Merck & Co., Inc. Anti-hypercholesterolemic compounds
EP1741427A1 (en) * 2005-07-06 2007-01-10 KRKA, D.D., Novo Mesto Pharmaceutical composition comprising simvastatin and ezetimibe
WO2008068762A2 (en) * 2006-12-07 2008-06-12 Noah Ben-Shalom Chitosan formulation for cholesterol reduction in humans

Cited By (36)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008063766A3 (en) * 2006-10-10 2009-01-22 Isp Investments Inc Amorphous ezetimibe and the production thereof
WO2008063766A2 (en) * 2006-10-10 2008-05-29 Isp Investments Inc. Amorphous ezetimibe and the production thereof
EP2217214B1 (en) 2007-12-10 2017-07-19 ratiopharm GmbH Pharmaceutical formulation comprising ezetimibe
WO2010021608A1 (en) * 2008-08-22 2010-02-25 Mahmut Bilgic Solubility enhancing pharmaceutical formulation
WO2010021609A1 (en) * 2008-08-22 2010-02-25 Mahmut Bilgic Solubility and stability enhancing pharmaceutical formulation
EP2331074A4 (en) * 2008-09-17 2012-09-19 Mylan Inc Granulates, process for preparing them and pharmaceutical products containing them
AU2009292615B2 (en) * 2008-09-17 2015-12-03 Mylan Inc. Granulates, process for preparing them and pharmaceutical products containing them
EP2216016A1 (en) 2009-02-06 2010-08-11 LEK Pharmaceuticals d.d. Process for the preparation of a pharmaceutical composition comprising ezetimibe
WO2010089361A2 (en) 2009-02-06 2010-08-12 Lek Pharmaceuticals D.D. Process for the preparation of a pharmaceutical composition comprising ezetimibe
EP2229938A1 (en) 2009-03-13 2010-09-22 Sanovel Ilac Sanayi ve Ticaret A.S. Ezetimibe compositions
US9095515B2 (en) 2009-03-13 2015-08-04 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Ezetimibe compositions
WO2010144066A1 (en) 2009-06-10 2010-12-16 Levent Oner Method for the preparation of ezetimib nanocrystals
WO2011002424A3 (en) * 2009-07-02 2011-04-28 Bilgic Mahmut Solubility and stability enchancing pharmaceutical formulation comprising ezetimibe and simvastatin
WO2011002422A3 (en) * 2009-07-02 2011-04-28 Bilgic Mahmut Solubility enhancing pharmaceutical formulation
WO2011019326A3 (en) * 2009-07-02 2011-04-28 Mahmut Bilgic Solubility and stability enchancing pharmaceutical formulation
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
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
WO2011139256A3 (en) * 2010-05-04 2012-05-18 Bilgic Mahmut Stable rosuvastatin formulations
WO2012064307A1 (en) * 2010-11-11 2012-05-18 Bilgic Mahmut Pharmaceutical compositions comprising rosuvastatin
US20130338131A1 (en) * 2010-12-22 2013-12-19 Lek Pharmaceuticals D.D. Process for the preparation of a pharmaceutical composition comprising a low soluble pharmaceutically active ingredient
EP2468258A1 (en) 2010-12-22 2012-06-27 LEK Pharmaceuticals d.d. Process for the preparation of a pharmaceutical composition comprising a low soluble pharmaceutically active ingredient
WO2012085071A1 (en) 2010-12-22 2012-06-28 Lek Pharmaceuticals D.D. Process for the preparation of a pharmaceutical composition comprising a low soluble pharmaceutically active ingredient
US10357431B2 (en) 2010-12-22 2019-07-23 Lek Pharmaceuticals D.D. Process for the preparation of a pharmaceutical composition comprising a low soluble pharmaceutically active ingredient
RU2649811C2 (en) * 2013-12-18 2018-04-04 Алвоген Кореа Ко, Лтд. PHARMACEUTICAL COMBINATION PREPARATION CONTAINING THE INHIBITOR OF HMG-CoA REDUCTASE AND INHIBITOR OF CHOLESTEROL ABSORPTION
US10434067B2 (en) 2013-12-30 2019-10-08 Hanmi Pharm. Co., Ltd. Composite formulation for oral administration comprising ezetimibe and rosuvastatin
AU2014374552B2 (en) * 2013-12-30 2019-09-19 Hanmi Pharm. Co., Ltd. Composite formulation for oral administration comprising ezetimibe and rosuvastatin
WO2015102400A1 (en) * 2013-12-30 2015-07-09 Hanmi Pharm. Co., Ltd. Composite formulation for oral administration comprising ezetimibe and rosuvastatin
KR20160105044A (en) 2015-02-27 2016-09-06 한미약품 주식회사 Solid composite formulation for oral administration comprising ezetimibe and rosuvastatin
CN105287513A (en) * 2015-10-23 2016-02-03 浙江永宁药业股份有限公司 Ezetimibe medicine composition and preparation method thereof
CN105213342A (en) * 2015-10-29 2016-01-06 无锡福祈制药有限公司 Ezetimibe sheet
CN105310993A (en) * 2015-11-17 2016-02-10 深圳信立泰药业股份有限公司 Pharmaceutical composition containing ezetimibe and preparation method of pharmaceutical composition
JP2017210455A (en) * 2016-05-27 2017-11-30 ニプロ株式会社 Ezetimibe-containing pharmaceutical composition
JP2019006733A (en) * 2017-06-28 2019-01-17 大原薬品工業株式会社 Ezetimibe-containing oral preparation and method for producing the same
JP7115825B2 (en) 2017-06-28 2022-08-09 日医工株式会社 Oral formulation containing ezetimibe and its manufacturing method
CN115252565A (en) * 2022-05-30 2022-11-01 国药集团致君（深圳）制药有限公司 Ezetimibe tablets, preparation process and dissolution evaluation method thereof
CN115252565B (en) * 2022-05-30 2023-09-19 国药集团致君（深圳）制药有限公司 Ezetimibe tablet and preparation process and dissolution evaluation method thereof

Also Published As

Publication number Publication date
EP2120882A2 (en) 2009-11-25
WO2008101723A3 (en) 2008-11-27

Similar Documents

Publication Publication Date Title
EP2120882A2 (en) Pharmaceutical composition containing a cholesterol absorption inhibitor
EP2398468B1 (en) Pharmaceutical compositions comprising prasugrel base or its pharmaceutically acceptable acid addition salts and processes for their preparation
US8921352B2 (en) Pharmaceutical composition comprising simvastatin and ezetimibe
KR101445398B1 (en) Solid orally administerable pharmaceutical dosage forms with rapid active principle release
EP2442799B1 (en) Solid pharmaceutical composition comprising rivaroxaban
US7772273B2 (en) Stabilized atorvastatin
EP2691083A1 (en) Pharmaceutical composition of sitagliptin
WO2007075009A1 (en) Complex formulation comprising amlodipine camsylate and simvastatin and method for preparation thereof
EP4076402A1 (en) Dosage form comprising amorphous solid solution of empagliflozin with polymer
US20110097414A1 (en) Pharmaceutical compositions comprising adsorbate of fenofibrate
WO2011051967A2 (en) Pharmaceutical compositions comprising mycophenolate and processes for preparing thereof
EA027578B1 (en) New granulating process and thus prepared granulate
US20080038332A1 (en) Stable pharmaceutical formulation comprising atorvastatin calcium
EA023340B1 (en) Ropinirole composition
WO2011116973A1 (en) Method of preparing a granulated pharmaceutical composition comprising simvastatin and/or ezetimibe
US8062664B2 (en) Process for preparing formulations of lipid-regulating drugs
US20230270736A1 (en) Pharmaceutical compositions of cabozantinib
EP2345408A2 (en) Acid labile drug formulations
EP3620156A1 (en) Composition having improved water solubility and bioavailability
EP3833335B1 (en) Pharmaceutical composition comprising hmg-coa reductase inhibitors and fenofibrate
JP3547009B1 (en) Novel crystals of 5-[(1Z, 2E) -2-methyl-3-phenyl-2-propenylidene] -4-oxo-2-thioxo-3-thiazolidineacetic acid, a method for producing the same and a drug containing the crystal as an active ingredient
KR102363727B1 (en) Composition for preparing solid formulation containing pranlukast having enhanced bioavailability and production method thereof
WO2013072770A2 (en) Pharmaceutical formulations comprising atorvastatin and glimepiride
US20100285126A1 (en) Pharmaceutical compositions of fenofibrate
US20060177512A1 (en) Process for preparing formulations of lipid-regulating drugs

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08715987

Country of ref document: EP

Kind code of ref document: A2

WWE Wipo information: entry into national phase

Ref document number: 2008715987

Country of ref document: EP

NENP Non-entry into the national phase in:

Ref country code: DE