EP2120882A2 - Pharmazeutische zusammensetzung mit einem cholesterinabsorptionshemmer - Google Patents

Pharmazeutische zusammensetzung mit einem cholesterinabsorptionshemmer

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Publication number
EP2120882A2
EP2120882A2 EP08715987A EP08715987A EP2120882A2 EP 2120882 A2 EP2120882 A2 EP 2120882A2 EP 08715987 A EP08715987 A EP 08715987A EP 08715987 A EP08715987 A EP 08715987A EP 2120882 A2 EP2120882 A2 EP 2120882A2
Authority
EP
European Patent Office
Prior art keywords
pharmaceutical composition
cholesterol absorption
absorption inhibitor
hydrophilic polymer
previous
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP08715987A
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English (en)
French (fr)
Inventor
Vesna Kroselj
Matej Smrkolj
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
KRKA dd
Original Assignee
KRKA dd
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Publication date
Application filed by KRKA dd filed Critical KRKA dd
Publication of EP2120882A2 publication Critical patent/EP2120882A2/de
Withdrawn legal-status Critical Current

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    • 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.

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EP08715987A 2007-02-23 2008-02-22 Pharmazeutische zusammensetzung mit einem cholesterinabsorptionshemmer Withdrawn EP2120882A2 (de)

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