WO2004110431A1 - Compositions stables d'atorvastatine preparees par granulation par voie humide - Google Patents

Compositions stables d'atorvastatine preparees par granulation par voie humide Download PDF

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Publication number
WO2004110431A1
WO2004110431A1 PCT/IB2004/001862 IB2004001862W WO2004110431A1 WO 2004110431 A1 WO2004110431 A1 WO 2004110431A1 IB 2004001862 W IB2004001862 W IB 2004001862W WO 2004110431 A1 WO2004110431 A1 WO 2004110431A1
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Prior art keywords
atorvastatin
wet
composition
optionally
granules
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PCT/IB2004/001862
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English (en)
Inventor
Kenneth Craig Waterman
Michael Bruce Fergione
Barbara Alice Johnson
Original Assignee
Warner-Lambert Company Llc
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Application filed by Warner-Lambert Company Llc filed Critical Warner-Lambert Company Llc
Priority to MXPA05013281A priority Critical patent/MXPA05013281A/es
Priority to AU2004246868A priority patent/AU2004246868B2/en
Priority to EP04735614A priority patent/EP1635814A1/fr
Priority to BRPI0411344-6A priority patent/BRPI0411344A/pt
Priority to JP2006516512A priority patent/JP2006527260A/ja
Priority to NZ543337A priority patent/NZ543337A/en
Publication of WO2004110431A1 publication Critical patent/WO2004110431A1/fr
Priority to NO20060022A priority patent/NO20060022L/no

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    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics

Definitions

  • This invention relates to pharmaceutical compositions comprising atorvastatin and pharmaceutically acceptable salts thereof and a process for the preparation of the same, kits containing such compositions, as well as methods of using such compositions to treat subjects suffering from hypercholesterolemia and/or hyperlipidemia, as well as osteoporosis, benign prostatic hyperplasia (BPH), and Alzheimer's disease.
  • HMG-CoA 3-hydroxy-3-methylglutaryl-coenzyme A
  • mevalonate is an early and rate-limiting step in the cholesterol biosynthetic pathway. This step is catalyzed by the enzyme HMG-CoA reductase.
  • Statins inhibit HMG-CoA reductase from catalyzing this conversion. As such, statins are collectively potent lipid lowering agents.
  • Atorvastatin calcium disclosed in United States Patent No. 5,273,995 which is incorporated herein by reference, is currently sold as Lipitor ® having the chemical name [R-(R*,R*)]-2-(4-fluorophenyl)- ⁇ , ⁇ -dihydroxy-5-(l-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-lH-pyrrole-l-heptanoic acid calcium salt (2: 1) trihydrate and the formula
  • Atorvastatin and pharmaceutically acceptable salts thereof are selective, competitive inhibitors of HMG-CoA reductase.
  • atorvastatin calcium is a potent lipid-lowering compound and is thus useful as a hypolipidemic and/or hypocholesterolemic agent, as well as in the treatment of osteoporosis, benign prostatic hyperplasia (BPH), and Alzheimer's disease.
  • Atorvastatin can exist in crystalline, liquid crystalline and non-crystalline and amorphous forms.
  • Crystalline forms of atorvastatin calcium are disclosed in United States Patent Numbers 5,969,156 and 6,121,461, which are herein incorporated by reference. Further crystalline forms of atorvastatin are disclosed United States Patent 6,605,729 which is herein incorporated by reference.
  • atorvastatin As well as processes for preparing amorphous atorvastatin. These include: WO 00/71116; WO 01/28999; WO 01/36384; WO 01/42209; WO 02/41834; WO 02/43667; WO 02/43732; WO 02/051804; WO 02/057228; WO 02/057229; WO 02/057274; WO 02/059087; WO 02/083637; WO
  • atorvastatin e.g., acute treatment of patients having strokes as described in Takemoto, M.; Node, K.; Nakagami, H.; Liao, Y.; Grimm, M.; Takemoto, Y.; Kitakaze, M.; Liao, J.K., Journal of Clinical Investigation, 2001; 108(10): 1429-1437
  • a rapid onset of activity may be highly beneficial in improving the efficacy of the drug.
  • atorvastatin is combined with a stabilizing additive, such as, an alkaline earth metal salt, and excipients and subjected to wet granulation using a combination of water and a surfactant (TweenTM 80).
  • a stabilizing additive such as, an alkaline earth metal salt
  • TweenTM 80 a surfactant
  • alkaline earth metal salt additives can affect atorvastatin bioavailability, there remains a need to provide atorvastatin in a wet granulated composition wherein said composition is substantially free of an alkaline earth metal salt additive.
  • One preferred unit dosage form for atorvastatin is a tablet.
  • active drugs in tablets to be rapidly absorbed once swallowed it is generally important for the tablet to disintegrate rapidly once exposed to fluids in the gastrointestinal tract.
  • -A- it is important that the tablets be sufficiently hard that they do not fracture or chip during manufacturing, handling or storage.
  • atorvastatin having a good disintegration rate and bioavailability. It is a further object of the present invention to provide a stable and pure composition of atorvastatin with minimal levels of alkaline earth metal salt additives or other added alkalizing agents in the composition.
  • the first aspect of the present invention is a wet granulated pharmaceutical composition of atorvastatin with less than about 5 weight% of an alkaline earth metal salt additive comprising:
  • a second aspect of the present invention is a wet granulated pharmaceutical composition of atorvastatin with less than about 5 weight% of an alkaline earth metal salt additive comprising:
  • a third aspect of the present invention is a method for preparing a wet-granulated composition of atorvastatin comprising:
  • atorvastatin or a pharmaceutically acceptable salt thereof with sodium starch glycolate, starch, sodium alginate, powdered cellulose, hydroxypropylcellulose, magnesium aluminum silicate or polacrilin potassium or combinations thereof, and optionally other excipients;
  • step (b) adding sufficient water, isopropanol, ethanol, or a mixture thereof to the atorvastatin blend from step (a) under shear to generate granules;
  • composition optionally, forming the composition into unit dosage forms.
  • a fourth aspect of the present invention is a method for preparing a wet granulated composition of atorvastatin comprising: (a) combining atorvastatin or a pharmaceutically salt thereof with a diluent with less than 2 weight % of a disintegrant;
  • step (b) adding sufficient water, isopropanol, ethanol, or a mixture thereof to the atorvastatin blend from step (a) under shear to generate granules;
  • composition optionally, forming the composition into unit dosage forms.
  • a fifth aspect of the present invention is a method for preparing a wet granulated composition of atorvastatin comprising: (a) combining atorvastatin or a pharmaceutically acceptable salt thereof and one or more excipients;
  • composition optionally, forming said composition into unit dosage forms.
  • a sixth aspect of the present invention is a method for preparing a wet-granulated composition of atorvastatin comprising:
  • atorvastatin or a pharmaceutically acceptable salt thereof in combination with at least one active drug with sodium starch glycolate, starch, sodium alginate, powdered cellulose, hydroxypropylcellulose, magnesium aluminum silicate or polacrilin potassium or combinations thereof, and optionally other excipients;
  • step (b) adding sufficient water, isopropanol, ethanol, or a mixture thereof to the atorvastatin blend from step (a) under shear to generate granules;
  • a seventh aspect of the present invention is a method for preparing a wet granulated composition of atorvastatin comprising:
  • step (b) adding sufficient water, isopropanol, ethanol, or a mixture thereof to the atorvastatin blend from step (a) under shear to generate granules;
  • An eighth aspect of the present invention is a method for preparing a wet granulated composition of atorvastatin comprising:
  • a ninth aspect of the present invention is a kit for achieving a therapeutic effect in a mammal comprising a therapeutically effective amount of tablets or capsules prepared from a wet granulated composition of atorvastatin prepared in the form of unit dosage forms from said compositions and a container for containing said dosage forms.
  • An tenth aspect of the present invention is a method of using the pharmaceutical composition to treat subjects suffering from hypercholesterolemia and/or hyperlipidemia, osteoporosis, benign prostatic hyperplasia (BPH), and Alzheimer's disease.
  • Atorvastatin can readily be prepared as described in United States Patent Numbers 4,681,893, 5,273,995 and 5,969,156, which are incorporated herein by reference.
  • the hemicalcium salt of atorvastatin is currently sold as Lipitor ® .
  • Atorvastatin exists in a number of morphological forms ranging from highly crystalline forms to forms with varying degrees of disorder. Some of these disordered forms still possess some structure as indicated by powder x-ray patterns.
  • all forms of atorvastatin benefit from the invention and are included in the scope of the invention.
  • Such forms can be prepared, for example, from the crystalline material using procedures disclosed in United States Patent Number 6,087,511, which is incorporated herein by reference.
  • amorphous atorvastatin material can be prepared according to the processes disclosed in United States Patent Application, commonly owned, attorney's case number PC-
  • non-crystalline and crystalline atorvastatin can be prepared by any method known in the art.
  • the following is a non- exclusive list of patents and published patent applications disclosing preferred forms of atorvastatin for the present invention: United States Patent 5,969,156; United States Patent 6,121,461; United States Patent 6,605,729; International Patent Application WO 01/36384; International Patent Application WO 02/41834; International Patent Application WO 02/43732; International Patent Application WO 02/051804; International Patent Application WO 02/057229; International Patent Application WO 03/011826; International Patent Application WO 03/050085;
  • the atorvastatin can be used in the form it is prepared, or it can be subjected to a process which changes the physical nature of the particles.
  • the material can be milled by any process known in the art. Non-exclusive examples of such processes include mechanical milling and jet milling.
  • the particles produced either directly from the process of forming noncrystalline atorvastatin or after a milling operation preferably provide average particle diameters in the range of 1-200 ⁇ m; more preferably between 5 and 150 ⁇ m.
  • Pharmaceutically acceptable base addition salts of atorvastatin are formed with metals or amines, such as alkaline and alkaline earth metals or organic amines.
  • metals used as cations are sodium, potassium, magnesium, calcium, and the like.
  • suitable amines are NjN'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine (see, for example, Berge, S.M., et al., "Pharmaceutical Salts", J. Pharm. Sci., 1977; 66:1).
  • the base addition salts of atorvastatin are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner.
  • the free acid form may be regenerated by contacting the salt form with an acid and isolating the free acid in the conventional manner.
  • the free acid forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free acid for purposes of the present invention.
  • atorvastatin can exist in unsolvated forms as well as solvated forms, including hydrated forms.
  • the solvated forms, including hydrated forms are intended to be encompassed within the scope of the present invention.
  • Forms of atorvastatin that are at least somewhat disordered or a mixture of crystalline and disordered forms of atorvastatin benefit most significantly from the present invention.
  • somewhat disordered it is meant that the line width (peak width at half the height of the peak) of any of the peaks measured using powder x-ray diffraction (PXRD) have 2 theta values greater than about 2°.
  • Amorphous or predominantly amorphous forms of atorvastatin which especially benefit from the present invention, are characterized by having very broad, featureless peaks. It should be noted that combinations of crystalline and at least somewhat disordered forms of atorvastatin will show both sharp (i.e., less than 2° values for 2 theta) and broad peaks (i.e., greater than 2°), and such combinations of forms benefit from the present invention. Atorvastatin has been found to be an effective drug even at relatively low doses.
  • the dose provided by the final dosage form of atorvastatin is preferably between 0.5 and 120 mgA (where mgA means milligrams of active drug based on the free acid); more preferably between 5 and 80 mgA.
  • these unit dosage forms are generally in the form of tablets and capsules.
  • the dosage form is preferably in the form of a capsule or tablet; most preferably in the form of a tablet.
  • the preparation of these forms involves a necessary step of filling a die or capsule with ' powder.
  • RSD relative standard deviation
  • the unit dosages to have the same potency within allowable margins (relative standard deviation, RSD, of less than 6% to meet Stage I, and less than 7.8% to meet Stage II of the United States Pharmacopoeia, USP, guidelines)
  • RSD relative standard deviation
  • the present invention discloses wet granulation processes and formulations that provide atorvastatin in a pure and stable form.
  • impurities describes materials in the drug substance present from the synthesis and purification process and any drug- based materials formed in the preparation of the unit dosage form.
  • degradationants refers to any drug-based materials generated after the preparation of the unit dosage form (during the shelf-life of the dosage form). Analysis of impurities and degradants is done using reverse phase high performance liquid chromatography, HPLC, techniques on extracted samples as is known in the art.
  • Calculations of the amount of impurities and degradants is expressed as the integrated area percent of all peaks other than the drug peak divided by the integrated area percent of all peaks, or where possible, based on a response factor for integration of peaks from samples of authentic materials.
  • combinations of diluents, binders, disintegrants, lubricants and other additives known in the art are used to provide the properties needed for the unit dosage form as is known in the art.
  • the combination provides for adequate tablet hardness upon compression while providing rapid disintegration in vivo.
  • atorvastatin typically such tablet formulations contain about 1-40% weightweight (w:w) drug, about 1-15% disintegrant, about 0-10% binder and about 0.5-2% lubricant, with the bulk comprising a diluent and/or other components.
  • Preferred binders include carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, dextrin, gelatin, guar gum, hydroxypropyl methylcellulose, maltodextrin, methylcellulose, polyethylene oxide, polymethacrylates and sodium alginate; a particularly preferred binder is hydroxypropylcellulose.
  • a preferred lubricant is magnesium stearate.
  • Preferred diluents include calcium phosphate, calcium sulfate, cellulose acetate, dextrates, dextrin, dextrose, fructose, kaolin, lactitol, lactose, maltitol, maltodextrin, maltose, microcrystalline cellulose, polymethacrylates, powdered cellulose, silicified microcrystalline cellulose, sodium chloride, sorbitol, sucrose and talc.
  • the level of alkaline earth metal salt additives in thejiomposition is preferably about 0-5% (w.w); more preferably, about 0- 3%; most preferably about 0-2%. It is also preferred that the level of other alkalizing agent additives in the composition be about 0-5% (w:w); more preferably, about 0-3%; most preferably about 0-2%. It is also preferred that amine polymers and amide polymers be less than about 0-5% (w:w); more preferably, about 0-3%; most preferably about 0-2% of the formulation. Examples of such polymers are disclosed in International Patent Application WO 01/76566A1.
  • Alkalizing agents are additives or excipients that have the property of increasing the pH of a formulation, when such formulations are added to water.
  • alkalizing agents include inorganic and organic bases (buffers).
  • inorganic alkalizing agents include sodium or potassium citrate, carbonate, bicarbonate, phosphate, sulfate, benzoate and ascorbate, and calcium carbonate and magnesium carbonate. The latter two examples also represent alkaline earth metal salts.
  • organic alkalizing agents include amines. Specific examples of amines include N- methylglucamine, guanine and arginine.
  • any technique known in the art for wet granulation can be used for the purposes of the present invention.
  • An important element to these processes is that the granulation solution is added to the atorvastatin composition while the powder blend is under shear.
  • the shear serves to break up incipient clumps and thereby provide a more uniform granulation.
  • shearing processes include high shear wet granulations, fluid-bed granulations, extrusion granulations and low shear wet granulations (such as stirrers, mixers and blenders, including bin blenders).
  • the amount of wet granulation solvent added is determined based on adequate wetting to bind the majority of the fine particles.
  • the wet granulation solvent addition can be carried out using any technique known in the art.
  • the liquid can be added in single or multiple rapid additions, sprayed onto a stirring powder bed, pumped directly onto the powder or introduced into fluidizing gas. Mixing times with the liquid are generally optimized such that the majority of fine particles are bound in granules, yet the granules themselves are not over-hardened.
  • the wet composition is preferably dried before use in formation of unit dosage forms. Such drying can be accomplished using any method known in the art. Non-limiting examples of these methods include air drying, fluid bed drying, microwave drying, oven drying, radio frequency drying vacuum oven drying and convection oven drying.
  • the drying temperature is important to control to provide low levels of atorvastatin impurities. Preferably the drying temperature does not exceed about 60 0 C; more preferably, the temperature does not exceed about 50 0 C; most preferably, the temperature does not exceed about 40 0 C.
  • a lubricant is typically added followed by a short (about 1-10 minute) mixing period, typically carried out in a low shear blender such as a tumbling blender.
  • a low shear blender such as a tumbling blender.
  • said tumbling blenders include bin-blenders, V-blenders and TurbulaTM blenders.
  • the preferred lubricant is magnesium stearate.
  • Capsules are prepared by filling shaped capsule shells then sealing. Such operations are preferably carried out using a rotary tablet press or commercial capsule-filling machine.
  • rotary tablet presses include those produced by Niro Pharma Systems (Columbia, MD), Kilian and Company (Horsham, PA), Korsch (Berline, Germany) and Elizabet-Hata International (North Huntingdon, PA).
  • Non-exclusive examples of commercial capsule filling equipment include those made by Capsugel (Morris Plains, NJ) and CapPlus Technologies (Phoenix, AZ). Tablets thus prepared can then optionally be coated with a film designed to provide ease of swallowing, a proprietary or identification appearance and/or protection of the dosage form.
  • the packaging is preferably in the form of foil-foil cold form blisters, plastic blisters or sealed bottles containing desiccants.
  • the packaging can contain active oxygen absorbing materials as is disclosed in EP1243524A2 or EP1241110Al, which are incorporated herein by reference.
  • Atorvastatin undergoes two major degradation pathways: lactonization and oxidation.
  • the lactone is formed by internal condensation (loss of water) of the alcohol and carboxylic acid to form a six-membered ring. This is the major degradant of atorvastatin found upon wet granulation and tablet formation, especially in the absence of alkaline earth metal salts.
  • a disintegrant is desirable to provide for rapid disintegration of the tablet in the gastrointestinal tract and thereby assure that the drug is rapidly available for absorption.
  • a large number of disintegrants are disclosed in the prior art for use with atorvastatin.
  • the following list of disintegrants is disclosed in International Patent Publication Number WO03/011283 Al in combination with an alkalizing agent and a second active pharmaceutical ingredient: calcium carboxymethylcellulose, sodium carboxymethylcellulose, silica, croscarmellose sodium, crospovidone, guar gum, magnesium aluminum silicate, methylcellulose, polacrilin potassium, cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate and starch.
  • the examples have focused on use of croscarmellose sodium (see for example U.S. Patent Numbers 5686014, 6126971,
  • This disintegrant is also used in the commercial product Lipitor ® . While many of these disintegrants provide for adequate disintegration properties, in wet granulations of atorvastatin with less than 5% (w:w) alkalizing agent additives, we have unexpectedly determined that only some of the many possible disintegrants provide for adequate drug purity. In fact, the disintegrant used in the majority of examples (croscarmellose sodium), was unexpectedly found to provide poor drug purity.
  • Preferred disintegrants provide atorvastatin formulations with a level of atorvastatin lactone less than about 3% (based on area percent of the lactone peak compared to all drug-related peaks by HPLC integration) after wet granulation and drying; more preferred disintegrants provide lactone levels less than about 1%; and still more preferred disintegrants provide lactone levels less than about 0.5%.
  • Disintegrants suitable for the current invention also provide for disintegration times of tablets produced therein of preferably less than 30 minutes; still more preferably less than 15 minutes; and still more preferably less than 8 minutes. Disintegration times are measured using pH 6.8 phosphate buffer solutions with commercially available disintegration measurement devices.
  • Preferred disintegrants for compositions useful for wet granulation of atorvastatin with less than about 5 weight% alkalizing agent additives or alkaline earth metal salts include starches, sodium starch glycolate, sodium alginate, powdered cellulose, hydroxypropylcellulose, magnesium aluminum silicate and polacrilin potassium.
  • Particularly preferred starches include cornstarch and pregelatinized starch. These disintegrants are preferably used in compositions of atorvastatin at levels between about 1 and about 10% (w:w) of the overall formulation; more preferably between about 3 and about 8% (w:w).
  • Preferred wet granulation solvents have the property of inducing adhesion between particles without significant dissolution of the atorvastatin, which could cause the drug to change morphological forms.
  • preferred granulation solvents for atorvastatin are water and alcohols. Particularly preferred alcohols are ethanol and isopropanol. In many cases, combinations of solvents can be advantageous.
  • such combinations involve water with ethanol or isopropanol.
  • ingredients can be added to the granulation solvent, as is known in the art.
  • binding agents, wetting agents and stabilizers can be incorporated as part of the granulation solvent and are within the scope of the present invention.
  • the wetting agent TweenTM 80 (polysorbate 80) is detrimental to the stability of the atorvastatin. This is surprising since this additive is commonly used in most prior art formulations of atovastatin (see for example, US Patent numbers 5,686,104 and 6,126,971). Therefore, it is preferable that the level of Tween 80 used in wet granulated compositions of atorvastatin be less than 0.5% (w.w); more preferably less than 0.2%; and still more preferably, less than 0.1%.
  • Preferred processes for preparing a wet granulation of atorvastatin with less than about 5 weight% alkalizing agent additives or alkaline earth metal salts with preferred disintegrants comprise the following steps: (a) blending of the atorvastatin with a preferred disintegrant and optionally some or all of the remaining excipients needed for the final composition. These other excipients can include diluents, binders and other such materials necessary for processing, flow, stability or formation of unit dosage forms; (b) adding a granulation solvent while the material from step (a) is under shear.
  • Preferred granulation solvents include, water, ethanol, isopropanol and combinations thereof. Other ingredients can be added to the granulation solvent as is known in the art.
  • binders examples include binders, wetting agents, stabilizers and buffers.
  • the solvent can be applied by any technique known in the art. Preferred methods of applying the solvent while imparting shear include high shear granulation, low shear granulation, fluid bed granulation and extrusion granulation;
  • the material from step (b) can be milled, ground or sieved.
  • This wet material is then dried, preferably using air drying, fluid bed drying, oven drying or microwave drying.
  • the drying is preferably carried out such that the drying temperature does not exceed about 60 0 C; more preferably, the temperature does not exceed about 50 0 C; most preferably, the temperature does not exceed about 4O 0 C; (d) optionally this material is then milled or sieved;
  • composition is optionally formed into a unit dosage form, preferably a tablet or a capsule.
  • the preferred steps in this process comprise: (a) blending of the atorvastatin with at least some of the excipients needed for the final composition, but with no significant amount of a disintegrant. A significant amount of disintegrant is considered greater than about 2% (w:w) of the formulation.
  • excipients can include diluents, binders and other such materials necessary for processing, flow, stability or formation of unit dosage forms; (b) adding a granulation solvent while the material from step (a) is under shear.
  • Preferred granulation solvents include water, ethanol and isopropanol and combinations thereof.
  • Other ingredients can be added to the granulation solvent as is known in the art. Examples of such additives are binders, wetting agents, stabilizers and buffers.
  • the liquid can be applied by any technique known in the art. Preferred methods of applying the liquid while imparting shear include high shear granulation, low shear granulation, fluid bed granulation and extrusion granulation;
  • step (c) optionally, the material from step (b) can be milled, ground or sieved.
  • This wet material is then dried, preferably using air drying, fluid bed drying, oven drying or microwave drying; such drying is preferably carried out such that the drying temperature does not exceed about 6O 0 C; more preferably, the temperature does not exceed about 50 0 C; most preferably, the temperature does not exceed about 40 0 C;
  • this material is then milled, ground or sieved; (e) this composition is then blended with one or more disintegrants and optionally additional excipients, preferably including a lubricant, and (f) the final composition is optionally formed into a unit dosage form, preferably a tablet or a capsule.
  • Such preferred volatile bases include ammonium hydroxide, tetraalkylammonium hydroxides, secondary and tertiary alkyl and aryl amines, diethanolamine and monoethanolamine.
  • Particularly preferred volatile bases include ammonium hydroxide and tetrabutyl ammonium hydroxide.
  • These bases can be added with the granulation solvent (preferably water, isopropanol, ethanol, or combination thereof) at a level selected to be effective at providing good purity and stability for the final atorvastatin dosage form without themselves inducing drug degradation or discoloration of the formulation.
  • the concentration of volatile base used in the granulation water preferably ranges between about 0.001 and about 50% (w:w); more preferably, between about 0.1 and about 40% (w:w).
  • the amount of granulation solution of base added to the granulation preferably is between about 40 and about 100% (w.w) of the solid material.
  • the present invention provides for compositions of atorvastatin which are particularly well suited for combination products with other drug substances because of the greater atorvastatin stability imparted by the disintegrants of the present invention. This is especially true when the second drug (with its associated excipients) can destabilize atorvastatin.
  • Non-limiting examples of drugs which may benefit from combinations with the inventive atorvastatin compositions and processes include torcetrapib and amlodipine and its pharmaceutically acceptable salts.
  • compositions of atorvastatin according to the present invention can be combined with a least one other active drug to form unit dosage forms.
  • Preferred unit dosage forms include tablets and capsules.
  • the following non-limiting list describes options for such unit dosage forms: (a) a blend of wet-granulated atorvastatin with the other active drug itself (i.e., extragranular addition of the other drug to the wet granulated atorvastatin), as a blend with excipients (i.e., extragranular addition of the other drug plus excipients to the wet granulated atorvastatin), or as a granulation (i.e., combination of the other drug granulation with the wet granulated atovastatin), formed into tablets or capsules; (b) a single wet granulation of atorvastatin with the other drug, formed into tablets of capsules; (c) a bilayer tablet comprising wet-granulation of atorvastatin with the other drug, formed into tablets of capsule
  • the present invention relates to the treatment of diseases and conditions in a subject, such as, hyperlipidemia and/or hypercholesterolemia, osteoporosis, benign prostatic hyperplasia (BPH), and Alzheimer's disease with atorvastatin or a pharmaceutically acceptable salt thereof as described above that may be administered in a unit dosage form having low levels of degradation products and/or impurities contained in a therapeutic package or kit.
  • the kit includes the unit dosage form and a container.
  • the kit includes directions for administration of the dosage form.
  • the container can be in any conventional shape or form as known in the art, for example, a paper box, a glass or plastic bottle, or a blister pack with individual dosage forms pressing out of the back according to a therapeutic schedule.
  • Amorphous atorvastatin an example of disordered atorvastatin as previously described and used in the following examples was prepared according to the process disclosed in concurrently filed U.S. Patent Application, commonly owned, attorney case number PC-25825, serial number , by first dissolving atorvastatin calcium (U.S.
  • Patent No. 5,273,995 in methanol to make a 5% (w:w) solution.
  • This solution was sprayed into a Niro PSD-I spray dryer at a rate of 170 gram/minute (g/min) using nitrogen as the atomizing gas.
  • the inlet temperature was 195°C and the outlet temperature was 60 0 C.
  • the powder was tray-dried in an oven at 40 0 C for 12 hrs to afford amorphous atorvastatin.
  • Amorphous atorvastatin calcium prepared as described in Example 1 (1.3 g), 39.0 g of microcrystalline cellulose (Avicel PH102TM, FMC Biopolymer, Philadelphia, PA), 50.7 g of lactose, hydrous (Foremost Farms USA, Rothschild,WI), and 2.0 g of hydroxypropyl cellulose (Klucel EXFTM, Hercules Incorporated, Aqualon Division, Wilmington, DE) were combined in a 500-cc bottle and mixed for 10 min. using a
  • Turbula Shaker Mixer (Willy A. Bachofen AG Maschinenfabrik, Basel, Switzerland). The formulation was then granulated using a Pro-C-epT Mi Mi Pro high shear wet granulator (Pro-C-epT n.v., B- 9060 Zelzate, Belgium) using a 0.9 L bowl. The formulation was dry-mixed for 2 min. at an impeller speed of 400 revolutions per minute (rprn) and chopper speed of 1000 rpm. Wet mixing was done at a 600-rpm impeller speed and 1000-rpm chopper speed. Water was added in increments of 10-30 g at 20-30 g/min.
  • Tablets were made under manual power using a single station Manesty F-Press (Manesty, Liverpool, United Kingdom). A 13/32" standard round concave (SRC) punch and die was used to produce tablets with weights of 450 mg each.
  • the target tablet hardness was 12 kP with a range of 10-14 kP (tablet hardness was tested using a Schleuniger Tablet Hardness Tester, Dr. Schleuniger
  • Amorphous atorvastatin calcium prepared as described in Example 1 (1.3 g), 39.0 g of microcrystalline cellulose (Avicel PH102TM, FMC Biopolymer, Philadelphia, PA), 50.7 g of lactose, hydrous (Foremost Farms USA, Rothschild,WI), 3.0 g of croscarmellose sodium (Ac-Di-SolTM, FMC Biopolymer, Philadelphia, PA) and 2.0 g of hydroxypropyl cellulose (Klucel EXFTM, Hercules Incorporated, Aqualon Division, Wilmington, DE) were combined in a 500-cc bottle and mixed for 10 min. using a Turbula Shaker Mixer (Willy A.
  • the formulation was then granulated using a Pro-C-epT Mi Mi Pro high shear wet granulator (Pro-C-epT n.v., B- 9060 Zelzate, Belgium) using a 0.9 L bowl.
  • the formulation was dry-mixed for 2 min. at an impeller speed of 400 rpm and chopper speed of 1000 rpm. Wet mixing was done at a 600-rpm impeller speed and 1000-rpm chopper speed. Water was added in increments of 10-30 g at 20-30 g/min. for a total of 60 g using a standard 60-cc syringe.
  • the material was wet-mixed for a total of 5.5 min.
  • the granulation was wet sieved through a #10 mesh sieve by hand to achieve a more uniform granule size before drying.
  • the granulation was tray-dried overnight at 50 0 C for 16 hrs. in a forced hot air dryer (Gruenberg Forced Hot Air Oven, Gruenberg Oven Co., Williamsport, PA).
  • the granulation was then milled using a Fitzpatrick LlA mill with a 0.040" Conidur rasping plate at 500 rpm. Material was analyzed as described in Example 2, and results are reported in Table 1.
  • Amorphous atorvastatin calcium prepared as described in Example 1 (1.3 g), 39.0 g of microcrystalline cellulose (Avicel PH102TM, FMC Biopolymer, Philadelphia, PA), 50.7 g of lactose, hydrous (Foremost Farms USA, Rothschild,WI), 3.0 g of sodium starch glycolate, (ExplotabTM, Penwest Pharmaceuticals Co., Cedar Rapids, IA) and 2.0 g of hydroxypropyl cellulose (Klucel EXFTM, Hercules Incorporated, Aqualon Division,
  • Amorphous atorvastatin calcium prepared as described Example 1 (1.3 g), 39.0 g of microcrystalline cellulose (Avicel PH102TM, FMC Biopolymer, Philadelphia, PA), 50.7 g of lactose, hydrous (Foremost Farms USA, Rothschild.WI), 3.0 g of corn starch - Purity 21 (National Starch and Chemical Corp., Bridge water, NJ) and 2.0 g of hydroxypropyl cellulose (Klucel EXFTM, Hercules Incorporated, Aqualon Division, Wilmington, DE) were combined in a 500-cc bottle and mixed for 10 min. using a Turbula Shaker Mixer (Willy A. Bachofen AG Maschinenfabrik, Basel, Switzerland).
  • the formulation was then granulated using a Pro-C-epT Mi Mi Pro high shear wet granulator (Pro-C-epT n.v., B- 9060 Zelzate, Belgium) using a 0.9 L bowl.
  • the formulation was dry-mixed for 2 min. at an impeller speed of 400 rpm and chopper speed of 1000 rpm. Wet mixing was done at a 600-rpm impeller speed and 1000-rpm chopper speed. Water was added in increments of 10-30 g at 20-30 g/min. for a total of 45 g using a standard 60-cc syringe. The material was wet-mixed for a total of 2.5 min.
  • the granulation was wet sieved through a #8 mesh sieve by hand to achieve a more uniform granule size before drying.
  • the granulation was tray-dried overnight at 5O 0 C for 16 hrs. in a forced hot air dryer (Gruenberg Forced Hot Air Oven, Gruenberg Oven Co., Williamsport, PA).
  • the granulation was then milled using a Fitzpatrick LlA mill with a 0.040" Conidur rasping plate at 500 rpm. Material was analyzed as described in Example 2, and results are reported in Table 1.
  • Amorphous atorvastatin calcium prepared as described in Example 1 (1.3 g), 39.0 g of microcrystalline cellulose (Avicel PH102TM, FMC Biopolymer, Philadelphia, PA), 50.7 g of lactose, hydrous (Foremost Farms USA, Rothschild, WI), 3.0 g of pregelatinized starch (Starch 1500, Colorcon, West Point, PA) and 2.0 g of hydroxypropyl cellulose (Klucel EXFTM, Hercules Incorporated, Aqualon Division, Wilmington, DE) were combined in a 500-cc bottle and mixed for 10 min. using a Turbula Shaker Mixer (Willy A. Bachofen AG Maschinenfabrik, Basel, Switzerland).
  • the formulation was then granulated using a Pro-C-epT Mi Mi Pro high shear wet granulator (Pro-C-epT n.v., B- 9060 Zelzate, Belgium) using a 0.9 L bowl.
  • the formulation was dry-mixed for 2 min. at an impeller speed of 400 rpm and chopper speed of 1000 rpm. Wet mixing was done at a 600-rpm impeller speed and 1000-rpm chopper speed. Water was added in increments of 10-30 g at 20-30 g/min. for a total of 40 g using a standard 60-cc syringe. The material was wet-mixed for a total of 3 min.
  • the granulation was wet sieved through a #8 mesh sieve by hand to achieve a more uniform granule size before drying.
  • the granulation was tray-dried overnight at 5O 0 C for 16 hrs. in a forced hot air dryer (Gruenberg Forced Hot Air Oven, Gruenberg Oven Co., Williamsport, PA).
  • the granulation was then milled using a Fitzpatrick LlA mill with a 0.040" Conidur rasping plate at 500 rpm. Material was analyzed as described in Example 2, and results are reported in Table 1.
  • Amorphous atorvastatin calcium prepared as described in Example 1 (40.5 mg), 1.22 g of microcrystalline cellulose (Avicel PH102TM, FMC Biopolymer, Philadelphia, PA), 1.58 g of lactose, hydrous (Foremost Farms USA, Rothschild, WI), 93.9 mg of alginic acid (ProtacidTM, FMC BioPolymer, Philadelphia, PA) and 62.4 mg of hydroxypropyl cellulose (Klucel EXFTM, Hercules Incorporated, Aqualon Division, Wilmington, DE) were combined in a 30-cc bottle and mixed for 10 min. using a Turbula Shaker Mixer (Willy A. Bachofen AG Maschinenfabrik, Basel, Switzerland).
  • the mixture was then granulated in the 30-cc bottle, using a bent micro-spatula impeller with a 1/2" blade on a variable speed mini-drill press (Micro-Drill model 164C-7, Cameron Precision Engineering Co., Sonora, CA 95370).
  • the blade Prior to use, the blade was bent to an angle sufficient to sweep the material being granulated, and to allow a portion of this material to flow over the top of the blade.
  • the blade was bent to an angle about 30° from vertical.
  • the granulating fluid was pipetted in 1.0 to 0.5 mL increments, wet mixing for 2.5 min. until a suitable granulation was formed based upon visual observations (total of 1.5 mL added).
  • the mixture was then granulated in the 30-cc bottle, using a bent micro- spatula impeller with a 1/2" blade on a variable speed mini-drill press (Micro-Drill model 164C-7, Cameron Precision Engineering Co., Sonora, CA 95370).
  • the blade Prior to use, the blade was bent to an angle sufficient to sweep the material being granulated, and to allow a portion of this material to flow over the top of the blade.
  • the blade was bent to an angle about 30° from vertical.
  • the granulating fluid was pipetted in 1.0 to 0.5 mL increments, wet mixing for 2.5 min. until a suitable granulation was formed based upon visual observations (total of 1.5 mL added).
  • Amorphous atorvastatin calcium prepared as described in Example 1 (40.5 mg), 1.22 g of microcrystalline cellulose (Avicel PH102TM, FMC Biopolymer, Philadelphia, PA), 1.58 g of lactose, hydrous (Foremost Farms USA, Rothschild, WI), 93.9 mg of hydroxypropylcellulose (low substitution grade, Shin-Etsu Chemical Co., Tokyo, Japan) and 62.4 mg of hydroxypropyl cellulose (Klucel EXFTM, Hercules Incorporated, Aqualon Division, Wilmington, DE) were combined in a 30-cc bottle and mixed for 10 min. using a Turbula Shaker Mixer (Willy A. Bachofen AG Maschinenfabrik, Basel, Switzerland).
  • the mixture was then granulated in the 30-cc bottle, using a bent micro-spatula impeller with a 1/2" blade on a variable speed mini-drill press (Micro-Drill model 164C-7, Cameron Precision Engineering Co., Sonora, CA 95370).
  • the blade Prior to use, the blade was bent to an angle sufficient to sweep the material being granulated, and to allow a portion of this material to flow over the top of the blade.
  • the blade was bent to an angle about 30° from vertical.
  • the granulating fluid was pipetted in 1.0 to 0.5 mL increments, wet mixing for 2.5 min. until a suitable granulation was formed based upon visual observations (total' of 1.5 mL added).
  • Amorphous atorvastatin calcium prepared as described in Example 1 (40.5 mg), 1.22 g of microcrystalline cellulose (Avicel PH102TM, FMC Biopolymer, Philadelphia, PA), 1.58 g of lactose, hydrous (Foremost Farms USA, Rothschild, WI), 93.9 mg of magnesium aluminum silicate (VeegumFTM, R.T. Vanderbilt Co., Norwalk, CT) and 62.4 mg of hydroxypropyl cellulose (Klucel EXFTM, Hercules Incorporated, Aqualon Division, Wilmington, DE) were combined in a 30-cc bottle and mixed for 10 min. using a Turbula Shaker Mixer (Willy A. Bachofen AG Maschinenfabrik, Basel, Switzerland).
  • the mixture was then granulated in the 30-cc bottle, using a bent micro-spatula impeller with a 1/2" blade on a variable speed mini-drill press (Micro-Drill model 164C-7, Cameron Precision Engineering Co., Sonora, CA 95370).
  • the blade Prior to use, the blade was bent to an angle sufficient to sweep the material being granulated, and to allow a portion of this material to flow over the top of the blade.
  • the blade was bent to an angle about 30° from vertical.
  • the granulating fluid was pipetted in 1.0 to 0.5 mL increments, wet mixing for 2.5 min. until a suitable granulation was formed based upon visual observations (total of 1.5 mL added).
  • the granulation was tray-dried for 16 hrs at 5O 0 C in a forced hot air dryer
  • Amorphous atorvastatin calcium prepared as described in Example 1 (40.5 mg), 1.22 g of microcrystalline cellulose (Avicel PH102TM, FMC Biopolymer, Philadelphia, PA), 1.58 g of lactose, hydrous (Foremost Farms USA, Rothschild, WI), 93.9 mg of polacrilin potassium (Amberlite IRP88TM, Rohm and Haas Co., Philadelphia, PA) and 62.4 mg of hydroxypropyl cellulose (Klucel EXFTM, Hercules Incorporated, Aqualon Division, Wilmington, DE) were combined in a 30-cc bottle and mixed for 10 min. using a Turbula Shaker Mixer (Willy A. Bachofen AG Maschinenfabrik, Basel, Switzerland).
  • the mixture was then granulated in the 30-cc bottle, using a bent micro-spatula impeller with a 1/2" blade on a variable speed mini-drill press (Micro-Drill model 164C-7, Cameron Precision Engineering Co., Sonora, CA 95370).
  • the blade Prior to use, the blade was bent to an angle sufficient to sweep the material being granulated, and to allow a portion of this material to flow over the top of the blade.
  • the blade was bent to an angle about 30° from vertical.
  • the granulating fluid was pipetted in 1.0 to 0.5 mL increments, wet mixing for 2.5 min. until a suitable granulation was formed based upon visual observations (total of 1.5 mL added).
  • Example 2 To 13.30 g of material prepared in Example 2 was added 0.858 g of one of the following disintegrants: (a) sodium starch glycolate; (b) croscarmellose sodium; (c) corn starch, or (d) pregelatinized starch in a 60-cc bottle. The blends were mixed for 5 min. using a Turbula Shaker Mixer. To this blend was added, in each case, 0.143 g of magnesium stearate (Mallinckrodt Co., St. Louis, MO). The formulations were then blended 3 min. using a Turbula Shaker Mixer. Material was analyzed for the level of lactone as described in Example 2 and results are reported in Table 2.
  • disintegrants (a) sodium starch glycolate; (b) croscarmellose sodium; (c) corn starch, or (d) pregelatinized starch in a 60-cc bottle.
  • the blends were mixed for 5 min. using a Turbula Shaker Mixer. To this blend was added, in each
  • Tablets were made under manual power using a single station Manesty F-Press (Manesty, Liverpool, United Kingdom). A 13/32" SRC punch and die was used to produce tablets with weights of 450 mg each.
  • the target tablet hardness was 12 kP with a range of 10-14 kP (tablet hardness was tested using a Schleuniger Tablet Hardness Tester, Dr. Schleuniger Pharmatron AG, Solothurn, Switzerland). Material was analyzed a described in Example 2 and results are reported in Table 2.
  • the mixture was then granulated in the 30-cc bottle, using a bent micro-spatula impeller with a 1/2" blade on a variable speed mini-drill press (Micro-Drill model 164C-7, Cameron Precision Engineering Co., Sonora, CA 95370).
  • the blade Prior to use, the blade was bent to an angle sufficient to sweep the material being granulated, and to allow a portion of this material to flow over the top of the blade.
  • the blade was bent to an angle about 30° from vertical.
  • the granulating fluid was pipetted in 0.5 to 1.0 mL increments, wet mixing for 4 min. until a suitable granulation was formed based upon visual observations (total of 2.5 mL added).
  • the wet granulation was dried overnight at 5O 0 C for 16 hr. in a forced hot air tray dryer. Material was analyzed for the level of lactone as described in Example 2, with the modification of using 275 mg granulation instead of 400 mg. Results are reported in Table 3.
  • Amorphous atorvastatin calcium prepared as described in Example 1 (62.1 mg), 1772.1 mg of microcrystalline cellulose (Avicel PH102TM, FMC Biopolymer, Philadelphia, PA), 1010.4 mg of lactose, hydrous (Foremost Farms USA, Rothschild,WI), 62. lmg of hydroxypropyl cellulose (Klucel EXFTM, Hercules
  • Amorphous atorvastatin calcium as prepared in Example 1 (40.5 mg), 1218.8 mg of microcrystalline cellulose (Avicel PH102TM, FMC Biopolymer, Philadelphia, PA), 1572.1 mg of lactose, hydrous (Foremost Farms USA, Rothschild, WI), 62.5mg of hydroxypropyl cellulose (Klucel EXFTM, Hercules Incorporated, Aqualon Division, Wilmington, DE), and 93.8 mg of sodium starch glycolate (ExplotabTM , Penwest Pharmaceuticals Co., Cedar Rapids, IA) were placed in a 30-cc glass bottle. The combined dry components were mixed for 10 min. using a Turbula Shaker Mixer (Willy A.
  • the granulating liquid made in excess, was made by combining 99g Of H 2 O with Ig of polysorbate 80 (Tween 80TM, Spectrum Chemicals & Lab Products, Gardena, CA) in a 125 mL flask and mixing. The powder mixture was then granulated as described in Example 1 using 2.5 mL of the granulating liquid, wet mixing for 4 min. The wet granulation was then divided into three approximately equal portions. Each portion was dried under the following conditions for 16 hr.: (a) 30 0 C vacuum oven, (b) 50 0 C convection oven, and (c) 70 0 C vacuum oven.

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Abstract

L'invention concerne une composition pharmaceutique granulée par voie humide qui contient de l'atorvastatine ou un de ses sels pharmaceutiquement acceptables avec moins de 5 % en poids d'un additif en un sel d'un métal alcalino-terreux et un désintégrant, ce qui donne de l'atorvastatine avec moins de 3 % environ de lactone d'atorvastatine, sur la base du rapport entre l'aire de pic de lactone et les aires intégrées totales de pic associées au médicament. L'invention concerne également cette composition pharmaceutique granulée par voie humide qui contient de l'atorvastatine ou un de ses sels pharmaceutiquement acceptables associé à au moins un autre médicament actif, des procédés de préparation de ces compositions, des kits qui contiennent ces compositions et un procédé de traitement de l'hypercholestérolémie et/ou de l'hyperlipidémie, de l'ostéoporose, de l'hyperplasie prostatique bénigne et de la maladie d'Alzheimer au moyen d'une quantité thérapeutiquement efficace de ces compositions pharmaceutiques.
PCT/IB2004/001862 2003-06-12 2004-06-01 Compositions stables d'atorvastatine preparees par granulation par voie humide WO2004110431A1 (fr)

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MXPA05013281A MXPA05013281A (es) 2003-06-12 2004-06-01 Composiciones farmaceuticas de atorvastatina.
AU2004246868A AU2004246868B2 (en) 2003-06-12 2004-06-01 Stable compositions of atorvastatin prepared with wet granulation
EP04735614A EP1635814A1 (fr) 2003-06-12 2004-06-01 Compositions stables d'atorvastatine preparees par granulation par voie humide
BRPI0411344-6A BRPI0411344A (pt) 2003-06-12 2004-06-01 composições farmacêuticas granuladas de atorvastatina, forma de dosagem unitária, método para preparar as mesmas, uso e kit
JP2006516512A JP2006527260A (ja) 2003-06-12 2004-06-01 湿式顆粒化で調製されたアトルバスタチンの安定な組成物
NZ543337A NZ543337A (en) 2003-06-12 2004-06-01 Stable compositions of atorvastatin prepared with wet granulation
NO20060022A NO20060022L (no) 2003-06-12 2006-01-03 Stabile sammensetninger av atorvastatin fremstilt ved vat granulering

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WO2009000286A1 (fr) * 2007-06-25 2008-12-31 Parmatheen S.A. Formulation pharmaceutique améliorée contenant un inhibiteur de la hmg-coa réductase et son procédé de préparation
WO2010033179A1 (fr) * 2008-09-17 2010-03-25 Mylan Laboratories, Inc. Granulés, leur procédé de préparation et produits pharmaceutiques les contenant
WO2011154755A1 (fr) 2010-06-08 2011-12-15 Nanoform Cardiovascular Therapeutics Ltd. Atorvastatine nanostructurée, ses sels pharmaceutiquement acceptables et des compositions de ceux-ci, procédé pour leur préparation et compositions pharmaceutiques les contenant
WO2013072770A2 (fr) 2011-11-15 2013-05-23 Dr. Reddy's Laboratories Ltd. Formulations pharmaceutiques comprenant de l'atorvastatine et du glimépiride
CN107427462A (zh) * 2015-03-12 2017-12-01 Fmc有限公司 固态分散体
US10596178B2 (en) 2014-07-25 2020-03-24 Novartis Ag Tablet formulation of 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl) imidazo [1,2-B] [1,2,4] triazin-2-yl] benzamide
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US8414958B2 (en) * 2008-02-27 2013-04-09 Thommen Medical Ag Implant and method for the manufacture thereof
CN104069078B (zh) * 2014-05-22 2019-06-11 西藏九瑞健康股份有限公司 阿托伐他汀钙药物组合物及其制备方法
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WO2002072073A2 (fr) * 2001-03-14 2002-09-19 Lek Pharmaceutical And Chemical Company D.D. Atorvastatine calcique sous forme pharmaceutique, composition de celle-ci et formulation pharmaceutique contenant de l'atorvastatine calcique

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US8821932B2 (en) 2006-07-13 2014-09-02 David John Duncalf Pharmaceutical compositions
WO2008006715A3 (fr) * 2006-07-13 2008-05-08 Unilever Plc Compositions pharmaceutiques améliorées
WO2009000286A1 (fr) * 2007-06-25 2008-12-31 Parmatheen S.A. Formulation pharmaceutique améliorée contenant un inhibiteur de la hmg-coa réductase et son procédé de préparation
AU2007355452B2 (en) * 2007-06-25 2011-12-15 Pharmathen S.A. Improved pharmaceutical formulation containing an HMG-CoA reductase inhibitor and method for the preparation thereof
WO2010033179A1 (fr) * 2008-09-17 2010-03-25 Mylan Laboratories, Inc. Granulés, leur procédé de préparation et produits pharmaceutiques les contenant
EP2331074A4 (fr) * 2008-09-17 2012-09-19 Mylan Inc Granulés, leur procédé de préparation et produits pharmaceutiques les contenant
WO2011154755A1 (fr) 2010-06-08 2011-12-15 Nanoform Cardiovascular Therapeutics Ltd. Atorvastatine nanostructurée, ses sels pharmaceutiquement acceptables et des compositions de ceux-ci, procédé pour leur préparation et compositions pharmaceutiques les contenant
WO2013072770A2 (fr) 2011-11-15 2013-05-23 Dr. Reddy's Laboratories Ltd. Formulations pharmaceutiques comprenant de l'atorvastatine et du glimépiride
WO2013072770A3 (fr) * 2011-11-15 2013-10-24 Dr. Reddy's Laboratories Ltd. Formulations pharmaceutiques comprenant de l'atorvastatine et du glimépiride
US10596178B2 (en) 2014-07-25 2020-03-24 Novartis Ag Tablet formulation of 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl) imidazo [1,2-B] [1,2,4] triazin-2-yl] benzamide
CN107427462A (zh) * 2015-03-12 2017-12-01 Fmc有限公司 固态分散体
EP3267977A4 (fr) * 2015-03-12 2018-10-17 FMC Corporation Dispersions solides
CN107427462B (zh) * 2015-03-12 2023-08-29 杜邦营养美国有限公司 固态分散体
US11413295B2 (en) 2016-03-31 2022-08-16 Intercept Pharmaceuticals, Inc. Oral preparation of obeticholic acid

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CN1805741A (zh) 2006-07-19
NZ543337A (en) 2008-03-28
JP2006527260A (ja) 2006-11-30
KR100814218B1 (ko) 2008-03-17
NO20060022L (no) 2006-01-03
TW200503690A (en) 2005-02-01
BRPI0411344A (pt) 2006-07-11
AR044774A1 (es) 2005-10-05
AU2004246868B2 (en) 2008-01-17
CN100434069C (zh) 2008-11-19
KR20060020666A (ko) 2006-03-06
CA2465565A1 (fr) 2004-12-12
CO5650230A2 (es) 2006-06-30
RU2332211C2 (ru) 2008-08-27
RU2005136745A (ru) 2006-07-27
EP1635814A1 (fr) 2006-03-22
AU2004246868A1 (en) 2004-12-23
MXPA05013281A (es) 2006-03-09

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