WO2011001450A1 - Composition pharmaceutique orale comprenant de l'atorvastatine - Google Patents

Composition pharmaceutique orale comprenant de l'atorvastatine Download PDF

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Publication number
WO2011001450A1
WO2011001450A1 PCT/IN2010/000436 IN2010000436W WO2011001450A1 WO 2011001450 A1 WO2011001450 A1 WO 2011001450A1 IN 2010000436 W IN2010000436 W IN 2010000436W WO 2011001450 A1 WO2011001450 A1 WO 2011001450A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutically acceptable
atorvastatin
acceptable salt
pharmaceutical composition
oral pharmaceutical
Prior art date
Application number
PCT/IN2010/000436
Other languages
English (en)
Inventor
Senapati Manoj
Ranjan Pradhan Manas
V. Satyanaryana
Rampal Ashok
Original Assignee
Alkem Laboratories Ltd.
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 Alkem Laboratories Ltd. filed Critical Alkem Laboratories Ltd.
Publication of WO2011001450A1 publication Critical patent/WO2011001450A1/fr

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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
    • A61K31/40—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
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • 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
    • A61K9/2009—Inorganic compounds
    • 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

Definitions

  • the present invention relates to a stable oral pharmaceutical composition
  • atorvastatin or its pharmaceutically acceptable salt comprising atorvastatin or its pharmaceutically acceptable salt.
  • Atorvastatin calcium an HMG-CoA reductase inhibitor, disclosed in the U. S. Pat. Mo. 5,273,995, is currently sold in United States of America as Lipitor® having chemical name [R-(R*,R*)]-2-(4-fluorophenyl)- ⁇ , ⁇ -dihydroxy-5-(l- methylethyl)-3-phenyl-4-[(phenylamino) carbonyljlH-pyrroie-l-heptanoic acid, calcium salt (2:1) trihydrate. It is indicated for prevention _of cardiovascular disease and hypercholesterolemia. Atorvastatin is susceptible to a low pH environment and can degrade to the corresponding lactone in an acidic environment.
  • Amlodipine besylate a long-acting calcium channel blocker is chemically described as 3-Ethyl-5- methyl ( ⁇ )-2-[(2-aminoethoxy)methy!]-4-(o- chlorophenyl)-l,4-dihydro-6-methyl-3 f 5-pyridinedicarboxyiate,
  • Amiodipine may readily be prepared as described in U.S. Pat. No. 4,572, 909, Amiodipine besylate, which is currently sold as Norvasc®, may be prepared as described in U.S. Pat. No. 4,879,303, which is incorporated herein by reference. Amiodipine and amiodipine besylate are potent and long lasting calcium channel blockers. A combination of amlodipine besyiate and atorvastatin calcium tablets is available as CADUET® tablets in the United States of America. This combination is indicated in treatment of cardiovascular disease, hypercholesterolemia, hypertension and Coronary Artery Disease (CAD).
  • CAD Coronary Artery Disease
  • U.S. Patent No. 5,686,104 discloses that HMG-CoA reductase inhibitors in an oral pharmaceutical composition for the treatment of hypercholesterolemia or hyperlipidemia are stabilized by combination with at least one alkaline earth metal salt such as calcium carbonate, calcium hydroxide, magnesium carbonate, magnesium hydroxide, magnesium silicate, magnesium aluminate or aluminium magnesium hydroxide.
  • alkaline earth metal salt such as calcium carbonate, calcium hydroxide, magnesium carbonate, magnesium hydroxide, magnesium silicate, magnesium aluminate or aluminium magnesium hydroxide.
  • U.S. Patent No. 6,680,341 discloses a stabilized pharmaceutical formulation containing as an active ingredient an HMG-CoA reductase inhibitor, and a buffering agent, wherein the active composition has a pH in the range from 7 to 11; at least one constituent selected from the group consisting of a filler, a binder, a disintegrating agent and a glidant; and additional buffering agent, wherein the pharmaceutical formulation has a pH below 9.
  • U.S. Patent No. 6,531,507 discloses a composition comprising a homogeneous mixture of a HMG-CoA reductase inhibitor with a buffering substance or a basifying substance in a finely distributed form, obtained by co-crystallization and/or co- precipitation of said HMG-CoA reductase inhibitor and said buffering substance or basifying substance.
  • the basifying substance used for co-crystallization and/or co-precipitation is selected from the group consisting of metal oxides, inorganic bases, organic bases and organic acids with basic character.
  • U.S. Patent No. 7,030,151 discloses a pharmaceutical formulation comprising atorvastatin calcium as active ingredient and a pH adjusting substance to provide the pharmaceutical formulation when dissolved in a liquid aqueous medium increases the pH of said medium to a pH equal to or greater than pK a +l of atorvastatin calcium,
  • the pH adjusting substance is selected from the group consisting of metal oxides, inorganic bases, organic bases, and salts of organic and inorganic aids.
  • U.S. Patent Application No. 2003175338 discloses a pharmaceutical formulation comprising aton/astatin and an alkali metal salt additive, the alkali metal salt additive being present at a concentration of between approximately 1.2% w/w and less than 5% w/w by weight of the formulation.
  • U.S. Patent Application No. 2004247673 discloses a wet granulated pharmaceutical composition
  • atorvastatin or a pharmaceutically acceptable salt thereof with less than about 5 weight % of an alkaline earth metal salt additive with a disintegrant which provides the atorvastatin with not more than about 3% atorvastatin lactone based on the ratio of lactone peak area compared to the total drug-related peak integrated areas.
  • the alkalizing agents include inorganic and organic bases (buffers).
  • U.S. Patent Application No. 2004072894 discloses a stable solid pharmaceutical formulation containing as an active substance a HMG-CoA reductase inhibitor which is capable of providing a pH in the range from 7 to 11.
  • the active substance is contained the buffering agent having an amount of less than 1% w/w.
  • PCT Application No. 2003097039 discloses solid compositions for oral administration comprising atorvastatin calcium and a sodium or potassium compound which is capable of producing an aqueous dispersion having a pH above 11.
  • the sodium or potassium compound may be a hydroxide or a salt of a weak acid.
  • the present invention provides a stable oral pharmaceutical composition
  • atorvastatin or its pharmaceutically acceptable salt and suitable alkali metal salt additives in an amount of more than 5 % w/w so as to prevent degradation of the atorvastatin or its pharmaceutically acceptable salt.
  • the present invention also provides a stable oral pharmaceutical composition
  • a stable oral pharmaceutical composition comprising a combination of atorvastatin or its pharmaceutically acceptable salt, amlodipine or its pharmaceutically acceptable salt and suitable alkali metal salt additives in an amount of more than 5 % w/w so as to prevent degradation of the atorvastatin or its pharmaceutically acceptable salt.
  • the present invention provides a process for preparing a stable oral pharmaceutical composition of atorvastatin or its pharmaceutically acceptable salt and optionally amlodipine or its pharmaceutically acceptable salt, comprising mixing atorvastatin or its pharmaceutically acceptable salt and optionally amlodipine or its pharmaceutically acceptable salt with alkali metal salt additives in an amount of more than 5 % w/w so as to prevent degradation of the atorvastatin or its pharmaceutically acceptable salt; and other excipients and converting the mixture into a pharmaceutical composition.
  • stable refers to chemical stability of atorvastatin in solid dosage forms wherein there is no change in assay values, dissolution data and impurities percentages are below 3% w/w, when kept at 40 0 C /75% RH for 3 months.
  • the present invention provides a stable oral pharmaceutical composition
  • atorvastatin or its pharmaceutically acceptable salt and suitable alkali metal salt additives in an amount of more than 5 % w/w so as to prevent degradation of the atorvastatin or its pharmaceutically acceptable salt.
  • the present invention also provides a stable oral pharmaceutical composition
  • a stable oral pharmaceutical composition comprising a combination of atorvastatin or Its pharmaceutically acceptable salt, amlodipine or its pharmaceutically acceptable salt and suitable alkali metat salt additives in an amount of more than 5 % w/w so as to prevent degradation of the atorvastatin or its pharmaceutically acceptable salt.
  • the present invention provides a process for preparing a stable oral pharmaceutical composition of ato ⁇ /astatfn or its pharmaceutically acceptable salt and optionally amlodipine or its pharmaceutically acceptable salt, comprising mixing atorvastatin or its pharmaceutically acceptable salt and optionally amlodipine or its pharmaceutically acceptable salt with alkali metal salt additives in an amount of more than 5 % w/w so as to prevent degradation of the atorvastatin or its pharmaceutically acceptable salt; and other excipients and converting the mixture into a pharmaceutical composition.
  • a stable oral pharmaceutical composition comprising atorvastatin or its pharmaceutically acceptable salt can be obtained by providing, in a pharmaceutical composition, suitable alkali metal salt additives in a stabilizing effective amount of more than 5 % w/w.
  • the present invention is particularly adapted to stable oral pharmaceutical compositions comprising atorvastatin or its pharmaceutically acceptable salt, as the active component of the composition.
  • atorvastatin or its pharmaceutically acceptable salt are metal and amine salts.
  • pharmaceutically acceptable salt thus includes, but is not limited to sodium, potassium, lithium, calcium, magnesium, aluminum, iron and zinc salts of atorvastatin.
  • the atorvastatin is in the form of calcium salt.
  • the atorvavstatin calcium may be in crystalline or amorphous form.
  • the atorvastatin or its pharmaceutically acceptable salt is used in a therapeutically effective amount in the stable oral pharmaceutical compositions of the present invention.
  • the atorvastatin or its pharmaceutically acceptable salt will generally be present in an amount ranging from about 0,05 to about 70% w/w, preferably in an amount ranging from about 1.0 to about 60% w/w, and most preferably from about 1% to about 40% w/w of the composition.
  • the therapeutic effective amount of atorvastatin or its pharmaceutically acceptable salt that may be used in the stable composition of the present invention is in the range from about 10 to about 100 mg, equivalent to the base.
  • the stable oral pharmaceutical compositions of the present invention may also include amfodipine or its pharmaceutical! 1 / acceptable salt.
  • pharmaceutically-acceptable acid addition salts is intended to define but is not limited to such salts as the hydrochloride, hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogenphosphate, acetate, besylate, succinate, citrate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts.
  • Other acid addition salts of amiodipine may be prepared by reacting the free base form of amlodipine with the appropriate acid.
  • the salt is of a monobasic acid (e.g., the hydrochloride, the hydrobromide, the p-toluenesulfonate, the acetate)
  • the hydrogen form of a dibasic acid e.g., the hydrogen sulfate, the succinate
  • the d ⁇ hydrogen form of a tribasic acid e.g., the dihydrogen phosphate, the citrate
  • at least one molar equivalent and usually a molar excess of the acid is employed.
  • the appropriate and exact chemical equivalents of acid will generally be used.
  • the free base of amiodipine and the acid are usually combined in a co-solvent from which the desired salt precipitates, or can be otherwise isolated by concentration and/or addition of a non-solvent.
  • a particularly preferred salt of amiodipine is the besylate salt.
  • the amiodipine or its pharmaceutically acceptable salt is used in a therapeutically effective amount in the stable oral pharmaceutical compositions of the present invention.
  • the amfod ⁇ pine or its pharmaceutically acceptable salt may generally be present in an amount ranging from about 0.01 to about 60% w/w, preferably in an amount ranging from about 0.05 to about 40% w/w, and most preferably from about 0.2 to about 20% w/w of the composition.
  • the therapeutic effective amount of amlodipine or its pharmaceutically acceptable salt that may be used in the stable composition of the present invention is in the range from about 2.5 to about 20 mg, equivalent to the base.
  • aikaSi metal salt additive(s) in a stabilizing effective amount of more than 5 % w/w.
  • the suitable alkali metal salt additives are used in an amount of more than 5 % w/w so as to prevent degradation of the atorvastatin or its pharmaceutically acceptable salt.
  • the amount of suitable alkali metal salt additives that may be used in the stable oral pharmaceutical composition of the subject invention ranges from about 5.1 % w/w to about 70% w/w of the total weight of the composition.
  • the suitable alkali metals of the invention may be selected from the group comprising compounds of group IA of periodic table such as sodium, potassium or lithium & the suitable aSka ⁇ metal salt additives of the invention may be selected from the group comprising one or more of disodium hydrogen phosphate, sodium hydrogen carbonate, sodium hydroxide, sodium silicate, sodium aluminate and the like or mixtures thereof.
  • the pharmaceutical composition of the present invention may further comprise conventional pharmaceutically acceptable excipients.
  • Conventional pharmaceutical excipients include those which function in a dosage form, for example, as a disintegrant, lubricant, glidant, fillers or diluents, wicking agents, carrier, colorant or coating material.
  • the composition of the present invention is formed into tablets.
  • the fillers or diluents that may be used in the stable oral pharmaceutical composition of the present invention include microcrystalline cellulose, mannitol, dextrates, dextrins, dextrose, fructose, lactose, lactitol, maltitoi, maitodextrins, maltose and the like and mixtures thereof.
  • a preferred filler is microcrystalline cellulose or lactose or a combination thereof.
  • the diluents or fillers may be used in amounts ranging from about 10 to about 95% w/w. It is preferred that the fillers are used in amounts ranging from about 20% to about 80% w/w of the composition.
  • the disintegrants that may be used in pharmaceutical composition of the present invention include carboxymethylcellulose calcium, carboxymethyicellulose sodium, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminium silicate, methylceliulose, microcr/stalline cellulose, polacriSin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch giycolate, and starch and the like or mixtures thereof.
  • the disintegrants may be used in amounts ranging from about 0.1 to about 70% w/w. It is preferred that the disintegrants are used in amounts ranging from about 1 to about 60% w/w of the composition.
  • the lubricants used in the present invention may be selected from the group consisting of talc, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oils, polyethylene glycol and the like and mixtures thereof. Generally the amount of the lubricants used in the present invention may vary from about 0.001 to about 5 % w/w of the composition.
  • the typical giidants that may be included in the present invention include colloidal silicon dioxide, talc and the like. The amounts of giidants used in the present invention may vary from about 0,1 to about 5% w/w of the composition.
  • wicking agents examples include colloidal silicon dioxide, kaolin, titanium dioxide, fumed silicon dioxide, m-pyrol, vinylpyrrolidone polymers such as povidone, or crosslinked polyvinylpyrrolidone such as crospovidone; cellulose and cellulose derivatives such as microcrystaHine cellulose, methylcellulose, ethyicelluiose, hydroxypropylcellulose, hydroxypropyl cellulose, carboxyalicyl celluloses and their alkali salts; sodium starch glycolate, starch and starch derivatives, ion- exchange resins and the like and mixtures thereof.
  • the binders used in the present invention may be selected from the group comprising of starch, gelatin, dextrin, maitodextrin, natural and synthetic gums like acacia, aiginic acid, sodium alginate, guar gum, extract of fish moss, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methyicellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyi methylcellulose, polyvinylpyrrolidone, veegum, arabogalactan and the like and mixtures thereof.
  • the film forming polymer used in the the present invention may be selected from the group comprising opadry®, ethyf cellulose, hydroxypropy! cellulose, hydroxypropyl methylcellulose,, polyvinyl pyrrolidone; and the like and mixtures thereof.
  • composition of the present invention may also use solubilizers known in the art such as polysorbate 80 and the like; and antioxidants known in the art such as butylated hydroxyl anisol, butylated hydroxy! toluene and the like.
  • composition includes solid oral dosage forms such as pellets, beads, granules and the iike, which may be encapsulated or compressed into tablets.
  • the pellets, beads, granules in turn may be prepared by conventional methods known to a person skilled in the art.
  • the compressed tablets may optionally be coated with film-coat.
  • compositions of the present invention maybe prepared by the conventional processes such as wet granulation, dry granulation or direct compression.
  • atorvastatin or its pharmaceutically acceptable salt is mixed with suitable alkali metal salt additives and various excipients and granulated, followed by screening and drying of the damp mass.
  • the dried mass may be screened, lubricated and compressed.
  • Dry granulation can be done by two processes: (1) slugging, which involves mixing the atorvastatin or its pharmaceutically acceptable salt with suitable alkali metal salt additives and the excipients, slugging, dry screening, lubrication and compression, or (2) roller compaction process.
  • Direct compression involves corn pressing tablets directly from the physical mixture of atorvastatin or its pharmaceutically acceptable salt, suitable alkali metal salt additives and the excipients.
  • the pharmaceutical compositions of the present invention may be obtained by preparing placebo granules comprising the suitable alkali metal salt additives and pharmaceutically acceptable excipients, and mixing these with atorvastatin to obtain a blend to be compacted using a roll compacter. The compact was broken down, sieved and mixed in suitable lubricating agents and which may be encapsulated or compressed into tablets. This method provides compositions of atorvastatin that are stable.
  • the following examples are intended to illustrate the scope of the present invention in a!! its aspects but not to limit it thereto.
  • the stable oral pharmaceutical composition comprising atorvastatin or its pharmaceutically acceptable salt may be prepared as given in Table 1.
  • the atorvastatin calcium, di-sodium hydrogen phosphate, microcrystalline cellulose, lactose monohydrate and Croscarmeiiose sodium were sifted through suitable sieve and mixed for 10 minutes in a RMG.
  • Purified water was heated to 40 - 50 0 C and polysorbate 80 was added to it with stirring.
  • the Butyiated hydroxy! anisol was dissolved in ethanoi and was added to the above poiysorbate 80 solution.
  • the previously prepared dry mix was granulated in RHG using the prepared Poiysorbate 80 and BHA solution. The granules were dried in rapid drier at 5O 0 C till LOD below 4 % w/w was obtained.
  • the dried granule was screened & sized using appropriate screen & sieve. Croscarmeilose sodium, m ⁇ cro ⁇ ystaiHn ⁇ ceifulose and sodium hydrogen carbonate were sifted & mixed in cone blender with the above sized granules for 25 minutes. Magnesium stearate was sifted, added to the above granules and mixed for 5 minutes, The resulting blend was tabietted using suitable tooling. The tablets were then film coated using opadry white.
  • compositions comprising atorvastatin or its pharmaceutically acceptable salt and amlod ⁇ pine or its pharmaceutically acceptable salt may be prepared as given in Table 3.
  • composition was prepared as given as per the procedure given in example 1.
  • EAAHPLE 3 The stable oral pharmaceutical compositions comprising atorvastatin or its pharmaceutically acceptable salt may be prepared as given as table 4
  • the stable oral pharmaceutical compositions comprising atorvastatin or its pharmaceutically acceptable salt was manufactured by the following method: The lactose monohydrate was sifted through suitable sieve. The BHA was dissolved in ethanol and to it was added the poiysorbate 80 with stirring. This was added on lactose monohydrate and dried. Atorvastatin calcium, di- sodium hydrogen phosphate, croscarmeilose sodium, microcrystalline cellulose, pregelatinized starch, sodium hydrogen carbonate and dried lactose monohydrate previously made were sifted through suitable sieve and mixed for 25 minute in blender. This mixture was then compacted in roller compactor and the compacted flakes were screened. Sifted magnesium stearate was mixed with these granules and compressed into tablets. The tablets were then coated,
  • composition was prepared as given as per the procedure given in example 1.

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

Abstract

L'invention concerne une composition pharmaceutique orale stable comprenant de l'atorvastatine ou son sel de qualité pharmaceutique et des additifs de sel de métal alcalin adaptés à raison de plus de 5% masse/masse afin d'empêcher la dégradation de l'atorvastatine ou son sel de qualité pharmaceutique.
PCT/IN2010/000436 2009-06-29 2010-06-25 Composition pharmaceutique orale comprenant de l'atorvastatine WO2011001450A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1526/MUM/2009 2009-06-29
IN1526MU2009 2009-06-29

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WO2011001450A1 true WO2011001450A1 (fr) 2011-01-06

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013083674A1 (fr) * 2011-12-08 2013-06-13 Hexal Ag Nouvelle composition pharmaceutique à base de statine

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008117154A2 (fr) * 2007-03-26 2008-10-02 Torrent Pharmaceuticals Limited Compositions pharmaceutiques stables d'inhibiteur de hmg-coa réductase et leur procédé de préparation
CN101288670A (zh) * 2007-04-20 2008-10-22 石药集团中奇制药技术（石家庄）有限公司 一种阿托伐他汀和左旋氨氯地平的组合物及其制备方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008117154A2 (fr) * 2007-03-26 2008-10-02 Torrent Pharmaceuticals Limited Compositions pharmaceutiques stables d'inhibiteur de hmg-coa réductase et leur procédé de préparation
CN101288670A (zh) * 2007-04-20 2008-10-22 石药集团中奇制药技术（石家庄）有限公司 一种阿托伐他汀和左旋氨氯地平的组合物及其制备方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE WPI Derwent World Patents Index; AN 2009-A02424 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013083674A1 (fr) * 2011-12-08 2013-06-13 Hexal Ag Nouvelle composition pharmaceutique à base de statine
US9717707B2 (en) 2011-12-08 2017-08-01 Hexal Ag Pharmaceutical statin composition

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