WO2012050539A1 - Composition pharmaceutique comprenant l'eplérenone - Google Patents

Composition pharmaceutique comprenant l'eplérenone Download PDF

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Publication number
WO2012050539A1
WO2012050539A1 PCT/TR2011/000210 TR2011000210W WO2012050539A1 WO 2012050539 A1 WO2012050539 A1 WO 2012050539A1 TR 2011000210 W TR2011000210 W TR 2011000210W WO 2012050539 A1 WO2012050539 A1 WO 2012050539A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
composition according
range
eplerenone
cellulose
Prior art date
Application number
PCT/TR2011/000210
Other languages
English (en)
Inventor
Mahmut Bilgic
Original Assignee
Mahmut Bilgic
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 Mahmut Bilgic filed Critical Mahmut Bilgic
Publication of WO2012050539A1 publication Critical patent/WO2012050539A1/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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin
    • 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
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to new, soluble and easily-produceable pharmaceutical formulations comprising eplerenone.
  • the present invention relates to eplerenone formulation which is effective in the treatment of cardiovascular diseases such as congestive heart failure, congestive heart failure after myocardial infarction, heart disorders, and hypertension.
  • Eplerenone, 9a, 11 -epoxy-7a-(methoxycarbonyl)-3 -oxo, 17a-pregn-4-ene-21 , 17-carbolactone is an antihypertensive agent which is an aldosterone antagonist.
  • Eplerenone is described in the patent numbered US 4559332 (A) in detail.
  • the molecule eplerenone, synthesis method for the molecule eplerenone and pharmaceutical compositions comprising eplerenone are disclosed in the molecule patent.
  • Eplerenone is an aldosterone antagonist which can be used in the treatment of cardiovascular diseases, and hyperaldosteronism-related diseases such as hypertension.
  • Eplerenone is sparingly soluble in water. This brings along some problems during production. Eplerenone which has lipophilic nature does not dissolve well in gastrointestinal channel. This solubility problem complicates to formulate eplerenone.
  • Purpose of the invention is to eliminate the existing problems by formulating eplerenone which has low water solubility and poses disadvantages during production due to its lipophilic nature with effective amounts of appropriate excipients.
  • the pharmaceutical formulation comprising eplerenone provides the required solubility without decreasing the particle size of the active agent eplerenone therefore encountering the problem of agglomeration in the present invention.
  • the inventors Using the active agent and the other excipients in specified ranges, the inventors have obtained therapeutically effective compositions which have far better solubility than expected.
  • composition of the present invention is characterized by comprising;
  • Microcrystalline cellulose in the range of 15-50%, preferably in the range of 26-36%) by weight;
  • the characteristic feature of the composition of the present invention is that the ratio of eplerenone to microcrystalline cellulose by weight varies in the range of 1 :2 to 1 :0.5.
  • the characteristic feature of the composition of the present invention is that the ratio of eplerenone to the diluent by weight varies in the range of 1 : 1.5 to 1 :0.4.
  • the pharmaceutical composition obtained in the case that the diluent in the composition of the present invention is direct compression lactose (which will henceforward be called “lactose D.C.") have better solubility characteristics.
  • Avicel PH 102 is preferably used in the pharmaceutical composition as microcrystalline cellulose, which is present in the composition as a disintegrant.
  • the most soluble composition has been obtained by using the diluent which has the average particle size in the range of 50 and 200 ⁇ , preferably 50 and 175 ⁇ and microcrystalline cellulose which has the average particle size in the range of 50 and 200 ⁇ , preferably 50 and 150 ⁇ .
  • compositions of the present invention can be selected from a group comprising sodium lauryl sulfate, polyoxyethylene sorbitan fatty acid esters (polysorbates), polyoxyethylene alkyl ethers, sorbitan fatty acid esters, polyethylene glycols, polyoxyethylene castor oil derivatives, docusate sodium, quaternary ammonium compounds; sugar esters and glycerides of fatty acids.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising eplerenone.
  • pharmaceutically acceptable excipients can optionally be used in the composition of the present invention.
  • eplerenone in the composition of the present invention can be in free form or pharmaceutically acceptable salt, enantiomer, racemate, solvate, hydrate, different polymorphic form and amorphous form thereof.
  • Particle size of the active agent eplerenone in the pharmaceutical composition of the present invention is in the range of 10-300 ⁇ , preferably in the range of 10-25 ⁇ .
  • composition of the present invention can be used in the treatment, alleviation of the symptoms or slowing the progression of cardiovascular diseases, hyperaldosteronism-related diseases such as hypertension.
  • compositions of the present invention can be used in people suffering from heart failure, systolic function disorder of left ventricle and in the treatment of cardiovascular diseases such as congestive heart failure after myocardial infarction, diseases such as hypertension, edema associated with hepatic impairment and hepatic cirrhosis.
  • compositions of the present invention can be prepared as a medicament composition effective in the treatment of people suffering from heart failure, systolic function disorder of left ventricle and in the treatment of cardiovascular diseases such as congestive heart failure after myocardial infarction, diseases such as hypertension, edema associated with hepatic impairment and hepatic cirrhosis.
  • the present invention relates to administration of the pharmaceutical formulation on mammals including human in the treatment of cardiovascular diseases and hypertension.
  • composition of the present invention which relates to a pharmaceutical composition for use in the production of a medicament effective in the treatment of diseases such as cardiovascular diseases and hypertension is characterized by comprising the active agent eplerenone.
  • compositions comprising the active agent eplerenone and effective amounts of excipients to reduce the symptoms of diseases such as cardiovascular diseases and hypertension, slowing the progression of the disease and treatment of the disease.
  • reducing the symptoms refers to reducing the number of the symptoms observed in the patients who are diagnosed with said disease by administration of the pharmaceutical combination comprising eplerenone.
  • slowing the progression of the disease refers to the administration of the pharmaceutical combination comprising eplerenone to the patients who are at the first stage of the disease and diagnosed with said disease.
  • treatment of the disease refers to administration of the pharmaceutical composition comprising eplerenone in the treatment of people diagnosed with said disease or in any stage of said disease.
  • dose of the active agent in the composition of the present invention depends on factors such as status of the disease to be treated; patient's state of health, age, weight, gender.
  • the active agent in said composition can be in the range of 10-100 mg, preferably in the range of 13.5-72 mg, more preferably in the range of 18-54 mg.
  • composition of the present invention can be prepared as administrable by the oral route.
  • compositions of the present invention can comprise oral dosage forms and pharmaceutical formulations with pharmaceutically acceptable excipients.
  • Oral dosage forms can be in solid forms such as tablets; capsules; enteric-coated or modified release tablets; prolonged release tablets; delayed release tablet; fast soluble tablets; effervescent tablets; effervescent granules; fast soluble powder mixture; granule; pellet, minitablet; granule capsule; pellet capsule; minitablet capsule; microtablet capsule; dry powder mixture for syrup preparation; dragee; orally disintegrated tablets; water-soluble powder, tablet or granule or in liquid form such as suspension.
  • oral dosage form is in tablet form and optionally coated by a film coating composition.
  • the film coating composition according to the invention can comprise the following components lactose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, triacetin, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate phthalate, polyvinyl acetatae phthalate, diethyl phthalate, sugar derivatives, polyvinyl derivatives (such as polyvinyl alcohol), polyethylene glycol, waxes, oils and gelatins, triethyl citrate, glyceride, titanium oxide, red and/or black iron oxide, talc, sodium alginate, stearic acid, lecitine or mixtures thereof.
  • the film coating composition comprises polyvinyl alcohol, polyethylene glycol, lecitine, yellow and/or black iron oxide and at least one other component.
  • the film coating composition is in the range of 1 and 5 %, preferably 1 and 4 % by total weight of the composition.
  • composition of the present invention is produced by conventional methods.
  • pharmaceutically acceptable excipients can also be used in addition to the active agents used in the oral formulations comprising the present invention.
  • These excipients can be selected from a group comprising substances such as pharmaceutically acceptable disintegrant, binder, lubricant, glidant and/or coating material.
  • Preffered excipient composition according to the invention does not comprise binder.
  • Pharmaceutically acceptable disintegrants of the present invention can be selected from a group comprising microcrystalline cellulose, croscarmellose sodium (such as Ac-Di-Sol), starch, clay, methyl cellulose, carboxymethylcellulose, sodium carboxymethyl cellulose, alginate, crospovidone; gums such as agar, guar, pectin and tragant; pregelatinized starch, starch.
  • croscarmellose sodium such as Ac-Di-Sol
  • starch such as Ac-Di-Sol
  • clay methyl cellulose, carboxymethylcellulose, sodium carboxymethyl cellulose, alginate, crospovidone
  • gums such as agar, guar, pectin and tragant
  • pregelatinized starch starch.
  • the composition can comprise croscarmellose sodium as another disintegrant together with microcrystalline cellulose.
  • the amount of croscarmellose sodium in the composition is in the range of 1 and 4 %, preferably 1 and 3.5 %.
  • the ratio of microcrystalline cellulose to croscarmellose sodium by weight is at least 10, preferably between 10 and 20, more preferably between 12 and 17.5.
  • Pharmaceutically acceptable diluents of the present invention can be selected from a group comprising lactose, dry lactose, lactose monohydrate, direct compression lactose (lactose D.C.), starch, hydrolyzed starch, mannitol, sorbitol, xylitol, dextrose, dextrose monohydrate, dibasic calcium phosphate dihydrate, monobasic calcium, sulphate monohydrate, calcium sulphate dihydrate, amylose, cellulose and cellulose derivatives, calcium carbonate, glycine, bentonite, polyvinylpyrrolidone.
  • binders of the present invention can be selected from a group comprising ethyl cellulose, hydroxyethyl cellulose, methylcellulose, microcrystalline cellulose (such as Avicel PH 101, Avicel PH 102), hydroxymethyl cellulose, hydroxypropyl cellulose, gelatin, hypromellose, magnesium aluminum silicate, maltodextrin, polyethylene oxide, povidone, sorbitol and water or a combination thereof.
  • Pharmaceutically acceptable lubricants of the present invention can be selected from a group comprising metallic stearates (such as magnesium stearate, calcium stearate, aluminum stearate), fatty acid esters (such as sodium stearyl fumarate), fatty acids (such as stearic acid), fatty alcohols, glyceryl behenate, mineral oil, paraffins, hydrogenated vegetable oil, leucine, polyethylene glycols, metallic lauryl sulfates (such as sodium lauryl sulfate, magnesium lauryl sulfate), sodium chloride, sodium benzoate, sodium acetate and talc.
  • metallic stearates such as magnesium stearate, calcium stearate, aluminum stearate
  • fatty acid esters such as sodium stearyl fumarate
  • fatty acids such as stearic acid
  • fatty alcohols such as sodium stearic acid
  • fatty alcohols such as sodium stearyl fumarate
  • fatty alcohols
  • Pharmaceutically acceptable glidants of the present invention can be selected from a group comprising talc, silicon dioxide, magnesium trisilicate, cellulose powder, starch, tribasic calcium phosphate, metallic stearates, calcium silicate and metallic lauryl sulfate.
  • the formulation can further comprise other pharmaceutically acceptable excipients such as solubility enhancers, electrolytes, sweeteners, coloring agents and coating agents.
  • composition of the present invention can be produced by conventional methods in the prior art.
  • Eplerenone, Avicel PH 102, lactose D.C. and sodium lauryl sulfate are mixed in a container for some time. Afterwards, sufficient amounts of glidant and lubricant are added into this mixture. Mixing goes on until a homogeneous mixture is obtained. The final mixture is loaded into tablet compression machine and tablets are compressed. Compressed tablets are coated with a film coating solution prepared by dissolving in a sufficient amount of deionized water and the tablets formulations are finalized.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Cardiology (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne de nouvelles formulations pharmaceutiques solubles pouvant être produites facilement et comprenant l'Eplérenone.
PCT/TR2011/000210 2010-09-20 2011-09-19 Composition pharmaceutique comprenant l'eplérenone WO2012050539A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2010/07653 2010-09-20
TR2010/07653A TR201007653A2 (tr) 2010-09-20 2010-09-20 Eplerenon içeren farmasötik kompozisyon

Publications (1)

Publication Number Publication Date
WO2012050539A1 true WO2012050539A1 (fr) 2012-04-19

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Application Number Title Priority Date Filing Date
PCT/TR2011/000210 WO2012050539A1 (fr) 2010-09-20 2011-09-19 Composition pharmaceutique comprenant l'eplérenone

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TR (4) TR201007653A2 (fr)
WO (1) WO2012050539A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109925293A (zh) * 2019-03-15 2019-06-25 南京卡文迪许生物工程技术有限公司 依普利酮口服固体制剂及其制备方法
CN113995719A (zh) * 2021-10-19 2022-02-01 河南中盛动物药业有限公司 羧甲基纤维素钠在改善阿莫西林硫酸粘菌素注射液中的应用

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4559332A (en) 1983-04-13 1985-12-17 Ciba Geigy Corporation 20-Spiroxanes and analogues having an open ring E, processes for their manufacture, and pharmaceutical preparations thereof
WO2000033847A1 (fr) * 1998-12-09 2000-06-15 G.D. Searle & Co. Compositions d'eplerenone microfine
EP1175220A2 (fr) 1999-12-08 2002-01-30 Pharmacia Corporation Compositions d'eplerenone nanoparticulaire
US20020132001A1 (en) * 2000-05-11 2002-09-19 Garthwaite Susan M. Aldosterone antagonist composition for release during aldosterone acrophase
WO2007012960A1 (fr) * 2005-07-29 2007-02-01 Glenmark Pharmaceuticals Limited Compositions pharmaceutiques à base d’éplérénone
WO2008074098A1 (fr) * 2006-12-21 2008-06-26 Alphapharm Pty Ltd Composition pharmaceutique

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4559332A (en) 1983-04-13 1985-12-17 Ciba Geigy Corporation 20-Spiroxanes and analogues having an open ring E, processes for their manufacture, and pharmaceutical preparations thereof
WO2000033847A1 (fr) * 1998-12-09 2000-06-15 G.D. Searle & Co. Compositions d'eplerenone microfine
EP1175220A2 (fr) 1999-12-08 2002-01-30 Pharmacia Corporation Compositions d'eplerenone nanoparticulaire
EP1175220B1 (fr) * 1999-12-08 2005-04-27 Pharmacia Corporation Compositions d'eplerenone nanoparticulaire
US20020132001A1 (en) * 2000-05-11 2002-09-19 Garthwaite Susan M. Aldosterone antagonist composition for release during aldosterone acrophase
WO2007012960A1 (fr) * 2005-07-29 2007-02-01 Glenmark Pharmaceuticals Limited Compositions pharmaceutiques à base d’éplérénone
WO2008074098A1 (fr) * 2006-12-21 2008-06-26 Alphapharm Pty Ltd Composition pharmaceutique

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109925293A (zh) * 2019-03-15 2019-06-25 南京卡文迪许生物工程技术有限公司 依普利酮口服固体制剂及其制备方法
CN113995719A (zh) * 2021-10-19 2022-02-01 河南中盛动物药业有限公司 羧甲基纤维素钠在改善阿莫西林硫酸粘菌素注射液中的应用
CN113995719B (zh) * 2021-10-19 2023-06-23 河南中盛生物工程有限公司 羧甲基纤维素钠在改善阿莫西林硫酸粘菌素注射液中的应用

Also Published As

Publication number Publication date
TR201109158A2 (tr) 2012-04-24
TR201109160A2 (tr) 2012-04-24
TR201007653A2 (tr) 2012-04-24
TR201109159A2 (tr) 2012-04-24

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