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WO2016135740A1 - Procédé de préparation de compositions orales stables à base d'évérolimus - Google Patents

Procédé de préparation de compositions orales stables à base d'évérolimus Download PDF

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Publication number
WO2016135740A1
WO2016135740A1 PCT/IN2015/000182 IN2015000182W WO2016135740A1 WO 2016135740 A1 WO2016135740 A1 WO 2016135740A1 IN 2015000182 W IN2015000182 W IN 2015000182W WO 2016135740 A1 WO2016135740 A1 WO 2016135740A1
Authority
WO
WIPO (PCT)
Prior art keywords
everolimus
pharmaceutically acceptable
drug solution
granules
solvents
Prior art date
Application number
PCT/IN2015/000182
Other languages
English (en)
Inventor
Krishna Murthy Bhavanasi
Rama Swamy Chowdary TRIPURANENI
Rami Reddy BHIMAVARAPU
Venkaiah Chowdary Nannapaneni
Original Assignee
Natco Pharma Limited
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 Natco Pharma Limited filed Critical Natco Pharma Limited
Publication of WO2016135740A1 publication Critical patent/WO2016135740A1/fr

Links

Classifications

    • 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
    • A61K9/1682—Processes
    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • 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
    • 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

Definitions

  • the present invention relates to a process for preparing stable solid oral compositions comprising 40-O-(2- hydroxy) ethyl-Rapamycin or its pharmaceutically acceptable salts thereof:
  • Everolimus is chemically designated as (1R,9S,12S,15R,16E,18R,19R,21R, 23S,24E,26E, 28E,30S,32S,35R)-l,18-dihydroxy-12- ⁇ (lR)-2-[(l S,3R,4R)-4-(2- hydroxyethoxy)-3 -methoxy cyclohexyl] - 1 -methylethyl ⁇ - 19,30-dimethoxy-
  • Everolimus is available as oral tablets with the name of Afinitor® for the treatment of tumour diseases, and under the name of Zortress® for the prevention of organ rejection.
  • U.S. Patent No. 5665772 disclose Everolimus.
  • U.S. Patent No. 6004973 disclosed pharmaceutical compositions in the form of solid dispersion comprising 40-O-(2 -hydroxy) ethyl-Rapamycin (Everolimus, RADOOl) and a carrier medium. These compositions provide high bioavailability of drug substance, convenient to administer and are stable.
  • U.S. Patent No. 8617598 disclosed oral pharmaceutical compositions comprising solid dispersion of 40-O-(2-hydroxy) ethyl-Rapamycin, a disintegrant comprising cross- linked polyvinyl pyrrolidone and colloidal silicon dioxide.
  • Solid dispersion is complex process, involves higher quantity of solvents and higher cost for preparation, there is a need to develop alternative stable compositions of Everolimus using simplified and robust process, which is cost effective and having good dissolution rates and bioavailability. Accordingly, inventors of the present invention have developed a simple process for preparing stable oral compositions of Everolimus.
  • the present invention relates to a process for preparing stable oral compositions comprising Everolimus and. one or more pharmaceutically acceptable excipients.
  • the present invention particularly relates to a wet granulation process for preparing stable oral compositions comprising Everolimus and one or more pharmaceutically acceptable excipients.
  • One embodiment of the present invention provides a process for preparing composition comprising Everolimus and one or more pharmaceutically acceptable excipients by wet granulation using drug solution.
  • Another embodiment of the present invention provides a process for preparing composition comprising Everolimus and one or more pharmaceutically acceptable excipients by wet granulation using drug solution obtained by dissolving Everolimus in one or more pharmaceutically acceptable solvents.
  • Another embodiment of the present invention provides a wet granulation process for preparing stable oral compositions of everolimus comprising the steps of: (a) sifting one or more pharmaceutically acceptable excipients, (b) dissolving Everolimus in solvent and (or) mixture of solvents to form drug solution, (c) granulating the dry mix of step (a) with the drug solution of step (b) to obtain wet mass, (d) drying and sieving the wet mass to obtain granules, (e) blending the granules with extra granular excipients followed by lubrication and (f) compressing the lubricated blend into tablets or filled into capsules.
  • Another embodiment of the present invention provides a process for preparation of stable oral compositions of everolimus comprising the steps of: (a) sifting one or more pharmaceutically acceptable excipients, (b) dissolving Everolimus in solvent and (or) mixture of solvents to form drug solution, (c) suspending one or more pharmaceutically acceptable excipients in to drug solution to form suspension, (d) granulating the dry mix of step (a) with the suspension of step (c) to obtain wet mass, (e) drying and sieving the wet mass to obtain granules, (f) blending the granules with extra granular excipients, followed by lubrication, and (g) compressing the lubricated blend into tablets or filled into capsules.
  • the present invention relates to a process for preparing stable oral compositions comprising Everolimus and one or more pharmaceutically acceptable excipients.
  • the present invention relates to a wet granulation process for preparing stable oral compositions comprising Everolimus and one or more pharmaceutically acceptable excipients.
  • the present invention relates to a wet granulation process for preparing stable oral compositions comprising Everolimus and one or more pharmaceutically acceptable excipients using drug solution.
  • drug solution includes solution obtained by dissolving Everolimus or its pharmaceutically acceptable salt thereof in solvent and (or) mixture of solvents.
  • One embodiment the present invention provides adding one or more pharmaceutically acceptable excipients in drug solution to form a suspension.
  • Epolimus or 40-O-(2-hydroxy)ethyl-Rapamycin as used herein according to the present invention includes, Everolimus in the form of free base, a pharmaceutically acceptable salt thereof, amorphous Everolimus, crystalline Everolimus, any isomer, derivative, hydrate, solvate or prodrug or a combination thereof.
  • composition or “solid oral composition” or “dosage form” or “pharmaceutical composition” as used herein synonymously include solid dosage forms such as tablets, capsules, powder, particles, granules, pellets, mini-tablets and the like meant for oral administration.
  • a “composition” comprises an active pharmaceutical ingredient and at least one pharmaceutically acceptable excipient.
  • drug herein refers to Everolimus or a pharmaceutically acceptable salt thereof.
  • pharmaceutically acceptable excipient includes a pharmaceutically acceptable material such as diluents, disintegrates, binders, lubricants, antioxidants, and the like, suitable for administering an active pharmaceutical ingredient. Each excipient should be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • Another embodiment of the present invention provides a wet granulation process for preparing stable oral compositions of everolimus comprising the steps of: (a) sifting one or more pharmaceutically acceptable excipients, (b) dissolving Everolimus in solvent and (or) mixture of solvents to form drug solution, (c) granulating the dry mix of step (a) with the drug solution of step (b) to obtain wet mass, (d) drying and sieving the wet mass to obtain granules, (e) blending the granules of step (d) with extra granular excipients if any, followed by lubrication and (f) compressing the lubricated blend of step (e) into tablets or filled into capsules.
  • Another embodiment of the present invention provides a wet granulation process for preparing stable oral compositions of everolimus comprising the steps of: (a) sifting one or more pharmaceutically acceptable excipients, (b) dissolving Everolimus in solvent and (or) mixture of solvents to form drug solution, (c) suspending one or more pharmaceutically acceptable excipients in to drug solution to form a suspension, (d) granulating the dry mix of step (a) with the suspension of step (c) to obtain wet mass, (e) drying and sieving the wet mass to obtain granules, (f) blending the granules of step (e) with extra granular excipients if any, followed by lubrication, and (g) compressing the lubricated blend of step (f) into tablets or filled into capsules.
  • solvents suitable for processing the pharmaceutical compositions include one or more of organic solvents such as organic solvents such as an alcohol, for example methanol, ethanol, or isopropanol; an ester, e.g. ethyl acetate; an ether, e.g. diethyl ether; a ketone, e.g. acetone; or a halogenated hydrocarbon, e.g. dichloroethane and mixtures thereof.
  • organic solvents such as an alcohol, for example methanol, ethanol, or isopropanol
  • an ester e.g. ethyl acetate
  • an ether e.g. diethyl ether
  • a ketone e.g. acetone
  • halogenated hydrocarbon e.g. dichloroethane and mixtures thereof.
  • Suitable excipients include but are not limited to antioxidants, diluents, binders, disintegrants and lubricants.
  • Antioxidants include, but are not limited to butylated hydroxytoluene (BHT), Butylated hydroxy anisole, tocopherols, ascorbic acid derivatives, propyl gallate and fumaric acid and mixtures thereof.
  • BHT butylated hydroxytoluene
  • Butylated hydroxy anisole butylated hydroxy anisole
  • tocopherols butylated hydroxy anisole
  • ascorbic acid derivatives propyl gallate and fumaric acid and mixtures thereof.
  • Diluents, fillers, or bulking agents for this purpose include, but are not limited to lactose, microcrystalline cellulose, dibasic calcium phosphate, calcium phosphate, powdered cellulose, dextrates, isomalt, calcium carbonate, magnesium carbonate, starch, pre-gelatinized starch, and mixtures thereof.
  • Binders include, but are not limited to hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone (povidone), gum arabic and sugars such as sucrose, glucose, dextrose, lactose, polyvinyl alcohol and mixtures thereof.
  • Disintegrants include, but are not limited to crospovidone, croscarmellose sodium, starch, potato starch, pregelatinized starch, corn starch, sodium starch glycolate, microcrystalline cellulose, low substituted hydroxypropyl cellulose and mixtures thereof.
  • Suitable lubricants include but are not limited to fatty acids, fatty acid salts, and fatty acid esters such as magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, hydrogenated vegetable oil and mixtures thereof.
  • Example 1 Tablet compositions of Everolimus prepared by wet granulation method
  • step (3) Obtained suspension of step (3) was added to anhydrous lactose in granulator bowl to obtain wet mass
  • step (4) was dried, sifted and milled to obtain granules
  • step (5) Obtained granules of step (5) were blended with extra granular crospovidone and lubricated with magnesium stearate 7.
  • the lubricated blend of step (6) was finally filled into capsules or compressed into tablets.
  • Example 2 Tablet compositions of Everolimus prepared by wet granulation method
  • step (4) was added to dry blend of step (1) in granulator bowl to obtain wet mass
  • step (5) Wet mass of step (5) was dried, sifted and milled to obtain granules
  • step (6) Obtained granules of step (6) were mixed with extra granular anhydrous lactose, crospovidone and lubricated with magnesium stearate
  • Example 3 Tablet compositions of Everolimus prepared by wet granulation method
  • step (2) Blend of step (2) was granulated with drug solution of step (1) to form granules which are dried and milled
  • Milled Granules of step (3) were blended with extra granular anhydrous lactose, crospovidone and lubricated with magnesium stearate
  • step (4) The lubricated blend of step (4) was finally filled into capsules or compressed into tablets.
  • Dissolution test was performed for tablets prepared as per the Examples 1, 2, 3 Comparative reference (Afinitor), using USP apparatus type II, at 50 rpm, in 500 ri purified water with 0.4 % sodium lauryl sulphate. (Cumulative % drug dissolved)
  • tablets prepared according to the present invention were acceptable.

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

Abstract

La présente invention concerne un procédé de préparation d'une composition comprenant du évérolimus ou ses sels pharmaceutiquement acceptables et un ou plusieurs excipients pharmaceutiquement acceptables par granulation par voie humide en dissolvant du évérolimus dans un ou plusieurs solvants pharmaceutiquement acceptables.
PCT/IN2015/000182 2015-02-23 2015-04-23 Procédé de préparation de compositions orales stables à base d'évérolimus WO2016135740A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN839CH2015 2015-02-23
IN839/CHE/2015 2015-02-23

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Publication Number Publication Date
WO2016135740A1 true WO2016135740A1 (fr) 2016-09-01

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117982495A (zh) * 2024-04-07 2024-05-07 国药集团川抗制药有限公司 一种依维莫司固体分散体及其制备方法、依维莫司片剂

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5665772A (en) 1992-10-09 1997-09-09 Sandoz Ltd. O-alkylated rapamycin derivatives and their use, particularly as immunosuppressants
US6004973A (en) 1995-07-14 1999-12-21 Novartis Ag Pharmaceutical compositions comprising rafamycin coprecipitates
CN102138903B (zh) * 2011-03-17 2012-12-12 苏州特瑞药业有限公司 一种依维莫司固体口服药物组合物
WO2013022201A1 (fr) * 2011-08-11 2013-02-14 Dong-A Pharm. Co., Ltd. Procédé de préparation d'une formulation stabilisée et solubilisée de dérivés de sirolimus
US8617598B2 (en) 2001-09-28 2013-12-31 Novartis Ag Pharmaceutical compositions comprising colloidal silicon dioxide
CN103610646A (zh) * 2013-12-05 2014-03-05 江苏奥赛康药业股份有限公司 一种含依维莫司的组合物及其制备方法和含有这一组合物的药物制剂
WO2014186581A1 (fr) * 2013-05-15 2014-11-20 Tobira Therapeutics, Inc. Compositions de cénicriviroc et leurs procédés de fabrication et d'utilisation

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5665772A (en) 1992-10-09 1997-09-09 Sandoz Ltd. O-alkylated rapamycin derivatives and their use, particularly as immunosuppressants
US6004973A (en) 1995-07-14 1999-12-21 Novartis Ag Pharmaceutical compositions comprising rafamycin coprecipitates
US8617598B2 (en) 2001-09-28 2013-12-31 Novartis Ag Pharmaceutical compositions comprising colloidal silicon dioxide
CN102138903B (zh) * 2011-03-17 2012-12-12 苏州特瑞药业有限公司 一种依维莫司固体口服药物组合物
WO2013022201A1 (fr) * 2011-08-11 2013-02-14 Dong-A Pharm. Co., Ltd. Procédé de préparation d'une formulation stabilisée et solubilisée de dérivés de sirolimus
WO2014186581A1 (fr) * 2013-05-15 2014-11-20 Tobira Therapeutics, Inc. Compositions de cénicriviroc et leurs procédés de fabrication et d'utilisation
CN103610646A (zh) * 2013-12-05 2014-03-05 江苏奥赛康药业股份有限公司 一种含依维莫司的组合物及其制备方法和含有这一组合物的药物制剂

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117982495A (zh) * 2024-04-07 2024-05-07 国药集团川抗制药有限公司 一种依维莫司固体分散体及其制备方法、依维莫司片剂

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