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WO2009106954A1 - Formes pharmaceutiques stables de lamivudine et de ténofovir - Google Patents

Formes pharmaceutiques stables de lamivudine et de ténofovir Download PDF

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Publication number
WO2009106954A1
WO2009106954A1 PCT/IB2009/000339 IB2009000339W WO2009106954A1 WO 2009106954 A1 WO2009106954 A1 WO 2009106954A1 IB 2009000339 W IB2009000339 W IB 2009000339W WO 2009106954 A1 WO2009106954 A1 WO 2009106954A1
Authority
WO
WIPO (PCT)
Prior art keywords
granules
lamivudine
weight
tenofovir
dosage form
Prior art date
Application number
PCT/IB2009/000339
Other languages
English (en)
Inventor
Nishant Babanrao Naware
Chandrasekhar Panchagnula
Shailesh Suresh Bhamare
Kishor Dattatray Deo
Sivakumaran Meenakshisunderam
Original Assignee
Aurobindo 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 Aurobindo Pharma Limited filed Critical Aurobindo Pharma Limited
Publication of WO2009106954A1 publication Critical patent/WO2009106954A1/fr

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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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present invention relates to stable pharmaceutical dosage forms of combination of antiretroviral agents. More particularly, the present invention relates to stable dosage forms comprising lamivudine and tenofovir disoproxil fumarate prepared by wet granulation.
  • HIV human immunodeficiency virus
  • AIDS acquired immunodeficiency syndrome
  • ARC AIDS-related complex
  • Anti-retroviral drugs such as reverse transcriptase inhibitors and viral protease inhibitors, have been used to treat HIV infection. These treatments can effectively suppress viral production when used in combinations known as HAART (Highly Active Anti-Retroviral Therapy).
  • Tenofovir disoproxil fumarate (a prodrug of tenofovir) is a fumaric acid salt of bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir.
  • tenofovir disoproxil fumarate (tenofovir DF) is 9-[(R)-2- [[bis[[(isopropoxycarbonyl)oxy]methoxy]phosphinyl]methoxy]pr ⁇ pyl]adenine fumarate and is commercially available as tablets under the trade name Viread®.
  • Tenofovir disoproxil fumarate was first disclosed in US patent No. 5,922,695.
  • lamivudine is (2R,cis)-4-amino-l-(2-hydroxymethyl-l,3- oxathiolan-5-yl)-(lH)-pyrimidin-2-one and is commercially available as tablets and oral solution under the trade name Epivir ® .
  • Lamivudine and method of treating HIV using lamivudine was first disclosed in US 5,047,407.
  • FDCs when compared to the separate ARV regimens are ease of use, better adherences to the dosage schedules, reduced risk of drug resistance and increased affordability.
  • Combination therapy reduces the daily dosages to be taken by patients and simplifies dosing schedule thereby increases patient compliance.
  • US 5,627,186 disclose combination of lamivudine and zidovudine for treating HIV infections.
  • US 6,417,191 discloses combination of abacavir and lamivudine; abacavir, lamivudine and zidovudine for treating HIV infections.
  • US 2004/0224917 discloses therapeutic combinations of emtricitabine and tenofovir DF useful for treatment of HIV infections.
  • US 2007/0077295 discloses composition of tenofovir DF and emtricitabine prepared by dry granulation for treating HIV infections.
  • US 2007/099902 discloses a multi component unitary dosage form comprising tenofovir DF and emtricitabine in first component and efavirenz in second component useful for treatment of HIV infections.
  • ZA 2001/10500 discloses pharmaceutical composition of lamivudine, zidovudine and nevirapine and process, which comprises wet granulating lamivudine, zidovudine, nevirapine and diluent with water; drying, sizing and blending the granules with disintegrant; lubricating the granules; and compressing the lubricated granules into tablets.
  • WO 2004/089382 discloses combination of lamivudine, zidovudine and efavirenz for treating HIV infections.
  • WO 2004/089383 discloses combination of lamivudine, stavudine and efavirenz for treating HIV infections.
  • WO 2006/001029 discloses a process for preparing a composition of lamivudine, zidovudine and nevirapine and process which comprises granulating lamivudine, zidovudine, nevirapine, microcrystalline cellulose, starch, croscarmellose sodium with a solution of polyvinylpyrrolidone k-30 and drying the granules, blending the dried granules with magnesium stearate, croscarmellose sodium, colloidal anhydrous silica, crospovidone and compressing the blend into tablets.
  • WO 2006/086865 discloses a composition comprising lamivudine, zidovudine and nevirapine in a single coated tablet prepared by dry granulation.
  • WO 2006/114709 discloses a composition comprising lamivudine, zidovudine and nevirapine prepared by a granulation process comprising the steps of preparing granules of lamivudine plus zidovudine and granules of nevirapine separately, blending the obtained granules with excipients and finally compressing the granules into tablets.
  • WO 2007/026156 discloses a composition comprising lamivudine, stavudine and nevirapine for pediatric treatment of viral infections.
  • WO 2007/068934 discloses a bilayered formulation comprising lamivudine and tenofovir. It is disclosed in this publication that lamivudine and tenofovir DF when intimately mixed to form a single layered tablet showed undesirable properties in stability testing. The appearance of tablets changed to brown colour at controlled room temperature (25 0 C) and even at accelerated temperature (4O 0 C). Inorder to avoid the discoloration, lamivudine and tenofovir DF are formulated as a bilayered tablet. This patent publication further discloses a kit comprising bilayered tablet of lamivudine and tenofovir as first formulation and efavirenz tablet as second formulation.
  • WO 2008/043829 discloses combination of emtricitabine, tenofovir and nevirapine for once a day administration.
  • WO 2008/096369 discloses a formulation comprising lamivudine and tenofovir DF prepared by granulating tenofovir DF seperately by dry granulation and blending the granules with extragranular lamivudine and finally compressing into tablets.
  • This publication further discloses monolithic tablets comprising emtricitabine/lamivudine, tenofovir DF and efavirenz.
  • compositions of various combinations of antiretroviral agents prepared as single and/or double layered tablets disclose compositions of various combinations of antiretroviral agents prepared as single and/or double layered tablets.
  • stable single layer dosage form comprising lamivudine and tenofovir which avoids the common problems associated with bilayered tablets like layer seperation, insufficient hardness, inaccurate individual layer weight control, cross contamination between the layers, reduced yield etc.
  • the inventors of the present invention during their continuous efforts to develop a stable composition of lamivudine and tenofovir disoproxil fumarate found that lamivudine and tenofovir can be prepared as single layer tablets which are stable.
  • the inventors of the present invention have surprisingly found that when lamivudine and tenofovir were granulated separately and compressed into a single layered tablet resulted in a stable dosage form.
  • the main objective of the present invention is to provide stable dosage forms comprising lamivudine and tenofovir and process for preparing the dosage form.
  • Yet another objective of the present invention is to provide stable dosage form of lamivudine and tenofovir in such a way that it will comply with the reference products of each of these approved individual drugs in terms of in vitro parameters like dissolution, disintegration, etc and in vivo parameters like bioequivalence.
  • the present invention provides stable single layer tablet form comprising lamivudine and tenofovir disoproxil fumarate prepared by wet granulation process.
  • the dosage form further comprises one or more excipients selected from diluents, binders, disintegrants, surfactants, glidants and lubricants.
  • Suitable diluents of the present invention are selected from mannitol, lactose, microcrystalline cellulose, maltitol, sorbitol, maltodextrin, maltose, starch, calcium carbonate, calcium phosphate dibasic, calcium sulfate or a combination thereof.
  • the diluent may be used in the range of 5-50% by weight of the tablet.
  • Suitable binders of the present invention are selected from hydroxy propyl cellulose, hydroxypropyl methylcellulose, gelatin, hydroxy ethyl cellulose, povidone, starch and methylcellulose or a combination thereof.
  • the binder may be used in the range of 0.5-10% by weight of the tablet.
  • Suitable disintegrants of the present invention are selected from sodium starch glycolate, croscarmellose sodium, crospovidone, starch, hydroxypropyl cellulose, magnesium aluminum silicate, pregelatinized starch or a combination thereof.
  • the disintegrant may be used in the range of 1-15% by weight of the tablet.
  • Suitable surfactants of the present invention are selected from sodium lauryl sulphate, polysorbate, sorbitan monolaurate, polyoxyethylene- polyoxypropylene block copolymer (poloxamer), polyethylene glycol derivatives, cetyl alcohol or a combination thereof.
  • the surfactant may be used in the range of 0.01-1% by weight of the tablet.
  • Suitable glidants of the present invention are selected from magnesium trisilicate, talc, tribasic calcium phosphate, glyceryl monostearate, glyceryl stearate and silica dioxide or a combination thereof.
  • the glidant may be used in the range of 0.1-2% by weight of the tablet.
  • Suitable lubricants of the present invention are selected from calcium stearate, magnesium stearate, hydrogenated vegetable oil, stearic acid, magnesium aluminum silicate, sodium stearyl fumarate, glyceryl behenate or a combination thereof.
  • the lubricant may be used in the range of 0.1-5% by weight of the tablet.
  • Tenofovir as used herein refers to tenofovir disoproxil fumarate.
  • the stable dosage form comprises 50-500 mg of lamivudine and 50-500 mg of tenofovir.
  • the stable tablet dosage form comprises compressed granules of i) lamivudine granules comprising 10-50% by weight of diluent selected from microcrystalline cellulose, lactose and mannitol, 0.5-10% by weight of binder selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose and povidone, 1-15% by weight of disintegrant selected from croscarmellose sodium, sodium starch glycolate and crospovidone and ii) tenofovir granules comprising 10-50% by weight of diluent selected from microcrystalline cellulose, lactose and mannitol, 0.5-10% by weight of binder selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose and povidone, 1-15% by weight of disintegrant selected from croscarmellose sodium, sodium starch glycolate and crospovidone prepared by wet granulation.
  • the stable tablet dosage form comprises lamivudine, tenofovir, 10-50% by weight of diluent selected from microcrystalline cellulose, lactose and mannitol, 0.5-10% by weight of binder selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose and povidone, 1-15% by weight of disintegrant selected from croscarmellose sodium, sodium starch glycolate and crospovidone, 0.1-2% by weight of glidant selected from colloidal silicon dioxide and talc, 0.1-5% by weight of glidant selected from magnesium stearate and stearic acid of the total composition, wherein the tablets are prepared by wet granulation.
  • diluent selected from microcrystalline cellulose, lactose and mannitol
  • binder selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose and povidone
  • disintegrant selected from croscarmellose sodium, sodium starch glycolate and crospovidone
  • the stable tablet dosage form comprising lamivudine and tenofovir prepared by wet granulation process, comprises the steps of: a) granulating lamivudine and tenofovir and one or more pharmaceutically acceptable excipients using solvent or with a binder solution, b) drying the wet granules, c) sieving the dried granules to obtain uniform granules of lamivudine and tenofovir, d) blending the granules of step (c) with one or more extragranular excipients, e) lubricating the granules and compressing into tablets.
  • an alternative process for the preparation of the stable tablet dosage form comprising lamivudine and tenofovir by wet granulation process which comprises the steps of: a) preparing granules comprising lamivudine and one or more pharmaceutically acceptable excipients, b) preparing granules comprising tenofovir and one or more pharmaceutically acceptable excipients, c) blending the granules of step (a) and (b), with pharmaceutically acceptable excipients, d) blending the granules of step (c) with extragranular excipients, e) lubricating the blended granules and finally compressing the blend into tablets.
  • the solvents used for granulation process may be selected from water, isopropyl alcohol, acetone, ethanol, methylene chloride or combination thereof.
  • the tablets of the present invention may optionally be coated to prevent the degradation of lamivudine from light with coating polymers.
  • Suitable film forming polymers used according to the present invention are selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxy ethyl cellulose, xanthan gum and the like or a combination there of.
  • the stable dosage form of the present invention is used for the treatment or prevention of symptoms of HIV infections in an infected individual.
  • step (i) preparation of granules of lamivudine plus tenofovir: i) lamivudine and tenofovir were sifted and blended with microcrystalline cellulose and croscarmellose sodium, ii) the blend of step (i) was granulated using water, iii) the wet mass was dried and sized and blended with extragranular microcrystalline cellulose and croscarmellose sodium, iv) lubricated the blend of step (iii) with magnesium stearate and compressed into tablets and v) the tablets of step (iv) were coated with Opadry II blue.
  • Dissolution profile of lamivudine and tenofovir tablets prepared according to example 1 was carried out in 0.1 N HCl as dissolution medium using USP Apparatus II with 900 ml at 75 rpm speed.
  • the release profile (% drug dissolved in min) is given in Table 1.
  • Dissolution profile of lamivudine and tenofovir tablets prepared according to example 2 was carried out in 0.1 N HCl as dissolution medium using USP Apparatus II with 900 ml at 75 rpm speed.
  • the release profile (% drug dissolved in min) is given in Table 1.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne des formes pharmaceutiques stables d'une combinaison d'agents antirétroviraux. Elle concerne plus particulièrement des formes pharmaceutiques stables comprenant de la lamivudine et du fumarate de ténofovir disoproxil, qui sont élaborées par granulation par voie humide.
PCT/IB2009/000339 2008-02-27 2009-02-23 Formes pharmaceutiques stables de lamivudine et de ténofovir WO2009106954A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN492/CHE/2008 2008-02-27
IN492CH2008 2008-02-27

Publications (1)

Publication Number Publication Date
WO2009106954A1 true WO2009106954A1 (fr) 2009-09-03

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103211826A (zh) * 2013-05-14 2013-07-24 福建广生堂药业股份有限公司 一种抗病毒药物组合物及其制备方法和用途
WO2015085976A1 (fr) * 2013-12-09 2015-06-18 Zentiva, K.S. Composition pharmaceutique stable contenant du fumarate de disoproxil de tenofovir
CN105213332A (zh) * 2014-06-17 2016-01-06 广州朗圣药业有限公司 一种富马酸替诺福韦二吡呋酯的口服片剂及其制备方法
CN105853380A (zh) * 2016-04-29 2016-08-17 广州白云山医药集团股份有限公司白云山制药总厂 富马酸替诺福韦二吡呋酯片剂及其制备方法
WO2017171222A1 (fr) * 2016-03-31 2017-10-05 한미약품 주식회사 Préparation solide pour administration orale contenant du ténofovir disoproxil et son procédé de préparation
CN109010317A (zh) * 2018-07-20 2018-12-18 南京海纳医药科技股份有限公司 一种富马酸替诺福韦二吡呋酯颗粒及其制备方法
EP2854773B1 (fr) * 2012-05-31 2020-05-06 Pharmascience Inc. Composition pharmaceutique d'entecavir, et procédé de fabrication
CN113288905A (zh) * 2021-07-14 2021-08-24 石家庄龙泽制药股份有限公司 含多替拉韦钠、拉米夫定和富马酸诺福韦酯的药物组合物

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WO2007068934A2 (fr) * 2005-12-14 2007-06-21 Cipla Limited Combinaison pharmaceutique
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WO2009037449A1 (fr) * 2007-09-18 2009-03-26 Cipla Limited Compositions pharmaceutiques solides comprenant un ou plusieurs inhibiteurs du virus de l'herpès et un ou plusieurs inhibiteurs de la transcriptase inverse

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007068934A2 (fr) * 2005-12-14 2007-06-21 Cipla Limited Combinaison pharmaceutique
WO2008096369A2 (fr) * 2007-02-05 2008-08-14 Matrix Laboratories Limited Préparation pharmaceutique utilisable en thérapie anti-vih
WO2009037449A1 (fr) * 2007-09-18 2009-03-26 Cipla Limited Compositions pharmaceutiques solides comprenant un ou plusieurs inhibiteurs du virus de l'herpès et un ou plusieurs inhibiteurs de la transcriptase inverse

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Title
FDA: "Guidance for Industry Fixed Dose Combination and Co-Packaged Drug Products for Treatment of HIV", INTERNET CITATION, XP002417855, Retrieved from the Internet <URL:http://www.fda.gov/oc/initiatives/hiv/hivguidance.html> [retrieved on 20070131] *
MENENDEZ-ARIAS L: "Targeting HIV: antiretroviral therapy and development of drug resistance", TRENDS IN PHARMACOLOGICAL SCIENCES, ELSEVIER, HAYWARTH, GB, vol. 23, no. 8, 1 August 2002 (2002-08-01), pages 381 - 388, XP004386181, ISSN: 0165-6147 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2854773B1 (fr) * 2012-05-31 2020-05-06 Pharmascience Inc. Composition pharmaceutique d'entecavir, et procédé de fabrication
CN103211826A (zh) * 2013-05-14 2013-07-24 福建广生堂药业股份有限公司 一种抗病毒药物组合物及其制备方法和用途
WO2015085976A1 (fr) * 2013-12-09 2015-06-18 Zentiva, K.S. Composition pharmaceutique stable contenant du fumarate de disoproxil de tenofovir
CN105213332A (zh) * 2014-06-17 2016-01-06 广州朗圣药业有限公司 一种富马酸替诺福韦二吡呋酯的口服片剂及其制备方法
WO2017171222A1 (fr) * 2016-03-31 2017-10-05 한미약품 주식회사 Préparation solide pour administration orale contenant du ténofovir disoproxil et son procédé de préparation
CN105853380A (zh) * 2016-04-29 2016-08-17 广州白云山医药集团股份有限公司白云山制药总厂 富马酸替诺福韦二吡呋酯片剂及其制备方法
CN109010317A (zh) * 2018-07-20 2018-12-18 南京海纳医药科技股份有限公司 一种富马酸替诺福韦二吡呋酯颗粒及其制备方法
CN113288905A (zh) * 2021-07-14 2021-08-24 石家庄龙泽制药股份有限公司 含多替拉韦钠、拉米夫定和富马酸诺福韦酯的药物组合物

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