WO2008026048A2 - Compositions pharmaceutiques injectables stables de docétaxel - Google Patents

Compositions pharmaceutiques injectables stables de docétaxel Download PDF

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Publication number
WO2008026048A2
WO2008026048A2 PCT/IB2007/002495 IB2007002495W WO2008026048A2 WO 2008026048 A2 WO2008026048 A2 WO 2008026048A2 IB 2007002495 W IB2007002495 W IB 2007002495W WO 2008026048 A2 WO2008026048 A2 WO 2008026048A2
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WO
WIPO (PCT)
Prior art keywords
acid
docetaxel
pharmaceutical composition
injectable pharmaceutical
composition according
Prior art date
Application number
PCT/IB2007/002495
Other languages
English (en)
Other versions
WO2008026048A3 (fr
Inventor
Bhaveshkumar Vallabhbhai Patel
Amit Gupta
Bhushan Subhash Yeola
Ranjith K. Kumar
Girish Kumar Jain
Original Assignee
Wockhardt Research Centre
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 Wockhardt Research Centre filed Critical Wockhardt Research Centre
Publication of WO2008026048A2 publication Critical patent/WO2008026048A2/fr
Publication of WO2008026048A3 publication Critical patent/WO2008026048A3/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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof

Definitions

  • the present invention relates to stable injectable pharmaceutical compositions of docetaxel or salts thereof, comprising a stock solution and a diluent solution, wherein the stock solution comprises docetaxel or salts thereof along with pharmaceutically acceptable excipients and ethanol and the diluent solution essentially consists of water.
  • the present invention also relates to stable injectable pharmaceutical compositions of docetaxel, wherein pH of the injectable compositions is maintained from between about 3 to about 6.
  • Docetaxel is an antineoplastic agent that acts by disrupting the micro-tubular network in cells that is essential for mitotic and interphase cellular functions. Chemically it is (2R, 3S)-N-carboxy-3-phenylisoserine, N-tert-butyl ester, 13-ester with 5b-20-epoxy-1 , 2a, 4,7b, 10b, 13a-hexahydroxytax-11-en-9-one 4-acetate 2- benzoate, trihydrate.
  • Docetaxel is indicated for the treatment of locally advanced or metastatic breast cancer.
  • Docetaxel is also indicated for the treatment of locally advanced or metastatic small cell lung cancer.
  • Docetaxel is indicated for the treatment of prostrate cancer.
  • U.S. Patent No. 5,438,072 and European Patent EP 671 , 912 disclose an injectable compositions of docetaxel which comprises a stock solution having docetaxel & polysorbate and a diluent solution having ethanol as dilution additive in water.
  • U.S. Patent Nos. 5,714,512; 5,698,582 and 5,403,858 disclose an injectable composition having a stock solution of docetaxel and a surface-active agent, wherein the composition is essentially free or free of ethanol.
  • U.S. Patent No. 5,750,561 discloses an injectable composition of docetaxel wherein the injectable composition has a stock solution comprising docetaxel and a surface-active agent.
  • U.S. Patent No. 5,977,163 discloses a pharmaceutical composition comprising a water-soluble conjugate of an anti-tumor with a polyglutamic acid polymer to form.
  • U.S. Patent Nos. 5,616,330; 6,660,286 and 5,670,536, US Application No. 2006067952, International Publication Nos. WO2005065676 and WO2005065677 disclose intravenous compositions of docetaxel wherein the docetaxel is formulated as a stable oil-in-water emulsion.
  • U.S. Patent Nos. 6,153,644 and 6,071 ,952 disclose an injectable composition and a method for preparing stabilized parenteral pharmaceutical composition of docetaxel by adding an antioxidant.
  • U.S. Application No. 20070082838 discloses stabilized pharmaceutical composition of docetaxel having a stabilizing agent.
  • International Publication Nos. WO 2007085067; 2007027941 ; and 2006133510 disclose the stabilized pharmaceutical compositions containing docetaxel and a degradation inhibitor.
  • an injectable pharmaceutical composition comprising docetaxel or salts thereof dissolved in surface active agent; ethanol and an acid, wherein pH of the composition is from between about 3 to about 6.
  • a method of stabilizing docetaxel or salts thereof in an injectable pharmaceutical composition comprising a step of adjusting pH of a mixture of surface active agent and ethanol from between about 3 to about 6 by using an acid, followed by dissolving docetaxel in the mixture.
  • injectable pharmaceutical composition refers to an injectable composition which may retain at least about 80% of the potency of docetaxel after storage for three months at 4O 0 C and 75% relative humidity.
  • the injectable composition comprises docetaxel or salts thereof wherein the docetaxel or salts thereof can be docetaxel trihydrate.
  • Embodiments of the injectable composition may include one or more of the following features.
  • the composition may further include one or more other pharmaceutically acceptable excipients that include preservatives, nonaqueous vehicle, chelating agents, antioxidants, reducing agents, buffers, pH adjusting agents, tonicity adjustors, and the like.
  • a stable injectable pharmaceutical composition of docetaxel or salts thereof comprising a stock solution and a diluent solution, wherein the stock solution comprises docetaxel or salts thereof along with pharmaceutically acceptable excipients and 5 to 50% of ethanol.
  • the diluent solution essentially consists of water and is free or essentially free of ethanol.
  • essentially consists of water herein refers to an aqueous diluent solution which does not include an additive that promotes the dissolution of stock solution comprising docetaxel.
  • free or essentially free of ethanol refers to either complete elimination of ethanol or to that extent where it does not promote the dissolution of stock solution in a diluent.
  • compositions of docetaxel can be prepared by dissolving docetaxel in a suitable surface active agent and ethanol and adjusting pH of the composition from between about 3 to about 6 by the addition of a suitable acid.
  • the injectable pharmaceutical composition of docetaxel can be prepared by mixing accurately measured amount of surface active agent and ethanol. This mixture can be acidified to a pH from about 3 to about 6 with a suitable acid. Docetaxel or salts thereof can be dissolved in acidified surface active agent and ethanol mixture to form a clear solution. This solution may be sterilized by passing through a sterile 0.22 ⁇ filter. The sterilized solution may optionally be sparged with an inert gas.
  • the injectable pharmaceutical compositions containing docetaxel or salts thereof can also be prepared by first adjusting pH of an accurately measured amount of surface active agent from between about 3 to about 6 with an acid, followed by adding ethanol.
  • Docetaxel can be dissolved in the resultant mixture to form a clear solution. This solution may be sterilized by passing through a sterile 0.22 ⁇ filter and an inter gas may optionally be sparged into the final solution.
  • the injectable composition comprises docetaxel or salts thereof wherein the docetaxel or salts thereof can be docetaxel trihydrate.
  • the concentration of absolute ethanol (95% v/v) may vary from about 5% to about 50% v/v.
  • the acid can be an organic or a mineral acid.
  • the mineral acid can be selected from one or more of hydrochloric acid, sulphuric acid, nitric acid, phosphoric acid, and the like.
  • the organic acid can be selected from one or more of ascorbic acid, aspartic acid, benzoic acid, benzene sulphonic acid, tartaric acid, diatriazoic acid, glutamic acid, lactic acid, maleic acid, succinic acid, fumaric acid, citric acid anhydrous, citric acid monohydrate, edetic acid, and the like.
  • the present inventors have surprisingly found that the injectable compositions of docetaxel can be stabilized by adding 5 to 50% of ethanol in the stock solution along with other pharmaceutically acceptable excipients.
  • the stock solution can be diluted with a diluent solution, which essentially consists of water and is free or essentially free of ethanol.
  • free or essentially free herein refers to either complete elimination of ethanol or to that extent where it does not promote the dissolution of stock solution in diluent.
  • essentially consists herein refers to an aqueous solution, which does not include an additive that promotes the dissolution of stock solution comprising docetaxel.
  • the process for preparing a stable injectable pharmaceutical composition includes the step of mixing a stock solution and a diluent solution to achieve a concentration of 10 mg/ml of docetaxel in the composition.
  • the composition so obtained is stable for at least 8 hours at room temperature wherein the solution remains clear and does not precipitate.
  • the stock solution of the injectable pharmaceutical composition of docetaxel can be prepared by mixing accurately measured amount of surface active agent and ethanol. This mixture can be acidified from between about pH 3 to about 6 with a suitable acid. Docetaxel or salts thereof can be dissolved in the acidified surface active agent and ethanol mixture to form a clear solution. This solution may be sterilized by passing through a sterile 0.22 ⁇ filter. The sterilized solution may optionally be sparged with an inert gas.
  • the stock solution of the stable injectable pharmaceutical composition can be prepared by dissolving docetaxel in ethanol followed by gradually adding a surface-active agent.
  • the pH of the stock solution can be adjusted from between about 3 to about 6 with a suitable mineral or organic acid.
  • the stock solution can thus be prepared having 20 to 100 mg/ml of docetaxel and about 50 to 90% v/v of surface-active agent.
  • the stable injectable pharmaceutical composition containing docetaxel or salts thereof can also be prepared by first adjusting pH of an accurately measured amount of surface active agent from between about 3 to about 6 with an acid, followed by adding ethanol to the acidified surface active agent.
  • Docetaxel can be dissolved in the resultant solution to form a clear solution. This solution may be sterilized by passing through a sterile 0.22 ⁇ filter and an inter gas may optionally be sparged into the final solution.
  • the stock solution of the stable injectable composition may include a mineral acid or an organic acid as a pH-adjusting agent.
  • the methods may give stable injectable compositions of docetaxel which can effectively retain at least about 80% of the potency of docetaxel after storage for three months at 40 0 C and 75% relative humidity.
  • the pharmaceutically acceptable excipients may be selected from one or more of preservatives, non-aqueous vehicle, chelating agents, antioxidants, reducing agent, buffers, pH adjusting agents, tonicity adjustors, and the like.
  • Suitable surface-active agents of the present invention are those known to ordinary skilled in the art and include but not limited to amphoteric, non-ionic, cationic or anionic surfactants.
  • surfactants examples include polysorbates, sodium lauryl sulfate, monooleate, monolaurate, m ⁇ nopalmitate, monostearate or another ester of polyoxyethylene sorbitane, sodium dioctylsulfosuccinate (DOSS), lecithin, stearylic alcohol, cetostearylic alcohol, cholesterol, polyoxyethylene ricin oil, polyoxyethylene fatty acid glycerides, poloxamer, cremophore RH 40 and the like. Mixtures of surfactants are also suitable.
  • Suitable preservatives include one or more of benzyl alcohol, methyl paraben, propyl paraben, benzyl paraben, and the like.
  • Suitable non-aqueous vehicles include one or more of polysorbates, cremophore, polyethylene glycols, oils like castor oil or sesame oil, ethanol, benzyl alcohol, propylene glycol, and the like.
  • Suitable chelating agents include one or more of ethylenediaminetetraacetic acid, diethylene triamine pentaacetic acid, dimercaptosuccinic acid, deferoxamine, and the like.
  • Suitable antioxidants and reducing agents include one or more of ascorbic acid, gentisic acid tocopherol-derived compounds, butylated hydroxyanisole, butylated hydroxytoluene, citric acid, and the like.
  • Suitable buffers and pH adjusting agents include one or more of hydrochloric acid, sulphuric acid ascorbic acid, aspartic acid, benzoic acid, potassium dihydrogen phosphate, sodium hydrogen phosphate, and the like.
  • the pharmaceutical composition of docetaxel is provided in Table 1.

Abstract

La présente invention concerne des compositions pharmaceutiques injectables stables de docétaxel ou de sels de celui-ci, comprenant une solution mère et une solution de diluant, la solution mère comprenant du docétaxel ou des sels de celui-ci ainsi que des excipients acceptables du point de vue pharmaceutique et de l'éthanol et la solution de diluant étant essentiellement constituée d'eau. La présente invention concerne également des compositions pharmaceutiques injectables stables de docétaxel, caractérisées en ce que leur pH est maintenu à une valeur comprise entre environ 3 et environ 6.
PCT/IB2007/002495 2006-08-31 2007-08-30 Compositions pharmaceutiques injectables stables de docétaxel WO2008026048A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IN1391/MUM/2006 2006-08-31
IN1384/MUM/2006 2006-08-31
IN1391MU2006 2006-08-31
IN1384MU2006 2006-08-31

Publications (2)

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WO2008026048A2 true WO2008026048A2 (fr) 2008-03-06
WO2008026048A3 WO2008026048A3 (fr) 2009-08-27

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010023321A1 (fr) * 2008-09-01 2010-03-04 Stragen Pharma S.A. Formulation liquide contenant un dérivé taxane
US7772274B1 (en) 2009-10-19 2010-08-10 Scidose, Llc Docetaxel formulations with lipoic acid
KR101074936B1 (ko) * 2009-05-25 2011-10-18 보령제약 주식회사 도세탁셀 주사제용 조성물 및 그의 제조방법
US8476310B2 (en) 2009-10-19 2013-07-02 Scidose Llc Docetaxel formulations with lipoic acid
JP2014131966A (ja) * 2013-01-04 2014-07-17 Nagase Iyakuhin Kk ドセタキセル含有医薬組成物
US8912228B2 (en) 2009-10-19 2014-12-16 Scidose Llc Docetaxel formulations with lipoic acid
US9468602B2 (en) 2009-01-05 2016-10-18 Azad Pharma Ag Pharmaceutical microemulsion for preventing supramolecular aggregation of amphiphilic molecules
US9763880B2 (en) 2012-10-01 2017-09-19 Teikoku Pharma Usa, Inc. Non-aqueous taxane formulations and methods of using the same
CN111557934A (zh) * 2020-06-10 2020-08-21 四川汇宇制药股份有限公司 一种含多西他赛的药物组合物及其制备方法和用途
US10842770B2 (en) 2010-05-03 2020-11-24 Teikoku Pharma Usa, Inc. Non-aqueous taxane pro-emulsion formulations and methods of making and using the same

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5403858A (en) * 1991-07-08 1995-04-04 Rhone-Poulenc Rorer, S.A. New compositions containing taxane derivatives
US5750561A (en) * 1991-07-08 1998-05-12 Rhone-Poulenc Rorer, S.A. Compositions containing taxane derivatives
US5977163A (en) * 1996-03-12 1999-11-02 Pg-Txl Company, L. P. Water soluble paclitaxel prodrugs

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5403858A (en) * 1991-07-08 1995-04-04 Rhone-Poulenc Rorer, S.A. New compositions containing taxane derivatives
US5750561A (en) * 1991-07-08 1998-05-12 Rhone-Poulenc Rorer, S.A. Compositions containing taxane derivatives
US5977163A (en) * 1996-03-12 1999-11-02 Pg-Txl Company, L. P. Water soluble paclitaxel prodrugs

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010023321A1 (fr) * 2008-09-01 2010-03-04 Stragen Pharma S.A. Formulation liquide contenant un dérivé taxane
US9468602B2 (en) 2009-01-05 2016-10-18 Azad Pharma Ag Pharmaceutical microemulsion for preventing supramolecular aggregation of amphiphilic molecules
KR101074936B1 (ko) * 2009-05-25 2011-10-18 보령제약 주식회사 도세탁셀 주사제용 조성물 및 그의 제조방법
US7772274B1 (en) 2009-10-19 2010-08-10 Scidose, Llc Docetaxel formulations with lipoic acid
US8476310B2 (en) 2009-10-19 2013-07-02 Scidose Llc Docetaxel formulations with lipoic acid
US8912228B2 (en) 2009-10-19 2014-12-16 Scidose Llc Docetaxel formulations with lipoic acid
US10842770B2 (en) 2010-05-03 2020-11-24 Teikoku Pharma Usa, Inc. Non-aqueous taxane pro-emulsion formulations and methods of making and using the same
US9763880B2 (en) 2012-10-01 2017-09-19 Teikoku Pharma Usa, Inc. Non-aqueous taxane formulations and methods of using the same
JP2014131966A (ja) * 2013-01-04 2014-07-17 Nagase Iyakuhin Kk ドセタキセル含有医薬組成物
CN111557934A (zh) * 2020-06-10 2020-08-21 四川汇宇制药股份有限公司 一种含多西他赛的药物组合物及其制备方法和用途

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