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WO2009043226A1 - Composition liquide stable comprenant des dérivés de taxane, et son procédé de préparation - Google Patents

Composition liquide stable comprenant des dérivés de taxane, et son procédé de préparation Download PDF

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Publication number
WO2009043226A1
WO2009043226A1 PCT/CN2008/001426 CN2008001426W WO2009043226A1 WO 2009043226 A1 WO2009043226 A1 WO 2009043226A1 CN 2008001426 W CN2008001426 W CN 2008001426W WO 2009043226 A1 WO2009043226 A1 WO 2009043226A1
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WO
WIPO (PCT)
Prior art keywords
liquid composition
composition according
acid
ethanol
solution
Prior art date
Application number
PCT/CN2008/001426
Other languages
English (en)
Chinese (zh)
Inventor
Piaoyang Sun
Yuxia Wu
Yan Xu
Original Assignee
Jiangsu Hengrui Medicine Co., 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 Jiangsu Hengrui Medicine Co., Ltd. filed Critical Jiangsu Hengrui Medicine Co., Ltd.
Publication of WO2009043226A1 publication Critical patent/WO2009043226A1/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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • 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
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a liquid composition, and more particularly to a stable liquid composition of a triterpenoid compound, a process for its preparation and its use. Background technique
  • the taxane derivative is a biguanide compound which can be used in the field of medicine and has been used as a therapeutic agent for tumors such as ovarian cancer, breast cancer, and lung cancer.
  • docetaxel is currently a clinically effective drug. It is also a semi-synthetic antitumor drug developed by Rone-Poulenc Rorer of France. It was first launched in 1995. It can promote the assembly of microtubules, prevent the dissociation of microtubules, inhibit the differentiation of tumor cells, and ultimately lead to the death of tumor cells. It has shown reliable efficacy against many common tumors and has become the most widely used anticancer drug in clinical application.
  • Taxane derivatives such as docetaxel are generally used clinically in liquid dosage forms for concentrated infusion.
  • the conventional recommended dosing regimen for docetaxel is 1 time / 3 weeks, 1 hour intravenous infusion of 75 mg / m 2 .
  • An injectable composition containing a taxane derivative which dissolves the taxane compound docetaxel in a surfactant such as Tween 80 is described in Chinese Patent Application Nos. 93119653.1 and 02147245.9.
  • a diluent solution such as ethanol is added, and the diluent solution may be separated or mixed with the surfactant solution, and the mixed liquid is used as a drug solution for preparing a clinical infusion.
  • Example 1 of U.S. Patent No. 5,403,858 A discloses a method for preparing docetaxel mother liquor, which is dissolved in anhydrous ethanol, followed by addition of Tween 80, and then ethanol is removed to obtain a mother liquor, and the mother liquor is 5%.
  • the glucose perfusate was diluted to concentrations of 0.1, 0.3, and 0.5 mg/ml, the stability of the resulting diluted solution was observed.
  • the applicant of the present invention has studied it and surprisingly found that by adjusting the production process of the mother liquor, the stability of the mother liquor is greatly improved, the degradation of the active ingredient or the related substances is significantly reduced, and the safety of the drug is markedly improved. Sex. Summary of the invention
  • the technical problem to be solved by the present invention is to provide a liquid composition of a triterpenoid derivative having high stability.
  • the liquid composition of the present invention is particularly suitable for use in the preparation of an injection of a triterpenoid derivative, such as a liquid composition or an injection preparation (also known as an injection) of docetaxel, which is less susceptible to degradation during storage and is more safe and effective.
  • a surfactant solution also referred to as "mother liquor”
  • a surfactant solution also referred to as "mother liquor”
  • the pH of the mother liquor after the mother liquor is diluted with a diluent (such as glucose solution or sodium chloride solution), the pH of the resulting injection is suitable for physiological needs. Since the product itself meets physiological needs, the skilled person does not need or adjust the acidity and alkalinity according to the preparation method of the general preparation.
  • the applicant of the present invention unexpectedly found that when a certain amount of acidic reagent (also called an acidic regulator) is added to the surface active solution of the mother liquor to make it weakly acidic, the mother liquor Stability is greatly improved.
  • acidic reagent also called an acidic regulator
  • the inventors prepared a mother liquor containing a surfactant having a pH of 6.0 to 8.0 when no acidity adjusting agent was added to adjust its acidity and alkalinity. The inventors have found through experiments that if the acid regulator is added to the solution and the acidity is adjusted to be weakly acidic, the solution is more stable.
  • the mother liquor was prepared by the original prescription process, and placed at 40 ° C for 10 days, and the content of the relevant substance was 11.7%.
  • the mother liquor was prepared according to the formulation process of the present invention, and placed at 40 ° C for 10 days, and the content of the relevant substance was found to be 0.84%. It can be seen that the transportation and storage conditions of the products prepared by the original prescription process are more severe, and the products of the invention can be placed under normal temperature conditions for a long time, which is beneficial to the transportation and storage of the products. The above results are expected by those skilled in the art.
  • the obtained mother liquor not only improves the stability, but also the pH of the obtained injection is suitable for physiological needs after being diluted by a diluent such as a glucose solution or a sodium chloride solution.
  • a diluent such as a glucose solution or a sodium chloride solution.
  • whether the acid regulator is added to the mother liquor and the solution obtained by dilution with the diluent are clinically acceptable physiological pH, such as pH 4-4.5.
  • a liquid composition which is a surfactant solution in which a taxane derivative is dissolved, characterized in that the pH of the surfactant solution is 5 or less, preferably pH. It is 3-5, more preferably 3.5-4.5.
  • the taxane derivative described herein is preferably a compound of the formula: or a pharmaceutically acceptable ester thereof:
  • R represents a hydrogen atom or an acetyl group
  • R t represents a tert-butoxycarbonylamino or benzoylamino group, preferably docetaxel or an ester thereof.
  • an acidic regulator may be added to the composition, and the most suitable composition for clinical use may consist of only a taxane derivative, a surfactant, and an acid regulator, but not Other substances, preferably the taxane derivative is docetaxel or an ester thereof.
  • the acidity adjusting agent may be any one of an organic acid or an inorganic acid conventionally adjusted in the art, or a combination thereof.
  • the acidic modifier used is preferably in the form of a solution, which can be prepared as a suitable solution for solid organic or inorganic acids, preferably using ethanol to prepare an acidic modifier.
  • the organic acid or inorganic acid to be used may be an acid commonly used in the art, such as citric acid, fumaric acid, maleic acid, malic acid, hydrochloric acid, sulfuric acid, tartaric acid, etc., preferably citric acid, more preferably ruthenium. Acidic ethanol solution.
  • the content of the acidic regulator in the composition is generally from 0.01 to 20 mg/ml, preferably from 0.05 to 10 mg/ml, more preferably from 0.1 to 5 mg/ml, and most preferably from 0.1 to 2.8 mg/ml.
  • the surfactant for dissolving a drug of the present invention is a surfactant conventionally used in the art, in particular, a surfactant used in the prior art for a taxane, such as polyoxyethyl ether, ethylene oxide, glycerin. Any one or combination of ester, hydrogenated castor oil, polyoxyethylene castor oil, castor oil, preferably polyoxyethyl ether, especially Tween 80.
  • the liquid content of the liquid for injection of the taxanes in the surfactant solution should be reduced as much as possible to facilitate the stability of the solution of the triterpenoids. Accordingly, the content of ethanol in the liquid composition is preferably not more than 10%, preferably not more than 5%, more preferably not more than 3%, particularly preferably not more than 1.5%.
  • the concentration in the surfactant can be selected according to the needs of use and the solubility of the triterpenoid derivative in the surfactant.
  • concentration of the injectable preparation for clinical use is generally 1 - 10 g per 100 ml of the surfactant solution, and the usual concentration of docetaxel injection is 4 g / 100 ml.
  • the invention specifically provides a liquid composition, in particular a liquid composition for injection, consisting of docetaxel, citric acid and Tween 80, wherein the ethanol content is 1.5%, docetaxel
  • the content can be 4g/100ml.
  • the present invention provides the use of the above liquid composition for the preparation of a medicament for treating a tumor.
  • Another aspect of the present invention provides a method of preparing a taxane derivative injection preparation, particularly a method of preparing a docetaxel injection preparation.
  • a surfactant solution for obtaining a taxane compound is prepared according to a conventional method, and an acidic regulator is added to the surfactant solution to adjust the pH to 3-5, preferably a triterpenoid derivative. It is docetaxel or its ester.
  • the invention specifically provides a method for preparing docetaxel injection, which is dissolved in docetaxel plus absolute ethanol, then added to Tween 80, stirred evenly, and adjusted to pH value by using citric acid anhydrous ethanol solution to 3- 5. Remove ethanol to 1.5% ethanol.
  • the method of preparing a surfactant solution of a taxane compound can be carried out by a method disclosed in the prior art. E.g:
  • the triterpene derivative is directly dissolved in the surfactant.
  • the preferred method is to prepare a surfactant solution containing 1-2% ethanol, then continuously add the taxane derivative, and pulverize it by using a screw mixer or centrifugally. The machine is constantly stirring.
  • mother liquor means a surfactant solution in which a taxane compound is dissolved.
  • the method for determining the pH value of the mother liquor is as follows: Take appropriate amount of the liquid, add 13% (V/V) ethanol solution, dilute it to about 10 mg/ml of the taxane compound solution, and measure the pH value, preferably the taxane.
  • the derivative is docetaxel or an ester thereof.
  • Docetaxel mother liquor was prepared according to the method disclosed in Example 1 of US 5,403,858 A.
  • Example 2 Preparation of docetaxel mother liquor
  • Preparation method Weigh 20g of docetaxel, add 1000ml of absolute ethanol, stir to dissolve, then add the prescription amount of Tween-80 (polysorbate-80), stir evenly, with citric acid (formed with anhydrous ethanol) Appropriate amount, adjust the pH value, filter through 0.22 ⁇ microporous membrane, disperse in the vial, remove the ethanol under vacuum and reduce the ethanol content. When the ethanol content is 1.5%, add the plug and roll the outer cover.
  • Tween-80 polysorbate-80
  • citric acid formed with anhydrous ethanol
  • Example 10 mother liquids containing an acid regulator (Examples 3-9) and no acid regulator (Example 10) were separately prepared and placed at 30 ° C and 2 to 8 ° C, respectively. 30 days, determine the relevant assessment items.
  • Example 10 The pH of the mother liquor was adjusted without adding a rubber acid solution, and the pH was 6.0 to 8.0. The results are shown in Table 1:
  • Example 3 4 5 6 7 8 9 10 Amount of citric acid (mg/ml) 14 8 4.8 3.6 3 2 1 0 Starting 3.01 3.50 3.96 4.26 4.56 4.88 5.67 6.26 Determination 30 ° C 30 days 3.05 3.52 4.00 4.21 4.60 4.90 5.66 6.20 pH 2 ⁇ 8°C
  • Thick liquid thick liquid thick liquid thick liquid thick liquid thick liquid thick liquid thick liquid thick liquid thick liquid thick liquid thick liquid thick liquid thick liquid thick liquid thick liquid results show: When the pH value of the mother liquid is less than 5.0, placed under 30 ⁇ conditions for one month, the content of related substances is significantly smaller than the mother liquor with pH greater than 5.0; When the pH is 3.5 to 4.5, it is left at a temperature of 30 Torr for one month, and the contents of the substances are basically the same.
  • the pH of the rubber was adjusted without adding barium, and the pH was determined to be 6.26.
  • the substrate was placed at 30 ° C for one month, and the related substance was significantly higher than the mother liquid having a pH of less than 5.0. It is concluded that when the pH of the mother liquor is weakly acidic, the liquid is more stable, especially when the pH is 3.0 to 5.0.
  • liquid composition of the present invention contains an acid regulator which is more stable than the tadazine derivative mother liquor known in the prior art and can be placed at a normal temperature for a long period of time, facilitating transportation and storage.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Engineering & Computer Science (AREA)
  • Dermatology (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une composition liquide et son procédé de préparation. Ladite composition comprend des dérivés de taxane et un tensioactif dont le pH est inférieur à 5.
PCT/CN2008/001426 2007-09-30 2008-08-05 Composition liquide stable comprenant des dérivés de taxane, et son procédé de préparation WO2009043226A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN200710162304.8 2007-09-30
CN2007101623048A CN101396354B (zh) 2007-09-30 2007-09-30 一种稳定的塔三烷类化合物液体组合物及其制备方法和其应用

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WO2009043226A1 true WO2009043226A1 (fr) 2009-04-09

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PCT/CN2008/001426 WO2009043226A1 (fr) 2007-09-30 2008-08-05 Composition liquide stable comprenant des dérivés de taxane, et son procédé de préparation

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CN (1) CN101396354B (fr)
HK (1) HK1126405A1 (fr)
TW (1) TW201004656A (fr)
WO (1) WO2009043226A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8940786B2 (en) 2012-10-01 2015-01-27 Teikoku Pharma Usa, Inc. Non-aqueous taxane nanodispersion formulations and methods of using the same
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

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3679925B1 (fr) 2017-09-07 2024-10-23 Shenzhen Salubris Pharmaceuticals Co. Ltd Composition pharmaceutique de conjugué de docétaxel et procédé de préparation

Citations (8)

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Publication number Priority date Publication date Assignee Title
CN1096673A (zh) * 1992-11-27 1994-12-28 福丁有限公司 注射用药物组合物
CN1209059A (zh) * 1995-12-21 1999-02-24 基因实验室技术有限公司 紫杉烷类组合物及方法
CN1382038A (zh) * 1999-10-25 2002-11-27 苏伯俭股份有限公司 新的和改进的紫杉醇制剂
CN1636560A (zh) * 1992-12-02 2005-07-13 阿文蒂斯药物股份有限公司 以塔三烷衍生物为主组分的新组合物
CN1676125A (zh) * 2004-03-31 2005-10-05 张昊 含有紫杉碱类或难溶药物的纳米级乳剂
WO2006037089A2 (fr) * 2004-09-28 2006-04-06 Sd Pharmaceuticals, Inc. Compositions faiblement huileuses pour la liberation de taxoides et d'autres medicaments insolubles
EP1666069A1 (fr) * 2004-11-24 2006-06-07 Yung Shin Pharm. Ind. Co., Ltd. Solutions aqueuses injectables de Paclitaxel et procédé pour leur préparation
CN1946394A (zh) * 2004-04-09 2007-04-11 智雄吉 用于治疗癌症的可注射组合物

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BRPI0600194A (pt) * 2006-01-30 2007-10-23 Quiral Quimica Do Brasil S A composições farmacêuticas contendo docetaxel e um inibidor de degradação e processo de obtenção das mesmas

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1096673A (zh) * 1992-11-27 1994-12-28 福丁有限公司 注射用药物组合物
CN1636560A (zh) * 1992-12-02 2005-07-13 阿文蒂斯药物股份有限公司 以塔三烷衍生物为主组分的新组合物
CN1209059A (zh) * 1995-12-21 1999-02-24 基因实验室技术有限公司 紫杉烷类组合物及方法
CN1382038A (zh) * 1999-10-25 2002-11-27 苏伯俭股份有限公司 新的和改进的紫杉醇制剂
CN1676125A (zh) * 2004-03-31 2005-10-05 张昊 含有紫杉碱类或难溶药物的纳米级乳剂
CN1946394A (zh) * 2004-04-09 2007-04-11 智雄吉 用于治疗癌症的可注射组合物
WO2006037089A2 (fr) * 2004-09-28 2006-04-06 Sd Pharmaceuticals, Inc. Compositions faiblement huileuses pour la liberation de taxoides et d'autres medicaments insolubles
EP1666069A1 (fr) * 2004-11-24 2006-06-07 Yung Shin Pharm. Ind. Co., Ltd. Solutions aqueuses injectables de Paclitaxel et procédé pour leur préparation

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
US8940786B2 (en) 2012-10-01 2015-01-27 Teikoku Pharma Usa, Inc. Non-aqueous taxane nanodispersion formulations and methods of using the same
US9308195B2 (en) 2012-10-01 2016-04-12 Teikoku Pharma Usa, Inc. Non-aqueous taxane formulations and methods of 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

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CN101396354A (zh) 2009-04-01
HK1126405A1 (en) 2009-09-04
TW201004656A (en) 2010-02-01

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