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WO2009079878A1 - Injection comprenant du docétaxel et sa préparation - Google Patents

Injection comprenant du docétaxel et sa préparation Download PDF

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Publication number
WO2009079878A1
WO2009079878A1 PCT/CN2007/071274 CN2007071274W WO2009079878A1 WO 2009079878 A1 WO2009079878 A1 WO 2009079878A1 CN 2007071274 W CN2007071274 W CN 2007071274W WO 2009079878 A1 WO2009079878 A1 WO 2009079878A1
Authority
WO
WIPO (PCT)
Prior art keywords
injection
docetaxel
ethanol
mother liquid
water
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/CN2007/071274
Other languages
English (en)
Chinese (zh)
Inventor
Yufang Hu
Chunchou Lin
Yaokun Huang
Shoumin Huang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
TTY Biopharm Co Ltd
Original Assignee
TTY Biopharm 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 TTY Biopharm Co Ltd filed Critical TTY Biopharm Co Ltd
Priority to CN200780101762.9A priority Critical patent/CN101883563B/zh
Priority to PCT/CN2007/071274 priority patent/WO2009079878A1/fr
Priority to JP2010538312A priority patent/JP2011506495A/ja
Priority to KR1020107016036A priority patent/KR20100113527A/ko
Publication of WO2009079878A1 publication Critical patent/WO2009079878A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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 provides an injection containing a docetaxel compound, in particular, an injection containing a docetaxel compound which can prolong stability and is convenient for medical personnel, and the injection is a three-component injection containing docetaxel compound. . Background technique
  • Paclitaxel a taxane
  • FDA US Food and Drug Administration
  • patients receiving this paclitaxel were found to have severe allergic reactions.
  • the allergen is not the paclitaxel, but the solvent Cremophor EL used to dissolve paclitaxel. In order to solve the allergic reaction caused by Cremophor EL, it is the current research direction to find a solvent to replace Cremophor EL.
  • the liposome dosage form will precipitate during storage, making the drug insufficiently stable, so it is stored as a frozen crystal powder during storage, but the liposome is to be stored.
  • the drying of the dosage form into a frozen crystal powder must be subjected to a high-cost freeze-drying preparation process, so that it does not meet economic benefits and makes the product lose its commercial significance.
  • paclitaxel Since paclitaxel has a very low solubility in water and it is extremely difficult to find a good solvent, a docetaxel having a higher solubility than paclitaxel is synthesized by chemical synthesis, and the docetaxel intravenous preparation prepared by the docetaxel ( Taxotere®) has been approved by the US FDA for dissolution with surfactants, which is a considerable breakthrough in this field of research.
  • Taxotere® docetaxel intravenous preparation prepared by the docetaxel
  • the surfactant uses Tween, it can reduce the toxicity of conventional organic solvents as a solvent, but when injected, When Tween dissolves docetaxel, it must be mixed with a perfusate such as 5% dextrose water, but at this point the mixture will form a gel due to being too viscous and must be stirred to dissolve.
  • Rone-Poulenc proposed a two-component composition to add an intermediate solution to avoid gelation (Jen McBee, Patrick, German) , Randy, Gillis Quarry, Mitchell Villard, "Two-component injection composition containing a taxane derivative in a surfactant and an additive for preventing dilution", Taiwanese invention patent Announcement No.
  • the intermediate solution includes an organic compound such as a molecular weight of less than 200 or an additive such as sodium chloride, and water, that is, the intermediate solution is an aqueous solution of the additive, and its concentration It is 6 wt% larger than the surfactant.
  • the concentration of the intermediate solution is diluted with water to 13% by weight of ethanol.
  • the addition of the intermediate solution causes the following problems:
  • the present inventors have invented the three-component injection containing the docetaxel compound in view of the fact that the above solvent for dissolving the docetaxel intravenous preparation (Taxotere®) still does not provide good stability of the preparation.
  • An object of the present invention is to provide a three-component injection containing a docetaxel compound which can extend stability and is convenient for medical personnel.
  • the three-component injection of the docetaxel compound of the present invention comprises: a mother liquor which is a solution containing docetaxel and a pharmaceutically acceptable surfactant;
  • Ethanol which is an anti-gelling agent for preventing gel formation after mixing of injections
  • Water which is a flow agent for blending the aforementioned ethanol to make the mother liquid uniform.
  • weight ratio of the anti-gelling agent to the surfactant is not less than one percent; and the weight ratio of the flow agent to the surfactant is not less than ten percent.
  • the invention can avoid the gel produced by mixing the mother liquor with the perfusate, such as 5% glucose water, by adding the anti-gelling agent, and the flow agent can be combined with the anti-gelling agent to adjust the viscosity of the mother liquor, so
  • the three-component injection prepared by the preparation method of the present invention has a reduced viscosity and is made homogeneous, and does not cause gelation, so that the medical staff can take the injection with a syringe and confirm the amount of extraction.
  • the docetaxel-containing compound-containing injection according to the present invention wherein the pharmaceutically acceptable surfactant is preferably Tween.
  • the concentration of ethanol used is preferably not less than 90%, more preferably not less than 95%; the concentration of docetaxel in the mother liquor is preferably from 20 mg/ml to 60 mg/ml; and the weight of the antigelling agent is preferably At least 1% by weight of the Tween; the weight of the water is preferably at least 10% by weight of the Tween.
  • the present invention also provides a method of preparing the injection agent containing the docetaxel compound according to claim 1, the steps comprising: a) mixing the mother liquid with ethanol to form a mixed solution; b) adding water to the above mixed solution, And mix well.
  • Figure 1 is a top plan view of a round injection bottle in the uniformity test of the present invention. Specific implementation
  • the injection of the docetaxel compound of the present invention comprises:
  • a mother liquor comprising docetaxel and one or more pharmaceutically acceptable surfactant solutions, the surfactant being tween (polysorbate), and the concentration of the docetaxel in tween From 20 mg/ml (mg/ml) to 60 mg/ml (mg/ml);
  • Anti-gelling agent which can prevent the mother liquor from mixing with the perfusate such as 5% glucose water during use.
  • the gel produced which is preferably 95% ethanol, having a weight of not less than one percent by weight of tween (1 wt% tween of ethanol); a flow agent which is formulated with an antigelling agent
  • the mother liquid is uniformly water, and its function is to adjust the viscosity of the mother liquid.
  • the flow agent is pure water or water for injection, and its weight is not less than 10% by weight of tween (water 10 wt/c ⁇ tween).
  • the three-component injection composed of the anti-gelling agent, the flow agent and the mother liquid is more flexible than the combination of the intermediate solution and the mother liquid in the prior art, and elastically adjusts the viscosity of the mother liquid.
  • the method for preparing a three-component injection containing a docetaxel compound of the present invention comprises mixing a mother liquid with an anti-gelling agent, adding a flow agent, and uniformly mixing.
  • the above preparation method is such that the components can be uniformly mixed during mixing by hand-handling at room temperature or in a machine-assisted manner such as a tabletop Vortex.
  • the advantages of the docetaxel-containing injection of the present invention are explained below in several examples: Example 1 Observing the phenomenon of gel formation by different mixing methods
  • Control group The present invention can be mixed using different methods for ease of use and to observe the situation in which the gel is produced.
  • the intermediate solution of the mother liquor anti-gelling agent mixed with the flow agent docetaxel is mixed with 0.24 ml of ethanol and 1.26 ml of water to form 1.5 ml of 13-agent tween total 0.5 ml wt% ethanol.
  • Table 2 The intermediate solution of the mother liquor anti-gelling agent mixed with the flow agent docetaxel is mixed with 0.24 ml of ethanol and 1.26 ml of water to form 1.5 ml of 13-agent tween total 0.5 ml wt% ethanol.
  • the composition of the final mixed solution is the same, but the local composition around the tween molecule is different, wherein the anti-gelling agent and the flow agent of the mixing method 1 are first adsorbed on the tween molecule, so that the tween molecule is surrounded by more
  • the anti-gel molecule that is, the anti-gelling agent of the surfactant molecule has a higher local concentration, so that the gel can be avoided; and in the mixing method 2, when the mother liquor containing tween is injected into the perfusion solution
  • the anti-gelling agent and the flow agent have been first diluted by the perfusion solution, causing the concentration of the anti-gel molecules around the tween molecule to be too low, thus causing a gelation phenomenon of varying degrees in the overall solution.
  • the amount of anti-gelling agent is not the main cause of gelation, and the main reason is that whether the anti-gelling agent can be fully mixed with the surfactant molecules in the mother liquor during the mixing process, thereby Aggregation with other surfactant molecules can be avoided.
  • test group
  • the mother liquor, anti-gelling agent and flow agent used in this group are shown in Table 4, but the mixing step is different from the control group.
  • the anti-gelling agent and the flow agent are separately mixed with the mother liquor, and the mixing steps and observation results are shown in the table. 5, and compared with the control group. Table 4.
  • the anti-gelling agent and the flow agent are sequentially put into the mother liquid (unlike the mixing method 2, the mixed solution of the anti-gelling agent and the flowing agent is put into the mother liquid), and it is observed that the anti-gelling agent molecule is used in the surfactant. There is a higher concentration around the molecule.
  • This mixing method allows the ratio of the antigelling agent molecule to the surfactant molecule to be 5 wt% ( ⁇ 6 wt%) without gel formation.
  • the mixture was prepared by different agitation, and the uniformity was tested.
  • the uniformity test is based on the top view of the circular injection bottle, taking the center point of the circular radial cross-sectional area and the uniformity of the circumference of 0 degree, 90 degree, 180 degree and 270 degrees. Point, analysis by high performance liquid chromatography (High Performance Liquid Chromatography). Control group:
  • the anti-gelling agent and the flow agent are first mixed into an intermediate solution, and then the intermediate solution is extracted and slowly injected into the mother liquid, and stirred by different stirring methods, and then analyzed.
  • the mother liquor, antigelling agent and flow agent used are shown in Table 7, and the observation results after stirring are shown in Table 8 and Table 9. Table 7.
  • the anti-gelling agent of the three-component injection composition of the above-mentioned test items 3, 4, 5, and 6 was separately added to the mother liquid, and then vigorously stirred by a table vortex machine (Vortex) for at least 20 seconds, and then separately added to the flow.
  • the agent is stirred for a minimum of 20 seconds by gentle rotary stirring, which means that the final solution does not generate bubbles upon stirring, and the obtained analysis results are as follows:
  • the concentration unit is mg/ml.
  • the anti-gelling agent of the three-component injection composition of the above-mentioned test items 3, 4, 5, and 6 is separately added to the mother liquid, and then vigorously stirred by a table vortex machine (Vortex). After 20 seconds, the flow agent was then separately added and vigorously stirred by a Vortex for at least 20 seconds to cause bubbles in the mixed liquid of the anti-gelling agent and the mother liquid, and the obtained analysis results were as follows: Table 12. Intense Stirring Uniformity Test of Three-Component Injectable Composition
  • Example 1 (Concentration in milligrams per milliliter) It is known from Example 1 that the local concentration of the anti-gelling agent around the surfactant molecule is higher, so that in addition to lowering the ratio of the gel in solution to the gel itself In addition to the uniformity resistance produced; in contrast, the two-component injection of the control group was compared to the experimental group of the present invention, since the surfactant of the two components was previously diluted, thereby causing the surfactant molecules to The anti-gelling agent has a low local concentration, so the gel ratio and the resistance generated by the gel itself cannot be lowered, and even after vigorous stirring, the uniformity of the solution is inferior to that of the three-component injection of the present invention.
  • Control group After extracting the intermediate solution of the test items 1 and 2 in Table 7, slowly inject it into the mother liquid, and then vigorously stir it with a table vortex machine (Vortex) for at least 40 seconds to carry out a stability test.
  • Table 13 Table 13. Crystallization test of two-component injection composition after intense stirring
  • test group
  • the anti-gelling agent of the three-component injection composition of the test items 3, 4, 5, and 6 in Table 10 was separately added to the mother liquid, and then vigorously stirred by a table vortex machine (Vortex) for at least 20 seconds, and then The flow agents were separately added with a tabletop vortex machine (Vortex) for at least 20 seconds, and then the stability test was carried out.
  • Table 14 Three-component injection composition Crystallization test item after intense stirring 0 hours 4 hours 8 hours 12 hours 24 hours 48 hours
  • Example 6 no crystal, no crystal, no crystal, no crystal, no crystal, no crystal, no crystal
  • the local concentration of the anti-gelling agent around the surfactant molecule is high, so that in addition to reducing the proportion of the gel in the solution and the uniformity of the gel itself In addition to the degree of resistance, it can also improve the energy barrier between the surfactant molecules, avoiding the precipitation of docetaxel molecules due to intermolecular aggregation; in contrast, the surfactant component of the two-component injection of the control group
  • the surrounding anti-gelling agent has a lower local concentration, so the energy barrier between the surfactant molecules is lower, so the two-component injection will produce a crystalline precipitate after being placed for 12 hours, and the experimental group of the present invention The three-component injection did not produce a crystalline precipitate within 48 hours of standing.
  • the addition of the anti-gelling agent can avoid the gel produced by mixing the mother liquor with the perfusate during use, and the flow agent can be combined with the anti-gelling agent to adjust the viscosity of the mother liquor, so the three formulated by the preparation method of the present invention
  • the viscosity of the component injection is lowered, and it is made homogeneous, and does not produce a gelatinous state, which is convenient for medical personnel to take the injection with a syringe and confirm the amount of extraction, and also extend the docetaxel from the injection.
  • the time during which the crystal precipitates are generated in the solution thereby increasing the stability of the injection to reduce the fatal danger of the patient's medication, thereby improving the quality of the medical treatment.

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  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une injection comprenant du docétaxel, qui comprend la solution mère, de l'éthanol pour empêcher la formation de gel dans l'injection, de l'eau pour assurer l'état d'écoulement uniforme de la solution mère. La solution mère est une solution contenant du docétaxel et un ou plusieurs surfactants pharmaceutiquement acceptables. L'invention concerne également un procédé de préparation de l'injection consistant à mélanger la solution mère avec de l'éthanol, puis à ajouter l'eau et à mélanger uniformément. L'injection est très homogène et très stable, et elle peut rallonger la durée de formation de cristaux par précipitation du docétaxel dans la solution injectable.
PCT/CN2007/071274 2007-12-19 2007-12-19 Injection comprenant du docétaxel et sa préparation Ceased WO2009079878A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CN200780101762.9A CN101883563B (zh) 2007-12-19 2007-12-19 含多烯紫杉醇化合物的注射剂及其配制方法
PCT/CN2007/071274 WO2009079878A1 (fr) 2007-12-19 2007-12-19 Injection comprenant du docétaxel et sa préparation
JP2010538312A JP2011506495A (ja) 2007-12-19 2007-12-19 ドセタキセル化合物含有注射剤及びその調製方法
KR1020107016036A KR20100113527A (ko) 2007-12-19 2007-12-19 도세탁셀 화합물 함유 주사제 및 그 배합 제조 방법

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2007/071274 WO2009079878A1 (fr) 2007-12-19 2007-12-19 Injection comprenant du docétaxel et sa préparation

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WO2009079878A1 true WO2009079878A1 (fr) 2009-07-02

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101862319A (zh) * 2010-06-28 2010-10-20 江苏奥赛康药业有限公司 一种供注射用的多西他赛组合物及其制备方法

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP6124633B2 (ja) * 2013-03-18 2017-05-10 ダイト株式会社 安定なドセタキセル注射剤
CN117214053A (zh) * 2023-10-17 2023-12-12 海南卫康制药(潜山)有限公司 一种注射用头孢呋辛钠肌注混悬液的粒度测定方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5750561A (en) * 1991-07-08 1998-05-12 Rhone-Poulenc Rorer, S.A. Compositions containing taxane derivatives
WO2007124700A2 (fr) * 2006-05-03 2007-11-08 I.Q.A., A.S. Composition pharmaceutique contenant un dérivé de taxane, destinée à l'élaboration d'une solution pour perfusion, sa méthode d'élaboration et ses applications

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005225818A (ja) * 2004-02-13 2005-08-25 Otsuka Pharmaceut Factory Inc パクリタキセル又はドセタキセルの医薬組成物

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5750561A (en) * 1991-07-08 1998-05-12 Rhone-Poulenc Rorer, S.A. Compositions containing taxane derivatives
WO2007124700A2 (fr) * 2006-05-03 2007-11-08 I.Q.A., A.S. Composition pharmaceutique contenant un dérivé de taxane, destinée à l'élaboration d'une solution pour perfusion, sa méthode d'élaboration et ses applications

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101862319A (zh) * 2010-06-28 2010-10-20 江苏奥赛康药业有限公司 一种供注射用的多西他赛组合物及其制备方法

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CN101883563B (zh) 2014-07-09
JP2011506495A (ja) 2011-03-03
CN101883563A (zh) 2010-11-10
KR20100113527A (ko) 2010-10-21

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