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EP2155189A2 - Direct dissolution of docetaxel in a solvent in polysorbate 80 - Google Patents

Direct dissolution of docetaxel in a solvent in polysorbate 80

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Publication number
EP2155189A2
EP2155189A2 EP08805654A EP08805654A EP2155189A2 EP 2155189 A2 EP2155189 A2 EP 2155189A2 EP 08805654 A EP08805654 A EP 08805654A EP 08805654 A EP08805654 A EP 08805654A EP 2155189 A2 EP2155189 A2 EP 2155189A2
Authority
EP
European Patent Office
Prior art keywords
docetaxel
polysorbate
solvent
solution
acetonitrile
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.)
Withdrawn
Application number
EP08805654A
Other languages
German (de)
French (fr)
Inventor
Jean-René Authelin
Eric Didier
Elie Fouque
Mostafa Nakach
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.)
Aventis Pharma SA
Original Assignee
Rhone Poulenc Rorer SA
Aventis Pharma SA
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
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Application filed by Rhone Poulenc Rorer SA, Aventis Pharma SA filed Critical Rhone Poulenc Rorer SA
Publication of EP2155189A2 publication Critical patent/EP2155189A2/en
Withdrawn legal-status Critical Current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
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems

Definitions

  • the present invention relates to a novel process for preparing a solution of docetaxel " in polysorbate 80.
  • It relates, according to a first means of implementing the invention, more particularly the solubilization of docetaxel in an organic solvent, its mixture with polysorbate 80 and the evaporation of the solvent.
  • the ethanol used in the final formulation of the commercial composition containing docetaxel is not the only solvent usable in the context of the present invention.
  • solvents capable of solubilizing docetaxel and miscible in all proportions with polysorbate are usable. It is thus possible to use solvents having a boiling point of between 40 and 153 ° C. at atmospheric pressure, among these solvents, mention may be made of chloroalkanes and in particular dichloromethane, chloroform, amides such as dimethylformamide, dimethylacetamide, esters such ethyl acetate, ketones such as acetone, methyl isobutyl ketone, nitriles such as acetonitrile.
  • the preferred solvents are selected from acetone, acetonitrile, methylene chloride, dimethylformamide.
  • the docetaxel used as raw material in the context of the present invention may be an amorphous docetaxel or a crystallized docetaxel in any form such as an acetonate, an alcoholate, a hydrate or a crystal with acetonitrile.
  • the process according to the invention is not limited to the dissolution of docetaxel in solid form in a solvent followed by the addition of polysorbate and distillation of the solvent but may also consist in using the docetaxel solution obtained at the outlet of a purification column.
  • This solution may be a solution of docetaxel in a single solvent such as ethyl acetate, acetone, methylene chloride, or tetrahydrofuran, but may also be a solution in a mixture of the solvents mentioned above.
  • This column is usually made of a silica column but any other material for purification is usable.
  • a silica and in particular a silica sold under the trade name Lichrospher.
  • a Lichrospher silica with a particle diameter of 12 ⁇ m is most preferably used.
  • the docetaxel solution to be purified is preferably a solution of docetaxel in ethyl acetate or a mixture of ethyl acecate with a hydrocarbon such as cyclohexane, hexanes or toluene.
  • the solution from the purification column if the docetaxel content has the required purity, can be mixed directly with the polysorbate and the solvent (s) evaporated (s) without intermediate step of crystallization of docetaxel in any solvate form. This presents a considerable advantage from the economic point of view.
  • docetaxel trihydrate 4.3320 g of docetaxel trihydrate are dissolved in 37.9 g of absolute ethanol, 108.0 g of polysorbate 80 are added dropwise, and a large foam appears. It is distilled under a pressure of 50 mbar with a bath temperature of 40 ° C. After 4 hours and 10 minutes of distillation, 33.9 g of distillate and 167.8 g (to be verified) of docetaxel solution in polysorbate are obtained. containing less than 0.01% ethanol and 0.28% impurities.
  • the method consists in the deprotection (detaching) of the docetaxel diprotected in prosition 7 and 10 to give docetaxel which is isolated by crystallization in a toluene / acetonitrile mixture.
  • 90OmL of ethyl acetate, 7.8 mg of 4-methoxyphenol and 78 g of docetaxel di were charged. protected by a trichlroethoxycarbonyl group.
  • the reaction medium is stirred and then distilled under reduced pressure 12OmL of ethyl acetate. Back at 23 ° C, 37g of zinc is charged. 74 g of acetic acid are then poured while maintaining the temperature at 25 ⁇ 2 ° C.
  • docetaxel trihydrate 4.33 g of docetaxel trihydrate are dissolved in 165.4 g of dichloromethane, 108.0 g of polysorbate 80 are added dropwise. It is distilled under a pressure of 84 mbar with a bath temperature of 38 ° C. After 5 hours 5 minutes of distillation, 101.2 g of docetaxel solute are obtained in the polysorbate containing 0.11% of dichloromethane and 0.35% of impurities.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Epoxy Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Processes Of Treating Macromolecular Substances (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

The invention relates to the solubilisation of docetaxel in an organic solvent, to the mixture thereof with polysorbate 80 and to the evaporation of the solvent.

Description

DISSOLUTION DIRECTE DU DOCETAXEL DANS UN SOLVANT DANS LE POLYSORBATE 80 DIRECT DISSOLUTION OF DOCETAXEL IN A SOLVENT IN POLYSORBATE 80
La présente invention concerne un nouveau procédé de préparation d'une solution du docétaxel" dans le polysorbate 80.The present invention relates to a novel process for preparing a solution of docetaxel " in polysorbate 80.
Elle concerne, selon un premier moyen de mettre en œuvre l'invention, plus particulièrement la solubilisation du docétaxel dans un solvant organique, son mélange avec le polysorbate 80 et l' évaporation du solvant.It relates, according to a first means of implementing the invention, more particularly the solubilization of docetaxel in an organic solvent, its mixture with polysorbate 80 and the evaporation of the solvent.
La solubilisation du docétaxel directe dans le polysorbate même si elle est possible est une étape difficile. Elle exige des systèmes d'agitation extrêmement performants ou une augmentation de la température nuisible au principe actif. Jusqu'à ce jour les solutions de docétaxel dans le polysorbate 80 ont été réalisées par un procédé en trois étapes, la première constituant la dissolution du docétaxel dans l'éthanol, suivie du mélange avec le polysorbate puis enfin de l' évaporation de l'éthanol.Solubilization of direct docetaxel in polysorbate even if it is possible is a difficult step. It requires high performance stirring systems or an increase in temperature harmful to the active ingredient. To date, the docetaxel solutions in polysorbate 80 have been produced by a three-step process, the first one constituting the dissolution of docetaxel in ethanol, followed by mixing with the polysorbate and then finally evaporation of the ethanol.
Il est apparu que l'éthanol utilisé dans la formulation finale de la composition commerciale contenant le docétaxel n'était pas le seul solvant utilisable dans le cadre de la présente invention. Ainsi de nombreux solvants capables de solubilliser le docétaxel et miscible en toutes proportions avec le polysorbate sont utilisables. On peut ainsi utiliser les solvants présentant un point d'ébullition compris entre 40 et 153°C à la pression atmosphérique parmi ces solvants on peut citer les chloroalkanes et notamment le dichlorométhane, le chloroforme, les amides tels que le diméthylformamide, le diméthylacétamide, les esters tels que l'acétate d'éthyle, les cétones telles que l'acétone, la méthylisobutylcétone, les nitriles tels que l' acétonitrile . Les solvants préférés sont choisis parmi l'acétone, l' acétonitrile, le chlorure de méthylène, le diméthylformamide. Le docétaxel utilisé comme matière première dans le cadre de la présente invention peut être un docétaxel amorphe ou un docétaxel cristallisé sous une forme quelconque tel qu'un acétonate, un alcoolate, un hydrate ou un cristal avec l' acétonitrile . Le procédé selon l'invention n'est pas limité à la dissolution de docétaxel sous forme solide dans un solvant suivi de l'addition de polysorbate et distillation du solvant mais peut aussi consister à utiliser la solution de docétaxel obtenue à la sortie d'une colonne de purification. Cette solution peut être une solution de docétaxel dans un solvant unique tel que l'acétate d'éthyle, l'acétone, le chlorure de méthylène, ou le tétrahydrofurane, mais peut aussi être une solution dans un mélange des solvants précédemment cités. Cette colonne est généralement constituée d'une colonne de silice mais tout autre matériau permettant la purification est utilisable. Nous préférons dans le cadre de la présente invention utiliser une silice et notamment une silice vendue sous la marque Lichrospher. On utillise de façon tout à fait préférentielle une silice Lichrospher présentant un diamètre de particules de 12μm.It has been found that the ethanol used in the final formulation of the commercial composition containing docetaxel is not the only solvent usable in the context of the present invention. Thus, many solvents capable of solubilizing docetaxel and miscible in all proportions with polysorbate are usable. It is thus possible to use solvents having a boiling point of between 40 and 153 ° C. at atmospheric pressure, among these solvents, mention may be made of chloroalkanes and in particular dichloromethane, chloroform, amides such as dimethylformamide, dimethylacetamide, esters such ethyl acetate, ketones such as acetone, methyl isobutyl ketone, nitriles such as acetonitrile. The preferred solvents are selected from acetone, acetonitrile, methylene chloride, dimethylformamide. The docetaxel used as raw material in the context of the present invention may be an amorphous docetaxel or a crystallized docetaxel in any form such as an acetonate, an alcoholate, a hydrate or a crystal with acetonitrile. The process according to the invention is not limited to the dissolution of docetaxel in solid form in a solvent followed by the addition of polysorbate and distillation of the solvent but may also consist in using the docetaxel solution obtained at the outlet of a purification column. This solution may be a solution of docetaxel in a single solvent such as ethyl acetate, acetone, methylene chloride, or tetrahydrofuran, but may also be a solution in a mixture of the solvents mentioned above. This column is usually made of a silica column but any other material for purification is usable. We prefer in the context of the present invention to use a silica and in particular a silica sold under the trade name Lichrospher. A Lichrospher silica with a particle diameter of 12 μm is most preferably used.
La solution de docétaxel à purifier est de préférence une solution de docétaxel dans l'acétate d'éthyle ou dans un mélange d'acécate d'éthyle avec un hydrocarbure tel que le cyclohexane, les hexanes ou le toluène. La solution issu de la colonne de purification, si le docétaxel contenu a la pureté requise, pourra être mélangée directement avec le polysorbate puis le (s) solvant (s) évaporé (s) sans étape intermédiaire de cristallisation de docétaxel sous une forme solvate quelconque. Cela présente un avantage considérable du point de vue économique.The docetaxel solution to be purified is preferably a solution of docetaxel in ethyl acetate or a mixture of ethyl acecate with a hydrocarbon such as cyclohexane, hexanes or toluene. The solution from the purification column, if the docetaxel content has the required purity, can be mixed directly with the polysorbate and the solvent (s) evaporated (s) without intermediate step of crystallization of docetaxel in any solvate form. This presents a considerable advantage from the economic point of view.
La présente invention sera plus complètement décrite à l'aide des exemples suivants qui ne doivent pas être considérés comme limitatifs de l'invention.The present invention will be more fully described with the aid of the following examples which should not be considered as limiting the invention.
EXEMPLE 1 (FTA 152)EXAMPLE 1 (FTA 152)
On dissout 4,3320 g de docétaxel trihydrate dans 37,9g d'éthanol absolu, on ajoute 108,0g de polysorbate 80 au goutte à goutte, une mousse importante apparaît. On distille sous une pression de 50 mbars avec une température de bain de 400C. Après 4 heures et 10 minutes de distillation on obtient 33,9 g de distillât et 167,8 g (à vérifier) de soluté de docétaxel dans le polysorbate contenant moins de 0.01% d'éthanol et 0.28% d'impuretés.4.3320 g of docetaxel trihydrate are dissolved in 37.9 g of absolute ethanol, 108.0 g of polysorbate 80 are added dropwise, and a large foam appears. It is distilled under a pressure of 50 mbar with a bath temperature of 40 ° C. After 4 hours and 10 minutes of distillation, 33.9 g of distillate and 167.8 g (to be verified) of docetaxel solution in polysorbate are obtained. containing less than 0.01% ethanol and 0.28% impurities.
EXEMPLE 2 (FTA 153)EXAMPLE 2 (FTA 153)
On dissout 4 ,2017 g de docétaxel sous forme de solvate acetonitrile dans 533ml d' acétonitrile (419,2g), on ajoute 108,0ml de polysorbate 80 au goutte à goutte. On distille sous une pression moyenne de 55mPa avec une température de bain de 400C. Après 6 heures 25 minutes de distillation on otient 99,2 g de soluté de docétaxel dans le polysorbate contenant 0.06% d' acétonitrile et 0.41% d'impuretés. Le solvat acétonitrile est préparé de la façon suivante :4, 2017 g of docetaxel in the form of solvate acetonitrile are dissolved in 533 ml of acetonitrile (419.2 g), 108.0 ml of polysorbate 80 are added dropwise. It is distilled at an average pressure of 55 mPa with a bath temperature of 40 ° C. After 6 hours 25 minutes of distillation, 99.2 g of docetaxel solute are contained in the polysorbate containing 0.06% of acetonitrile and 0.41% of impurities. . The acetonitrile solvate is prepared as follows:
Le procédé consiste en la déprotection (détrocage) du docétaxel diprotégé en prosition 7 et 10 pour donner du docétaxel qui est isolé par cristallisation dans un mélange toluène / acétonitrile. Dans un réacteur d' IL, on charge : 90OmL d'acétate d'éthyle, 7 , 8mg de 4-méthoxyphénol et 78g de docétaxel di protégé par un groupe trichlroethoxycarbonyle . Le milieu réactionnel est mis sous agitation puis on distille sous pression réduite 12OmL d'acétate d'éthyle. De retour à 23°C, on charge 37g de zinc. On coule alors 74g d'acide acétique en maintenant la température à 25±2°C. Cette coulée dure Ihl5. On maintien l'agitation pendant Ihl5, temps au bout duquel la réaction est complète. On filtre le milieu réactionnel sous azote (gâteau de zinc) et on lave le gâteau trois fois par de l'acétate d'éthyle. On rassemble les jus mères et les jus de lavages puis on les lave à l'eau puis avec une solution aqueuse de bicarbonate de sodium. On charge sur la phase organique une solution de 7 , 2mg de 4-méthoxyphénol dans 2mL d'acétate d'éthyle, puis on lave à l'eau. On effectue ensuite un changement de solvant vers l' acétonitrile . En fin de changement de solvant, la température est ramenée à 25°C puis on coule en 2h 113mL de toluène. On maintient l'agitation à cette température pendant la nuit puis on refroidit le milieu réaction à O0C en 3h. On filtre la bouillie obtenue à 00C. Le gâteau est rincé par du toluène froid.The method consists in the deprotection (detaching) of the docetaxel diprotected in prosition 7 and 10 to give docetaxel which is isolated by crystallization in a toluene / acetonitrile mixture. In an IL reactor, 90OmL of ethyl acetate, 7.8 mg of 4-methoxyphenol and 78 g of docetaxel di were charged. protected by a trichlroethoxycarbonyl group. The reaction medium is stirred and then distilled under reduced pressure 12OmL of ethyl acetate. Back at 23 ° C, 37g of zinc is charged. 74 g of acetic acid are then poured while maintaining the temperature at 25 ± 2 ° C. This casting lasts Ihl5. Stirring is maintained for 1.5 h, at which time the reaction is complete. The reaction medium is filtered under nitrogen (zinc cake) and the cake is washed three times with ethyl acetate. The mother liquors and the washings are pooled and then washed with water and then with an aqueous solution of sodium bicarbonate. The organic phase is charged with a solution of 7.2 mg of 4-methoxyphenol in 2 ml of ethyl acetate and then washed with water. The solvent is then changed to acetonitrile. At the end of the change of solvent, the temperature is reduced to 25 ° C. and 113 ml of toluene are then poured in. Stirring is maintained at this temperature overnight and then the reaction medium is cooled to 0 ° C. over 3 hours. The slurry obtained is filtered at 0 ° C. The cake is rinsed with cold toluene.
Le gâteau ainsi obtenu est séché à l'étuve à poids constant (27h) . On obtient ainsi 51,7g d'une poudre blanche.The cake thus obtained is dried in an oven at constant weight (27h). 51.7 g of a white powder are thus obtained.
Somme des impuretés% 0,73 Sum of impurities% 0.73
EXEMPLE 3 (FTA 154)EXAMPLE 3 (FTA 154)
On dissout 4,3324 g de docetaxel sous forme de trihydrate dans 85 g de diméthylformamide (), on ajoute 108,0g de polysorbate 80 au goutte à goutte. On distille sous une pression de 48 mPa avec une température de bain de 670C. Après 6 heures 15 minutes de distillation on obtient 106,1 g de (à vérifier) de soluté de docetaxel dans le polysorbate contenant 0.01% de diméthylformamide et 0.43% d' impuretés . EXEMPLE 4 (FTA 155)4.334 g of docetaxel in the form of trihydrate are dissolved in 85 g of dimethylformamide (), 108.0 g of polysorbate 80 are added dropwise. It is distilled under a pressure of 48 mPa with a bath temperature of 67 ° C. After 6 hours 15 minutes of distillation, 106.1 g of (to be verified) of solution of docetaxel in polysorbate containing 0.01% dimethylformamide and 0.43% are obtained. % of impurities. EXAMPLE 4 (FTA 155)
On dissout 4,1792 g de docetaxel sous forme d'acétonate dans 21ml d'acétone, on ajoute 108,0 g de polysorbate 80 au goutte à goutte. On distille sous une pression de 46mbars avec une température de bain de 380C. Après 4 heures 45 minutes de distillation on obtient 99,7 g de soluté de docetaxel dans le polysorbate contenant 0.01% d'acétone et 0.34% d'impuretés.4,1792 g of docetaxel in the form of acetonate are dissolved in 21 ml of acetone, 108.0 g of polysorbate 80 are added dropwise. It is distilled under a pressure of 46mbars with a bath temperature of 38 ° C. After 4 hours 45 minutes of distillation, 99.7 g of docetaxel solute are obtained in the polysorbate containing 0.01% of acetone and 0.34% of impurities.
EXEMPLE 5 (FTA 156)EXAMPLE 5 (FTA 156)
On dissout 4,33 g de docetaxel trihydrate dans 165,4 g de dichlorométhane, on ajoute 108,0 g de polysorbate 80 au goutte à goutte. On distille sous une pression de 84mbars avec une température de bain de 380C. Après 5 heures 5 minutes de distillation on obtient 101,2 g de soluté de docetaxel dans le polysorbate contenant 0.11% de dichlorométhane et 0.35% d'impuretés.4.33 g of docetaxel trihydrate are dissolved in 165.4 g of dichloromethane, 108.0 g of polysorbate 80 are added dropwise. It is distilled under a pressure of 84 mbar with a bath temperature of 38 ° C. After 5 hours 5 minutes of distillation, 101.2 g of docetaxel solute are obtained in the polysorbate containing 0.11% of dichloromethane and 0.35% of impurities.
EXEMPLE 6 (FTA 151)EXAMPLE 6 (FTA 151)
On mélange 148,1 g de docetaxel issu de la purification sur colonne de silice et dissout dans de l'acétate d'éthyle à une concentration de 2,7 % en poids/poids, on ajoute 108,2 g de polysorbate 80 au goutte à goutte. On distille sous une pression de 55mbars avec une température de bain de 4O0C. Après 3 heures 15 minutes de distillation on obtient 95,1 g de soluté de docétaxel dans le polysorbate contenant 0.01% de dichlorométhane en poids et 0.64% d'impuretés. 148.1 g of docetaxel obtained from the purification on a silica column and dissolved in ethyl acetate at a concentration of 2.7% by weight / weight are mixed. 108.2 g of polysorbate 80 are added dropwise. It is distilled under a pressure of 55 mbar with a bath temperature of 40 ° C. After 3 hours 15 minutes of distillation 95.1 g of docetaxel solute are obtained in the polysorbate containing 0.01% of dichloromethane by weight and 0.64% of impurities. .

Claims

REVENDICATIONS
1/ Procédé de préparation de solution de docétaxel dans le polysorbate 80 caractérisé en ce que l'on dissout le docétaxel dans un solvant organique ayant un point d'ébullition compris entre 40 et 153°C à l'exclusion de l'éthanol, on mélange la solution obtenue avec le polysorbate 80 et on évapore sous pression réduite le solvant de dissolution. 2/ Procédé selon la revendication 1 caractérisé en ce que le docétaxel est sous forme cristalline.1 / A process for the preparation of docetaxel solution in polysorbate 80, characterized in that the docetaxel is dissolved in an organic solvent having a boiling point of between 40 and 153 ° C., excluding ethanol, the resulting solution is mixed with polysorbate 80 and the dissolution solvent is evaporated under reduced pressure. 2 / A method according to claim 1 characterized in that the docetaxel is in crystalline form.
3/ Procédé selon la revendication 2 caractérisé en ce que le docétaxel est sous forme de trihydrate, d'acétonate ou de solvate d' acétonitrile . 4/ Procédé selon la revendication 1 caractérisé en ce que le solvant de dissolution est choisi parmi l'acétone, 1' acétonitrile, le chlorure de méthylène ou le DMF. 3 / A method according to claim 2 characterized in that the docetaxel is in the form of trihydrate, acetonate or acetonitrile solvate. 4 / A method according to claim 1 characterized in that the dissolution solvent is selected from acetone, acetonitrile, methylene chloride or DMF.
EP08805654A 2007-06-08 2008-06-06 Direct dissolution of docetaxel in a solvent in polysorbate 80 Withdrawn EP2155189A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR0704095A FR2917088B1 (en) 2007-06-08 2007-06-08 DIRECT DISSOLUTION OF DOCETAXEL IN A SOLVENT IN POLYSORBATE 80
PCT/FR2008/000766 WO2009004188A2 (en) 2007-06-08 2008-06-06 Direct dissolution of docetaxel in a solvent in polysorbate 80

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CR11144A (en) 2010-03-23
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