WO1998057630A1 - Pharmaceutical form for administering paclitaxel, method for preparing a ready-for-use paclitaxel composition and thereof - Google Patents
Pharmaceutical form for administering paclitaxel, method for preparing a ready-for-use paclitaxel composition and thereof Download PDFInfo
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- WO1998057630A1 WO1998057630A1 PCT/BE1998/000078 BE9800078W WO9857630A1 WO 1998057630 A1 WO1998057630 A1 WO 1998057630A1 BE 9800078 W BE9800078 W BE 9800078W WO 9857630 A1 WO9857630 A1 WO 9857630A1
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- paclitaxel
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- 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
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- 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
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- 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
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- 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
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
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- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
Definitions
- the present invention relates to a pharmaceutical form for the administration of paclitaxel, to the preparation of a ready-to-use, stable composition of paclitaxel and to the use of the latter in the preparation of infusion liquids.
- Paclitaxel or taxol a well-known anti-leukemia and anti-tumor product, has the major drawback of having such a low solubility in water that it is necessary to prepare it in the form of an injectable formulation generally based on ethanol. .
- Etha ⁇ ol is the best solvent which makes it possible to dissolve paclitaxel and in general all products related to it.
- effective concentrations of active principle that is to say for example between about 0.3 and 1 mg / ml into the infusion liquid, it is necessary to use mixtures of two or more solvents to obtain a sufficiently effective solubilization of paclitaxel.
- Cremophors are condensation products of ethylene oxide and castor oil or hydrogenated castor oil. They are in fact complex mixtures of various hydrophobic and hydrophilic compounds. However, it has been found that the Cremophors combined with ethanol as a cosolvent, although they prove effective in solubilizing most pharmaceutical agents and in particular paclitaxel, produce compositions for injection which show some instability over extended periods of time.
- the object of the present invention is to remedy the aforementioned drawbacks by providing a pharmaceutical form for the administration of paclitaxel of an extremely simple design which does not require any particular adjustment or step of adjusting the complementary pH or else the presence of another product than the active ingredient and the solubilizing solvents.
- the pharmaceutical form comprises two separate vials, one of which contains an ethanolic solution of paclitaxel and the other of which contains an ethanolic solution of Cremophor EL, Cremophor EL-P or a mixture of these, the contents of these two vials being intended to be at least partially mixed with each other and to be added to the infusion liquid at the time of injection into the patient.
- the ethanolic solution of Cremophor is an ethanolic solution of Cremophor EL-P.
- the ethanolic solution of paclitaxel contains approximately 28 to
- Cremophor EL-P contains approximately 2.5 to 2.7 g and preferably 2.635 g of Cremophor EL-P for 4.0 ml of solute.
- the invention also relates to the preparation of a ready-to-use, stable, paclitaxel composition which consists in preparing two separate ethanolic solutions, one containing paclitaxel and the other of Cremophor EL, of Cremophor EL- P or a mixture thereof, and at least partially mixing these two solutions when said composition is used.
- the invention also relates to the infusion liquids prepared from the aforementioned paclitaxel composition.
- the pharmaceutical form for the administration of paclitaxel comprises a first vial containing an ethanolic solution of paclitaxel and a second vial containing an ethanolic solution of Cremophor EL, Cremophor EL-P or a mixture of those these, the contents of these two separate vials being intended to be mixed at least partially and preferably completely with one another and to be added to the infusion liquid at the time of injection into the patient.
- Cremophors are in fact complex mixtures of various hydrophobic and hydrophilic compounds.
- the hydrophobic constituents represent approximately 83% of the total mixture and their main constituent is polyethylene glycol glycerol ricinoleate, the hydrophilic constituents (approximately 17%) being polyethylene glycol and glycerol ethoxylate.
- Cremophor EL-P is in fact a purified variety of Cremophor EL complying in particular with the following severe requirements:
- Cremophor EL-P An ethanolic solution of Cremophor EL-P will advantageously be used as the ethanolic solution of Cremophor.
- Cremophor EL or possibly a mixture of Cremophors EL and EL-P.
- the ethanolic solution of paclitaxel contains approximately 28 to 32 mg of paclitaxel per 1.0 ml of solute and the ethanolic solution of Cremophor contains approximately 2.5 to 2.7 g of Cremophor per 4.0 ml of solute .
- absolute ethanol will be used for the ethanolic solutions of the two bottles.
- a ready-to-use, stable composition of paclitaxel two separate ethanolic solutions are prepared, one containing paclitaxel and the other of Cremophor EL, Cremophor EL-P or a mixture of these. ci and at least partially and advantageously totally mixing these two solutions at the time of use of the composition, that is to say at the time of adding it to the infusion liquid to be injected into the patient.
- the efficacy of paclitaxel will be the best when using Cremophor EL-P and absolute ethanol for the preparation of the two ethanolic solutions.
- the content of paclitaxel and the content of Cremophor will be the same as in the context of the ethanolic solutions of the two vials of the pharmaceutical form of the invention, that is to say that the ethanolic solution of paclitaxel will contain approximately 28 to 32 mg active ingredient for 1.0 ml of solute and the ethanolic solution of Cremophor will contain approximately 2.5 to 2.7 g of Cremophor (EL or EL-P) or mixture of Cremophors for 4.0 ml of solute.
- Liquid infusions prepared from ethanolic solutions preferably contain 0.3 to 1.2 mg of paclitaxel, 26 to 106 mg of Cremophor (EL, EL-P or their mixtures) and 19 to 79 mg of ethanol absolute per milliliter.
- paclitaxel retains all its activity and is in no case altered by the presence of the carboxylate anions of Cremophor.
- Paclitaxel treatment consists of several administration cycles separated by 3 weeks. An average dose of 300 mg of paclitaxel (dose calculated according to the body surface area of each patient) is administered during each cycle. In order to initiate easy treatment, vials containing 30, 100 and 200 mg of paclitaxel have been developed, as well as vials containing correspondingly necessary amounts of Cremophor and absolute ethanol.
- Example 2 Packaging of 100 mg of paclitaxel.
- the contents of the two vials are mixed and added to conventional infusion solutions such as 5% glucose solution, 0.9% sodium chloride solution or Ringer's solution.
- conventional infusion solutions such as 5% glucose solution, 0.9% sodium chloride solution or Ringer's solution.
- the final concentrations of the solutions thus obtained for the infusion can vary from 0.3 to 1.2 mg of paclitaxel per milliliter.
- the quantities of Cremophor EL-P and ethanol in the final infusion solutions are given below for two specific amounts of paclitaxel: a) Infusion solution containing 0.3 mg / ml of paclitaxel
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Abstract
Description
"Forme pharmaceutique pour l'administration de paclitaxel, procédé de préparation d'une composition de paclitaxel prête à l'emploi et utilisation de cette composition." "Pharmaceutical form for the administration of paclitaxel, process for the preparation of a ready-to-use composition of paclitaxel and use of this composition."
La présente invention est relative à une forme pharma- ceutique pour l'administration de paclitaxel, à la préparation d'une composition de paclitaxel prête à l'emploi, stable et à l'utilisation de cette dernière dans la préparation de liquides de perfusion.The present invention relates to a pharmaceutical form for the administration of paclitaxel, to the preparation of a ready-to-use, stable composition of paclitaxel and to the use of the latter in the preparation of infusion liquids.
Le paclitaxel ou taxol, produit antileucémique et antitumoral bien connu, présente l'inconvénient majeur d'avoir une solubilité dans l'eau tellement faible qu'il est nécessaire de le préparer sous la forme d'une formulation injectable généralement à base d'éthanol. L'éthaπol est le meilleur solvant qui permette de solubiliser le paclitaxel et d'une manière générale tous les produits apparentés à celui-ci. Toutefois, pour pouvoir injecter des concentrations en principe actif efficaces, c'est-à- dire comprises par exemple entre environ 0,3 et 1 mg/ml dans le liquide de perfusion, il est nécessaire d'utiliser des mélanges de deux ou plusieurs solvants pour obtenir une solubilisation du paclitaxel suffisamment efficace. C'est ainsi que l'on utilise des systèmes de solvants à base d'éthanol et de Cremophor, qui sert de solubilisant non ionique. Les Cremophors sont des produits de condensation d'oxyde d'éthylène et d'huile de ricin ou d'huile de ricin hydrogénée. Ce sont en fait des mélanges complexes de divers composés hydrophobes et hydrophiles. On a toutefois constaté que les Cremophors combinés à l'éthanol comme cosolvant, bien que s'avérant efficaces pour solubiliser la plupart des agents pharmaceutiques et notamment le paclitaxel, produisent des compositions pour injection qui montrent une certaine instabilité sur des périodes de temps prolongées. C'est ainsi qu'il a été montré que les formulations à base de paclitaxel dans un cosolvant de 50/50 en volume d'éthanol et de Cremophor EL montrent une baisse d'activité très sensible après une conservation de 3 à 4 mois à la température de 50°C. Cette baisse d'activité est attribuée à la décomposition du paclitaxel en cours de conservation. Un certain nombre de procédés ont été décrits dans la technique pour abaisser la teneur en anion carboxylate du cosolvant à un niveau suffisamment bas pour empêcher toute dégradation (catalysée par l'anion carboxylate) du paclitaxel mais ces procédés pour la plupart comportent une étape de traitement supplémentaire, par exemple par un ajustement du pH de la solution ou par la mise en contact préalable du Cremophor avec de l'oxyde d'aluminium pour réduire la teneur en anions carboxylate du cosolvant.Paclitaxel or taxol, a well-known anti-leukemia and anti-tumor product, has the major drawback of having such a low solubility in water that it is necessary to prepare it in the form of an injectable formulation generally based on ethanol. . Ethaπol is the best solvent which makes it possible to dissolve paclitaxel and in general all products related to it. However, in order to be able to inject effective concentrations of active principle, that is to say for example between about 0.3 and 1 mg / ml into the infusion liquid, it is necessary to use mixtures of two or more solvents to obtain a sufficiently effective solubilization of paclitaxel. This is how solvent systems based on ethanol and Cremophor, which serves as a nonionic solubilizer, are used. Cremophors are condensation products of ethylene oxide and castor oil or hydrogenated castor oil. They are in fact complex mixtures of various hydrophobic and hydrophilic compounds. However, it has been found that the Cremophors combined with ethanol as a cosolvent, although they prove effective in solubilizing most pharmaceutical agents and in particular paclitaxel, produce compositions for injection which show some instability over extended periods of time. It was thus shown that the formulations based on paclitaxel in a cosolvent of 50/50 by volume of ethanol and of Cremophor EL show a very significant drop in activity after a conservation of 3 to 4 months at the temperature of 50 ° C. This drop in activity is attributed to the breakdown of paclitaxel during storage. A number of methods have been described in the art for lowering the cosolvent anion carboxylate content to a level low enough to prevent any degradation (catalyzed by the carboxyl anion) of paclitaxel but these methods for the most part include a treatment step additional, for example by adjusting the pH of the solution or by placing Cremophor in contact with aluminum oxide beforehand in order to reduce the content of carboxylate anions in the cosolvent.
La présente invention a pour but de remédier aux inconvénients précités en prévoyant une forme pharmaceutique pour l'administration de paclitaxel d'une conception extrêmement simple qui ne nécessite aucune mise au point particulière ou étape d'ajustement de pH complémentaire ou encore la présence d'un autre produit que le principe actif et les solvants de solubilisation.The object of the present invention is to remedy the aforementioned drawbacks by providing a pharmaceutical form for the administration of paclitaxel of an extremely simple design which does not require any particular adjustment or step of adjusting the complementary pH or else the presence of another product than the active ingredient and the solubilizing solvents.
A cet effet, suivant l'invention, la forme pharmaceutique comprend deux flacons distincts dont l'un contient une solution éthanolique de paclitaxel et dont l'autre contient une solution éthanolique de Cremophor EL, de Cremophor EL-P ou d'un mélange de ceux-ci, les contenus de ces deux flacons étant destinés à être mélangés au moins partiellement l'un à l'autre et à être ajoutés au liquide de perfusion au moment de l'injection au patient.To this end, according to the invention, the pharmaceutical form comprises two separate vials, one of which contains an ethanolic solution of paclitaxel and the other of which contains an ethanolic solution of Cremophor EL, Cremophor EL-P or a mixture of these, the contents of these two vials being intended to be at least partially mixed with each other and to be added to the infusion liquid at the time of injection into the patient.
Avantageusement, la solution éthanolique de Cremophor est une solution éthanolique de Cremophor EL-P. Suivant une forme de réalisation avantageuse de l'invention, la solution éthanolique de paclitaxel contient environ 28 àAdvantageously, the ethanolic solution of Cremophor is an ethanolic solution of Cremophor EL-P. According to an advantageous embodiment of the invention, the ethanolic solution of paclitaxel contains approximately 28 to
32 mg et de préférence 30 mg de paclitaxel pour 1 ,0 ml de soluté et la solution éthanolique de Cremophor EL-P contient environ 2,5 à 2,7 g et de préférence 2,635 g de Cremophor EL-P pour 4,0 ml de soluté.32 mg and preferably 30 mg of paclitaxel for 1.0 ml of solute and the ethanolic solution of Cremophor EL-P contains approximately 2.5 to 2.7 g and preferably 2.635 g of Cremophor EL-P for 4.0 ml of solute.
L'invention se rapporte également à la préparation d'une composition de paclitaxel prête à l'emploi, stable, qui consiste à préparer deux solutions éthanoliques séparées, l'une contenant du paclitaxel et l'autre du Cremophor EL, du Cremophor EL-P ou un mélange de ceux-ci, et à mélanger au moins partiellement ces deux solutions au moment de l'emploi de ladite composition.The invention also relates to the preparation of a ready-to-use, stable, paclitaxel composition which consists in preparing two separate ethanolic solutions, one containing paclitaxel and the other of Cremophor EL, of Cremophor EL- P or a mixture thereof, and at least partially mixing these two solutions when said composition is used.
L'invention concerne encore les liquides de perfusion préparés au départ de la composition de paclitaxel précitée.The invention also relates to the infusion liquids prepared from the aforementioned paclitaxel composition.
Comme on vient de le préciser, la forme pharmaceutique pour l'administration de paclitaxel comprend un premier flacon contenant une solution éthanolique de paclitaxel et un second flacon contenant une solution éthanolique de Cremophor EL, de Cremophor EL-P ou d'un mélange de ceux-ci, les contenus de ces deux flacons distincts étant destinés à être mélangés au moins partiellement et de préférence totalement l'un à l'autre et à être ajoutés au liquide de perfusion au moment de l'injection au patient.As has just been specified, the pharmaceutical form for the administration of paclitaxel comprises a first vial containing an ethanolic solution of paclitaxel and a second vial containing an ethanolic solution of Cremophor EL, Cremophor EL-P or a mixture of those these, the contents of these two separate vials being intended to be mixed at least partially and preferably completely with one another and to be added to the infusion liquid at the time of injection into the patient.
Comme on l'a déjà précisé et ainsi que cela est bien connu, les Cremophors sont en fait des mélanges complexes de divers composés hydrophobes et hydrophiles. Dans le Cremophor EL, les constituants hydrophobes représentent environ 83 % du mélange total et leur constituant principal est le ricinoléate de polyéthylène glycol glycerolé, les constituants hydrophiles (environ 17 %) étant du polyéthylène glycol et de l'éthoxylate de glycérol. Le Cremophor EL-P est en fait une variété purifiée de Cremophor EL se conformant notamment aux exigences sévères suivantes :As already stated and as is well known, Cremophors are in fact complex mixtures of various hydrophobic and hydrophilic compounds. In Cremophor EL, the hydrophobic constituents represent approximately 83% of the total mixture and their main constituent is polyethylene glycol glycerol ricinoleate, the hydrophilic constituents (approximately 17%) being polyethylene glycol and glycerol ethoxylate. Cremophor EL-P is in fact a purified variety of Cremophor EL complying in particular with the following severe requirements:
- teneur en eau : maximum 0,5 % - teneur en potassium : maximum 5 ppm- water content: maximum 0.5% - potassium content: maximum 5 ppm
- indice d'acide : maximum 0,3- acid number: maximum 0.3
- teneur en sodium : maximum 10 ppm- sodium content: maximum 10 ppm
- teneur en acides gras libres (Cι2-Cι8) : maximum 1 ,0 %- free fatty acid content (Cι 2 -Cι 8 ): maximum 1.0%
- teneur en acide ricinoléique : maximum 0,2 % - teneur en acide oléique : maximum 0,1 %- ricinoleic acid content: maximum 0.2% - oleic acid content: maximum 0.1%
- teneur en acide palmitique : maximum 0,1 %- palmitic acid content: maximum 0.1%
- propreté microbienne : maximum 100 CFU/g.- microbial cleanliness: maximum 100 CFU / g.
On utilisera avantageusement comme solution éthanolique de Cremophor une solution éthanolique de Cremophor EL-P. On pourrait bien entendu également envisager, comme on vient de le dire, l'utilisation de Cremophor EL ou éventuellement un mélange de Cremophors EL et EL-P.An ethanolic solution of Cremophor EL-P will advantageously be used as the ethanolic solution of Cremophor. One could of course also envisage, as we have just said, the use of Cremophor EL or possibly a mixture of Cremophors EL and EL-P.
Suivant l'invention, la solution éthanolique de paclitaxel contient environ 28 à 32 mg de paclitaxel pour 1 ,0 ml de soluté et la solution éthanolique de Cremophor contient environ 2,5 à 2,7 g de Cremophor pour 4,0 ml de soluté. On utilisera de préférence de l'éthanol absolu pour les solutions éthanoliques des deux flacons.According to the invention, the ethanolic solution of paclitaxel contains approximately 28 to 32 mg of paclitaxel per 1.0 ml of solute and the ethanolic solution of Cremophor contains approximately 2.5 to 2.7 g of Cremophor per 4.0 ml of solute . Preferably, absolute ethanol will be used for the ethanolic solutions of the two bottles.
Pour préparer suivant l'invention une composition de paclitaxel prête à l'emploi, stable, on prépare deux solutions éthanoliques séparées, l'une contenant du paclitaxel et l'autre du Cremophor EL, du Cremophor EL-P ou un mélange de ceux-ci et on mélange au moins partiellement et avantageusement totalement ces deux solutions au moment de l'emploi de la composition, c'est-à-dire au moment de l'ajouter au liquide de perfusion à injecter au patient. Bien entendu, comme dans le cadre de la forme pharmaceutique de l'invention, l'efficacité du paclitaxel sera la meilleure lorsque l'on utilisera le Cremophor EL-P et l'éthanol absolu pour la préparation des deux solutions éthanoliques. La teneur en paclitaxel et la teneur en Cremophor seront les mêmes que dans le cadre des solutions éthanoliques des deux flacons de la forme pharmaceutique de l'invention, c'est-à-dire que la solution éthanolique de paclitaxel contiendra environ 28 à 32 mg de principe actif pour 1 ,0 ml de soluté et la solution éthanolique de Cremophor contiendra environ 2,5 à 2,7 g de Cremophor (EL ou EL-P) ou mélange de Cremophors pour 4,0 ml de soluté.To prepare according to the invention a ready-to-use, stable composition of paclitaxel, two separate ethanolic solutions are prepared, one containing paclitaxel and the other of Cremophor EL, Cremophor EL-P or a mixture of these. ci and at least partially and advantageously totally mixing these two solutions at the time of use of the composition, that is to say at the time of adding it to the infusion liquid to be injected into the patient. Of course, as in the pharmaceutical form of the invention, the efficacy of paclitaxel will be the best when using Cremophor EL-P and absolute ethanol for the preparation of the two ethanolic solutions. The content of paclitaxel and the content of Cremophor will be the same as in the context of the ethanolic solutions of the two vials of the pharmaceutical form of the invention, that is to say that the ethanolic solution of paclitaxel will contain approximately 28 to 32 mg active ingredient for 1.0 ml of solute and the ethanolic solution of Cremophor will contain approximately 2.5 to 2.7 g of Cremophor (EL or EL-P) or mixture of Cremophors for 4.0 ml of solute.
Les perfusions de liquide préparées à partir des solutions éthanoliques contiennent préférentiellement de 0,3 à 1 ,2 mg de paclitaxel, de 26 à 106 mg de Cremophor (EL, EL-P ou leurs mélanges) et de 19 à 79 mg d'éthanol absolu par millilitre. Le mélange des solutions éthanoliques se faisant au moment ou juste avant l'injection au patient, le paclitaxel conserve toute son activité et n'est en aucun cas altéré par la présence des anions carboxylate du Cremophor. On n'observe pas non plus avec ces solutions les phénomènes de chocs anaphylactiques ou d'éthylisme que l'on observait avec certaines solutions connues de la technique.Liquid infusions prepared from ethanolic solutions preferably contain 0.3 to 1.2 mg of paclitaxel, 26 to 106 mg of Cremophor (EL, EL-P or their mixtures) and 19 to 79 mg of ethanol absolute per milliliter. The mixing of the ethanolic solutions being done at the moment or just before the injection to the patient, paclitaxel retains all its activity and is in no case altered by the presence of the carboxylate anions of Cremophor. We also do not observe with these solutions the phenomena of anaphylactic shock or ethylism that we observed with certain solutions known in the art.
On donne ci-après des exemples non limitatifs de la forme pharmaceutique suivant l'invention.Non-limiting examples of the pharmaceutical form according to the invention are given below.
Le traitement au paclitaxel consiste en plusieurs cycles d'administration séparés par 3 semaines. Une dose moyenne de 300 mg de paclitaxel (dose calculée en fonction de la surface corporelle de chaque patient) est administrée lors de chaque cycle. Afin d'instaurer un traitement aisé, des flacons contenant 30, 100 et 200 mg de paclitaxel ont été mis au point, ainsi que des flacons contenant des quantités nécessaires correspondantes de Cremophor et d'éthanol absolu. EXEMPLESPaclitaxel treatment consists of several administration cycles separated by 3 weeks. An average dose of 300 mg of paclitaxel (dose calculated according to the body surface area of each patient) is administered during each cycle. In order to initiate easy treatment, vials containing 30, 100 and 200 mg of paclitaxel have been developed, as well as vials containing correspondingly necessary amounts of Cremophor and absolute ethanol. EXAMPLES
Forme pharmaceutique présentée sous forme de deux flacons Exemple 1 : Conditionnement de 30 mg de paclitaxel. Flacon I : • Paclitaxel : 30 mgPharmaceutical form presented in the form of two vials Example 1: Packaging of 30 mg of paclitaxel. Bottle I: • Paclitaxel: 30 mg
• Ethanol absolu : quantité suffisante pour obtenir 1 ,0 ml Flacon II :• Absolute ethanol: sufficient quantity to obtain 1.0 ml Bottle II:
• Cremophor EL-P : 2,635 g• Cremophor EL-P: 2,635 g
• Ethanol absolu : quantité suffisante pour obtenir 4,0 ml. Exemple 2 : Conditionnement de 100 mg de paclitaxel.• Absolute ethanol: sufficient quantity to obtain 4.0 ml. Example 2: Packaging of 100 mg of paclitaxel.
Flacon IBottle I
• Paclitaxel : 100 mg• Paclitaxel: 100 mg
• Ethanol absolu : quantité suffisante pour obtenir 3,34 ml. Flacon II • Cremophor EL-P : 8,80 g• Absolute ethanol: sufficient quantity to obtain 3.34 ml. Bottle II • Cremophor EL-P: 8.80 g
• Ethanol absolu : quantité suffisante pour obtenir 13,36 ml. Exemple 3 : Conditionnement de 200 mg de paclitaxel. Flacon I :• Absolute ethanol: sufficient quantity to obtain 13.36 ml. Example 3: Packaging of 200 mg of paclitaxel. Bottle I:
• Paclitaxel : 200 mg • Ethanol absolu : quantité suffisante pour obtenir 6,67 ml Flacon II :• Paclitaxel: 200 mg • Absolute ethanol: sufficient quantity to obtain 6.67 ml Bottle II:
• Cremophor EL-P : 17,60 g• Cremophor EL-P: 17.60 g
• Ethanol absolu : quantité suffisante pour obtenir 26,70 ml.• Absolute ethanol: sufficient quantity to obtain 26.70 ml.
Au moment de l'emploi, les contenus des deux flacons sont mélangés et ajoutés à des solutions de perfusion classiques telles qu'une solution de glucose à 5 %, une solution de chlorure sodique à 0,9 % ou encore une solution de Ringer. Les concentrations finales des solutions ainsi obtenues pour la perfusion peuvent varier de 0,3 à 1 ,2 mg de paclitaxel par millilitre. On donne ci-après pour deux quantités spécifiques de paclitaxel les quantités de Cremophor EL-P et d'éthanol dans les solutions finales de perfusion : a) Solution de perfusion à 0,3 mg/ml de paclitaxelAt the time of use, the contents of the two vials are mixed and added to conventional infusion solutions such as 5% glucose solution, 0.9% sodium chloride solution or Ringer's solution. The final concentrations of the solutions thus obtained for the infusion can vary from 0.3 to 1.2 mg of paclitaxel per milliliter. The quantities of Cremophor EL-P and ethanol in the final infusion solutions are given below for two specific amounts of paclitaxel: a) Infusion solution containing 0.3 mg / ml of paclitaxel
- Paclitaxel 0,3 mg/ml- Paclitaxel 0.3 mg / ml
- Cremophor EL-P 26,35 mg/ml- Cremophor EL-P 26.35 mg / ml
- Ethanol absolu 19,70 mg/ml- Absolute ethanol 19.70 mg / ml
- Liquide de perfusion quantité suffisante pour obtenir 1 ,0 ml b) Solution de perfusion à 1 ,2 mg/ ml de paclitaxel- Infusion liquid sufficient to obtain 1.0 ml b) 1.2 mg / ml infusion solution of paclitaxel
-- P Paacclliittaaxxeell 1 ,2 mg/ml- P Paacclliittaaxxeell 1, 2 mg / ml
- Cremophor EL-P 105,4 mg/ml- Cremophor EL-P 105.4 mg / ml
- Ethanol absolu 78,80 mg/ml- Absolute ethanol 78.80 mg / ml
- Liquide de perfusion quantité suffisante pour obtenir 1 ,0 ml.- Infusion liquid sufficient to obtain 1.0 ml.
Comme on le notera, à condition d'utiliser un Cremophor EL adéquat, la présentation en deux flacons séparés, à mélanger au moment de l'emploi est un gage de meilleure stabilité du principe actif puisqu'on réduit au maximum le temps de contact entre celui-ci et l'agent dégradant. As will be noted, provided that an adequate Cremophor EL is used, the presentation in two separate vials, to be mixed at the time of use, is a guarantee of better stability of the active ingredient since the contact time between this and the degrading agent.
Claims
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU76321/98A AU7632198A (en) | 1997-06-13 | 1998-06-02 | Pharmaceutical form for administering paclitaxel, method for preparing a ready-for-use paclitaxel composition and thereof |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| BE9700515A BE1011216A3 (en) | 1997-06-13 | 1997-06-13 | Pharmaceutical form for the administration of paclitaxel, method of preparation of a composition paclitaxel ready to employment and use thereof. |
| BE9700515 | 1997-06-13 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1998057630A1 true WO1998057630A1 (en) | 1998-12-23 |
Family
ID=3890575
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/BE1998/000078 Ceased WO1998057630A1 (en) | 1997-06-13 | 1998-06-02 | Pharmaceutical form for administering paclitaxel, method for preparing a ready-for-use paclitaxel composition and thereof |
Country Status (5)
| Country | Link |
|---|---|
| AR (1) | AR012972A1 (en) |
| AU (1) | AU7632198A (en) |
| BE (1) | BE1011216A3 (en) |
| WO (1) | WO1998057630A1 (en) |
| ZA (1) | ZA984832B (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1221908A4 (en) * | 1995-10-26 | 2002-10-09 | Baker Norton Pharma | Oral pharmaceutical compositions containing taxanes and methods of treatment employing the same |
| EP1498143A1 (en) * | 2003-07-18 | 2005-01-19 | Aventis Pharma S.A. | Self-emulsifying and self-microemulsifying formulations for the oral administration of taxoids |
| WO2005017079A1 (en) * | 2003-07-24 | 2005-02-24 | Dabur Research Foundation | Process for the purification of non-ionic solvants for stabilized injectable pharmaceutical formulaitons |
| WO2006111085A1 (en) * | 2005-04-19 | 2006-10-26 | Shanghai Tianbo Biotechnology Co., Ltd. | A method, formulation and use thereor with improved oral absorption of drugs or nutrients |
| US7169819B2 (en) | 2000-12-05 | 2007-01-30 | Childrens Hospital Los Angeles | Pharmaceutical compositions of fenretinide having increased bioavailability and methods of using the same |
| US7699987B2 (en) | 2003-07-24 | 2010-04-20 | Dabur Pharma Ltd. | Stabilized formulation |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0253738A1 (en) * | 1986-07-17 | 1988-01-20 | Rhone-Poulenc Sante | Taxol derivatives, their preparation and pharmaceutical compositions containing them |
| US4960790A (en) * | 1989-03-09 | 1990-10-02 | University Of Kansas | Derivatives of taxol, pharmaceutical compositions thereof and methods for the preparation thereof |
| EP0522937A1 (en) * | 1991-07-08 | 1993-01-13 | Aventis Pharma S.A. | Taxane derivatives containing compositions |
| WO1994012198A1 (en) * | 1992-11-27 | 1994-06-09 | F.H. Faulding & Co. Limited | Injectable taxol composition |
| WO1994012030A1 (en) * | 1992-11-27 | 1994-06-09 | Napro Biotherapeutics, Inc. | Injectable composition |
| WO1994012171A1 (en) * | 1992-12-02 | 1994-06-09 | Rhone-Poulenc Rorer S.A. | Injectable taxane derivative based compositions |
| EP0645145A2 (en) * | 1993-09-29 | 1995-03-29 | Bristol-Myers Squibb Company | Stabilized pharmaceutical composition and stabilizing solvent |
| WO1996029070A1 (en) * | 1995-03-17 | 1996-09-26 | The Board Of Regents, The University Of Texas System | Extended stability formulations for paclitaxel |
-
1997
- 1997-06-13 BE BE9700515A patent/BE1011216A3/en not_active IP Right Cessation
-
1998
- 1998-06-02 WO PCT/BE1998/000078 patent/WO1998057630A1/en not_active Ceased
- 1998-06-02 AU AU76321/98A patent/AU7632198A/en not_active Abandoned
- 1998-06-04 ZA ZA984832A patent/ZA984832B/en unknown
- 1998-06-11 AR ARP980102786A patent/AR012972A1/en unknown
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0253738A1 (en) * | 1986-07-17 | 1988-01-20 | Rhone-Poulenc Sante | Taxol derivatives, their preparation and pharmaceutical compositions containing them |
| US4960790A (en) * | 1989-03-09 | 1990-10-02 | University Of Kansas | Derivatives of taxol, pharmaceutical compositions thereof and methods for the preparation thereof |
| EP0522937A1 (en) * | 1991-07-08 | 1993-01-13 | Aventis Pharma S.A. | Taxane derivatives containing compositions |
| EP0522936A1 (en) * | 1991-07-08 | 1993-01-13 | Aventis Pharma S.A. | Taxane derivatives containing compositions |
| WO1994012198A1 (en) * | 1992-11-27 | 1994-06-09 | F.H. Faulding & Co. Limited | Injectable taxol composition |
| WO1994012030A1 (en) * | 1992-11-27 | 1994-06-09 | Napro Biotherapeutics, Inc. | Injectable composition |
| WO1994012171A1 (en) * | 1992-12-02 | 1994-06-09 | Rhone-Poulenc Rorer S.A. | Injectable taxane derivative based compositions |
| EP0645145A2 (en) * | 1993-09-29 | 1995-03-29 | Bristol-Myers Squibb Company | Stabilized pharmaceutical composition and stabilizing solvent |
| WO1996029070A1 (en) * | 1995-03-17 | 1996-09-26 | The Board Of Regents, The University Of Texas System | Extended stability formulations for paclitaxel |
Non-Patent Citations (3)
| Title |
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| B.D.TARR ET AL.: "A NEW PARENTERAL VEHICLE FOR THE ADMINISTRATION OF SOME POORLY SOLUBLE ANTI-CANCER DRUGS", J. PARENTER. SCI. TECHNOL., vol. 41, no. 1, 1987, pages 31 - 33 * |
| CHEMICAL ABSTRACTS, vol. 106, no. 22, 1 June 1987, Columbus, Ohio, US; abstract no. 182581c, XP002054344 * |
| E.K.ROWINSKY ET AL.: "TAXOL: A NOVEL INVESTIGATIONAL ANTIMICROTUBULE AGENT", JOURNAL OF THE NATIONAL CANCER INSTITUTE, vol. 82, no. 15, 1 August 1990 (1990-08-01), pages 1247 - 1259, XP002054343 * |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1221908A4 (en) * | 1995-10-26 | 2002-10-09 | Baker Norton Pharma | Oral pharmaceutical compositions containing taxanes and methods of treatment employing the same |
| US6964946B1 (en) | 1995-10-26 | 2005-11-15 | Baker Norton Pharmaceuticals, Inc. | Oral pharmaceutical compositions containing taxanes and methods of treatment employing the same |
| US7169819B2 (en) | 2000-12-05 | 2007-01-30 | Childrens Hospital Los Angeles | Pharmaceutical compositions of fenretinide having increased bioavailability and methods of using the same |
| EP1498143A1 (en) * | 2003-07-18 | 2005-01-19 | Aventis Pharma S.A. | Self-emulsifying and self-microemulsifying formulations for the oral administration of taxoids |
| WO2005014048A1 (en) * | 2003-07-18 | 2005-02-17 | Aventis Pharma S.A. | Self-emulsifying and self-microemulsifying formulations for the oral administration of taxoids |
| WO2005017079A1 (en) * | 2003-07-24 | 2005-02-24 | Dabur Research Foundation | Process for the purification of non-ionic solvants for stabilized injectable pharmaceutical formulaitons |
| US7699987B2 (en) | 2003-07-24 | 2010-04-20 | Dabur Pharma Ltd. | Stabilized formulation |
| WO2006111085A1 (en) * | 2005-04-19 | 2006-10-26 | Shanghai Tianbo Biotechnology Co., Ltd. | A method, formulation and use thereor with improved oral absorption of drugs or nutrients |
Also Published As
| Publication number | Publication date |
|---|---|
| BE1011216A3 (en) | 1999-06-01 |
| ZA984832B (en) | 1999-01-04 |
| AR012972A1 (en) | 2000-11-22 |
| AU7632198A (en) | 1999-01-04 |
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