WO2000016770A1 - Preparation pharmaceutique contenant du taxane et procede de preparation d'une telle composition - Google Patents

Preparation pharmaceutique contenant du taxane et procede de preparation d'une telle composition Download PDF

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Publication number
WO2000016770A1
WO2000016770A1 PCT/EP1999/007059 EP9907059W WO0016770A1 WO 2000016770 A1 WO2000016770 A1 WO 2000016770A1 EP 9907059 W EP9907059 W EP 9907059W WO 0016770 A1 WO0016770 A1 WO 0016770A1
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Prior art keywords
pharmaceutical preparation
taxanes
fatty acids
taxane
triglycerides
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PCT/EP1999/007059
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German (de)
English (en)
Inventor
Hans Dietl
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Hans Dietl
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Publication date
Application filed by Hans Dietl filed Critical Hans Dietl
Priority to AU61948/99A priority Critical patent/AU6194899A/en
Publication of WO2000016770A1 publication Critical patent/WO2000016770A1/fr

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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

Definitions

  • the invention relates to a new taxane-containing pharmaceutical preparation, a manufacturing process for this pharmaceutical preparation and its use, in particular for intravenous administration.
  • Taxanes are anticancerogenic drugs that structurally have a taxane core that consists of a diterpene carbon skeleton (M. T. Huizing et al .: Cancer Investigation 13, pp. 381-404 (1995)).
  • paclitaxel Texol
  • docetaxel docetaxel
  • Taxanes such as B. Paclitaxel and Docetaxel are only poorly absorbed when administered orally and are therefore administered by intravenous infusion.
  • Taxanes are only slightly soluble in water. This leads to serious problems in the use of taxanes, since a simple water-soluble pharmaceutical preparation is not possible.
  • the pharmaceutical formulations used hitherto for the intravenous use of taxanes contain large amounts of nonionic emulsifiers such as, for example, B. polyoxyethylene castor oil, polysorbate and alcohol.
  • a commercially available formulation contains only 6 mg paclitaxel, but 520 mg, in one milliliter
  • Another pharmaceutical formulation contains in one
  • Emulsifier polysorbate 80 Emulsifier polysorbate 80.
  • the problems due to side effects of the non-ionic solvents used are even more serious. As these can cause severe anaphylactic shocks, premedication with corticosteroids, antibistamines and H2 ⁇ antagonists is necessary before use.
  • the solvents are also nephrotoxic, cell toxic and cardiotoxic. They also have an unfavorable influence on the pharmacokinetics and the distribution of taxanes in the organism. The solvents used probably even reduce the clinical effectiveness of the taxanes.
  • Paclitaxel dissolves in solvents such as ethanol, dimethyl sulfoxide or polyethylene glycol 400 (PEG 400). With the necessary dilution for infusion, however, the taxanes fail again both in the infusion solution and in the blood and also lose their effectiveness (JM Meerum Terwogt et al.: Canc. Treatment Rev. 23, 87-95 (1997), and JD Adam et al.: Monogr. Natl. Cancer Inst. 15, 141-147 (1993)).
  • solvents such as ethanol, dimethyl sulfoxide or polyethylene glycol 400 (PEG 400).
  • solubility of taxanes can be increased by complexation with cyclodextrins (U.S. Sharma et al.: Am. Chem. Soc. Am. Pharm. Ass. 84, 1223-1230 (1995)). However, the solutions become viscous and contain solid particles. In addition, the solubility is not high enough to administer a sufficient amount of active ingredient.
  • Liposomes are carrier systems that consist of one or more fat-like membranes that enclose an aqueous phase. These carrier systems can absorb fat-soluble substances in the membranes and thus enable intravenous use. Numerous liposomal dosage forms have been developed with taxanes, in particular paclitaxel (see: J. Meerum Terwogt et al.: Cancer Treatment Review 23, 83-87 (1997)).
  • liposomes are extremely sensitive to heat and heat. Therefore, they cannot be heat sterilized as required for infusion solutions. They are also unstable during storage. They can only be produced sterile in the necessary larger quantities with great effort. Therefore, none of the numerous liposomal forms developed has been developed to production maturity.
  • Micelles e.g. B. from bile salts and phospholipids were loaded with paclitaxel and then liposomes prepared therefrom. Such micelles are unstable, sterilization is difficult and large-scale production is very complicated.
  • fat emulsions In contrast to liposomes, fat emulsions consist of an oil-in-water emulsion, the 01 being surrounded by one or more emulsifiers for stabilization.
  • the type of preparation and the 01 used and the emulsifiers used are decisive for the quality of fat emulsions, since numerous emulsifiers, in particular the frequently used non-ionic emulsifiers, are toxic and, for fat emulsions, the size of the fat particles generally below 5 microns, the best should be less than 1.5 microns (PK Hansrani et al.: J. Parent. Sci. Technol. 4, 145-150 (1983)).
  • soybean oil is mostly used as fat in fat emulsions. According to J. M. Meerum Terwogt et al. (Cancer Treatment Review 23, 87-95 (1997)), and J.D. Adams et al. (Monogr. Natl. Cancer Inst. 15, 141-147 (1993)), the use of soybean oil is not possible since taxanes do not dissolve sufficiently in soybean oil. For example, the solubility of paclitaxel in soybean oil is said to be only 0.3 mg / ml.
  • Soybean oil is a triglyceride that contains fatty acids with 16-18 carbon atoms, such as palmitic acid, linolenic acid, linoleic acid and oleic acid.
  • WO 96/02247 describes an oil-in-water emulsion containing taxanes, which contains at least one taxane, an oil, water and a surface-active agent.
  • co-solvents such as alcohols have to be used, which then have to be removed again in a complex process. Even the smallest residual amounts in the end product would prevent intravenous administration. Salts of free fatty acids are also not added.
  • the emulsion obtained is not heat sterilizable; consequently, such heat sterilization is also not described.
  • BD Tarr et al. (Pharmaceutical Res. 4, 162-165 (1987)) describe an emulsion which, in addition to water, contains 1% paclitaxel, 50% triacetin, 2.0% ethyl oleic ester, 1.5% Pluronic F 68 and 1.5% soy lecithin. Although the emulsion was not heat sterilized, the average particle size increased from 1 micron to 4 micron after 2 months and 2 phases were observed after 6 months, meaning that it was no longer an emulsion available. The emulsion itself was found to be toxic and the formulation no longer exhibited anti-tumor activity.
  • the component Pluronic F 68 is also a synthetic non-ionic emulsifier with toxic effects.
  • Triolein glycerol trioleate
  • dipalmitoyl-phosphatidylcholine in combination with the non-ionic emulsifier polysorbate 80 was used as the emulsifier.
  • polyethylene glycol had to be used to increase solubility and stabilization.
  • the emulsion cannot be heat sterilized, but must be cleaned using complex dialysis processes.
  • the emulsion had to be stored in a lyophilized state. It can only be used after dilution with infusion solutions such as saline or glucose solution.
  • the emulsion contains non-physiological, toxic emulsifiers such as Polysorbate 80 and non-physiological substances such as polyethylene glycol. Dipalmityol phosphatidylcholine is extremely expensive. The particle size is also too large at 20 - 40 microns. The production is complicated and extremely complex. B.
  • the aim of the present invention is therefore a pharmaceutical dosage form containing taxanes in the form of an oil in water emulsion, which is also suitable for intravenous use.
  • the pharmaceutical dosage form according to the invention essentially contains no synthetic nonionic emulators, for example polyoxyethylene castor oil, hydrogenated polyoxyethylene castor oil; Polysorbate, Pluronic, etc.
  • no semisynthetic or naturally occurring non-ionic emulsifiers which have toxic side effects are also present.
  • the composition of the invention is characterized in more detail in claim 1.
  • the dosage form according to the invention has others Advantages because it is easy to handle, can be produced industrially in sterile form in large quantities and has excellent stability.
  • the expression "essentially no synthetic nonionic emulsifiers" means that small amounts of synthetic nonionic emulsifiers can be present, provided they do not have any adverse effects on the patient.
  • Synthetic nonionic emulsifiers can be used in an amount of ⁇ 5 g / l, preferably ⁇ lg / 1, more preferably ⁇ 0.5 g / 1 and further preferably ⁇ 0.3 g / 1.
  • the formulation contains no synthetic nonionic emulsifiers, further preferably the formulation contains no other nonionic emulsifiers with harmful side effects.
  • the phosphatidylethanolamine can be present in the pharmaceutical preparation according to the invention in an amount of 0.01 to 3% by weight, preferably 0.01-2% by weight, more preferably 0.05-2% by weight.
  • the dosage form according to the invention is a fat emulsion, in particular for intravenous use, which contains taxanes, triglycerides with 2 to 22 carbon atoms, 3-sn-phosphatidylcholine, alkali metal salts of free fatty acids and water.
  • the dosage form can still have
  • Contain phosphatidylethanolamine and substances that make the emulsion isotonic with blood e.g. B. glycerol and / or sorbitol and / or xylitol.
  • Fat emulsions for parenteral use and methods for their preparation are known. (See: DE-PS 1 1249 454, GP-PS 2 406 621, DE-OS 3 721 137, EP 071 995, DE-OS 3 032 300, US 5 589 508) These fat emulsions are oil in water emulsions in which the particle size of the droplets is less than 5 microns, so that the emulsions without the risk of occurring
  • Emboli can be infused.
  • oils used are, for example, soybean oil, safflower oil, olive oil, fish oils and medium-chain triglycerides.
  • MCT oils are preferably used alone or in combination with soybean oil or olive oil.
  • Phosphatidylcholines from egg lecithin or soy lecithin are used as emulsifiers.
  • the oils are emulsified with the emulsifiers until a particle size of the fat particles of less than 5 microns is obtained.
  • alcohols such as methanol, ethanol and isopropanol are not contained in the pharmaceutical preparation or are not used in the production of the pharmaceutical preparation.
  • taxanes e.g. B. Not sufficiently dissolve paclitaxel in triglycerides of fatty acids with a chain length of 6-18 carbon atoms in order to achieve therapeutically effective concentrations.
  • solubility in tributyrin was somewhat higher, it was not possible to produce a stable emulsion despite the use of nonionic emulsifiers.
  • BD Tarr et al. Pharmaceutical Research 4, 162-165 (1987); B. Lundberg: J. Pharm. Sei. 83, 72-75 (1994); Int. Journ. Pharmaceutics 134, 119-127 (1996) ; J. Pharm. Pharmacol.
  • taxanes are first dissolved in the triglyceride and / or triglyceride mixture used and then emulsified using 3-sn-phosphatidylcholine to form an emulsion whose fat particles are predominantly smaller than 5 microns.
  • Paclitaxel and docetaxel are preferably used as taxanes.
  • the following taxanes can also be used according to the invention:
  • Taxan-2 13-dione, 5th beta, 9th beta, 10th beta. - trihydroxy-, cyclo-9, 10-acetal with acetone, acetate; Taxan- 2,13-dione, 5th beta, 9th beta, 10th beta. -trihydroxy-, cyclo 9, 10-acetal with acetone; Taxan-2. beta. , 5th beta., 9th beta., 10th beta.
  • the triglycerides contain fatty acids with 2 - 22 carbon atoms.
  • triglycerides of the following fatty acids can be used: Name fatty acid - number of carbon atoms
  • Triolein 18 Trilinolein 18
  • triglycerides Mixtures of these triglycerides and / or naturally occurring and / or refined and / or transesterified triglycerides of natural oils such as medium-chain triglycerides (MCT oils), soybean oil, safflower oil, olives, fish oil etc. and / or mixtures of these triglycerides can also be used.
  • MCT oils medium-chain triglycerides
  • soybean oil soybean oil
  • safflower oil olives, fish oil etc.
  • olives olives, fish oil etc.
  • mixtures of these triglycerides can also be used.
  • Triglycerides of hydrogenated fatty acids can also be used. Triglycerides and / or triglyceride mixtures of fatty acids with 4-20 carbon atoms are preferred.
  • tributyrin itself appears to be anti-carcinogenic and can synergistically increase the effect of taxanes.
  • egg lecithins and soy lecithins are preferred.
  • Lecithins with a 3-sn-phosphatidylcholine content of more than 60% are preferred.
  • Egg lecithin with a phosphatidylcholine content of 60 to 90% is particularly preferred.
  • the 3-sn-phosphatidylcholine can also be partially or fully hydrogenated.
  • the lecithins used can also contain phosphatidylethanolamine.
  • the preparation of WO 96/2247 contains about 20 mg cholesterol / ml triglyceride, preferably the preparation according to the invention, amounts far below 10 mg, more preferably below 5 mg, e.g. approx. 1 mg cholesterol / ml triglyceride.
  • the alkali salt of a fatty acid contains an alkali salt of a fatty acid with 4 to 24 carbon atoms in order to adjust the pH of the emulsion to 5 to 9 and to facilitate emulsification and homogenization.
  • Fatty acids with 12-22 carbon atoms are preferred, fatty acids with 16-20 carbon atoms are particularly preferred.
  • the alkali salt of a fatty acid can also be prepared in situ by adding an alkali hydroxide to a mixture containing a fatty acid.
  • the sodium or potassium salts of palmitic acid, oleic acid, linoleic acid and linolenic acid are particularly preferred.
  • the concentration of the triglycerides in the dosage form according to the invention is 1-60%. Concentrations of 3 to 40% are preferred.
  • concentrations of the emulsifier used in the form of egg lecithin and / or soy lecithin are 0.2-4%, concentrations of 0.4-2.5% are preferred, the concentration of the emulsifier depending on the concentration of the triglycerides.
  • concentrations of the alkali metal salts of the fatty acids are generally 0.01-0.2%, preferably 0.02-0.1% by weight.
  • the taxanes used should be present in therapeutically effective concentrations. Generally these concentrations are 0.01-0.3% (0.1-3 mg / ml).
  • known isotonizing substances such as e.g. As glycerin, glucose, fructose, sorbitol, xylitol can be contained in the appropriate concentrations, with glycerol being preferred.
  • the pharmaceutical dosage form may contain vitamin E in the form of tocopherol or pharmaceutically acceptable tocopherol esters to act as a stabilizing antioxidant.
  • concentrations used are approximately 0.15 to 1.5% by weight, depending on the type and content of the triglycerides and emulsifiers used.
  • the particle size of the fat particles in the oil-in-water emulsion is as small as possible less than 5 microns. At least 97% of the particles should be smaller than 5 microns. In general, the particle size is on average 0.1-1 micron, preferably between 0.2-0.6 micron.
  • Possible suitable pharmaceutical dosage forms according to the invention as emulsions have, for example, the following composition:
  • Paclitaxel 100 mg / 100 ml
  • Paclitaxel 100 mg / 100 ml
  • Paclitaxel 100 mg / 100 ml
  • taxanes do not dissolve sufficiently in triglycerides in order to produce emulsions with therapeutically effective concentrations.
  • paclitaxel for example, 0.3 mg / ml is specified as solubility in triglycerides having 6 to 18 carbon atoms.
  • tributyrin cannot be used to produce stable emulsions with a small particle size.
  • the taxanes are added to the desired triglycerides or mixtures of different triglycerides and the mixture is heated, if necessary with stirring, until the taxane has dissolved.
  • the taxane is added, if necessary with stirring, to the triglyceride or mixture of triglycerides which has already been heated or heated.
  • the triglyceride should not be heated above the melting point of the taxane, which is around 210 ° C for paclitaxel, for example. The lower the number of carbon atoms of the fatty acids in the triglyceride used, the easier the taxane dissolves when heated.
  • Paclitaxel can be dissolved in tributyrin at 60 - 90 ° C, whereas it is advantageous to dissolve it in tricaprylin and / or tricaprin by heating to approx. 110 - 130 ° C.
  • the boiling point of the triglyceride (s) used should not be exceeded when loosening the taxane (s).
  • the active ingredients are dissolved with stirring at temperatures between 60 ° and 160 ° C., the temperature required being dependent on the number of carbon atoms in the fatty acids contained in the triglycerides.
  • paclitaxel can be easily dissolved in tributyrin at approx. 60 - 100 ° C.
  • the dissolving process is best carried out in the absence of oxygen, e.g. B. in a nitrogen atmosphere to avoid decomposition due to oxidation processes. It is advantageous to ensure the absence of oxygen during the entire manufacturing process. It is also possible to first use the taxane in a triglyceride of low carbon fatty acids, e.g. B. solve tributyrin at relatively low temperatures, for example 70-100 ° C and then add further triglycerides.
  • the amounts dissolved are sufficient to achieve the desired therapeutically effective concentrations in the emulsion according to the invention.
  • the triglycerides containing taxanes cooled to 20 - 60 ° C are filtered to remove any particles.
  • a raw emulsion is produced at a temperature of approx. 40 - 70 ° C by stirring with an Ultra-Turrax
  • the triglyceride solution and water containing taxanes are then added to the crude emulsion, and the pH is optionally adjusted to 5-9, preferably 6-8, by adding alkali metal salts of fatty acids.
  • the mixture which now contains taxanes, triglycerides, 3 - sn - phosphatidylcholine, water, an isotonizing agent such as e.g. B. contains glycerol and optionally alkali salts of fatty acids, is homogenized by stirring with an Ultra-Turrax, whereby a crude emulsion is obtained.
  • the mixture is adjusted by adding water so that the triglyceride content is 1-60% by weight.
  • the crude emulsion is then homogenized in a high-pressure homogenizer with three pistons at pressures between 100-700 bar, preferably between 300-600 bar, possibly several times, until an emulsion is obtained in which the particle size of at least 97% of all fat particles below 5 microns, preferably is less than 1.5 microns.
  • the emulsion is then diluted with water to the desired concentration and filled into ampoules or bottles and heat-sterilized.
  • Sterilization in a so-called rotary autoclave is preferred, in which the containers are rotated overhead during the sterilization. This leads to better heat transfer in the containers. This shortens the heating and cooling phases and reduces the risk of damage to the contents of the containers. It is advantageous to carry out the entire manufacturing process in the absence of oxygen.
  • paclitaxel 1000 mg are added with stirring to 200 g of a triglyceride mixture consisting of MCT oil (medium-chain triglycerides) with predominantly fatty acids with 8 and 10 carbon atoms and soybean oil in a ratio of 1: 1.
  • the mixture is heated to about 110-135 ° C. while stirring and gassing with nitrogen until a largely clear solution is obtained.
  • the paclitaxel (1000 mg) can first be dissolved in 100 g MCT oil at approx. 110 - 135 ° C and only afterwards soybean oil, heated to approx. 120 ° C, added. The mixture is allowed to cool to about 40-80 ° C. and filtered through a grease-resistant disinfection filter with a pore size of about 50 microns.
  • glycerol 25 g are then added to another vessel, and 200 ml of water and nitrogen are gassed in until the oxygen content is less than 0.5 mg / l.
  • 12 g of egg lecithin (iodine number 60-70) with a 3-sn-phosphatidylcholine content of approx. 80% and approx. 12% phosphatidylethanolamine are added and 0.4 g of sodium oleate.
  • a crude emulsion is produced by stirring vigorously with an Ultra-Turrax at a temperature of approx. 40 - 60 ° C.
  • the triglyceride solution containing the paclitaxel is added and strongly stirred with an Ultra-Turrax for a further 10 minutes.
  • the pH is checked and should be between 5 and 9, preferably between 6-8, particularly preferably between 6.5 and 7.5.
  • the crude emulsion obtained is filtered through a fat-resistant stainless steel filter (pore size between 5 - 50 microns) and then homogenized with a 2-stage high-pressure homogenizer with three pistons at pressures between 100 - 600 bar. The homogenization process is repeated until the desired particle size is reached. Less than 1% of the particles should be larger than 4 microns. The average diameter of the particles is 0.2-0.6 microns.
  • the emulsion In order to achieve a particle size that can be used well, it is generally necessary to repeat the homogenization process approximately 3 to 6 times. After each homogenization process the emulsion should be cooled to 30 - 60 ° C. The emulsion is then poured into 560 ml of oxygen-free water for injections. It is gassed with nitrogen again until the oxygen content is below 0.5 mg / 1.
  • the filter Before filling into 250 ml glass bottles, the filter is filtered through a stainless steel filter with an average pore size of 5 microns.
  • the filtration pressure should not exceed 0.2 bar in order to prevent the emulsion from breaking.
  • the particle size and the particle distribution can be determined, for example, using a microscope or a Coulter Counter.
  • the emulsion is filled into 250 ml glass bottles.
  • the bottles are gassed with nitrogen before filling. It is advantageous to cool the nitrogen used down to minus 20 - 30 ° C so that the nitrogen sinks more easily to the bottom of the bottle.
  • the bottles should continue to be gassed with nitrogen even during the filling process.
  • the emulsion obtained is heat sterilized at 121 ° C for 20 minutes.
  • a so-called rotary autoclave in which the bottles rotate overhead during the sterilization is advantageously used. This reduces the time required for filling and cooling and prevents the particle size from changing.
  • the particle distribution after sterilization is as follows:
  • Sterilization therefore does not lead to any significant change in particle size and particle distribution.
  • the emulsion is stable. After one year of storage at room temperature, there is no significant change in particle size and particle distribution. A stable emulsion with the following composition per 100 ml is obtained:
  • Soybean oil plus MCT oil 20 g
  • 250 to 500 ml of the emulsion can now be slowly infused over 3 to 10 hours, whereby a therapeutically effective amount of paclitaxel is added.
  • Example 2 The procedure of Example 1 is repeated using 800 mg of docetaxel instead of paclitaxel.
  • a pharmaceutical dosage form is obtained with the following composition per 100 ml:
  • tributyrin and 70 g of MCT oil are heated to approx. 110 - 130 ° C with stirring and 800 mg of paclitaxel are added with stirring until a clear solution is formed.
  • the mixture is allowed to cool to 30-60 ° C. and the rest of the preparation is carried out analogously to Example 1, except that the egg lecithin is replaced by soy lecithin with a 3-sn-phosphatidylcholine content of approximately 70-80%. Potassium oleate is used instead of sodium oleate.
  • paclitaxel 800 mg paclitaxel are dissolved in 150 g MCT oil while stirring at 120 - 140 ° C.
  • the MCT oil used contains 65% caprylic acid (C8) and 32% capric acid as triglycerides. Small amounts of caproic acid, lauric acid and myristic acid are also present as triglycerides. A further 0.6 g of free oleic acid are added. It is prepared analogously to Example 4, but using potassium hydroxide instead of potassium oleate for pH adjustment. This produces potassium oleate in situ as in Example 4.
  • An emulsion according to the invention having the following composition per 100 ml is obtained.
  • 500 mg paclitaxel are stirred and under a nitrogen atmosphere in a triglyceride mixture consisting of 100 g MCT oil and 50 g fish oil with a total of 40% omega-3 fatty acids, especially eicosapentaenoic acid and docosahexaenoic acid, at approx. 130 - 150 ° C solved.
  • the oxygen content of the triglycerides was previously adjusted to below 0.5 mg / l by gassing with nitrogen.
  • 10 mg of vitamin E was added.
  • Example 1 An emulsion according to the invention having the following composition per 100 ml is obtained.

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Abstract

La présente invention concerne une préparation pharmaceutique contenant du taxane, ladite préparation étant sous la forme d'une émulsion huile-dans-eau. La préparation selon l'invention est caractérisée en ce qu'elle contient au moins un taxane, au moins un triglycéride d'acides gras contenant 2 à 22 atomes de carbone, 3-sn-phosphaticholine et/ou phosphatidylethanolamine et des sels alcalins d'acides gras libres et de l'eau et essentiellement pas d'émulsifiants synthétiques non-ioniques.
PCT/EP1999/007059 1998-09-24 1999-09-22 Preparation pharmaceutique contenant du taxane et procede de preparation d'une telle composition WO2000016770A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU61948/99A AU6194899A (en) 1998-09-24 1999-09-22 Pharmaceutical preparation containing taxane and method for producing the same

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19843968.7 1998-09-24
DE1998143968 DE19843968A1 (de) 1998-09-24 1998-09-24 Taxane enthaltende pharmazeutische Zubereitung zur intravenösen Applikation und Verfahren zu ihrer Herstellung

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WO2000016770A1 true WO2000016770A1 (fr) 2000-03-30

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000040236A1 (fr) * 1999-01-04 2000-07-13 Hans Dietl Emulsion sterile et stable contenant des taxanes et son procede de production
WO2002080883A2 (fr) * 2001-03-27 2002-10-17 Phares Pharmaceutical Research N.V. Methode et composition permettant de solubiliser un compose biologiquement actif a faible solubilite dans l'eau

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19959546A1 (de) * 1999-12-09 2001-06-21 Rhone Poulenc Rorer Gmbh Pharmazeutische Zubereitung zur Behandlung von Tumorerkrankungen
US8557861B2 (en) * 2004-09-28 2013-10-15 Mast Therapeutics, Inc. Low oil emulsion compositions for delivering taxoids and other insoluble drugs
EP2025333A1 (fr) * 2007-08-14 2009-02-18 Pharmatex Italia Srl Formules pharmaceutiques injectables de taxoïdes

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0570829A1 (fr) * 1992-05-18 1993-11-24 Hans Dr. Dietl Composition pharmacéutique pour administration intraveneuse contenant de la cyclosporine et méthode pour sa préparation
WO1994007484A1 (fr) * 1992-10-01 1994-04-14 Research Corporation Technologies, Inc. Solutions pharmaceutiques et emulsions contenant du taxol
WO1996002247A1 (fr) * 1994-07-19 1996-02-01 Hemagen/Pfc Emulsions stables huile-dans-eau incorporant une taxine (taxol) et procede de preparation
EP0760237A1 (fr) * 1995-08-30 1997-03-05 Cipla Limited Microémulsions huile-dans-l'eau
WO1999004787A1 (fr) * 1997-07-26 1999-02-04 West Pharmaceutical Services Drug Delivery & Clinical Research Centre Limited Emulsion de taxol

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0570829A1 (fr) * 1992-05-18 1993-11-24 Hans Dr. Dietl Composition pharmacéutique pour administration intraveneuse contenant de la cyclosporine et méthode pour sa préparation
WO1994007484A1 (fr) * 1992-10-01 1994-04-14 Research Corporation Technologies, Inc. Solutions pharmaceutiques et emulsions contenant du taxol
WO1996002247A1 (fr) * 1994-07-19 1996-02-01 Hemagen/Pfc Emulsions stables huile-dans-eau incorporant une taxine (taxol) et procede de preparation
EP0760237A1 (fr) * 1995-08-30 1997-03-05 Cipla Limited Microémulsions huile-dans-l'eau
WO1999004787A1 (fr) * 1997-07-26 1999-02-04 West Pharmaceutical Services Drug Delivery & Clinical Research Centre Limited Emulsion de taxol

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000040236A1 (fr) * 1999-01-04 2000-07-13 Hans Dietl Emulsion sterile et stable contenant des taxanes et son procede de production
WO2002080883A2 (fr) * 2001-03-27 2002-10-17 Phares Pharmaceutical Research N.V. Methode et composition permettant de solubiliser un compose biologiquement actif a faible solubilite dans l'eau
WO2002080883A3 (fr) * 2001-03-27 2003-12-11 Phares Pharm Res Nv Methode et composition permettant de solubiliser un compose biologiquement actif a faible solubilite dans l'eau

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DE19843968A1 (de) 2000-04-13

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