WO2010023321A1

WO2010023321A1 - Liquid formulation containing a taxane derivative

Info

Publication number: WO2010023321A1
Application number: PCT/EP2009/061247
Authority: WO
Inventors: Isabelle Gimbert
Original assignee: Stragen Pharma S.A.
Priority date: 2008-09-01
Filing date: 2009-09-01
Publication date: 2010-03-04

Abstract

The present invention concerns a liquid pharmaceutical formulation comprising (a) a taxane derivative or a pharmaceutically acceptable salt thereof, (b) a solvent consisting in the mixture of a pharmaceutically acceptable alcohol, 30-50% water and a pharmaceutically acceptable polyethoxylated fatty acid ester.

Description

Liquid formulation containing a taxane derivative

The present invention concerns a liquid pharmaceutical formulation containing a taxane derivative, especially docetaxel, and water while being physically and chemically stable. Such a formulation is intended for parenteral administration.

Taxane derivatives, such as docetaxel and paclitaxel, are well known and established drugs in the treatment of malignant tumors. For example docetaxel is marketed by Sanofi-Aventis under the trade name Taxotere® and paclitaxel is marketed by Bristol- Myers-Squibb under the trade name Taxol®. The low solubility in water of these drugs is well documented.

In particular, Docetaxel (CAS 114977-28-5) is an antineoplasic agent belonging to the taxoϊd family which was identified in 1986 as an alternative to paclitaxel. It is prepared by a semi-synthetic process beginning with a precursor extracted from the needles of yew plants (Taxus baccata). The chemical name for docetaxel is (2b,5b,7b,10b,13a)-4- Acetoxy-13(((2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-3- phenylpropanoyl)oxy)-l ,7,10-trihydroxy-9-oxo-5,20-epoxytax-l l-en-2-yl benzoate, and it has the following chemical structure:

Docetaxel is a white to almost white powder with an empirical formula of C43H53NO14. It is very lipophilic and practically insoluble in water. Docetaxel was first described in EP 0 253 738.

Docetaxel acts by disrupting the microtubular network in cells that is essential for mitotic and interphase cellular functions. Docetaxel binds to free tubulin and promotes the assembly of tubulin into stable microtubules while simultaneously inhibiting their disassembly. This leads to the production of microtubules without normal function and to the stabilization of microtubules which results in the inhibition of mitosis (replication) in cells. Docetaxel's binding to microtubules does not alter the number of protofibro filaments in the bound microtubules, a feature which differs from most spindle poisons currently in clinical use. As such, it is widely understood that docetaxel is a useful and efficacious oncology agent, either alone or in combination with other agents. The commercial product Taxotere® was first approved in 1996. Taxotere® is formulated as a concentrate for dilution supplied with a solvent vial: the concentrate solution is a clear-yellow to brownish-yellow viscous solution. Each milliliter contains 40 mg docetaxel and 1040 mg polysorbate 80. The diluent for Taxotere® is 13% ethanol in water for injection. The medical practitioner must aseptically withdraw the entire contents of the diluent vial, transfer it to the vial containing the docetaxel concentrate and mix the components to produce a solution containing 10 mg/ml docetaxel. That mixture must be repeatedly inverted for 45 seconds in order to mix the solutions adequately. It cannot be shaken, as that leads to foaming and the potential loss of potency. This intermediate solution is then diluted in an infusion bag, typically 250 ml, containing either 0.9% sodium chloride solution or 5% dextrose solution to produce a concentration of 0.3 to 0.74 mg/ml of docetaxel. Therefore, the Taxotere® formulation needs to be manipulated a lot before being injected, which will cause an increase in the risk of contamination and of foaming as well as an increase in the human error risk. Due to the fact that docetaxel is practically insoluble in water, there have been a number of other attempts to develop appropriate injectable formulations. For example, docetaxel is known to be soluble in ethanol and one of the first such other formulations was 50% ethanol and 50% Emulphor EL® (a non-ionic solubilizer and emulsifier manufactured by reacting castor oil with ethylene oxide).

EP 0 593 656, EP 0 593 601 and EP 0 671 912 disclose a docetaxel formulation in which the quantity of ethanol has been decreased and containing a surfactant such as polysorbate (e.g. Tween®), polyoxyethylene glycol derivative (e.g. Emulphor®) or polyethoxylated castor oil (e.g. Cremophor EL®), in a single or double compartment. However the surfactants of the Cremophor ® type are known to cause allergies problems in a lot of patients. Cremophor® can contain polyethoxylated fatty acids esters. However, if any, they are present in very small amounts. Furthermore, formulation of docetaxel containing Cremophor® does not contain water. EP 0 932 399 discloses a pharmaceutical composition comprising a water-soluble conjugate of an anti-tumor with a polyglutamic acid polymer.

Other attempts to stabilize injectable solution of docetaxel include the use of one or more glycols (WO 2006/133510), a degradation inhibitor such as an organic acid with a pKa of between 2.5 and 4.5 (WO 2007/085067), glycofurol (WO 2007/020085), a fatty acid (EP 1 862 183), a stabilizing agent such as a chelating agent, citrate, sodium pyrophosphate or sodium gluconate, EDTA or sodium chloride (WO 2007/027941), a buffer (WO 2007/124700) or an acid in order to obtain a pH of between 3 and 6 (WO 2008/026048).

The patent US 5 922 754 describes a composition containing paclitaxel that is stable for extended period of time. The preferred organic solvent includes triacetin, glycerol and solutol HS-15. The acid used is citric acid. According to table 1, the water content is of maximum 25% by weight, whereas the preferred range weight is 8-10 % and the preferred composition contains 8.9 % by weight. This composition can contain as solvent other than fatty acid derived PEG esters. However, only solutol HS-15 is exemplified. Furthermore, all the given examples contain triacetin and propylene glycol. This is confirmed by table 3 which shows that the formulations that do not contain glycerin (formulation 3c or 4a) are not stable more than 48 hours. Therefore, in view of this patent, it is neither described nor suggested to use a water content higher than 25 % by weight. Furthermore, it is neither described nor suggested that the stability of the composition for extended period of time can be obtained without using triacetin, glycerol and solutol HS- 15.

The patent application WO 02/43765 describes pharmaceutical formulations comprising paclitaxel and its derivatives such as docetaxel. In particular, this pharmaceutical formulation can have the form of a liquid concentrate which is diluted in an aqueous medium before being used. Such liquid concentrate can contain ethanol and a paclitaxel solubilizer.

Its water content is less than 5 % by weight. It is further indicated that other excipients, in particular aqueous solutions can be added to this concentrate. However, the water content is not indicated. Furthermore, in case of aqueous formulations of paclitaxel, the paclitaxel content is comprised between 0.2 mg/ml and 3mg/ml. Therefore, it consists in this infusion solution intended for administering paclitaxel.

Moreover, no example describes the use of PEG monoacid ester alone as the only solubilizer of paclitaxel. Furthermore, no example concerns docetaxel. Finally, the stability of the compositions is not described. Therefore, this document does not describe nor suggest that the compositions comprising a high amount of water and a high amount of paclitaxel can be obtained and being stable for an extended period of time, in particular without the use of polysorbate or other products of the same type. Finally, this composition does not contain any acid.

However, none of these attempted formulations has resulted in a successful commercial product to compete with Taxotere® to date. There is thus still a need for alternative docetaxel formulations which have the necessary physicochemical properties and shelf life. Furthermore all the formulation of the prior art, except emulsion, do not contain any water because of the known instability of docetaxel in water. Furthermore, in the case of emulsion, the surfactants used are somewhat toxic and precipitation of the drug occurs when subjected to dilution.

The present inventors have surprisingly found a way to add at least 30 % by weight of water in a pharmaceutical formulation containing docetaxel, while preserving its stability, by using a particular surfactant: polyethoxylated fatty acid esters. Such a formulation is therefore easier to handle when preparing the infusion. Furthermore such a formulation consists in a one vial solution, which therefore does not need to be diluted before being added to an infusion solution, and therefore does not required too much manipulation of the docetaxel formulation before use. As a consequence there is no risk of foaming.

Therefore the present invention concerns a liquid pharmaceutical formulation comprising:

(a) a taxane derivative or a pharmaceutically acceptable salt thereof,

(b) a solvent consisting in the mixture of a pharmaceutically acceptable alcohol a pharmaceutically acceptable polyethoxylated fatty acid esters, and 30-50% by weight of water based on the total weight of the solvent.

In the sense of the present invention, the term "taxane derivative" is intended to mean any natural, hemisynthetic or synthetic drug which belongs to the taxoϊd family, i.e. which has the taxane skeleton, and mixture of these drugs. They may be isolated from the natural sources such as the Yew tree (paclitaxel for example) or from cell culture or chemically synthesized molecules such as docetaxel and which are poorly soluble in water. Examples of such a taxane derivative include paclitaxel, docetaxel, 7- epipaclitaxel, 10-desacetyl-paclitaxel, lO-desacetyl-7-epipaclitaxel, baccatin III, 10- desacetyl-baccatin III, 7-epidocetaxel, ortataxel and mixture thereof. Advantageously it has the following formula (I):

in which R represents a hydrogen atom or an acetyl radical, one of Rl or R2 represents a tertiobutoxycarbonylamino radical or a benzoylamino radical and the other one a OH group. Advantageously, the taxane derivative is chosen in the group consisting of paclitaxel, docetaxel, ortataxel and mixture thereof, still more advantageously in the group consisting of paclitaxel, docetaxel and mixture thereof, further still more advantageously the taxane derivative is docetaxel.

Advantageously, the taxane derivative used in the formulation according to the present invention can be in any possible form: crystalline (such as described in WO 2007/044950) or amorphous or any polymorph form or mixture of forms, hydrate, hemi hydrate, dihydrate, trihydrate, solvate or anhydrous form. Advantageously, in particular in the case of docetaxel, the taxane derivative is in an anhydrous or in a trihydrate form before being added to the liquid pharmaceutical formulation of the present invention, still more advantageously in the anhydrous form. Advantageously, in particular in the case of docetaxel, the taxane derivative is in a crystalline or amorphous state or mixture thereof before being added to the liquid pharmaceutical formulation of the present invention. In the sense of the present invention, the term "pharmaceutically acceptable" is intended to mean all that is useful in the preparation of a pharmaceutical composition, that is generally safe and non toxic and that is no biologically or else non desirable and that is acceptable for veterinary and human pharmaceutical use. In the sense of the present invention, the term "pharmaceutically acceptable salt" of a compound is intended to mean the salts which are pharmaceutically acceptable, as defined above, and which have the desired pharmacologic activity of the parent compound. Such salts include:

(1) acid addition salts formed with inorganic acids such as hydrochloric acid, sulphuric acid, nitric acid, hydrobromic acid, phosphoric acid an the like or formed with organic acids such as ascorbic acid, benzoic acid, aspartic acid, oxalic acid, benzene sulphonic acid, tartaric acid, diatriazoic acid, glutamic acid, lactic acid, maleic acid, succinic acid, fumaric acid, citric acid, edetic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, pantothenic acid, para-toluenesulfonic acid, acetic acid, gluconic acid, ethanesulfonic acid, proprionic acid, salicylic acid and the like; or

(2) salts formed when an acid proton present in the parent compound is either replaced by a metallic ion, for example alkali metal ion, alkaline-earth metal ion or aluminum ion; or is coordinated with an organic or inorganic base. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine and the like. Acceptable inorganic bases include aluminum hydroxide calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide. It should be understood that all references to pharmaceutically acceptable salt include solvates and polymorphs of the same acid addition salts.

In the sense of the present invention, the term "pharmaceutically acceptable alcohol" is intended to mean any alcohol which is pharmaceutically acceptable as defined above. Examples of such an alcohol include, but are not limited to, propanediol, benzyl alcohol, 2-propanol, ethanol and mixture thereof. Advantageously it is chosen in the group consisting of ethanol, benzyl-alcohol and mixture thereof. Still more advantageously it is ethanol. Advantageously, the proportion of alcohol in the solvent according to the present invention is in the range of 30-75 weight %, more advantageously in the range of 30-60 weight %, in an advantageous manner in the range of 35-45 weight %, still more advantageous of 35 or 40 weight %, in particular of 40 weight %, further still advantageously, the proportion of alcohol in the solvent is higher than the proportion of polyethoxylated fatty acid ester.

In the sense of the present invention, the terms "pharmaceutically acceptable polyethoxylated fatty acid ester" is intended to mean any polyethoxylated mono or diester of fatty acids which is pharmaceutically acceptable as defined above and which is soluble in the mixture of water and alcohol. Polyethoxylated fatty acid esters are produced by polyethoxylation of fatty acids. In particular, the polyethoxylated fatty acid ester according to the present invention has the following structural formula: (1) or

(2): (1) R-(CO)-(OCH₂CH₂)_n-OH,

(2) R₁-(CO)-(OCH₂CH₂)_n-O-(CO)-R₂ in which R, Ri and R₂ represents independently of each other the alkyl or alcenyl group of the parent fatty acid and n represents the polymer lenght, in oxy ethylene units, n is advantageously between 9 and 160, still more advantageously between 12 and 150, in particular between 20 and 60.

The fatty acid can be saturated or unsaturated and/or hydroxylated.

Advantageously, the fatty acid is not hydroxylated and therefore is not SOLUTOL HS-

15.

The most common saturated fatty acids are as follows:

Therefore, advantageously R, Ri or R₂ is a straight or branched chain, in particular straight, C₃-C₂₃ alkyl or alkenyl, more advantageously alkyl, in particular a Cn-C₂₃ alkyl or alkenyl, advantageously alkyl, still more advantageously a C₁₅-C₂₁ alkyl or alkenyl, in particular alkyl.

In particular, fatty acids are saturated fatty acids and are long chain fatty acids, i.e. having more than 16 carbon atoms.

Advantageously, the pharmaceutically acceptable polyethoxylated fatty acid ester is a pharmaceutically acceptable polyoxyethylene stearate, polyoxyethylene palmitate or mixture thereof, more advantageously a pharmaceutically polyoxyethylene stearate.

Advantageously, the proportion of polyethoxylated fatty acid ester in the solvent according to the present invention is in the range of 10-40 weight %, more advantageously in the range of 20-30 weight %, still more advantageously of 20 or 30 weight %, in particular of 20 weight %.

Advantageously, the polyethoxylated fatty acid is the only surfactant of the formulation according to the present invention.

In the sense of the present invention, the term "pharmaceutically acceptable po Iy oxy ethylene stearate" is intended to mean any po Iy oxy ethylene stearate, in particular polyoxyethylene monostearate, polyoxyethylene distearate or mixture thereof, advantageously polyoxyethylene monostearate, which is pharmaceutically acceptable as defined above and which is soluble in the mixture of water and alcohol. Polyoxyethylene stearates are nonionic surfactants produced by polyethoxylation of stearic acid. Examples of such a polyoxyethylene stearate include, but are not limited to polyoxyethylene 12 stearate, polyoxyethylene 20 stearate, polyoxyethylene 30 stearate, polyoxyethylene 40 stearate, polyoxyethylene 50 stearate, polyoxyethylene 100 stearate, polyoxyethylene 150 stearate, polyoxyethylene 32 distearate and mixture thereof. Advantageously the polyoxyethylene stearate is chosen in the group consisting of polyoxyethylene 20 stearate, polyoxyethylene 30 stearate polyoxyethylene 40 stearate, polyoxyethylene 50 stearate and mixture thereof, more advantageously in the group consisting of polyoxyethylene 40 stearate, polyoxyethylene 50 stearate and mixture thereof, still more advantageously, it is polyoxyethylene 40 stearate.

Advantageously, the proportion of water in the solvent is in the range of 30-50 weight %, in a more advantageous manner in the range of 35-45 weight %,still more advantageously of 35 or 40 weight % in particular of 40 weight %.

In a particular embodiment of the present invention the proportion of water in the solvent is identical to the proportion of alcohol.

In another particular embodiment of the present invention the proportion of water in the solvent is the higher than the proportion of polyethoxylated fatty acid ester. Advantageously, the water used is water for injection.

Advantageously, the solvent of the liquid pharmaceutical formulation according to the present invention consists in a mixture of 30-50 weight % of water, 30-60 weight % of the pharmaceutically acceptable alcohol and 10-40 weight % of the pharmaceutically acceptable polyethoxylated fatty acid ester, advantageously of 35-40 weight % of water, of 35-40 weight % of the pharmaceutically acceptable alcohol and 20-30 weight % of the pharmaceutically acceptable polyethoxylated fatty acid ester, more advantageously of 40 or 35 weight % of water, 40 or 35 weight % of the pharmaceutically acceptable alcohol and 20 or 30 weight % of the pharmaceutically acceptable polyethoxylated fatty acid ester, still more advantageously of 40 weight % of water, 40 weight % of the pharmaceutically acceptable alcohol and 20 weight % of the pharmaceutically acceptable polyethoxylated fatty acid ester.

Since the liquid pharmaceutical formulation according to the present invention contains water, it can be called an aqueous liquid pharmaceutical formulation.

Advantageously, the mixture of water, alcohol and polyoxyethylene stearate is the only solvent of the liquid pharmaceutical formulation according to the present invention.

Therefore the present invention also concerns the use of a mixture of alcohol, polyethoxylated fatty acid ester and 30-50 weight % of water as a solvent for a liquid formulation of a taxane derivative, advantageously docetaxel, and a process of the solubilization of a taxane derivative, advantageously docetaxel, which consist in the addition of the taxane derivative in a mixture of alcohol, polyethoxylated fatty acid ester and 30-50 weight % alcohol.

In an advantageous manner, the concentration of the taxane derivative in the liquid pharmaceutical formulation according to the present invention is a pharmaceutically effective amount, advantageously in the range of 5-15 mg/ml, more advantageously in the range of 10-15 mg/ml, still more advantageously of 10 mg/ml.

In a still more advantageous manner, the liquid pharmaceutical formulation according to the present invention is a one compartment formulation.

In the sense of the present invention, the term "one compartment formulation" is intended to mean that the liquid pharmaceutical formulation according to the present invention is not in a two compartments formulation composed of a vial of the solution of docetaxel (stock or concentrate or premix solution) and of a solvent vial (diluent solution) which have to be mixed before the injection in the infusion bag. On the contrary, the liquid pharmaceutical formulation according to the present invention is ready for dilution (i.e. the pharmaceutical composition needs only to be diluted with an infusion diluent before being injected or infused) and contained in a single vial, and therefore do not need to be reconstituted and homogenized before being injected in an infusion bag. There is therefore no risk of foaming and less risk of contamination.

In another advantageous manner, the liquid pharmaceutical formulation according to the present invention is suitable for intravenous or parenteral injection or infusion.

In the sense of the present invention, the term "suitable for intravenous or parenteral injection or infusion" is intended to mean that prior to be used, the formulation according to the present invention is diluted to the adequate medically recommended concentration for injection or infusion in 0.9% saline (NaCl), 5% glucose or another pharmaceutically acceptable medium for injection or infusion. Accordingly, following such a dilution, the formulation according to the present invention will be suitable for intravenous or parenteral injection or infusion.

Therefore, the present invention concerns also an infusion solution which contains the liquid pharmaceutical formulation according to the present invention and an infusion diluent, advantageously selected from glucose or sodium chloride aqueous solution, still more advantageously 0.9% saline or 5% glucose aqueous solution, advantageously a glucose aqueous solution, still more advantageously a 5% glucose aqueous solution. Surprisingly, the inventors have discovered that an infusion solution containing the liquid pharmaceutical formulation according to the present invention and a 5% glucose aqueous solution, in particular having a taxane derivative concentration of about 0.7 mg/mL, advantageously the taxane derivative being docetaxel, is stable when stored at 5°C for at least 72 hours. In particular no precipitation and no significant variation of the taxane derivative content and of the impurity content are observed.

In a particular embodiment of the present invention, the liquid pharmaceutical formulation according to the present invention is physically and/or chemically stable, advantageously physically and chemically stable, in particular at 5°C, more particularly when stored at least three months at 5°C, still more particularly at least 6 months at 5°C. In the sense of the present invention, the term "physically stable" is intended to mean that the formulation according to the present invention does not exhibit any visible precipitation after a minimum of three months in particular of six months when stored at 5°C, more particularly when stored at least three months at 25°C and 60 % relative humidity and in particular when stored at least one month under accelerated conditions (40⁰C / 75% relative humidity).

In the sense of the present invention, the term "chemically stable" is intended to mean that the formulation according to the present invention does not show any significant degradation, meaning that degradation products are formed at a level of less than 2%, preferably less than 1% by weight, even more advantageously less than 0.5% by weight when stored at least three months, in particular at least 6 months at 5°C. In an advantageous manner, in the formulation according to the present invention, the degradation products are formed at a level of less than 5% by weight, preferably less than 2% by weight, more preferably less than 1 % by weight when stored at least three months under the following conditions: 25°C and 60% relative humidity. In another advantageous manner, in the formulation according to the present invention, the degradation products are formed at a level of less than 5 % by weight, preferably less than 2 % by weight, more preferably less than 1 % by weight when stored at least one month under the following conditions: 30⁰C and 65 % relative humidity. In a further advantageous manner, in the formulation according to the present invention, the degradation products are formed at a level of less than 20%, preferably less than 10%, still preferably less than 5%, preferably less than 2% when stored at least one month under the following conditions: 40⁰C and 75% relative humidity.

Advantageously, the liquid pharmaceutical formulation according to the present invention retains at least 95% of the taxane derivative potency, more advantageously at least 97% after storage for at least three months, more particularly at least 6 months at 5°C. In an advantageous manner the liquid pharmaceutical formulation according to the present invention retains at least 90% of the taxane derivative potency more advantageously at least 95%, still more advantageously at least 97 % after storage for at least three months, in particular at least 6 months at 25 ⁰C and 60% relative humidity. Still more advantageously the liquid pharmaceutical formulation according to the present invention retains at least 75% of the taxane derivative potency after storage for et least one month at 40 ⁰C and 75% relative humidity, more advantageously at least 80%, further still more advantageously at least 90%.

In a another particular embodiment of the present invention the liquid pharmaceutical formulation according to present invention has a pH in the range of 3-8, advantageously of 4-7.5, still more advantageously of 4.5-6.5, even still more advantageously 4.5-6, in particular 5-6. Such a pH will impart stability (in particular chemical stability) to the formulation according to the present invention. In order to obtain a pH below 7.5, and in particular below 7, it would be advisable to add a pharmaceutically acceptable acid and/or a buffer agent to the formulation according to the present invention, advantageously a pharmaceutically acceptable acid. Therefore, the present invention concerns the liquid pharmaceutical formulation according to the present invention which further contains (c) a pharmaceutically acceptable acid and/or a buffer agent, more advantageously a pharmaceutically acceptable acid.

In the sense of the present invention, the term "pharmaceutically acceptable acid" is intended to mean any acid which is pharmaceutically acceptable as defined above and which does not saponify with po Iy oxy ethylene stearate. In particular it is intended to mean any nontoxic acid, including organic and inorganic acids and mixture thereof. Such inorganic acids include hydrochloric acid, sulphuric acid, nitric acid, hydrobromic acid, phosphoric acid and mixture thereof. Such organic acids include carboxylic or dicarboxylic acid, still more advantageously is selected from ascorbic acid, benzoic acid, aspartic acid, oxalic acid, benzene sulphonic acid, tartaric acid, diatriazoic acid, glutamic acid, lactic acid, maleic acid, succinic acid, fumaric acid, citric acid, edetic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, pantothenic acid, para-toluenesulfonic acid, acetic acid, gluconic acid, ethanesulfonic acid and mixture thereof. Advantageously it is an organic acid, still more advantageously a dicarboxylic acid, in particular a strong organic acid. The inventors have discovered that oxalic acid is particularly suitable to be used in the formulation according to the present invention. In fact oxalic acid is one of the strongest organic acid and therefore only a few amount is needed (few drops) in order to obtain the desired pH. Furthermore oxalic acid does not saponify with the pharmaceutically polyoxyethylene stearate.

The amount of the pharmaceutically acceptable acid is such as to obtain the desired pH. Advantageously it consists in a few drops.

In the sense of the present invention, the term pharmaceutically acceptable buffer agent is intended to mean any buffer agent, which is pharmaceutically acceptable as defined above and which allow the obtention of the desired pH. Suitable buffers include but are not limited to citrate buffer, tartrate buffer, lactate buffer and the like.

In a first embodiment of the present invention, the liquid pharmaceutical composition contains only the compounds (a), (b) and optionally (c), i.e. the taxane derivative, the solvent (water+ alcohol+ polyethoxylated fatty acid ester) and optionally the acid and/or the buffer agent.

In a second embodiment of the present invention, the liquid pharmaceutical formulation according to the present invention, contains also (d) one or more antioxidants, in particular a tocopherol-derived compound, advantageously α-tocopherol.

Suitable antioxidants include but are not limited to ascorbic acid, gentisic acid, tocopherol-derived compounds, butylated hydroxyanisole, butylated hydroxytoluene, citric acid and the like; advantageously it is a tocopherol-derived compounds, more advantageously α-tocopherol.

Advantageously, the liquid pharmaceutical formulation according to the present invention does not contain any polyethylene glycol and/or any polysorbate (e.g. Tween®) and/or any Emulphor® and/or any ester of polyethylene glycol and castor oil (e.g. Cremophor EL®) and/or any triacetin and/or any glycerol.

The present invention also concerns a method of preparation of the pharmaceutical formulation according to the present invention, wherein it consists in the following successive steps:

- preparation of the solvent (b) by mixing the water, the pharmaceutically acceptable alcohol and the pharmaceutically acceptable polyethoxylated fatty acid ester,

- optionally addition of the one or more antioxidants (d) and mixing, - addition of the taxane derivative (a), advantageously in the anhydrous or trihydrate form, in particular in the anhydrous form, and mixing and

- optionally addition of the pharmaceutically acceptable acid and/or buffer agent (c) in order to obtain a pH in the range of 3-8, advantageously in the range of 4-7.5, still more advantageously in the range of 4.5-6.5, in particular in the range 5-6.

Advantageously the: mixing of the water, the pharmaceutically acceptable alcohol and the pharmaceutically acceptable polyethoxylated fatty acid ester is carried out by methods well known by the one skilled in the art.

Advantageously the addition of the taxane derivative is as follow: almost all the solvent is added to a vessel containing the accurately weighed taxane derivative, followed by mixing and the filling up of the volume with the remainder of the solvent.

The present invention also concerns the liquid pharmaceutical formulation according to the present invention, for use as a medicament, advantageously intended for the treatment of a proliferative disorder, in particular cancer, more advantageously cancer with solid tumor, still more advantageously a cancer chosen in the group consisting of prostate cancer, breast cancer, head and neck cancer, pancreatic cancer, lung cancer, advantageously non-small lung cancer and advanced non small cell lung carcinoma, melanoma, gastric cancer, urothelial cancer, soft tissue sarcomas, AIDS-related Kaposi sarcoma and ovarian cancer, in particular a cancer chosen in the group consisting of prostate cancer, breast cancer, head and neck cancer and lung cancer, such as non-small lung cancer.

It concerns also a method for treating a proliferative disorder, in particular cancer, more advantageously cancer with solid tumor, still more advantageously a cancer chosen in the group consisting of prostate cancer, breast cancer, head and neck cancer, pancreatic cancer, lung cancer advantageously non-small lung cancer and advanced non small cell lung carcinoma, melanoma, gastric cancer, urothelial cancer, soft tissue sarcomas, AIDS-related Kaposi sarcoma and ovarian cancer, in particular a cancer chosen in the group consisting of prostate cancer, breast cancer, head and neck cancer and lung cancer, such as non-small lung cancer comprising the parenteral or intravenous or subcutaneous injection or infusion of a pharmaceutically effective amount of the liquid pharmaceutical formulation according to the present invention, to a patient in need thereof.

The taxane derivative can be used alone or in combination with another anticancer agent such as cyclophosphamide, trastuzumab, capecitabine, prednisone, prednisolone, camptothecin, epothilone, cisplatin, melphalan, etoposide, teniposide, fiudarabine, verapamil, cyclosporine, 5-fiuorouracil, fluorodeoxyuridine, doxorubicin or daunomycin and/or with external or internal irradiation, advantageously the other anticancer agent is selected in the group consisting of cyclophosphamide, trastuzumab, capecitabine, prednisone, prednisolone, cisplatin, 5-fiuorouracil, doxorubicin and mixture thereof.

EXAMPLE 1: PREPARATION OF LIQUID PHARMACEUTICAL FORMULATIONS ACCORDING TO THE PRESENT INVENTION WITH DIFFERENT WATER, POLYOXYETHYLENE STEARATE AND ETHANOL PROPORTIONS AND SOLUBILITY STUDY

Abbreviations:

Ethanol = EtOH ; Polyoxyethylene 40 stearate = P40S ;

0.9 % NaCl = NaCl ; 5 % Glucose = G5. I-COMBINATIONS OF H₂O/ ETOH / P40S WITHOUT DOCETAXEL

Some combinations of H₂O/ ETOH / P40S with increased amount of P40S in order to solubilize docetaxel were tested. In fact, P40S allows a better solubilization of Docetaxel and a better stability of the G5 and NaCl solution. The following liquid formulations have been tested:

Table 1: Composition of the mixture (i.e.; solvent) without Docetaxel

The appearance of each of these 5 mixtures has been visually controlled after preparation and after 24 hours and 96 hours of storage at ambient temperature.

Table 2: Evolution of the appearance of the mixtures without Docetaxel

These 5 mixtures are homogenous (no particles of P40S in suspension). P40S does not precipitate even after 4 days of storage at ambient temperature. These mixtures have been diluted 10 times in G5 and NaCl solutions in order to verify if P40S precipitate (storage at 4°C and at ambient temperature). Table 3: Evolution of the appearance of the diluted mixtures without Docetaxel

For all the different type of mixtures, dilution media (G5 or NaCl) and storage temperature, these different diluted mixtures remain limpid after 4 days. Therefore, P40S does not precipitate in these dilution mixtures.

II-COMBINATIONS OF H₂O/ ETOH / P40S WITH DOCETAXEL

The solubility of Docetaxel has been tested in the 2 following mixtures: D3 / El (docetaxel concentration of the mother solution = 10 mg/mL). The appearance of these formulations according to the present invention after dissolution is limpid (D'3 / E'l). These 2 mother solutions (D'3 / E'l) have been diluted in the G5 and NaCl media in order to reach the docetaxel concentration of 0.7 mg/mL.

The control of the appearance and dosage of the mother solutions and of the diluted solutions has been carried out immediately after preparation and after 72 hours of storage at ambient temperature. Table 4: Appearance and HPLC dosage of the mother solutions at Tn and Tγn

Table 5: Appearance and HPLC dosage of the diluted mother solutions at Tn and T 72h

As indicated in table 4, all the mother solutions of Docetaxel (D'3 / E'l) are totally stable after 72 hours of storage at ambient temperature. Docetaxel does not precipitate. As indicated in table 5, the preferred dilution media is G5 since E'l and D'3 diluted in G5 are stable after 72 hours of storage at 25°C. E'l and D'3 diluted in G or in NaCl are also stable after 72 hours of storage at 4°C

EXAMPLE 2: PREPARATION OF A 10MG/ML DOCETAXEL LIQUID PHARMACEUTICAL FORMULATION ACCORDING TO THE PRESENT INVENTION WITH PH = 6.9 AND STABILITY STUDY

The formulation is a 10 mg/mL Docetaxel formulation in the mixture (H₂OZEtOH/ Polyoxyethylene 40 stearate (P40S): 40/40/20: w/w/w)

The 10 mg/mL Docetaxel formulation was prepared according to the protocol described hereafter:

- The solvent (H₂O/EtOH/P40S : 40/40/20 : w/w/w) was prepared as follows : 40 g of deionised water, 40 g of ethanol and 20 g of P40S were mixed together and sonicated for 15 minutes in an Erlenmeyer.

Approximately 500 mg of accurately weighed Docetaxel were transferred into a 50.0 mL volumetric flask. 45 mL of the solvent were added and the mixture was sonicated until complete dissolution of the docetaxel. The solution was filled up to volume with the solvent. A stability study at different temperatures of storage has been conducted:

- Stability of the formulation at 25 ⁰C and 40 ⁰C over a period of 48 hours.

- Stability of the formulation at 5 ⁰C, 25 ⁰C / 60 % RH and 40 ⁰C / 75 % RH over a period of 1 month.

The following tests were carried out: • Appearance (visual examination).

• Docetaxel assay and related substances determination by HPLC/UV. The HPLC/UV method was previously qualified for the assay of Doxetaxel and determination of the impurities in the 10 mg/mL formulation. I - SHORT TERM STABILITY RESULTS:

Ll -APPEARANCE

The appearance of the formulation was determined (visual inspection) at To, after 24 hours and 48 hours of storage at 25 ⁰C and 40 ⁰C. The results are summarized in the following table 6.

Table 6: Appearance

No modification of the appearance of the formulation was observed after 48 hours of storage under both conditions. Therefore the formulation is physically stable after a minimum of 48 hours when stored at 25 ⁰C and at 40 ⁰C.

I.2-ASSAY OF DOCETAXEL AND RELATED SUBSTANCES

The assay of Docetaxel and the determination of its related substances were carried out using the previously qualified HPLC/UV method. Two independent sample solutions were prepared, each injected once in the chromatographic system. The reporting threshold for impurities is 0.05 %. The results obtained, expressed as the mean of two independent determinations, are reported in tables 7 and 8. The Docetaxel content (expressed as % w/w) is calculated relative to the theoretical concentration of the solution taking into account of the actual weighing of Docetaxel used for the preparation of the formulation.

Table 7: Docetaxel content

Table 8: Docetaxel related substances determination

The content of the impurities is expressed versus the nominal content of Docetaxel in the formulation (i.e. 10 mg/mL).

The temperature of storage has an impact on the stability of the 10 mg/mL Docetaxel formulation. In fact, Docetaxel is known to be instable at high temperature that is why Taxotere® has a storage temperature of less than 25°C. However, in the formulation according to the present invention, the slow decrease in Docetaxel content which is observed within 48 hours of storage at 40⁰C is not significant (the Docetaxel content being higher than 90%) and there is no significant increase of the impurities (less than

2%).

Storage at 25°C of this formulation shows no significant modification of the Docetaxel content after 48 hours, even if a slight increase (however not significant) of impurities is observed.

Therefore the formulation according to the present invention is chemically stable after storage of at least 48 hours at 40⁰C.

II - 1 MONTH STABILITY RESULTS

The stability of the formulation was also studied during 1 month under three storage conditions: 5°C; 25°C / 60 % RH; 40⁰C / 75 % RH.

ILl -APPEARANCE

The appearance (visual inspection) of the formulation was determined again after 1 month of storage. The results are summarized in the following table 9.

Table 9: Appearance

(*): manual shaking of the solution allows dissolution of the flakes. No modification of the appearance of the formulation was observed after 1 month of storage at 25 ⁰C / 60 % RH and 40 ⁰C / 75 % RH, whereas a slight precipitation was observed for the same formulation stored at 5°C. This precipitation (flakes) re-dissolves after manual shaking of the solution. Therefore the formulation is physically stable after a minimum of one month when stored under accelerated conditions (40⁰C / 75% relative humidity) or under conditions of25 °C / 60 % RH.

II.2-ASSAY OF DOCETAXEL AND RELATED SUBSTANCES The assay of Docetaxel and the determination of its related substances were carried out using the previously qualified HPLC/UV method. The reporting threshold for impurities is 0.05 %. Two independent sample solutions were prepared, each injected once at To and twice at Ti _month. The results obtained, expressed as the mean of two independent determinations, are reported in tables 10 and 11. The Docetaxel content is calculated relative to the theoretical concentration of the solution taking into account of the actual weighing of Docetaxel used for the preparation of the formulation.

Table 10: Docetaxel content

Table 11: Docetaxel related substances determination

The content of the impurities is expressed versus the nominal content of Docetaxel in the formulation (i.e. 10 mg/mL). The main impurity is Epi-docetaxel which is the known major impurity of Docetaxel formulation.

The temperature of storage has an impact on the stability of the formulation as previously seen in the short term storage. The storage of formulation for 1 month at 25 ⁰C and 40 ⁰C showed an increase of impurities and the appearance of new impurities, especially at 40 ⁰C. A slight increase of the impurity was also observed for the formulation stored at 5 ⁰C. However such increase is not significant since it is less than 1 % after storage of at least one month at 5°C, less than 5% after storage of at least one month at 25°C and 60% relative humidity and less than 20% after storage of at least one month at 40⁰C and 75% relative humidity. Furthermore the docetaxel content of the formulation does not vary after storage of at least one month at 25°C and 60% relative humidity and decreases after storage of at least one month at 40⁰C and 75% relative humidity but not significantly. Therefore the formulation is chemically stable.

II.3-PH MEASUREMENT

The pH of the formulation "as is" after 1 month of storage at 5°C was measured.

After 1 month of storage at 5°C, the pH of the 10 mg/mL Docetaxel formulation was 6.9.

EXAMPLE 3: PREPARATION OF A DILUTED SOLUTION IN 0.9 % NaCl CONTAINING THE LIQUID PHARMACEUTICAL FORMULATION ACCORDING TO EXAMPLE 1 AND STABILITY STUDY

A 0.7 mg/mL Docetaxel diluted solutions in 0.9 % NaCl was prepared by dilution of the formulation of example 1 as follows: transfer 700 μL of the formulation according to example 1 into a 10.0 mL volumetric flask and fill up to volume with 0.9 % NaCl.

A stability study at 5°C and 25 ⁰C of storage over a period of 48 hours has been conducted.

The following tests were carried out:

• Appearance (visual examination). • Docetaxel assay and related substances determination by HPLC/UV.

The HPLC/UV method was previously qualified for the assay of Doxetaxel and determination of the impurities in the diluted formulation.

The following instruments were used for this study:

I - SHORT TERM STABILITY RESULTS: Ll -APPEARANCE

The appearance (visual inspection) of the Docetaxel diluted solutions (0.7 mg/mL) in 0.9 % NaCl was determined at To, after 24 hours and 48 hours of storage at 25°C and 5°C. The results are summarized in the following table 12. Table 12: Appearance

No modification of the appearance of the diluted solutions in 0.9 % NaCl was observed after 48 hours at 5°C. However, a precipitation was observed for diluted solutions in 0.9 % NaCl after 24 hours of storage at 25°C. Therefore the diluted solution is physically stable after 48 hours of storage at 5°C.

I.2-ASSAY OF DOCETAXEL AND RELATED SUBSTANCES

The assay of Docetaxel and the determination of its related substances were carried out using the previously qualified HPLC/UV method.. Two independent sample solutions were prepared, each injected once in the chromatographic system. The reporting threshold for impurities is 0.05 %. The results obtained, expressed as the mean of two independent determinations are reported in tables 13 and 14. The Docetaxel content is calculated relative to the theoretical concentration of the solution taking into account of the actual weighing of Docetaxel used for the preparation of the formulation. Table 13: Docetaxel content

Table 14: Docetaxel related substances determination

The assay of Docetaxel in diluted solution in 0.9% NaCl, stored 24 hours at 25 ⁰C, showed an important decrease that is correlated to the precipitation observed at the same time. The storage at 5°C of the Docetaxel diluted solution in 0.9 % NaCl showed a decrease in Docetaxel content after 48 hours, even if the determination of impurities did not show a significant variation of the impurity after 48 hours (and no additional impurities were detected). This decrease could be explained by a slight precipitation of Docetaxel that could not be detected during the visual inspection test at each stability point. However, since such a decrease is not significant, the Docetaxel diluted solution in 0.9 % NaCl is chemically stable after 48 hours storage at 5°C. EXAMPLE 4: PREPARATION OF A DILUTED SOLUTION IN 5 % GLUCOSE CONTAINING THE LIQUID PHARMACEUTICAL FORMULATION ACCORDING TO EXAMPLE 1 AND STABILITY STUDY

A 0.7 mg/mL Docetaxel diluted solutions in 5 % glucose was prepared by dilution of the formulation of example 1 as follows:

Transfer 700 μL of the formulation according to example 1 into a 10.0 mL volumetric flask and fill up to volume with 5 % Glucose. A stability study at 5°C and 25 ⁰C of storage over a period of 48 hours has been conducted. The following tests were carried out:

• Appearance (visual examination).

• Docetaxel assay and related substances determination by HPLC/UV. The HPLC/UV method was previously qualified for the assay of Doxetaxel and determination of the impurities in the diluted formulation. The following instruments were used for this study:

I - SHORT TERM STABILITY RESULTS: Ll -APPEARANCE

The appearance (visual inspection) of the Docetaxel diluted solutions (0.7 mg/mL) in 5 % glucose was determined at To, after 24 hours and 48 hours of storage at 25°C and 5°C. The results are summarized in the following table 15. Table 15: Appearance

No modification of the appearance of the diluted solutions in 5 % Glucose was observed after 48 hours at 5°C. However, a precipitation was observed for diluted solutions in 5 % Glucose after 24 hours of storage at 25°C. Therefore the diluted solution is physically stable after 48 hours of storage at 5°C.

I.2-ASSAY OF DOCETAXEL AND RELATED SUBSTANCES

The assay of Docetaxel and the determination of its related substances were carried out using the previously qualified HPLC/UV method. Two independent sample solutions were prepared, each injected once in the chromatographic system. The reporting threshold for impurities is 0.05 %. The results obtained, expressed as the mean of two independent determinations are reported in tables 16 and 17. The Docetaxel content is calculated relative to the theoretical concentration of the solution taking into account of the actual weighing of Docetaxel used for the preparation of the formulation.

Table 16: Docetaxel content

Tαά/β i 7: Docetaxel related substances determination

The assay of Docetaxel in diluted solution stored 24 hours at 25 ⁰C showed an important decrease that is correlated to the precipitation observed at the same time. The storage at 5°C of Docetaxel diluted solution in 5 % Glucose showed no significant variation in Docetaxel content after 48 hours. Moreover, the determination of impurities did not show a significant variation of the impurity after 48 hours at 5°C and no additional impurities were detected.

The Docetaxel formulation diluted in 5 % Glucose is chemically stable for at least 48 hours at 5⁰C. EXAMPLE 5: PREPARATION OF LIQUID PHARMACEUTICAL FORMULATIONS ACCORDING TO THE PRESENT INVENTION WITH DIFFERENT PH AND STABILITY STUDY

10 mg/mL Docetaxel formulations (4 formulations) were prepared for the stability assessment according to the protocol described hereafter:

- The solvent (H₂O/EtOH/P40S : 40/40/20 : w/w/w) was prepared as follows : 80 g of deionised water, 80 g of ethanol and 40 g of P40S were mixed together and sonicated for 20 minutes in an Erlenmeyer. - Approximately 250 mg of accurately weighed Docetaxel were transferred into a 25.0 mL volumetric flask. 20 mL of the solvent were added and the mixture was sonicated until complete dissolution of the docetaxel. The solution was filled up to volume with the solvent.

In order to avoid the formation of oxidative degradation products of Docetaxel, the solvents were purged under N₂ and the formulations were also stored under N₂.

These formulations were adjusted to their target pH (i.e. 5.5 / 6.0 / 6.5) with a few drops of a 0.1 M solution of oxalic acid, except the fourth formulation that was not adjusted to pH (reference, pH 7.3).

Each formulation was sampled into 4 vials (5 mL per vial) and sealed under inert atmosphere (N₂). For each formulation tested, two vials were stored at 4 ⁰C for 72 hours (considered as "To") and two vials were stressed at 50 ⁰C for 72 hours. The stability of the formulations brought to pH 5.5, pH 6.0 and pH 6.5 as well as the formulation prepared without pH adjustment (i.e. pH 7.3) was determined after 72 hours of storage at 50⁰C by comparison with the same formulations stored 72 hours at 5°C (considered as "T₀").

The stability of the formulation brought to pH 5.5, pH 6.0 and pH 6.5 was determined after 1, 2, 3, 4, 5 and 6 months of storage at 5°C and 25°C/60 % RH and after one month of storage at 30°C/65 % RH and 40°C/75 % RH. I- SHORT TERM STABILITY RESULTS:

1-1 PH MEASUREMENT

The pH of the 4 formulations was determined after preparation (before sampling under N₂) and after 72 hours of storage at 4°C and at 50⁰C in order to assess the pH stability of each formulation. The results are summarized in the following table 18.

Table 18: pH measurement of formulation

Whatever the formulation, no significant evolution of the pH was observed after 72 hours of storage at 4 ⁰C or at 50 ⁰C. I-2-ASSAY OF DOCETAXEL AND RELATED SUBSTANCES

The assay of Docetaxel in the samples obtained for the stability study as well as the determination of its related substances were carried out using the previously qualified HPLC/UV method. The two vials stored 72 hours at 4 ⁰C are considered as To. Each solution was injected once in the chromatographic system. The Docetaxel content of these solutions, expressed in mg/mL, was determined as well as the recovery between the value obtained after 72 hours of storage at 50 ⁰C and the value obtained for the reference samples, stored at 4 ⁰C. The amount of impurities, expressed as weight percentage versus Docetaxel nominal content in the formulations (i.e. 10 mg/mL) was also determined for all these solutions. The results obtained (mean of two independent determinations) are reported in tables 19 and 20.

Table 19: Docetaxel content

Table 20: Docetaxel related substances determination

The results presented in the tables show that pH adjustment has an impact on the stability of the 10 mg/mL Docetaxel formulation. Lower pH values lead to more stable formulations as indicated by the recoveries obtained for the assay of Docetaxel after 72 hours of storage at 50 ⁰C. An increase of the impurities is observed in each sample after storage at 50 ⁰C but this increase is lower for lower pH values.

Therefore the adjustment to acid pH with oxalic acid of the 10 mg/mL Docetaxel formulation according to the present invention significantly reduces the degradation of Docetaxel. II- LONG TERM STABILITY RESULTS

II-l pH MEASUREMENT

The pH measurement of the three formulations was determined after preparation and sampling under N₂ (T₀) and after one month of storage at 5°C, 25°C/60 %RH, 30°C/65 % RH, 40°C/75 %RH, two months, three months, four months, five months and six months of storage at 5°C and 25°C/60 % RH. In order to assess the pH stability of each formulation the results are summarized in table 21.

Table 21 : pH measurement of formulation

Whatever the formulation, no significant evolution of the pH was observed even after 3 months or 6 months of storage at 5°C or at 25°C/60 RH.

II-2 ASSAY OF DOCETAXEL AND RELATED SUBSTANCES

The assay of Docetaxel in the samples obtained for the stability study as well as the determination of its related substances were carried out using the previously qualified HPLC/UV method. The two vials stored 72 hours at 4 ⁰C are considered as To. Each solution was injected once in the chromatographic system. The Docetaxel content of these solutions, expressed in mg/mL, was determined as well as the recovery between the value obtained after one month, two months, three, four, five and six months of storage at 5°C and at 25°C/60 % RH and after one month of storage at 30°C/65 % RH and 40°C/75 % RH. The amount of impurities, expressed as weight percentage versus Docetaxel nominal content in the formulations (i.e. 10 mg/mL) was also determined for all these solutions. The results obtained (mean of two independent determinations) are reported in tables 22 and 23. Table 22: Docetaxel content

Table 23: Docetaxel related substances determination

The results presented in the tables 22 and 23 show that pH adjustment has an impact on the stability of the 10 mg/mL Docetaxel formulation.

Lower pH values lead to more stable formulations as indicated by the recoveries obtained for the assay of Docetaxel after 1 month of storage at 40°C/65 % RH.

An increase of the impurities is observed in each sample after storage at 40°C/65 % RH but this increase is lower for lower pH values.

However, surprisingly almost no increase of the impurities is observed in each sample after storage for at least 3 months at 5°C and even for at least 6 months at 5°C. Therefore, all the formulations are chemically stable after storage of at least 3 months and even at least 6 months at 5°C (less than 0.5 % by weight of impurity), in particular at lower pH values. Therefore the adjustment to acid pH with oxalic acid of the 10 mg/mL Docetaxel formulation according to the present invention significantly reduces the degradation of Docetaxel.

Claims

1. A liquid pharmaceutical formulation comprising:

(a) a taxane derivative or a pharmaceutically acceptable salt thereof, (b) a solvent consisting in the mixture of a pharmaceutically acceptable alcohol, a pharmaceutically acceptable polyethoxylated fatty acid ester and 30-50 % by weight of water based on the total weight of the solvent.

2. The liquid pharmaceutical formulation according to claim 1, wherein the pharmaceutically acceptable alcohol is ethanol.

3. The liquid pharmaceutical formulation according to anyone of claims 1 or 2, wherein the taxane derivative is docetaxel.

4. The liquid pharmaceutical formulation according to anyone of claims 1 to 3, wherein the pharmaceutically acceptable polyethoxylated fatty acid ester is a pharmaceutically acceptable po Iy oxy ethylene stearate, in particular polyoxy ethylene 40 stearate.

5. The liquid pharmaceutical formulation according to anyone of claims 1 to 4, wherein it further contains (c) a pharmaceutically acceptable acid and/or a buffer agent.

6. The liquid pharmaceutical formulation according to claim 5, wherein the pharmaceutically acceptable acid is an organic acid, advantageously oxalic acid.

7. The liquid pharmaceutical formulation according to anyone of claims 1 to 6, wherein the pH is of between 3 to 8, advantageously of between 4 to 7.5, still more advantageously of between 4.5 and 6.5.

8. The liquid pharmaceutical formulation according to anyone of claims 1 to 7, wherein the solvent consists in a mixture of 30-50 weight % of water, of 30-60 weight % of the pharmaceutically acceptable alcohol and of 10-40 weight % of the pharmaceutically acceptable polyethoxylated fatty acid ester, advantageously of 35-40 weight % of water, 35-40 weight % of the pharmaceutically acceptable alcohol and 20- 30 weight % of the pharmaceutically acceptable polyethoxylated fatty acid ester.

9. The liquid pharmaceutical formulation according to anyone of claims 1 to 8 wherein the concentration of the taxane derivative is in the range of from 5 to 15 mg/ml, advantageously in the range of 10 to 15 mg/ml, still more advantageously of 10 mg/ml.

10. The liquid pharmaceutical formulation according to anyone of claims 1 to 9, wherein it is retains at least 75% of the taxane derivative potency after storage for one month at 40 ⁰C and 75% relative humidity, more advantageously at least 80%, still more advantageously at least 90%.

11. The liquid pharmaceutical formulation according to anyone of claims 1 to 10, wherein it further contains (d) one or more antioxidants.

12. A method of preparation of the pharmaceutical formulation according to anyone of claims 1 to 11, wherein it consists in the following successive steps:

- preparation of the solvent (b) by mixing water, the pharmaceutically acceptable alcohol and the pharmaceutically acceptable polyethoxylated fatty acid ester,

- optionally addition of the one or more antioxidants (d) and mixing,

- addition of the taxane derivative (a), advantageously in the anhydrous form, and mixing and - optionally addition of the pharmaceutically acceptable acid and/or buffer agent (c) in order to obtain a pH in the range of 3 to 8, advantageously in the range of 4 to 7.5, still more advantageously in the range of 4.5 to 6.5.

13. The liquid pharmaceutical formulation according to anyone of claims 1 to 11, for use as a medicament, advantageously intended for the treatment of a proliferative disorder, in particular cancer, still more advantageously a cancer chosen in the group consisting of prostate cancer, melanoma, gastric cancer, urothelial cancer, soft tissue sarcomas, breast cancer, head and neck cancer, pancreatic cancer, lung cancer, AIDS- related Kaposi sarcoma and ovarian cancer.

14. An infusion solution which contains a liquid pharmaceutical formulation according to anyone of claims 1 to 11 and an infusion diluent, advantageously selected from dextrose or sodium chloride aqueous solution.

15. The use of a mixture of a pharmaceutically acceptable alcohol, water and a pharmaceutically acceptable polyethoxylated fatty acid ester as a solvent in a liquid pharmaceutical formulation containing a taxane derivative.