TW201023911A - Liquid formulation containing a taxane derivative - Google Patents

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

201023911 · VI. Description of the invention: * Technical Field of the Invention The present invention relates to a liquid pharmaceutical formulation containing a taxane derivative (especially docetaxel) and water, and the liquid pharmaceutical formulation The object is physics and chemical stability. This formulation is intended for parental administration 〇 [Prior Art] Taxane derivatives, such as docetaxel and paclitaxel, are well-known drugs for the treatment of malignant tumors. For example, docetaxel is marketed by Sanofi-Aventis under the trade name Taxotere®, while paclitaxel is marketed by Bristol-Myers Squibb ( Bristol-Myers-Squibb) is marketed under the trade name Taxol®. The low water solubility of these drugs is well documented. Specifically, docetaxel (CAS 114977-28-5) is an anti-tumor tincture belonging to the taxois family (taxoi (i family) identified in 1986 as a substitute for paclitaxel. Docetaxel It is prepared by a semi-synthetic process initiated from the extraction of precursors from the needles of Taxus baccata. The chemical name of docetaxel is benzoic acid (2b, 5b, 7b, 10b' 13a)-4 -Ethyloxy-13(((2R,3S)-3-[(t-butoxycarbonyl)amino]-2-hydroxy-3-phenylpropanyl)oxy)-indole, 7, 1 〇_Trihydroxy-9-tertiaryoxy-5,20-epoxy yew-u-ene-2-yl ester [(2b, 5b, 7b, 10b, 13a)-4-Acetoxy-13 ((2R) , 3S)-3-[(tert -butoxycarbony1)ami no]-2-hydroxy-3-pheny1propanoy1 3 94738 201023911 * * )oxy)-l,7,10-trihydroxy-9-oxo-5, 20-epoxytax- Ll-en- 2-yl benzoate], and it has the following chemical structure:

Docetaxel is a white to nearly white powder with an experimental formula of C43H53N0h. Docetaxel is very lipophilic and is almost insoluble in water. Docetaxel is first disclosed in EP 0 253 738. Docetaxel acts by interfering with the microtubular network within the cell, which is required for mitotic and interphase cellular functions. Docetaxel binds to the free tubulin and promotes the assembly of tubulin into a stable microtubule while inhibiting its breakdown. This results in the production of microtubules that do not have a normal function and results in stabilization of the microtubules, which in turn results in inhibition of mitosis (replication) within the cells. The binding of docetaxel to the microtubules does not alter the number of protof ibrof ilaments within the bound micro-organ, which is different from most of the currently used clinically used spindle toxins. Therefore, it is widely understood that the docetaxel is a useful and effective oncology agent whether used alone or in combination with other agents. The commercially available Taxotere® was first approved in 1996. 4 94738 201023911 • Taxotere® is formulated as a concentrate to be diluted with a solvent vial. - The concentrate solution is a clear yellow (clear_yell〇w) to brownish-yellow viscous solution. Each milliliter contains 4 mg of '(mg) of docetaxel and 1 〇 4 mg of polysorbate 8 〇. - _ The diluent used for Taxotere* is 13% ethanolic water infiltration for injection. The medical practitioner must aseptically withdraw all of the contents of the diluent vial, transfer it to a vial containing the polycetaxel concentrate, and mix the ingredients to produce 1 mg/mL. Polyene purple shirt static solution. The mixture must be inverted for 45 seconds to fully mix the seepage. The mixture should not be shaken, causing foaming due to shaking and loss of potential cones. The intermediate solution is then diluted in a round bag of 250 mL 'containing 0.9% sodium sulphate solution or 5% dextrose solution to a polyglycoside concentration of 0.3 to 0.74 mg/mL. . Therefore, the Taxotere® formulation requires many operations prior to injection, which increases the risk of contamination and foaming and increases the risk of human error. Based on the fact that docetaxel is almost insoluble in water, numerous other attempts have been made to develop suitable injectable formulations. For example, it is known that paclitaxel is soluble in ethanol. Therefore, one of the other formulations developed for the first time is 50% ethyl yeast and 50% Emulphor EL® (made by reacting sesame oil with ethylene oxide). Nonionic solubilizers and emulsifiers). EP 0 593 656, EP 0 593 601 and EP 〇 671 912 disclose a docetaxel formulation in which the amount of ethanol has been reduced and the formulation is contained in a single compartment or two compartments. Surfactant such as

5 9473S 201023911 Polysorbate (eg Tween®), polyoxyethylene glycol derivatives (eg Emulphor®) or polyethoxylated cannabis oil (eg Cremophor EL®). However, Cremophor®-type surfactants are known to cause allergic problems in a large number of patients. Cremophor® may contain polyethoxylated fatty acid esters. However, if any polyethoxylated fatty acid ester is present, it is present in very small amounts. Furthermore, the docetaxel formulation containing Cremophor® does not contain water. EP 0 932 399 discloses pharmaceutical compositions comprising a water-soluble conjugate of an antitumor agent and a ruthenium polyglycolic acid polymer. Other attempts to stabilize the injectable solution of docetaxel include the use of one or more diols (WO 2006/133510), degradation inhibitors such as organic acids having a pKa between 2.5 and 4.5 (W0 2007/085067 ), tetrahydrofuran 0 (glycofurol) (W0 2007/020085), fatty acid (EP 1 862 183), stabilizers such as chelating agents, citrate, sodium pyrophosphate or sodium gluconate, EDTA or Sodium vaporized (W0 2007/027941), buffer (W0 2007/124700) or acid to obtain a pH between 3 and 6 (W0 2008/ ❹ 026048). U.S. Patent No. 5,922,754 discloses the composition of paclitaxel, which extends the period of stability. Preferred organic solvents include triacetin, glycerin and solutol HS-15. The acid used is citric acid. According to Table 1, the water content is at most 25% by weight, and preferably in the range of 8% by weight to 10% by weight, and preferably the composition contains 8.9% by weight of water. This composition may contain a solvent other than the fatty acid-derived PEG ester. However, 94738 6 201023911 ' • and ' is only exemplified by s〇lut〇i HS-15. Further, all of the examples provided S contained diacetin vinegar and propylene glycol. This was confirmed by Table 3, which shows that the formulation containing no glycerin (formulation 3c or 4a) was unstable after more than 48 hours. Therefore, from this patent, it is not explicitly or implicitly used that the water content exceeds 25% by weight. Further, there is no express or suggestion that a composition for prolonging the stability period can be obtained without using triacetin, glycerin, and slutol HS_15.专利 Patent application WO 02/43765 discloses pharmaceutical formulations comprising paclitaxel and its derivatives such as docetaxel. In particular, the pharmaceutical formulation may be in the form of a liquid concentrate which is diluted in an aqueous medium prior to use. These liquid concentrates may contain ethanol and a taxane solubilizing agent. Its water content is less than 5% by weight. This patent application further states that other excipients, especially aqueous solutions, can be added to the concentrate. However, the water content is not indicated. Further, in the example of the aqueous formulation of paclitaxel, the paclitaxel is contained in an amount of from 0.2 mg/mL to 3 mg/mL. Thus the formulation is an infusion solution designed for administration of paclitaxel. Further, no examples disclose the use of PEG monoester alone as the sole paclitaxel solubilizer. Furthermore, none of the examples relate to docetaxel. Finally, the stability of the composition was not revealed. Thus, this document does not express or imply that such compositions containing high amounts of water and high amounts of paclitaxel are extended for extended periods of time, especially without the use of polysorbates or other products of the same type. Finally, this composition does not contain any acid. However, as of now, none of the formulations tried have achieved a successful product that can compete with Taxotere®. Therefore, alternative docetaxel formulations with the required physicochemical properties and shelf life of 94738 7 201023911 are still urgently needed. Furthermore, in the prior art, all formulations except the emulsion did not contain any water because docetaxel was known to be unstable in water. Further, in the case of the emulsion, the surfactant used is slightly toxic, and precipitation of the drug occurs upon dilution. SUMMARY OF THE INVENTION The inventors of the present invention have unexpectedly discovered a method of adding at least 30% by weight of water to a pharmaceutical formulation containing docetaxel by using a specific surfactant: a polyethoxylated fatty acid ester. While still maintaining its stability. Therefore, this formulation will be easier to handle when preparing an infusion. In addition, the formulation is present in a vial of solution and therefore does not need to be diluted prior to addition to the infusion solution, so it is not necessary to perform excessive manipulation of the docetaxel formulation prior to use. Therefore, there is no risk of blistering. Accordingly, the present invention relates to a liquid pharmaceutical formulation comprising (a) a taxane derivative or a pharmaceutically acceptable salt thereof, (b) a solvent which is a pharmaceutically acceptable alcohol, a pharmaceutically acceptable poly An ethoxylated fatty acid ester and a mixture of 30 to 50% by weight water based on the total weight of the solvent. [Embodiment] In the concept of the present invention, the term "taxane derivative" means any natural, semi-synthetic or synthetic drug belonging to the paclitaxel-like family (that is, having a taxane skeleton), and the like. mixture. The taxane derivative can be isolated from a natural source such as a Yew tree (such as paclitaxel), or isolated from a cell culture or chemically synthesized such as Docetaxel 8 94738 201023911 alcohol, And its system is difficult to dissolve in water. Examples of such taxane derivatives include paclitaxel, docetaxel, 7-epipaclitaxel, 10-desacetyl-paclitaxel, 10-deacetylated paclitaxel , baccatin III, 10-de, ethionyl-baccatin III, 7-epidocetaxel, ortataxel, and mixtures thereof. Preferably, it has the structure of the following formula (I):

Wherein 'R represents a hydrogen atom or an ethylenic group, or one of R2 represents a third isobutoxycarbonylamino group or a claudamine group, and the other represents a group. Preferably, the taxane derivative is selected from the group consisting of paclitaxel, docetaxel, orta paclitaxel, and mixtures thereof, more preferably selected from the group consisting of paclitaxel, docetaxel, and mixtures thereof. The taxane derivative is more preferably a succulent paclitaxel. Preferably, the taxane derivative used in the formulation of the invention may be in any possible form, crystallized (as disclosed in WO 2007/044950) or in the form of amorphous or any polymorph or Mixtures of such forms, hydrates, hemihydrates, dihydrates, trihydrates, solvates or anhydrous forms. Preferably, especially in the case of docetaxel, the taxane derivative 94738 9 201023911 organism is in the form of an anhydrous form or a trihydrate, more preferably in the form of an anhydrous form, prior to being added to the liquid pharmaceutical formulation of the present invention. Preferably, especially in the case of dilute paclitaxel, the taxane derivative is in a crystalline or amorphous state or a mixture thereof prior to being added to the liquid pharmaceutical formulation of the present invention. In the context of the present invention, the term "pharmaceutically acceptable" means that there is a formulation suitable for use in a pharmaceutical composition which is generally safe and non-toxic, and which is not biologically or otherwise undesirable. And those who are acceptable for veterinary and human use. In the concept of the present invention, the term "pharmaceutically acceptable sulfonium salt" of the compound means a "pharmaceutically acceptable" salt as defined above, and the salt has the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, etc., or with organic acids such as ascorbic acid, benzoic acid, aspartic acid, oxalic acid, Benzenesulfonic acid, tartaric acid, diatHaz〇ic acid, glutamic acid, lactic acid 'maleic acid, succinic acid, fumaric acid, citric acid, ethylenediaminetetraacetic acid, malic acid, mandelic acid, sulphur An acid addition salt formed by acid, mucic acid, pantothenic acid, p-toluenesulfonic acid, acetic acid, gluconic acid, ethanesulfonic acid, propionic acid, salicylic acid, or the like; or (2) an acid present in the parent compound a salt formed when a proton is substituted with a metal ion such as an alkali metal ion, an alkaline earth metal ion or an aluminum ion, or a salt formed when an acid proton present in the parent compound is coordinated with an organic or inorganic base. Acceptable organic bases include diethanolamine, ethanolamine, N-methyl reduced glucosamine, triethanolamine, aminobutyric triol (formed as 3111) and the like. Acceptable inorganic bases include aluminum hydroxide, hydrogen 94738 10 201023911 calcium oxide, potassium hydroxide, sodium carbonate, and sodium hydroxide. It should be understood that all of the above mentioned artisan and the polymorphic form of the same acid addition salt: the salt is included in the concept of the present invention, the term "pharmaceutically acceptable" The definition of "pharmaceutically acceptable >" is intended to include, but is not limited to, propylene glycol, benzyl alcohol, and the like: a mixture of examples. Preferably, it is selected from the group consisting of ethanol alcohol and its e. More preferably, the proportion of the sterol and the mixture thereof is preferably from 30% by weight to 75% by weight of the solvent: % by weight of the alcohol to 6. Within the range of % by weight, it is better than °: within the range of 30% by weight, more preferably 35% 』 = • 在 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 ? ° Weight: ' Especially 4. The ratio of fatty acid g to 彳❸ is the concept of polyethoxylate in the present invention. The term "fatty fatty acid vinegar" means the definition of the above; = polyethoxylated polyethoxylated fatty acid monoacetate or The second and second can be connected to the party. The polyethoxylated fatty acid s is intended to be produced by mixing water with alcohol. In particular, the present invention is characterized in that the poly(ethoxy) group of the acid formula (1) or (2) is: C-oxygen (4) has the following (1) R-(C0)-(0CH2CH〇n-0H,

(2) Ri-(CO)-(OCH2CH2)n-〇-(CQ), R where R, Ri and R2 are independent of each other and the η system represents the stimuli of the oxygen-extended ethyl unit fatty acid or埽 is between 9 and 160, and better is between γ length. η is more than lanthanum (7) between U and 150, especially between 94 and 11 201023911 between 20 and 60. The fatty acid can be saturated or unsaturated and/or hydroxylated.

Preferably, the fatty acid is not hydroxylated and therefore is not SOLUTOL HS-15. The most common saturated fatty acids are the following: Common name IUPAC Name Chemical structure abbreviation melting point rc ) Butyric acid butyric acid CH3 (CH2) 2C00H C4 : 0 - 8 Linoleic acid caproic acid CH3 (CH2) 4C00H C6 : 0 -3 Alanine Octanoic acid CH3(CH2)6C00H C8 : 0 16 to 羊 succinic acid decanoic acid CH3(CH2)8C00H CIO 0 31 lauric acid dodecanoic acid CH3 (CH2), 〇COOH C12 0 44 to 46 myristic acid tetradecanoic acid CH3 ( CH2)i2C00H C14 0 58. 8 palmitic acid hexadecanic acid CH3(CH2)hC00H C16 0 63 to 64 stearic acid octadecanoic acid CH3(CH2)ibC00H C18 0 69. 9 arachidic acid twenty acid CH3(CH2)18C00H C20 0 75. 5 eucal acid tauric acid CH3(CH2)2dC00H C22 0 74 to 78 掏 tar acid tartrate CH3(CH2)22C00H C24 0 Therefore, R, Ri and R2 are preferably a direct bond or a branch bond. In particular, a direct bond C3-C23 alkyl or alkenyl group, more preferably an alkyl group, especially a Cu-C23 alkyl or alkenyl group, preferably an alkyl group, more preferably a C15-C21 alkyl group or an alkenyl group, especially an alkane. base. In particular, the fatty acid is a saturated fatty acid and is a long chain fatty acid, i.e. having more than 16 carbon atoms. The pharmaceutically acceptable polyethoxylated fatty acid ester is preferably a pharmaceutically acceptable polyoxyethylidene ethyl stearate, polyoxyethylidene palmitate or a mixture thereof, more preferably in medicine Accepted polyoxyethylidene ethyl stearate. 12 94738 201023911 In the solvent of the present invention, the proportion of the polyethoxylated fatty acid ester is preferably * in the range of 10% by weight to 40% by weight, more preferably 20% by weight / 30% by weight Within the range, it is more preferably 20% by weight or 30% by weight, especially 20% by weight. Preferably, the polyethoxylated fatty acid is the sole surfactant in the formulation of the invention. In the concept of the present invention, the term "pharmaceutically acceptable polyoxyethylidene ethyl stearate" means any polyoxyethylidene stearate, especially poly(oxyethyl)ethyl monostearate. Ester, polyoxyethylidene distearate or mixtures thereof, preferably polyoxyethylidene monostearate, as defined above as "pharmaceutically acceptable" and soluble in water and alcohol In the mixture. Polyoxyethylidene stearate is a nonionic surfactant produced by the polyethoxylation of stearic acid. Examples of such polyoxyethylidene ethyl stearate include, but are not limited to, polyoxyethylidene ethyl stearate, polyoxyethylidene 20 stearate, polyoxyethylidene 30 stearate , polyoxyethylene ethyl 40 stearate, q polyoxyethylene ethyl stearate, polyoxyethylene ethyl 100 stearate, polyoxyethylene ethyl stearate, polyoxyethylene Base 32 distearate and mixtures thereof. Preferably, the polyoxyethylidene stearate is selected from the group consisting of polyoxyethylene ethyl 20 stearate, polyoxyethylene ethyl 30 stearate, polyoxyethylene ethyl 40 stearate, polyoxygen More preferably, the group consisting of polyethyl epoxide ester and a mixture thereof is selected from the group consisting of polyoxyalkylene ethyl 40 stearate, polyoxyethylidene ethyl stearate, and mixtures thereof. And, more preferably, it is polyoxyethylidene ethyl 40 stearate. In the solvent, the proportion of water is preferably in the range of from 30% by weight to 50% by weight of 13 94738 201023911. More preferably, it is in the range of from 35 to 45% by weight, still more preferably 35% by weight or 4% by weight, especially 4% by weight. In a particular embodiment of the invention, the ratio of water to alcohol in the solvent is the same. In another particular embodiment of the invention, the ratio of water in the solvent is higher than the ratio of polyethoxylated fatty acid ester. The water used is preferably water for injection. Preferably, the solvent of the liquid pharmaceutical formulation of the present invention is 3% by weight t 5% by weight of water, 30% to 60% by weight of pharmaceutically acceptable = 乂 and 10% to 4% by weight a mixture of pharmaceutically acceptable polyethoxylated (tetra), preferably from 35% to 4% by weight water, &% to 40% by weight of pharmaceutically acceptable alcohol and 20% by weight to 30% by weight of a pharmaceutically acceptable polyethoxylated fatty acid_mixture, more preferably 40% by weight or 35% by weight water, 4% by weight or &% by weight of a medically acceptable alcohol and 20 Weight "or 30% by weight of a pharmaceutically acceptable, polyethoxylated fatty acid vinegar mixture, more preferably 40% by weight, 740% by weight of a pharmaceutically acceptable alcohol and acceptable polyethoxylation" a mixture of fat _. Since the liquid medical formulation of the present invention contains water, the formulation may be referred to as an aqueous pharmaceutical formulation. Preferably, the mixture of hydrazine, alcohol and polyoxyethylidene stearate is the sole solvent for the liquid pharmaceutical formulation of the present invention. Therefore, the present invention converts to a mixture of alcohol, poly-acidified fatty acid vinegar, and 3% by weight to % by weight of water as a liquid composition of a taxane derivative (compared to 94738 14 201023911, preferably docetaxel). a solvent, and a solubilization method involving a taxane derivative, preferably docetaxel, by adding the taxane derivative to an alcohol, a polyethoxylated fatty acid ester, and 3 to 5% by weight to 5混合物% by weight of water mixture _. Preferably, in the liquid pharmaceutical formulation of the present invention, the taxane derivative is pharmaceuticai iy effeive amount, preferably in the range of 5 to 15 mg/mL. More preferably, it is in the range of i 〇 to 15 mg/mL, and more preferably 1 〇 mg/mL. In a more preferred manner, the liquid pharmaceutical formulation of the present invention is a one compartment formulation. The term "single compartment formulation" as used in the present invention means that the liquid pharmaceutical formulation of the present invention is not a formulation accommodated in two compartments, the formulation of which is more than one A solution vial of docetaxel (base or concentrate or premix solution) consists of a solvent vial (diluent solution), and the contents of the two vials must be p-coupled prior to injection into the infusion bag. Conversely, the liquid pharmaceutical formulation of the present invention is ready for dilution (that is, the pharmaceutical composition only needs to be diluted with an infusion diluent prior to injection or infusion) and is contained in a single vial, so that it is not required to be injected into the infusion solution. The bag is reconstituted or homogenized before. So there is no risk of blistering and the risk of contamination is low. In another preferred embodiment, the liquid pharmaceutical formulation of the present invention is suitable for intravenous or parenteral injection or infusion. In the context of the present invention, the term "suitable for intravenous or parenteral injection or infusion" means that the formulation of the invention is applied to 〇9%魄94738 15 201023911 water (NaCl), 5% dextrose or prior to use. Other pharmaceutically acceptable injectable or infusion media are diluted to the appropriate medically recommended concentration for injection or infusion. Thus, after dilution herein, the formulations of the present invention will be suitable for intravenous or parenteral injection or infusion. Accordingly, the present invention also relates to an infusion solution comprising the liquid pharmaceutical composition of the present invention and an infusion diluent, preferably selected from the group consisting of glucose or an aqueous solution of sodium carbonate, more preferably 9%.9% saline or 5 The aqueous glucose solution is preferably an aqueous glucose solution, more preferably a 5% aqueous glucose solution. The inventors of the present invention have unexpectedly discovered that the liquid bear formulation of the present invention and the aqueous solution of saccharide (especially having a yew-burning indifference of about G 7 mg/mL and the yew riding organism is preferably polyene) The infusion solution of paclitaxel) is stable at 5X: storage for at least 72 hours. In a particular embodiment of the invention, the present formulation is a physics and/or data stabilizer, Qiansi Science and 于 ^ at = 5t, more particularly at least 3 months, and especially at 5 C is stable after at least 6 months of storage. The concept of the invention, the term "physical stabilizer" means that the current month, especially after 6 months, does not store for at least 3 months, B, its 2 generations and 6_ to the lower degree) Keep at least! : ^ It is in the accelerated condition (4 〇 尔 目 目 目 目 目 目 目 目 目 目 目 目 目 目 目 目 目 目 目 目 目 目 目 目 目 目 目 目 目 目 目 目 目 目 目 目 目 目 目 目 目 目 目 目 目In particular, after at least 6 months, the amount of degradation products formed is less than 94738 16 201023911 2% by weight, preferably less than % by weight, more preferably less than 5% by weight. In a preferred embodiment, The formulation of the present invention has a formation amount of the degradation product of less than 5% by weight, preferably less than 2% by weight, more preferably after storage for at least 3 months under the following conditions: 251 and 6% relative humidity. It is lower than i weight in another preferred mode, and the formulation of the present invention is under the following conditions: 3 dying and 6 眯 under humidity, after at least ! months, the amount of the degradation product is 0 to 5 weight. % ' is preferably less than 2% by weight, more preferably less than 1% by weight. In the preferred embodiment, the formulation of the present invention is prepared under the following conditions: at least humidity for at least one month after storage. The formation of the degradation product is less than 20% by weight, preferably less than 1% by weight, more preferably less than 5, Better than 2% by weight. Summer % ' months compared to liquid pharmaceutical formulations at 5. ° storage at least 3: month more especially after 6 months, maintain at least Na 3 = effectiveness, better maintain at least 97% of the efficacy 2, the liquid (four) hemp of the present invention is in the order of the best and less than 3 months, especially at least 6, "the efficiency of storage to the sage derivatives, better maintained at least ^ ^ ^ (10) The liquid pharmaceutical formulation of the invention of the present invention is preferably 4 () h ^ %, after the magic month, maintaining at least 80% of the performance of maintaining at least relative humidity to a better system, and Preferably, the system maintains at least 90% of the p-specificity of the other specific embodiment of the present invention in the liquid medicine range of 3 to 8 of the present invention, more preferably between 4.5 and 6.5. Preferably, it is within the range of 4 to 7.5, preferably in the range of 4.5 to 6 17 94738 201023911, especially in the range of 5 to 6. This pH will impart stability to the formulation of the present invention (especially Chemical stability). In order to obtain a pH lower than 7.5, especially below pH 7, it is recommended to add a doctor to the formulation of the present invention. An acceptable acid and/or buffering agent, preferably a pharmaceutically acceptable acid. Accordingly, the present invention is directed to further comprising (c) a pharmaceutically acceptable acid and/or buffer (more preferably pharmaceutically acceptable) The liquid pharmaceutical formulation of the present invention is accepted as an acid. In the concept of the present invention, the term "pharmaceutically acceptable acid" means any acid which is "pharmaceutically acceptable" as defined above, which does not Saponification of oxygen stearate. In particular, it means any non-toxic acid, including organic and inorganic acids and mixtures thereof. These inorganic acids include hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid and the like. Mixtures. These organic acids include carboxylic acids or dicarboxylic acids, more preferably selected from ascorbic acid, benzoic acid, aspartic acid, oxalic acid, benzenesulfonic acid, tartaric acid, diatrizoic acid, glutamic acid, lactic acid, Malay. Acid, succinic acid, fumaric acid, citric acid, ethylenediaminetetraacetic acid, malic acid, mandelic acid, abietic acid, mucic acid, pantothenic acid, p-benzoic acid, acetic acid, gluconic acid, ethyl can acid and mixtures thereof . Preferably, it is an organic acid, more preferably a dicarboxylic acid, especially a strong organic acid. The inventors of the present invention have found that oxalic acid is particularly suitable for use in the formulations of the present invention. In fact, oxalic acid is one of the strongest organic acids, so only a small amount (a few drops) is needed to obtain the desired pH. In addition, oxalic acid is not saponified with pharmaceutically acceptable polyoxyethylhexyl stearate. The amount of the pharmaceutically acceptable acid is, for example, used to obtain the desired pH. It is preferably a few drops. 1S 94738 201023911. In the context of the present invention, the term "pharmaceutically acceptable buffer" means any buffer which is "pharmaceutically acceptable" as defined above, which permits the desired pH to be obtained. Suitable buffering agents include, but are not limited to, citrate buffers, tartrate buffers, lactate buffers, and the like. In a first embodiment of the invention, the liquid pharmaceutical composition comprises only compounds (a), (b) and, if desired, (c), ie a taxane derivative, a solvent (water + alcohol + poly Ethoxylated fatty acid esters) and, if desired, acids and/or buffers. In a second embodiment of the invention, the liquid pharmaceutical formulation of the invention also contains (d) one or more antioxidants, especially tocopherol-derived compounds, preferably a-fertile. Suitable antioxidants include, but are not limited to, ascorbic acid, gentisic acid, tocopherol-derived compounds, butylated hydroxyanisole, butylated hydroxytoluene, citric acid, and the like; Compounds derived from fertility are more preferably α-fertility. The liquid pharmaceutical formulation of the present invention preferably does not contain any polyethylene glycol and/or any polysorbate (such as Tween®) and/or Emulphor® and/or any polyethylene glycol and castor oil vinegar ( Such as Cremophor EL®) and / or live glycerin and / or any glycerin. The invention also relates to a process for the preparation of a pharmaceutical formulation of the invention, wherein 'the process comprises the following sequential steps: - by mixing water, a pharmaceutically acceptable alcohol, and a pharmaceutically acceptable polyethoxylated fatty acid ester To prepare solvent (b), - if necessary, add one or more antioxidants (d) and mix, 201023911 - add the taxane derivative (a), preferably in anhydrous form or in the form of trihydrate, especially in anhydrous form And in the range of 3 to 8, preferably in the range of 4 to 7.5, more preferably, and if necessary, the pharmaceutically acceptable acid and/or buffer (c) is added. Preferably, it is in the range of from 4.5 to 6.5, especially in the range of from 5 to 6. Preferably, the mixing of the water, the pharmaceutically acceptable alcohol, and the pharmaceutically acceptable polyethoxylated fatty acid ester is carried out by methods well known to those skilled in the art. Preferably, the addition of the taxane derivative is as follows: almost all of the solvent is added to the container containing the accurately weighed taxane derivative, followed by mixing and filling the volume with the remaining solvent . The present invention also relates to the use of the liquid pharmaceutical formulation of the present invention as a medicament, preferably intended for the treatment of a proliferative disease, especially cancer, preferably a cancer having a solid tumor, more preferably selected from the group consisting of Cancer: prostate cancer, breast cancer, head and neck cancer, pancreatic cancer, lung cancer (preferably non-small cell lung cancer and advanced non-small cell lung cancer), melanoma, gastric cancer, urothelial cell carcinoma, soft tissue sarcoma, AIDS-related Kapos Kaposi sarcoma and ovarian cancer; especially cancers selected from the group consisting of prostate cancer, breast cancer, head and neck cancer, and lung cancer (such as non-small cell lung cancer). It also relates to a method for treating a proliferative disease, particularly cancer, which is more preferably a cancer having a solid tumor, and more preferably selected from the group consisting of prostate cancer, breast cancer, head and neck cancer, pancreatic cancer, and lung cancer (preferably non-small). Cell lung cancer and advanced non-small cell lung cancer), melanoma, gastric cancer, urothelial cell carcinoma, soft group 20 94738 201023911 Carcinoma, AIDS-related Kaposi's sarcoma and ovarian cancer group cancer, especially Cancer from a group consisting of prostate cancer, breast cancer, head and neck cancer, and lung cancer (such as non-small cell lung cancer); the method comprises administering a therapeutically effective amount of a non-oral or intravenous or subcutaneous injection or infusion to a patient in need thereof. - Bright liquid pharmaceutical formulations. The taxane derivative may be used alone or in combination with another anticancer agent and/or external or internal radiation; the other anticancer agent is, for example, cyclopamine, trastuzumab, cape Capecitabine, prednisone, prednisolone, camptothecin, epothilone, cisplatin, melphalan, backing Etoposide, teniposide, fludarabine, verapamil, cyclosporine (CyCl〇Sp〇rine), 5-fluorouracil, fluorodeoxyuridine ( Fluor〇deoxyuridine), doxorubicin or daunomycin, preferably, the other anticancer agent is selected from the group consisting of 10 cyclophosphamide, trastuzumab, capecitabine, pu A group consisting of Lai Su, Presino, Shun, 5-Fluorouracil, Doxorubicin, and mixtures thereof. Example 1: Preparation of liquid pharmaceutical formulations of the present invention and their solubility studies using different ratios of water, polyoxyethylhexyl stearate and ethanol: ethanol = EtOH; polyoxyethylene ethyl 40 hard fat Acid ester = P4 〇 S; 〇 · 9% NaCl = NaCl; 5% glucose = G5. 21 94738 201023911 Combination of H2〇/EtOH/P40S containing no docetaxel Several combinations of HZ〇/EtOH/P40S with increasing P40S to dissolve docetaxel were tested. In fact, P40S allows for better solubilization of paclitaxel and better stability of G5 and NaCl dissolution. The following liquid formulations were tested: Table 1 Mixture ratio (% w/w/v) HB〇/EtOH/P40S D3 40/40/20 E1 35/35/30 Stored 24 hours after preparation and at ambient temperature b oe The appearance of each of the five mixtures was visually examined after 96 hours. τ ratio gas compound (% w/w/w) outside $ίΤ〇 H2〇/EtQH/P4QS D3 40/40/20 colorless El 35/35/30 colorless appearance Τ24 small _ outer 鞔he.

The five mixtures were homogeneous (no suspended p4〇s particles). After 4 days of storage at ambient temperature, 'should still not (4). Dilute the mixture 1G times in the _ history to verify whether the p-think is suspended (stored at ambient temperature). ' 94738 22 201023911 Table 3: Appearance mixture ratio of the mixture of the right winter bridge 絷Mm (% w/v/w) H2〇/EtOH/P40S Dilution appearance To appearance T2", appearance 7^96 Hour D3 40/40/20 A4/4〇C/NaCl Clear and clear A4/25〇C/NaCl Clear and clear A4/4〇C/G5 Clear and clear A4/25〇C/G5 Clear and clear E1 35/35/30 B4/4〇C/NaCl Clear and clear B4/25〇C/NaCl Clear and clear B4/4〇C/G5 Clear and clear B4/25〇C/G5 Clear and clear and all different The mixture of the types, the dilution medium (G5 or NaCl) and the storage temperature 'these different diluted mixtures remain clear after 4 days. Therefore, P40S does not precipitate in these diluted mixtures.

Π-Combination of H2〇/Et〇H/p4〇s containing docetaxel in the following two mixtures·· D3/E1 (concentration z-10 mg/mL of docetaxel in mother liquor) Solubility. After dissolution, the appearance of the formulations on this day was clear 3,3/e (D, 3/E, l) at 65 and diluted with the medium. The two parental degrees are 0.7 mg/mL. After the preparation of docetaxel, 72 liquids were stored at ambient temperature and the contents of the material were tested for appearance and dosage immediately. 94438 23 201023911 Table 4: The mother liquor of Τ〇 and T72, 丨, 时Appearance and HPLC dose mother liquor ratio (% w/w/w) M)/EtOH/P40S Docetaxel concentration (mg/mL) Appearance D, 3 T. 40/40/20 10. 6 Colorless D' 3 T? 2 hours 10. 1 Colorless Ε, 1 Τ. 35/35/30 10.6 Colourless Ε' 1 Τ72 hours 9. 7 Colorless Table 5: Appearance of diluted mother liquor at Td and Τη,], and HPLC dose diluted mother liquor ratio (% w/w/w) H2 〇/EtOH/P40S Appearance D' 3 NaCl T. 40/40/20 Clear D'3 NaCl 4T: T72 hours clear D, 3 G5 Τ〇 clear __D, 3 G5 4〇C Τη small _ clear D'3 G5 25〇C T72 hours clear E* 1 NaCl T〇35/35/30 clear E 1 NaCl 4〇CT? 2 small peak clear E, 1 G5 T. Clear E'l G5 4〇CT" hour clear __E* 1 G5 25〇C Clear as shown in Table 4, all docetaxel mother liquor (D' 3 / Ε ' 1) stored at ambient temperature for 72 hours All are stable. Docetaxel does not precipitate. 24 94738 201023911 As shown in Table 5, the preferred release medium is G5, because E' 1 and D'3 diluted in G5 are stored at 25 ° C for 72 hours. After the storage of E'1 and D'3 in G5 or NaCl for 72 hours at 4 ° C is also - stability. Example 2: Preparation of pH = 6.9 of the invention Mg/mL docetaxel liquid pharmaceutical formulation and its stability study The formulation is in a mixture (H2〇/EtOH/polyoxyethylidene 4〇 stearate (P40S): 40/40/20: w/ 10 mg/mL polycetaxel tincture in w/w) The 10 mg/mL docetaxel formulation was prepared by the method described hereinafter: _ The solvent (H2〇/EtOH/P40S: 40/40/20: w/w/w) is prepared by the following method: mixing 40 g of deionized water, 4 〇g of Ethylene and 20 g of P40S, and then in a conical flask Shouyin wave treatment for 15 minutes. ❹ - will Approximately 500 mg of accurately weighed docetaxel was transferred to 5 〇 2 watts. Add 45 to the solvent and ultrasonically treat each mixture until the docetaxel completely fills the solution to the volume. The office _ stability study at different storage temperatures · :=:=Γ40" stability after the next 48 hours == 2r and one test: 94738 25 201023911 Test (visual inspection)藉 ϋ ϋ 进行 进行 进行 进行 进行 进行 多 多 多 多 多 多 多 多 多 多 多 多 多 多 多 多 多 多 多 HP HP HP HP HP HP HP HP HP HP HP HP HP HP HP HP HP HP HP HP HP HP HP HP HP HP HP HP HP HP HP HP Detection of impurities in 10 mg/mL formulation. Τ〇 Τ〇 and in gyp & stability time & The results are integrated in Table 6 below

[Manual inspections were carried out at 40 ° C for 24 hours and 48 hours after the test I visual inspection.) Table 6: Appearance ^ After storage for 48 hours under two conditions, no appearance of the formulation was observed. change. Therefore, after a minimum of 48 hours of storage at 25t and 40°C, the formulation is physically stable. Analysis of μ 1.2-Docetaxel and related substances The analysis of paclitaxel and the detection of related substances were carried out using a previously validated HPLC/UV method. Two separate sample solutions were prepared and injected into the chromatography system once. The reporting of impurities is limited to 0.05% for reporting "threshold. The results obtained by the average of the two measurements are reported in Tables 7 and 8. The docetaxel content (expressed in % w/w) is calculated relative to the theoretical concentration of the solution and taking into account the true weight of the docetaxel used to prepare the formulation. Table 7: Docetaxel content stability time point storage conditions Docetaxel content [%] To / 97. 2% T24 small 睥 25 〇 C 98. 3% T48 hours 98. 1% T24 hours 4 (TC 96 8% Ding 48 hours 94. 9% Table 8 · Detection of docetaxel-related substances Stability time point Storage conditions Total impurities [% w/w] To / 0. 31% T24 hours 25 〇 C 0. 30% T48 hours 0. 33% T24 hours 40 ° C 1.08% T48 hours 1.87% The content of this impurity is expressed relative to the nominal content of docetaxel in the formulation (ie 10 mg/mL). This has an effect on the stability of the 10 mg/mL docetaxel formulation. In fact, it is known that docetaxel is unstable at high temperatures, which is why the storage temperature of Taxotere® is lower than 25 ° C. However, the present invention The slow decrease in the docetaxel content of the formulation observed during storage for 48 hours at 40 ° C was not significant (the polyene 27 94738 201023911 paclitaxel content was higher than 90%) and impurities The increase was also not significant (less than 2%). The docetaxel was stored after storage of this formulation at 25 ° C for 48 hours. The content did not show a significant change, even though a slight (but not significant) increase in impurities was observed. Therefore, the formulation of the present invention is chemically stable after storage for at least 48 hours at 40 ° C. II-1 month stability results are also The stability of the formulation was studied under three conditions: 5 ° C; 25 ° C / 60% RH; 40 ° C / 75% RH, after storage for 1 month. 11. 1 - Appearance in storage of the formulation The appearance was visually checked again after 1 month (visual inspection). The results are integrated in Table 9. Table 9: Appearance stability time point Storage conditions Appearance To / Colorless solution Τι 5 °C A small amount of platelets (*) 25〇C/60% RH colorless solution 40〇C/75% RH colorless solution (*): shaking the solution by hand to dissolve the flake at 25 ° C / 60% RH and 40 ° No change in appearance was observed after 1 month of storage at C/75% RH, whereas microprecipitation was observed in the same formulation stored at 5 ° C. This precipitate (flake) was shaken by hand after shaking the solution. Redissolved. 28 94738 201023911 Therefore, under accelerated conditions (40 ° C / 75% relative humidity) or at 25 ° C / 60% After a minimum of 1 month of storage, the formulation is physically stable. 11. Analysis of 2-Docetaxel and related substances Analysis of docetaxel and detection of related substances using previously validated HPLC/UV methods . The reported limit of impurities is 0.05%. Two separate sample solutions were prepared, each solution was injected into the chromatography system once in Τβ and injected into the chromatography system twice at TMBa. The results obtained as the average of the two independent tests are reported in Tables 10 and 11. The docetaxel content (expressed in % w/w) is calculated relative to the theoretical concentration of the solution and taking into account the true weight of the docetaxel used to prepare the formulation. Table 10: Docetaxel content stability time point storage conditions docetaxel content [% w/w] To / 97. 2°/〇Τι * ^ 5°C 99. 0% 25〇C/60% RH 97.8 % 40〇C/75% RH 79. 1% 29 94738 201023911 Storage time chrome [% v/w] .31%

Sun impurities 11. Multi-baked yew, the detection of the phase 5..., and the composition of the docetaxel in the formulation (ie 10 mg/mL) is indicated. The main impurity is Epi-docetaxel, which is a major impurity known in the docetaxel formulation. It has been previously known in this short_save that the dependency temperature stability has an effect. In the pit and Huan, especially in prison, after storing the formulation for 1 month, it showed an increase in impurities and new impurities appeared. A slight increase in impurities was also observed for this formulation stored at 5C. However, this increase is not significant because of 5. 〇 After at least i months of storage, the increase is less than 1%; after storage for at least 1 month under muscle and _ relative humidity, the increase is less than 5%; and at 4 (TC and 75% relative humidity) After at least 1 month of storage, the increase is less than 20%. In addition, the content of docetaxel remains unchanged after 40 months of storage at 25 ° C and 60% relative humidity. After storage at 75% relative humidity for at least 1 month, the content of docetaxel decreased, and the decrease was not significant. Therefore, the formulation was chemically stable. II. Measurement of 3-pH 94738 30 201023911 (as is)』 The pH of the formulation was measured after storage at 5 ° C for 1 month. Stability time 躁 Storage conditions pH Τ « « month 5 ° C 6.9 After storage at 5 ° C for 1 month, the 10 mg The pH of the /mL docetaxel formulation was 6.9. Example 3: Preparation of a solution diluted with 0.9% ❿ NaCl containing the liquid pharmaceutical formulation of Example 1 and its stability study by the following method The formulation of Example 1 was diluted to prepare a diluted solution of 0.7 mg/mL docetaxel diluted by 0.9% NaCl: - implementation of 700 //L The formulation of 1 was transferred to a 1.0 mL vial and filled with 0.9% NaCl. The storage was carried out at 5 ° C and 25 ° C for 48 hours for stability studies. • Appearance (visual inspection) • Docetaxel analysis and detection of related substances by HPLC/UV. The HPLC/UV method has previously been demonstrated to be useful for the analysis of docetaxel and the detection of impurities in the diluted formulation. The study was conducted as follows: I-Short-term stability results: I. 1- Appearance to To and storage at 25 ° C and 5 ° C for 24 hours and 48 hours, 31 94738 201023911 measured by 0.9 ° /. The appearance of the dilute paclitaxel diluted with NaCl (0.7 mg/mL) (visual inspection). The results are integrated in Table 12 below. Table 12: Appearance stability time point Storage conditions Appearance To / Clear, colorless solution T24 hours 5 °C, clear, colorless solution T 4 8 hours clear, colorless solution T24 hours 25 ° C precipitation T 4 8 hours precipitation after storage at 5 ° C for 48 hours, no observed by the solution diluted with 0.9% NaCl Change. However, store at 25 ° C for 24 hours After that, it was observed that the solution diluted with 0.9% NaCl had a precipitate. Therefore, after storage for 48 hours at 5 ° C, the diluted solution was physically stable. I. Analysis of 2-Docetaxel and related substances Analysis of docetaxel and detection of related substances were performed using previously validated HPLC/UV methods. Two separate sample solutions were prepared and each solution was injected into the chromatography system once. 05%。 The reported limit of the impurity is 0. 05%. The results obtained as the average of two independent tests are reported in Tables 13 and 14. The docetaxel content is calculated relative to the theoretical concentration of the solution and taking into account the true weight of the docetaxel used to prepare the formulation. 32 94738 201023911 Table 13: Docetaxel content stability time point storage conditions docetaxel content [%] To / 109. 0% 1^4 hours 5 ° C 105. 7% Ϊ 48 hours 101. 6% T24 hours 25DC 65 0% Table 14: Detection of docetaxel-related substances Stability time point Storage conditions Total impurities [% w/w] To / 0. 33% T24 hours 5 ° C 0. 34% Ϊ 48 hours 0. 27% T24 hours 25 ° C 0. 20% After storage for 24 hours at 25 ° C, analysis of docetaxel in a solution diluted with 0.9% NaCl showed a significant decrease associated with the precipitation observed at the same time. After 48 hours of storage at 5 ° C, the docetaxel diluted by 0.9% NaCl showed a decrease in the content of docetaxel in the diluted solution, even though the detection of impurities did not show a significant change after 48 hours ( No additional impurities were detected). This reduction can be explained by some microprecipitation of docetaxel, which is not detected during visual inspection at each stability time point. However, since this reduction was not significant, the docetaxel diluted by 0.9% NaCl was stored in a diluted solution at 5 ° C for 48 hours and was chemically aged 94738 201023911. Example 4: Preparation of a 5% dextrose-diluted solution containing the liquid pharmaceutical formulation of Example 1 and its stability study The formulation of Example 1 was diluted by the following method to prepare a dilution of 5% glucose. 7 mg/mL docetaxel diluted solution: - 700//L of the formulation of Example i was transferred to a 1 Torr bottle and filled with 5% glucose. The stability study was carried out at 5 ° C and 25 ° C for 48 hours. Perform the following tests: • Appearance (visual inspection). • Docetaxel analysis and related substances are tested by the muscle (10). For this diluted formulation, use the following method to perform this test: ' I-Short-term stability results: 1.1- Appearance Appearance (visual inspection) of the polypyrimidine diluted by 5% dextrose at 4 hours and 48 hours after L and 25.4 generations. The neurite solution of sirolimus (〇·7 mg/mL), ',. It is integrated in Table 15 below. 94738 34 201023911 Table 15: Appearance stability time point Residual conditions Appearance To / Clear, colorless solution T24 hours 5 ° C Clear, colorless solution T48 hours clear, colorless solution T24 hours 25 〇C Precipitate butyl 48 hours precipitation ^ at 5 ° After 48 hours of storage, no change in appearance of the 5% glucose diluted solution was observed. However, after storage at 25 ° C for 24 hours, it was observed that the solution diluted with 5% glucose had a precipitate. Therefore, after storage at 5 ° C for 48 hours, the diluted solution is physically stable. I. Analysis of 2-Docetaxel and Related Substances The analysis of docetaxel and the detection of related substances were carried out using previously validated HPLC/UV methods. Two separate sample solutions were prepared and each solution was injected into the chromatography system once. 05%。 The reported limit of the impurity is 0. 05%. The results obtained by G from the average of two independent tests are reported in Tables 16 and 17. The docetaxel content is calculated relative to the theoretical concentration of the solution and taking into account the true weight of the docetaxel used to prepare the formulation. 35 94738 201023911 Table 16: Stabilized paclitaxel content stability time 靡 storage conditions Docetaxel content [%] To / 99. 0% T24 hours 5 ° C 100. 4% T48 hours 99. 1% T24 hours 25 〇C 74. 5% Table 17: Detection of docetaxel-related substances Stability time point Storage conditions mmw [% w/w] To / 0. 30% ΤΓ24 hours 5°C 0. 31% T48 hours 0. 31% Ding 24 hours 25 〇C 0. 20% After storage for 24 hours at 25 ° C, analysis of the diluted solution t of docetaxel showed a significant decrease associated with the precipitation observed at the same time. The content of docetaxel in the diluted solution of the docetaxel diluted with 5% dextrose did not show a significant change after 48 hours of storage at 5 °C. In addition, after 48 hours of storage at 5 ° C, the detection of impurities did not show a significant change in impurities and no additional impurities were detected. The 5% glucose-diluted docetaxel formulation was stored at 5 ° C for at least 48 hours and was chemically stable. Example 5: Preparation of liquid pharmaceutical formulations of the invention having different pH and their stability studies 36 94738 201023911 ❹ 〇 1 〇 mg/mL polychelate formulation (4 formulations) for stability assessment Prepared by the method described below: - The solvent (H2〇/EtOH/P40S: 40/40/20: w/w/w) was prepared by the following method: 80 g of deionized water, 8 The ethanol of 〇g and the 40 g of P40S were mixed together and ultrasonically treated for 20 minutes in an Erlenmeyer flask. - Transfer approximately 250 mg of accurately weighed docetaxel to a u mL measuring flask. 20 mL of this solvent was added to harden the mixture: the mixture was until the docetaxel was completely dissolved. The solution is filled to the volume using a reagent. < In order to avoid the formation of oxidative degradation products of docetaxel, the solvent is purged under N2 gas and the formulations are also stored in & a few drops of 0.1 oxalic acid solution will be used in addition to the Four formulations ρ. These formulations were adjusted to their target pH (ie 5.5/6.0/6.5), except for the above. • The first formulation was not pH adjusted (reference, pH 7.3). Each formulation was sampled into 4 vials (5 mL per vial) and sealed under an inert atmosphere (N2). For each of the formulations tested, two vials were stored at 4 ° C for 72 hours (denoted as "T.") while the other two bottles were stressed at 50 ° C for 72 hours. The formulations prepared at a pH of 5.5.6.0 and 6.5 and the formulation prepared without adjustment (i.e., 卩117.3) are at 50. (: After storage 72]1)11, the stability was measured and compared with the stability of the same formulation after storage for 72 hours at 5 ° C. The pH was 5. 5, 6 · 0 And 6 · 5 of the special formulation at 5 and 2 $ dissolved at 4:94738 37 201023911 /60 ° /. After RH stored 1, 2, 3, 4, 5 and 6 months, the stability was tested, and at 30 °C/65% RH and 40°C/75% RH were tested for stability after storage for 1 month. I-Short-term stability results: I-1 pH was measured after preparation (before sampling under N2 atmosphere) and After storage for 72 hours at 4 ° C and 50 ° C, the pH of the four formulations was tested to assess the pH stability of each formulation. The results are integrated in Table 18 below. Table 18: pH measurement formulation of the formulation Storage conditions pH Sol. A (pH 5. 5) Immediately after preparation 5. 52 4 ° C 5. 51 50 ° C 5. 48 Sol. B (pH 6.0) Immediately after preparation 6. 05 4 ° C 6. 13 50t 6. 06 Sol. C (pH 6.5) Immediately after preparation 6. 54 4°C 6. 67 50°C 6. 64 Sol. D (pH 7.3) Immediately after preparation, 7.26 4°C 7.40 5 (TC 7. 30 After storage for 72 hours at 4 ° C or 50 ° C, no matter what the formulation, No significant change in pH was observed. Analysis of 1-2-Docetaxel and related substances 38 94738 201023911 Analysis of docetaxel in the obtained samples for stability studies using previously validated HPLC/UV methods and Detection of related substances. Two vials stored at 4 ° C for 72 hours are recorded as T. Each solution is injected into the chromatography system once. The content of the multi-baked paclitaxel in these solutions is measured, expressed in mg/mL. And recovering the recovery between the value obtained after storage at 50 ° C for 72 hours and the value obtained from the reference sample stored at 4 ° C. The amount of impurities of all such solutions is also detected, The nominal content of docetaxel (ie, 10 mg/mL) in the formulations is expressed as a percentage by weight. The results obtained (average of two independent tests) are reported in Tables 19 and 20 Table 19. Docetaxel content formulation stability time remaining storage conditions docetaxel itch content [mg/mL] recovery rate T72 hours / T 〇 Sol. A (pH 5.5) To 4 ° C 9. 79 97. 8% T? 2 hours 50 ° C 9. 57 Sol. B (pH 6 .0) To 4°C 9. 82 96. 4% T72 hours 50°C 9.47 - Sol. C (pH 6.5) To rc 9. 77 92. 3% T72 hours 50°C 9. 02 Sol. D (pH 7.3) Reference To 4°C 9. 83 79. 1% T72 hours 50°C 7. 77 39 94738 201023911 Table 20: Determination of docetaxel-related substances. Formulation stability time point Residual conditions Total impurities (w/ w) Sol. A (pH 5. 5) To 4°C 0. 24% ΐ*Τ2 hours 50°C 1. 08% Sol. B (pH 6. 0) To 4°C 0. 24% Ding 72 hours 50°C 3. 08% Sol. C (pH 6. 5) To 4°C 0. 30% Τ·72 hours 50°C 7. 11% Sol. D (pH 7.3) Reference To 4°C 0. 26% T72 hours 50 °C 19.36% The results presented in this table show that pH adjustment has an effect on the stability of the 10 mg/mL docetaxel formulation. The recovery obtained from the analysis of docetaxel performed after storage at 50 ° C for 72 hours showed that a lower pH value resulted in a more stable formulation. This increase in impurities was observed in each sample after storage at 50 ° C, but this increase was also lower for lower pH values. Therefore, the 10 mg/mL docetaxel formulation of the present invention was adjusted to the acid pH with oxalic acid, which significantly reduced the degradation of docetaxel. II-Long-term stability results 11-1 pH measurement after preparation and sampling under N2 atmosphere (T.), at 5 ° C, 25 ° C / 60% RH, 30 ° C / 65% RH, 40 ° C /75°/〇RH Store after 1 month, and at 5 ° (: and 25 ° C / 60% RH for 2 months, 3 months, 4 months, 5 months and 40 94738 201023911

After 6 months, the pH of the three formulations was measured. In order to evaluate the pH stability of each formulation, the results are summarized in Table 21. Table 21: pH measurement of the formulation Storage conditions pH Sol. A (pH 5.5) To 5. 66 5 ° C 1 month 5. 58 2 months 5. 59 3 months 5. 50 4 months 5. 15 5 months 5. 28 6 months 5. 56 25〇C/60% RH 1 month 5. 61 2 months 5. 62 3 months 5. 56 4 months 5.42 5 months 5. 35 6 Month 5. 57 30〇C/65% RH 1 month 5. 57 40〇C/75% RH 1 month 5. 60 Sol B (pH 6.0) T〇6. 20 5°C 1 month 5.92 2 months 6. 05 3 months 6.07 4 months 5. 66 5 months 5.84 6 months 6. 02 25〇C/60% RH 1 month 6. 02 41 94738 201023911 2 months 6.08 3 months 6 09 4 months 5.88 5 months 5. 78 6 months 6.03 30〇C/65% RH 1 month 6. 06 40oC/75% RH 1 month 6. 03 Sol C (pH 6.5) To 6.75 5° C 1 month 6. 53 2 months 6.57 3 months 6. 62 4 months 6.36 5 months 6. 38 6 months 6.56 25〇C/60% RH 1 month 6.58 2 months 6.55 3 months 6 62 4 months 6. 15 5 months 6. 35 6 months 6.57 30〇C/65% RH 1 month 6.49 40〇C/75% RH 1 month 6.53 Even at 25°C/60 RH storage After 3 months or 6 months, 'no matter what kind of formulation, no observation Significant changes in the pH. Analysis of 11-Docetaxel and related substances using the previously validated HPLC/UV method for stability studies 94738 42 201023911 * 薅•二之: Analysis of docetaxel in the sample and examination of related substances ^ 2 4 ^ Storage 72 j, the two vials are recorded as Τβ. Each solution was injected into the β θ knife analysis system. Detecting the content of the docetaxel in these solutions is not expressed in mg/mL and is detected and stored in 1 month, 2 months, 3 months, 4 months, 5 months. The recovery between the value obtained after month and 6 months and the value obtained after 3 (rc/65% four and 4Qt/75% rh storage months). Also detect the impurities of all such solutions. The amount is expressed in weight percent relative to the nominal content of docetaxel in the formulation (ie 10 mg/mL). The results obtained (average of two independent tests) are reported in Table 22 and Table 23. Formulation stability time point casting condition Docetaxus itch content (mg/ml) Recovery rate (TxIBJi /To)% Sol A (pH 5. 5) To 9. 7 98. 9 Τι « ^ 5°C 9.4 96.5 1*2 months 9.5 97.2 Ίζη η 9.7 99.0 Τί 9.7 99.0 Th m Μ 9.7 100.2 Ding 6 锢 9.8 99.3 Ί\ m η 25°C/60°/〇RH 9.5 97.5 Τ2«月9.5 97.7 Month 9. 5 97. 5 T4 MM 9.7 99.2 9. 7 99. 1 Table Μ ·· 多席紫杉薜的景94738 43 201023911 Τδ « ^ 9. 5 97.8 T\ mb 30〇C/65% RH 9.5 97 . 5 Ί\ MB 40〇C/65% RH 9.4 95 .8 Sol B (pH 6.0) To 9. 6 98.2 «0 month 5°C 9. 5 96.4 T2 β month 9. 4 95.8 T3 « H 9. 6 97. 7 T4 «Month 9. 7 99. 1 Th mn 9.8 99. 7 Te ® month 9.8 99. 6 "Τι月25〇C/60% RH 9. 6 97.4 Ίζ^ n 9.4 95. 8 Tzm ^ 9. 5 96. 7 l months 9. 7 98. 5 Τδ月9. 6 98. 0 T6 months 9. 5 96.8 Τι »月30〇C/65% RH 9. 5 96. 6 Ί\ m η 40〇C/65% RH 9. 2 93. 9 Sol C (pH 6. 5) To 9. 7 98. 3 Τι « ^ 5°C 9. 6 96.8 Τ 2 months 9. 5 96. 0 Τ 3 months 9. 7 97. 8 Ti m η 9. 9 99 9 Τδ « ^ 9. 9 100. 0 Τε«^ 9. 7 98. 6 Ί\ m η 251/60% RH 9. 6 96. 9 Ί2 m η 9. 2 92. 6 Ϊ3 months 9. 4 95. 2

44 94738 201023911 T4 « ^ 9. 5 96.4 Ts sister month 9. 5 95. 8 Ϊ 6 indium month 9. 2 93.4 Tl « ^ 30〇C/65% RH 9. 4 95. 5 T\ m η 40〇C/ 65% RH 8. 7 88. 3 ❹ Table 23 · Detection of docetaxel-related substances. Stability of the formulation. Storage time conditions. Sol A (pH 5. 5) To 0. 18 limn 5°C 0. 23 T2 mh 0. 22 Ίζ mn 0. 24 T4 months 0. 29 Τδ « ^ 0. 25 T6 months 0. 24 ΐΐ 18月25〇C/60% RH 0. 34 Τ2 ® month 0.49 Τ3 fl. 50 Ta m 0. 74 Τδ « ^ 1. 13 Ϊ 6 months 1. 33 T】® month 30〇C/65% RH 0. 55 Tl AM 40〇C/65% RH 1. 78 Sol B (pH 6.0) To 0. 18 Tl months 5°C 0. 30 T2 months 0. 23 Ϊ3 ® ^ 0. 25 45 94738 201023911 Ία mn 0. 26 Is m ά 0.28 Τθ« ^ 0. 29 Ti « ^ 25〇C/ 60% RH 0. 53 Ί2 Μ M 0. 76 Ίζ m ^ 1. 35 Ίαμ H 1. 44 Τδ « H 2. 06 1*6 months 2. 23 Tl ® month 30〇C/65% RH 0.88 Tl « Month 40〇C/65% RH 3. 93 Sol C (pH 6.5) To 0. 23 Tl « ^ 5°C 0. 27 T2 ΊΒ Month 0. 28 T3 months 0. 32 Ία % η 0. 36 Ts Month 0. 39 Τδ月0.41 Tl « ^ 25〇C/60% RH 1. 16 Τ2 «a month 1.87 T3 months 2. 76 Ία^μ 3. 80 Τδ «月 4.42 Te« ^ 5. 52 Τι « ^ 30〇C/65% RH 2. 20 Τι « ^ 40〇C/65% RH 8. 50

46 94738 201023911 • The results presented in Tables 22 and 23 show that pH adjustment has an effect on the stability of the 10 r mg/mL docetaxel formulation. The recovery obtained from the analysis of docetaxel performed after storage for one month at 40 t/65% RH showed that a lower pH value resulted in a more stable formulation-compound. This increase in impurities was observed in each of the samples after storage at 40 ° C / 65% RH, but this increase was also lower for lower pH values. Surprisingly, however, almost no increase in this impurity was observed after storage of each sample at 5 ° C for at least 3 months ® and even at 5 ° C for at least 6 months. Therefore, after storage for at least 3 months at 5 ° C or even at 5 ° C for at least 6 months, all such formulations, especially those with lower pH values, are chemically stable (impurities less than 0.5 wt ° / 〇) ). Therefore, the 10 mg/mL docetaxel formulation of the present invention was adjusted to the acid pH with oxalic acid, which significantly reduced the degradation of docetaxel. [Simple description of the diagram] Q None. [Main component symbol description] None. 47 94738

Claims (1)

201023911 VII. Scope of application: 1. A liquid pharmaceutical formulation comprising: (a) a taxane derivative or a pharmaceutically acceptable salt thereof, (b) a solvent which is a pharmaceutically acceptable alcohol, medicine A mixture of the above acceptable polyethoxylated fatty acid vinegar and water in an amount of from 50% by weight based on the total weight of the solvent. 2. The liquid pharmaceutical formulation of claim 1, wherein the pharmaceutically acceptable alcohol is ethanol. 3. The liquid pharmaceutical formulation of claim 1, wherein the taxane derivative is docetaxel. 4. A liquid pharmaceutical formulation as claimed in any one of claims 1 to 3 wherein the pharmaceutically acceptable polyethoxylated fatty acid vinegar is a pharmaceutically acceptable polyoxyethylidene stearate. Ester, especially polyoxyethylidene 40 stearate. 5. A liquid pharmaceutical formulation according to any one of the preceding claims, wherein the liquid pharmaceutical formulation further comprises (c) a pharmaceutically acceptable acid and/or buffer. 6. The liquid pharmaceutical formulation of claim 5, wherein the pharmaceutically acceptable acid is an organic acid, preferably oxalic acid. The 'preferable system' between 4 and 7.5, preferably between 4 and 7.5, more preferably between 4 and 7.5. Between 4.5 and 6. 5. 8. The liquid pharmaceutical formulation of any one of claims 1 to 7 wherein 'the solvent is 30% by weight to 50% by weight of water, 3 〇 947 94738 48 201023911 \ " 5% to 60% by weight a mixture of the pharmaceutically acceptable alcohol and 10% by weight to 40% by weight of the pharmaceutically acceptable polyethoxylated fatty acid ester, preferably from 35% to 40% by weight Water, from 35% to 40% by weight of the pharmaceutically acceptable alcohol and from 20% to 30% by weight of a mixture of the pharmaceutically acceptable polyethoxylated fatty acid ester. 9. The liquid pharmaceutical formulation according to any one of claims 1 to 8, wherein the concentration of the taxane derivative is in the range of 5 to 15 mg/mL ® , preferably 10 to In the range of 15 mg/mL, more preferably 10 mg/mL °. 10. The liquid pharmaceutical formulation according to any one of claims 1 to 9, wherein the liquid pharmaceutical formulation is at 40 ° C and 75% The effectiveness of the taxane derivative is maintained at least 75%, preferably at least 80%, and more preferably at least 90% after one month of storage at relative humidity. 11. The liquid pharmaceutical formulation according to any one of claims 1 to 10, wherein the liquid pharmaceutical formulation further comprises (d) one or more antioxidants. 12. A method of preparing a liquid pharmaceutical formulation according to any one of claims 1 to 11, wherein the method comprises the following consecutive steps: - by mixing water, the pharmaceutically acceptable alcohol and The pharmaceutically acceptable polyethoxylated fatty acid ester to prepare the solvent (b), - if necessary, adding the one or more antioxidants (d) and mixing, - adding the taxane derivative (a), Preferably, the taxane derivative (a) is added in anhydrous form and mixed, and 49 94738 201023911 'V - the pharmaceutically acceptable acid and/or buffer (c) is added as needed to obtain范围内的范围内。 The range of the range of 4 to 7.5, more preferably in the range of 4.5 to 6.5. 13. The liquid pharmaceutical formulation according to any one of claims 1 to 11, which is used as a medicament, preferably for the treatment of a proliferative disease, especially cancer, and more preferably for use in The cancer is selected from the group consisting of prostate cancer, melanoma, gastric cancer, urothelial cell carcinoma, soft tissue sarcoma, breast cancer, head and neck cancer, pancreatic cancer, lung cancer, AIDS-related Kaposi's sarcoma, and ovarian cancer.输 14. An infusion solution comprising a liquid pharmaceutical formulation according to any one of claims 1 to 11 and an infusion diluent, preferably selected from the group consisting of aqueous dextrose or aqueous sodium chloride. 15. Use of a mixture of a pharmaceutically acceptable alcohol, water and a pharmaceutically acceptable polyethoxylated fatty acid ester for use as a solvent in a liquid pharmaceutical formulation containing a taxane derivative. 50 94738 201023911 Invention patent specification (Do not change the format and order of this manual, please do not fill in the ※ mark) <2 repair f^>^S{/)3] (2ϋ〇6.〇η m (2 〇〇b〇l) TAXANE DERIVATIVE ※Application number: 98 1 28 6 34 ※Application date: Category I, invention name: (Dealition / English) Liquid formulation containing taxane derivatives LIQUID formulation containing a Abstract: The present invention relates to a liquid pharmaceutical formulation comprising (a) a taxane derivative or a pharmaceutically acceptable salt thereof, (b) a solvent which is a pharmaceutically acceptable alcohol, 30 to 50 a mixture of water and a pharmaceutically acceptable polyethoxylated fatty acid ester. III. Summary of the invention: (a) a taxane derivative or a pharmaceutically ccqrtable salt thereof, ( b) a solvent consisting in the mixture of a pharmaceutically acceptable alcohol, 30-50% water and a pharmaceutically acceptable polyethoxylated fetty acid est» 94738 201023911 Invention patent specification (Do not change the format and order of this manual, please do not fill in the ※ mark) <2 repair f^>^S{/)3] (2ϋ〇6.〇η m (2 〇〇b〇l) TAXANE DERIVATIVE ※Application number: 98 1 28 6 34 ※Application date: Category I, invention name: (Dealition / English) Liquid formulation containing taxane derivatives LIQUID formulation containing a Abstract: The present invention relates to a liquid pharmaceutical formulation comprising (a) a taxane derivative or a pharmaceutically acceptable salt thereof, (b) a solvent which is a pharmaceutically acceptable alcohol, 30 to 50 a mixture of water and a pharmaceutically acceptable polyethoxylated fatty acid ester. III. Summary of the invention: (a) a taxane derivative or a pharmaceutically ccqrtable salt thereof, ( b) a solvent consisting in the mixture of a pharmaceutically acceptable alcohol, 30-50% water and a pharmaceutically acceptable polyethoxylated fetty acid est» 94738 201023911 IV. Designated representative map: There is no schema in this case. (1) The representative representative of the case is: (). (2) A brief description of the symbol of the representative figure: 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: There is no chemical formula in this case. 94738