Cabazitaxel solution pharmaceutical preparation

Abstract

The present invention relates to a solution pharmaceutical preparation of cabazitaxel which is an ethanol-free direct infusion dilution of cabazitaxel and has excellent storage stability. Specifically, the present invention relates to a solution pharmaceutical preparation containing cabazitaxel as an active ingredient that contains a glycol solvent selected from polysorbate, polyethylene glycol, and / or propylene glycol and an organic acid. The pH of the solution pharmaceutical preparation diluted by water to a cabazitaxel concentration of 0.1 mg / mL is from higher than 3.5 to 5.5.

Description

Cabazitaxel solution pharmaceutical preparation

[0001] The present invention relates to a liquid pharmaceutical formulation containing cabazitaxel as an active ingredient.

[0002] Cabazitaxel exerts its antitumor effect by inhibiting cell division through promoting tubulin polymerization and stabilizing microtubules. Clinically used cabazitaxel pharmaceutical formulations contain the acetone adduct of cabazitaxel as the active ingredient, dissolved in polysorbate 80 at a pH of 3.0-4.0 (10% aqueous solution of the formulation) (1.5 mL solution containing 60 mg of cabazitaxel). This formulation is used as a prostate cancer treatment via intravenous infusion. Cabazitaxel is poorly soluble, and for intravenous infusion, a formulation dissolved in the solubilizing agent polysorbate 80 is diluted with a dedicated solvent containing ethanol to prepare a premix solution, which is then mixed with an infusion solution such as saline or 5% glucose solution and administered intravenously (Non-Patent Document 1). Thus, the preparation of the drug solution for administration of cabazitaxel formulations requires two-stage dilution, making the administration process complicated. Furthermore, the ethanol used in the solvent for preparing the premix solution can cause problems such as alcohol sensitivity and hypersensitivity. For this reason, there is a need for a formulation that can be directly diluted with an infusion solution for administration. There is also a need for a formulation that can prepare an administration solution that does not contain ethanol. Patent Document 1 describes a cabazitaxel formulation that does not contain surfactants or ethanol, and that contains sulfobutylether-β-cyclodextrin. Patent Document 2 also describes a cabazitaxel formulation that does not contain polysorbate or ethanol, but contains cyclodextrin, a solubilizer such as polyethylene glycol, and additives such as polyvinylpyrrolidone and citric acid. As such, formulations that can be directly prepared into an administration solution from the cabazitaxel formulation and ethanol-free formulations have been reported. Meanwhile, Patent Document 3 discloses a polysorbate-free cabazitaxel solution formulation that contains a solubilizer, tocopherol polyethylene succinate, and polyethylene glycol.

[0003] Drug Interview Form "Jevtana (registered trademark) Intravenous Infusion 60 mg" October 2023 Revised Edition (8th Edition)

[0004] Special table 2016-508138 publication Special table 2021-510142 publication Special table 2014-521722 publication

[0005] An object of the present invention is to provide an ethanol-free cabazitaxel liquid pharmaceutical formulation that can be directly diluted with an infusion solution and has excellent storage stability.

[0006] [1] A liquid pharmaceutical formulation containing cabazitaxel as an active ingredient, comprising a glycol solvent selected from polysorbate, polyethylene glycol and / or propylene glycol, and an organic acid, wherein the liquid pharmaceutical formulation is diluted with water and the pH of the solution at a cabazitaxel concentration of 0.1 mg / mL is greater than 3.5 and less than 5.5. [2] The cabazitaxel liquid pharmaceutical formulation according to [1], which contains cabazitaxel at 5 to 30 mg / mL. [3] The cabazitaxel liquid pharmaceutical formulation according to [1] or [2], wherein the glycol solvent is 0.5 to 3.5 parts by mass per part by mass of polysorbate. [4] The cabazitaxel liquid pharmaceutical formulation according to any of [1] to [3], which contains the glycol solvent at 0.2 to 1.7 g / mL.

[0007] The cabazitaxel solution pharmaceutical formulation of the present invention does not cause precipitation of cabazitaxel when diluted with water and can be directly used to prepare an administration solution. Furthermore, in a storage stability test, the formation of related substances was suppressed, and a pharmaceutical formulation with excellent stability can be provided.

[0008] The present invention relates to a cabazitaxel solution pharmaceutical formulation comprising cabazitaxel, a glycol solvent selected from polysorbate, polyethylene glycol and / or propylene glycol, and an organic acid, the pH of which, when diluted with water, is greater than 3.5 and less than or equal to 5.5.

[0009] Cabazitaxel has the chemical name (1S,2S,3R,4S,5R,7S,8S,10R,13S)-4-acetoxy-2-benzoyloxy-5,20-epoxy-1-hydroxy-7,10-dimethoxy-9-oxotax-11-en-13-yl(2R,3S)-3-(1,1-dimethylethyl)oxycarbonylamino-2-hydroxy-3-phenylpropanoic acid. Cabazitaxel may be an anhydrate (especially not a hydrate or solvate), a hydrate, an acetone adduct, or other solvate, and can be used without particular limitation as long as it is of a quality suitable for use as an active ingredient in pharmaceuticals. In the liquid pharmaceutical formulation of the present invention, the cabazitaxel content is preferably 5 mg / mL or more and 30 mg / mL or less, and more preferably 10 mg / mL or more and 30 mg / mL or less.

[0010] Polysorbate is a polyoxyethylene sorbitan fatty acid ester. Known pharmaceutical additives include polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate, Tween® 20), polysorbate 60 (polyoxyethylene (20) sorbitan monostearate, Tween® 60), polysorbate 65 (polyoxyethylene (20) sorbitan tristearate, Tween® 65), and polysorbate 80 (polyoxyethylene (20) sorbitan monooleate, Tween® 80). These may be used alone or in combination of two or more. Polysorbate 80 is preferred. Polysorbates of a quality suitable for use as pharmaceutical additives can be used. The heavy metal content is preferably 20 ppm or less, more preferably 10 ppm or less. The peroxide value is also preferably 0.2 or less, more preferably 0.1 or less. Alternatively, the water content is preferably 0.2% or less, preferably 0.1% or less, and more preferably 0.05% or less. Additionally, the residue on ignition is preferably 0.1% or less, more preferably 0.05% or less. The heavy metal content is measured by Method 2 of the Heavy Metal Test Method in the Japanese Pharmacopoeia General Test Methods. The peroxide value is measured by the method described in the Japanese Pharmacopoeia Test Method for Polysorbate 80. The water content is measured by the Japanese Pharmacopoeia General Test Method for Water Determination - Volumetric Titration - Direct Titration. The residue on ignition is measured by the method described in the Japanese Pharmacopoeia Test Method for Polysorbate 80. In the liquid pharmaceutical formulation of the present invention, the polysorbate is preferably contained at a concentration of 0.2 g / mL or more and 1.0 g / mL or less, and more preferably 0.3 g / mL or more and 0.8 g / mL or less. Furthermore, the polysorbate is preferably used at a concentration of 30 to 60 mg / mL.

[0011] The cabazitaxel solution pharmaceutical formulation of the present invention contains a glycol solvent selected from polyethylene glycol and / or propylene glycol. The polyethylene glycol is preferably an ethylene glycol polymer that exists in a liquid state at temperatures above 30°C. Preferably, a polyethylene glycol that meets the standards set forth in the Japanese Pharmacopoeia (JP) or Pharmaceutical Additives Standards (Yakuzuki), and macrogol is preferably used. Macrogol 300, macrogol 400, or macrogol 600 is preferred. Macrogol 300, also known as polyethylene glycol 300, is a colorless, transparent, viscous liquid composed of a polymer of ethylene glycol molecules with an average molecular weight of 300. Macrogol 400, also known as polyethylene glycol 400, is a colorless, transparent, viscous liquid composed of a polymer of ethylene glycol molecules with an average molecular weight of 400. Macrogol 600, also known as polyethylene glycol 600, is a colorless, transparent, viscous liquid or a white, petrolatum-like solid composed of a polymer of ethylene glycol molecules with an average molecular weight of 600. It is more preferable to use polyethylene glycol 300 (Macrogol 300) and / or polyethylene glycol 400 (Macrogol 400). In the present invention, polyethylene glycol and / or propylene glycol can be used as the glycol solvent. Polyethylene glycol is preferred. In the liquid pharmaceutical formulation of the present invention, the glycol solvent is preferably contained at 0.2 g / mL or more and 1.7 g / mL or less, more preferably 0.2 g / mL or more and 1.0 g / mL or less. Furthermore, the concentration of cabazitaxel in the glycol solvent is preferably 5 to 120 mg / mL, more preferably 10 to 80 mg / mL.

[0012] The present invention is characterized by the use of a polysorbate and a glycol solvent in combination as a solvent for cabazitaxel. The combined solvent may be one that can stably dissolve cabazitaxel at temperatures above 0°C. Preferably, the polysorbate is used at a cabazitaxel concentration of 30 to 60 mg / mL, and the glycol solvent is used at a cabazitaxel concentration of 5 to 120 mg / mL, or the glycol solvent is used at a cabazitaxel concentration of 10 to 80 mg / mL. The mixing ratio of the polysorbate to the glycol solvent is preferably 0.5 to 3.5 parts by mass, more preferably 0.5 to 1.5 parts by mass, of the glycol solvent per 1 part by mass of the polysorbate.

[0013] The present invention includes an organic acid as a stabilizer for cabazitaxel. Examples of organic acids include citric acid, tartaric acid, succinic acid, maleic acid, fumaric acid, malic acid, lactic acid, and acetic acid. An organic acid selected from citric acid, tartaric acid, succinic acid, maleic acid, fumaric acid, and malic acid is preferred, and one or more organic acids selected from the group consisting of citric acid, tartaric acid, succinic acid, and malic acid are more preferred. The amount of organic acid applied is preferably such that, when the liquid pharmaceutical formulation of the present invention is diluted with water, the pH of the resulting solution at a cabazitaxel concentration of 0.1 mg / mL is greater than 3.5 and less than 5.5, more preferably greater than 4.0 and less than 5.0, or greater than 4.2 and less than 5.0. The amount of organic acid to be applied varies depending on the acid value, but for example, when citric acid is used, the amount is preferably 0.15 mg / mL or more and 40 mg / mL or less, more preferably 0.25 mg / mL or more and 25 mg / mL or less, and furthermore, 1.25 mg / mL or more and 25 mg / mL or less, or 1.5 mg / mL or more and 15.0 mg / mL or less, as citric acid equivalent.

[0014] The cabazitaxel solution pharmaceutical formulation of the present invention may contain an antioxidant, an isotonicity agent, a stabilizer, a cosolvent, etc. Antioxidants include one or more of lipoic acid, monothioglycerol and its analogs, ascorbic acid and its salts, propyl gallate, methionine, cysteine, metabisulfite, sodium formaldehyde sulfoxylate, phenol-containing aromatic and aliphatic compounds, and dihydrolipoic acid. Isotonicity agents include sodium chloride, calcium chloride, magnesium chloride, fructose, xylitol, sorbitol, trehalose, nicotinamide, glucose, refined sucrose, mannitol, etc. Examples of stabilizers include acetyltryptophan, alanine, arginine, albumin, benzoic acid, histidine, glycine, glutamic acid, cystine, inositol, fructose, lactose, xylitol, sorbitol, maltose, diethylenetriaminepentaacetic acid, nicotinamide, urea, sodium pyrophosphate, and meglumine. Examples of cosolvents include oleic acid, sesame oil, refined olive oil, refined oleic acid, sorbitan fatty acid ester, soybean oil, medium-chain fatty acid triglyceride, and polyoxyethylene hydrogenated castor oil 60. The cabazitaxel solution pharmaceutical formulation of the present invention is an ethanol-free solution formulation. Preferably, the solution formulation does not contain any organic solvent other than the polysorbate and glycol solvent.

[0015] The cabazitaxel solution pharmaceutical formulation of the present invention can suppress the formation of related substances by controlling the moisture content in the formulation to a low level. The moisture content of the solution formulation is preferably 5.0% or less, more preferably 2.0% or less, and particularly preferably less than 1.0%. The moisture content is measured by the Karl Fischer method.

[0016] The cabazitaxel solution pharmaceutical formulation of the present invention is prepared as a sealed formulation by aseptically filling a vial-shaped container and sealing it with an airtight rubber stopper. The container used may be any shape, such as a vial or syringe, as long as it can be sealed with a rubber stopper, but a vial shape is preferred. Examples of container materials include soda-lime glass, borosilicate glass, cyclic polyolefin polymer, and cyclic polyolefin copolymer. Furthermore, the container may be surface-treated for purposes such as improving stability or suppressing elution of glass components. Examples of surface-treated vials include Silicoat vial (Fuji Glass Co., Ltd.), VIST vial (Daiwa Special Glass Co., Ltd.), VIALEX (Nipro Corporation), and type 1 plus (SCHOTT Co., Ltd.). The rubber stopper is preferably made of butyl rubber, or a butyl rubber stopper laminated with fluororesin. These sealable containers are preferably made of packaging materials in which both the container and the rubber stopper have been sterilized by an appropriate method.

[0017] The liquid pharmaceutical formulation of the present invention is preferably in a sealed form under an inert gas atmosphere, and such a formulation can be prepared, for example, by directly injecting an inert gas such as nitrogen or argon into a container filled with the solution, and then sealing the container with a rubber stopper or the like after injecting a certain amount of the inert gas.

[0018] The liquid pharmaceutical formulation of the present invention can be prepared, for example, by the following manufacturing method: A mixed solvent containing polysorbate, a glycol solvent, and an organic acid is prepared, and cabazitaxel is dissolved in the mixed solvent, optionally in an inert gas atmosphere. The resulting mixture is sterilized by filtration, dispensed into vials, and sealed with rubber stoppers, optionally with an inert gas enclosed, to produce the cabazitaxel liquid pharmaceutical formulation of the present invention.

[0019] The cabazitaxel solution pharmaceutical formulation of the present invention can be diluted with an infusion solution for intravenous infusion as it is and provided for intravenous infusion administration.

[0020] Example 1 187.2 g of polysorbate 80 (IONET T-80DSK, Sanyo Chemical Industries, Ltd.; heavy metals: 20 ppm or less; peroxide value: 0.1; water: 0.0%; ignition residue: 0.03%) was mixed with 200.1 g of Macrogol 300 (NOF Corporation), and 0.9 g of Japanese Pharmacopoeia anhydrous citric acid (Junsei Chemical Co., Ltd.) and 7.8 g of cabazitaxel acetone adduct were dissolved therein to prepare a homogeneous drug solution. This drug solution was sterile filtered, filled into 3 mL aliquots into glass vials, purged with nitrogen, and then sealed with rubber stoppers to give a 3 mL solution formulation (Example 1) containing 64.14 mg of cabazitaxel acetone adduct, 1.56 g of polysorbate 80, 1.67 g of macrogol 300, and 7.5 mg of anhydrous citric acid. This formulation was diluted with water to a cabazitaxel concentration of 0.1 mg / mL, and the pH was 4.4.

[0021] Example 2 25 mg of Japanese Pharmacopoeia anhydrous citric acid (Junsei Chemical Co., Ltd.), 214 mg of cabazitaxel acetone adduct, and Macrogol 300 (NOF Corporation) were added to 5.2 g of polysorbate 80 (IONET T-80DSK, Sanyo Chemical Industries, Ltd.; heavy metals: 20 ppm or less; peroxide value: 0.1; water: 0.0%; ignition residue: 0.03%) and dissolved to prepare a 10 mL homogeneous solution. 0.9 mL of the solution was filled into glass vials, purged with nitrogen, and then sealed with rubber stoppers to prepare a 0.9 mL solution formulation (Example 2) containing 19.25 mg of cabazitaxel acetone adduct, 0.47 g of polysorbate 80, 0.48 g of macrogol 300, and 2.25 mg of anhydrous citric acid. This formulation was diluted with water to a cabazitaxel concentration of 0.1 mg / mL, and the pH was 4.4.

[0022] Example 3 25 mg of Japanese Pharmacopoeia anhydrous citric acid (Junsei Chemical Co., Ltd.), 214 mg of cabazitaxel acetone adduct, and macrogol 300 (NOF Corporation) were added to 5.2 g of polysorbate 80 (SUPER REFINED polysorbate 80-LQ-(MH), manufactured by CRODA Japan Co., Ltd.; heavy metals: 10 ppm or less; peroxide value: 0.00; water: 0.0%; ignition residue: 0.00%) and dissolved to prepare a 10 mL homogeneous solution. 0.9 mL of the solution was filled into glass vials, purged with nitrogen, and then sealed with rubber stoppers to prepare a 0.9 mL solution formulation (Example 3) containing 19.25 mg of cabazitaxel acetone adduct, 0.47 g of polysorbate 80, 0.48 g of macrogol 300, and 2.25 mg of anhydrous citric acid. When the formulation of Example 3 was diluted with water to a cabazitaxel concentration of 0.1 mg / mL, the pH was 4.3.

[0023] Comparative Example 1 291 mg of cabazitaxel acetone adduct was added to 7.0 g of polysorbate 80 (SUPER REFINED Polysorbate 80-LQ-(MH), manufactured by CRODA Japan, Inc.; heavy metals: 10 ppm or less; peroxide value: 0.00; water: 0.0%; ignition residue: 0.00%) and dissolved therein. The solution was filled into vials in 1.5 mL portions and sealed with rubber stoppers to give 1.5 mL solution formulations containing 64.14 mg of cabazitaxel acetone adduct and 1.54 g of polysorbate 80 (Comparative Example 1).

[0024] Comparative Example 2 Jevtana (registered trademark) intravenous infusion 60 mg was used as Comparative Example 2. The formulation of Comparative Example 2 contained 64.14 mg of cabazitaxel acetone adduct and 1.56 g of polysorbate 80. When Comparative Example 2 was diluted with the accompanying dissolving solution (13% ethanol in water) or water to a cabazitaxel concentration of 0.1 mg / mL, the pH was 5.1.

[0025] Comparative Example 3 214 mg of cabazitaxel acetone adduct and macrogol 300 (NOF Corporation) were added to 5.2 g of polysorbate 80 (SUPER REFINED polysorbate 80-LQ-(MH), CRODA Japan Co., Ltd.) and dissolved to prepare a 10 mL homogeneous solution. Each glass vial was filled with 0.9 mL of the solution, and after nitrogen substitution, the vial was sealed with a rubber stopper to prepare a 0.9 mL solution formulation (Comparative Example 3) containing 19.25 mg of cabazitaxel acetone adduct, 0.47 g of polysorbate 80, and 0.48 g of macrogol 300. The formulation of Comparative Example 3 was diluted with water to a cabazitaxel concentration of 0.1 mg / mL, and the pH was 6.2.

[0026] The formulation compositions of Examples 1 to 3 and Comparative Examples 1 to 3 are summarized in Table 1.

[0027] [Table 1]

[0028] Test Example 1: Solubility Test Using the preparations of Example 1 and Comparative Example 1, a mixing experiment and a crystal precipitation experiment from the mixed solution were carried out.

[0029] (1) Mixing test A solvent (Example 1: water for injection, Comparative Example 1: 13% ethanol water (solvent included with Jevtana (registered trademark) intravenous infusion 60 mg)) was added to each formulation, and the time required for the solution to mix was confirmed. Mixing was performed on three vials each using the following procedure, and the time required for mixing was confirmed. Procedure A: Gently mix by inversion for 1 minute. Procedure B: Leave to stand for 5 minutes. Procedure C: Continue to mix by gently inversion until mixed.

[0030] (2) Crystal Precipitation Test The mixed solution prepared in the mixing experiment was stored at 25°C in the dark, and it was confirmed whether crystals precipitated from the mixed solution for up to 24 hours.

[0031] The results of (1) the miscibility test and (2) the crystal precipitation test are shown in Table 2. Although the formulation of Example 1 was an ethanol-free dissolving solution, an aqueous solution could be quickly prepared. This demonstrated excellent miscibility when preparing a dosage solution. Furthermore, the formulation of Example 1 did not exhibit precipitation of cabazitaxel even after 24 hours, and was able to maintain a stable dissolved state. On the other hand, precipitation of cabazitaxel was observed in the formulation of Comparative Example 1 after 3 to 4 hours. The formulation of Example 1 was shown to have an excellent ability to maintain a dissolved state after preparation of a dosage solution.

[0032] [Table 2] Results of solubility tests ((1) miscibility test, (2) crystal precipitation test)

[0033] Test Example 2: Stability test under storage conditions of 60°C for 2 weeks The formulations of Examples 2 and 3 and Comparative Examples 2 and 3 were stored at 60°C for 2 weeks under light-protected conditions. Thereafter, the related substances in each formulation were quantitatively analyzed by HPLC to evaluate the formulation stability. The increase in the amount of hydrolyzed cabazitaxel related products and total related products from the initial value is summarized in Table 3. The increase in the amount of related products in Examples 2 and 3 was comparable to that in Comparative Example 2, an existing formulation, and the formulations were more stable than Comparative Example 3, which contained a glycol solvent but no organic acid.

[0034] [Table 3] Results of stability test after storage at 60°C for 2 weeks

[0035] Example 4 75 mg of Japanese Pharmacopoeia anhydrous citric acid (Junsei Chemical Co., Ltd.), 150 mg of cabazitaxel, and Macrogol 300 (NOF Corporation) were added to 3.9 g of polysorbate 80 (Junsei Chemical Co., Ltd.; heavy metals: 20 ppm or less; peroxide value: 1.8; water: 0.1%; ignition residue: 0.10%) and dissolved to prepare a 15 mL homogeneous solution. Each 1.3 mL of the solution was filled into a glass vial, purged with nitrogen, and then sealed with a rubber stopper to prepare a 1.3 mL solution formulation (Example 4) containing 13 mg of cabazitaxel, 0.34 g of polysorbate 80, 1.07 g of macrogol 300, and 6.5 mg of anhydrous citric acid. The formulation of Example 4 was diluted with water to a cabazitaxel concentration of 0.1 mg / mL, and the pH was 3.8.

[0036] Example 5 150 mg of Japanese Pharmacopoeia anhydrous citric acid (Junsei Chemical Co., Ltd.), 150 mg of cabazitaxel, and Macrogol 300 (NOF Corporation) were added to 3.9 g of polysorbate 80 (Junsei Chemical Co., Ltd.; heavy metals: 20 ppm or less; peroxide value: 1.8; water: 0.1%; ignition residue: 0.10%) and dissolved to prepare a 15 mL homogeneous solution. Each 1.3 mL of the solution was filled into a glass vial, purged with nitrogen, and then sealed with a rubber stopper to prepare a 1.3 mL solution formulation (Example 5) containing 13 mg of cabazitaxel, 0.34 g of polysorbate 80, 1.07 g of macrogol 300, and 13 mg of anhydrous citric acid. The formulation of Example 5 was diluted with water to a cabazitaxel concentration of 0.1 mg / mL, and the pH was 3.7.

[0037] Comparative Example 4: 225 mg of Japanese Pharmacopoeia anhydrous citric acid (Junsei Chemical Co., Ltd.), 150 mg of cabazitaxel, and Macrogol 300 (NOF Corporation) were added to 3.9 g of polysorbate 80 (Junsei Chemical Co., Ltd.; heavy metals: 20 ppm or less; peroxide value: 1.8; water: 0.1%; ignition residue: 0.10%) and dissolved to prepare a 15 mL homogeneous solution. Each 1.3 mL of the solution was filled into a glass vial, purged with nitrogen, and then sealed with a rubber stopper to prepare a 1.3 mL solution formulation (Comparative Example 4) containing 13 mg of cabazitaxel, 0.34 g of polysorbate 80, 1.06 g of Macrogol 300, and 19.5 mg of anhydrous citric acid. The formulation of Example 4 was diluted with water to a cabazitaxel concentration of 0.1 mg / mL, and the pH was 3.3.

[0038] Example 6 7.5 mg of Japanese Pharmacopoeia anhydrous citric acid (Junsei Chemical Co., Ltd.), 150 mg of cabazitaxel, and macrogol 300 (NOF Corporation) were added to 3.75 g of polysorbate 80 (Junsei Chemical Co., Ltd.; heavy metals: 20 ppm or less; peroxide value: 1.8; water: 0.1%; ignition residue: 0.10%) and dissolved to prepare a 15 mL homogeneous solution. Each 1.3 mL of the solution was filled into a glass vial, purged with nitrogen, and then sealed with a rubber stopper to prepare a 1.3 mL solution formulation (Example 6) containing 13 mg of cabazitaxel, 0.33 g of polysorbate 80, 1.09 g of macrogol 300, and 0.65 mg of anhydrous citric acid. The formulation of Example 6 was diluted with water to a cabazitaxel concentration of 0.1 mg / mL, and the pH was 5.0.

[0039] Comparative Example 5: 150 mg of cabazitaxel and Macrogol 300 (NOF Corporation) were added to 3.75 g of polysorbate 80 (Junsei Chemical Co., Ltd.; heavy metals: 20 ppm or less, peroxide value: 1.8, water: 0.1%, ignition residue: 0.10%) and dissolved to prepare a 15 mL homogeneous solution. Each 1.3 mL of the solution was filled into a glass vial, purged with nitrogen, and then sealed with a rubber stopper to prepare a 1.3 mL solution formulation (Comparative Example 5) containing 13 mg of cabazitaxel, 0.33 g of polysorbate 80, and 1.09 g of macrogol 300. The formulation of Example 5 was diluted with water to a cabazitaxel concentration of 0.1 mg / mL, and the pH was 6.6.

[0040] Comparative Example 6: 3.75 g of polysorbate 80 (Junsei Chemical Co., Ltd.; heavy metals: 20 ppm or less; peroxide value: 1.8; water content: 0.1%; ignition residue: 0.10%) was dissolved in 3.75 mg of JP anhydrous citric acid (Junsei Chemical Co., Ltd.), 150 mg of cabazitaxel, and macrogol 300 (NOF Corporation) to prepare a 15 mL homogeneous solution. Each 1.3 mL of the solution was filled into a glass vial, purged with nitrogen, and then sealed with a rubber stopper to prepare a 1.3 mL solution formulation (Comparative Example 6) containing 13 mg of cabazitaxel, 0.33 g of polysorbate 80, 1.09 g of macrogol 300, and 0.33 mg of anhydrous citric acid. The formulation of Comparative Example 6 was diluted with water to a cabazitaxel concentration of 0.1 mg / mL, and the pH was 5.7.

[0041] The formulation compositions of Examples 4 and 5 and Comparative Example 4, and Example 6 and Comparative Examples 5 and 6 are summarized in Table 4.

[0042] [Table 4]

[0043] Test Example 3: Stability test under 60°C / 2-week storage conditions The formulations of Examples 4 and 5 and Comparative Example 4, and Example 6 and Comparative Examples 5 and 6 were stored at 60°C for 2 weeks under light-protected conditions. Thereafter, the related substances in each formulation were quantitatively analyzed by HPLC to evaluate the formulation stability. The increases from the initial values ​​of hydrolyzed cabazitaxel related products and total related products in Examples 4 and 5 and Comparative Example 4 are summarized in Table 5. The increases from the initial values ​​of hydrolyzed cabazitaxel related products in Example 6 and Comparative Examples 5 and 6 are summarized in Table 6. The formation of related products was suppressed by adjusting the pH to 3.5 to 5.5.

[0044] [Table 5] Results of stability test after storage at 60°C for 2 weeks

[0045] Table 6: Results of stability test after storage at 60°C for 2 weeks

[0046] Example 7 10 mg of Japanese Pharmacopoeia anhydrous citric acid (Junsei Chemical Co., Ltd.), 214 mg of cabazitaxel acetone adduct, and macrogol 400 (NOF Corporation) were added to 5.2 g of polysorbate 80 (SUPER REFINED polysorbate 80-LQ-(MH), manufactured by CRODA Japan Co., Ltd.; heavy metals: 10 ppm or less; peroxide value: 0.00; water: 0.0%; ignition residue: 0.00%) and dissolved to prepare a 10 mL homogeneous solution. 0.9 mL of the solution was filled into glass vials, purged with nitrogen, and then sealed with rubber stoppers to prepare a 0.9 mL solution formulation (Example 7) containing 19.25 mg of cabazitaxel acetone adduct, 0.47 g of polysorbate 80, 0.51 g of macrogol 400, and 0.90 mg of anhydrous citric acid. This formulation was diluted with water to a cabazitaxel concentration of 0.1 mg / mL, and the pH was 4.9.

[0047] Example 8: 5.2 g of Japanese Pharmacopoeia polysorbate 80 (Sanyo Chemical Co., Ltd.; heavy metals: 20 ppm or less; peroxide value: 0.2; water content: 0.1% or less; ignition residue: 0.08%) was dissolved with 40 mg of Japanese Pharmacopoeia anhydrous citric acid (Junsei Chemical Co., Ltd.), 200 mg of cabazitaxel, and propylene glycol (Fujifilm Wako Pure Chemical Industries, Ltd.; food additive) to prepare a 10 mL homogeneous solution. Each 0.9 mL of the solution was filled into a glass vial, purged with nitrogen, and then sealed with a rubber stopper to prepare a 0.9 mL solution formulation (Example 8) containing 18 mg of cabazitaxel, 0.47 g of polysorbate 80, 0.47 g of propylene glycol, and 3.60 mg of anhydrous citric acid. This formulation was diluted with water to a cabazitaxel concentration of 0.1 mg / mL, and the pH was 4.1.

[0048] The formulation compositions of Examples 7 and 8 are summarized in Table 7.

[0049] [Table 7]

[0050] Test Example 4: Stability test under storage conditions of 60°C for 2 weeks The formulations of Examples 7 and 8 and Comparative Example 3 were stored for 2 weeks at 60°C under light-protected conditions. Thereafter, the related substances in each formulation were quantitatively analyzed by HPLC to evaluate the formulation stability. The increase in the amount of hydrolyzed cabazitaxel related products and total related products from the initial value is summarized in Table 8. The increase in the amount of related products in Examples 7 and 8 was higher than that in Comparative Example 3, which added glycol solvent but did not add any organic acid.

[0051] Table 8: Results of stability test after 2 weeks storage at 60°C

Claims

1. A liquid pharmaceutical formulation containing cabazitaxel as an active ingredient, comprising a glycol solvent selected from polysorbate, polyethylene glycol and / or propylene glycol, and an organic acid, wherein the liquid pharmaceutical formulation is diluted with water and the pH of the solution at a cabazitaxel concentration of 0.1 mg / mL is greater than 3.5 and less than 5.

5.

2. The cabazitaxel solution pharmaceutical formulation of claim 1, containing cabazitaxel at 5 to 30 mg / mL.

3. The cabazitaxel solution pharmaceutical formulation according to claim 1, wherein the glycol solvent is 0.5 to 3.5 parts by mass per 1 part by mass of polysorbate.

4. The cabazitaxel solution pharmaceutical formulation of claim 1, comprising a glycol solvent at 0.2 to 1.7 g / mL.

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