Cabazitaxel injection and preparation method thereof

Abstract

The invention discloses a cabazitaxel injection and a preparation method thereof, the cabazitaxel injection is prepared from the following raw materials: cabazitaxel, polysorbate 80 and a pH regulator, and the pH of the cabazitaxel injection is regulated to be acidic through the pH regulator. The cabazitaxel can be quickly dissolved in the polysorbate 80 in a heating manner, so that the dissolution temperature of the cabazitaxel does not need to be too high, the degradation of the cabazitaxel due to high-temperature instability is avoided, the dissolution time of the cabazitaxel is effectively shortened, the preparation time is shortened, the introduction of a large amount of cosolvents such as ethanol is avoided, and the preparation cost is reduced. A process step of removing a cosolvent is reduced; after the cabazitaxel is dissolved, the pH value of the system is adjusted, and compared with the traditional method that the pH value of polysorbate 80 is firstly adjusted, the pH value of the product can be more rapidly adjusted to a target value in one step; smooth filtering and filling are guaranteed through a liquid medicine heat preservation method, the heat preservation temperature is basically consistent with the liquid preparation temperature, operation and implementation in a workshop are easy, and the whole process is controllable.

Description

Technical Field

[0001] The present invention belongs to the technical field of paclitaxel pharmaceutical preparations, and particularly relates to a cabazitaxel injection and a preparation method thereof. Background Art

[0002] Cabazitaxel is a taxane anti-tumor drug semi-synthesized from 10-deacetylbaccatin III extracted from the needles of Taxus chinensis. It inhibits cell division and induces cell death by promoting tubulin polymerization and stabilizing microtubules, thereby suppressing tumor growth. Developed by Sanofi, Cabazitaxel injection was first approved by the FDA in June 2010 under the trade name JEVTANA. It is a second-line treatment for prostate cancer, used in combination with prednisone for the treatment of refractory metastatic prostate cancer.

[0003] According to the FDA package insert, the formulation of cabazitaxel injection contains 60 mg of the main ingredient, cabazitaxel, 1.56 g of the solvent, polysorbate 80, and citric acid to adjust the pH of polysorbate 80 to 3.3-3.8. During research, the applicant discovered two difficulties in the preparation of this cabazitaxel injection: First, polysorbate 80 accounts for 96% (w / w) of the formulation, and polysorbate 80 itself has high viscosity, which slows the dispersion and dissolution of cabazitaxel, increases resistance to sterilization filtration, and may lead to leakage and uneven filling during the filling process. Second, citric acid is difficult to dissolve directly in polysorbate 80 to adjust its pH. Furthermore, polysorbate 80 is susceptible to oxidation and deterioration, which also accelerates the degradation of cabazitaxel, resulting in poor product stability.

[0004] To address the above issues, Chinese invention patent application number 201510741289.7 discloses a cabazitaxel injection and its preparation method. Based on the solubility properties of cabazitaxel—it is readily soluble in methanol and acetone, soluble in ethanol and dichloromethane, slightly soluble in acetonitrile, and virtually insoluble in ethyl acetate, toluene, n-heptane, and water—the addition of anhydrous ethanol as a cosolvent resolves the difficulty in dissolving cabazitaxel and reduces the viscosity of polysorbate 80, making the solution easier to sterilize and filter, improving filling accuracy and reducing material waste. Finally, ethanol is removed through a freeze-drying process. While this formulation and preparation process are feasible, from a production perspective, ethanol's high volatility poses a safety hazard. Furthermore, the addition of a freeze-drying step to remove the anhydrous ethanol prolongs the product's production cycle and increases production costs.

[0005] Chinese invention patent application number 201911073861.1 discloses a cabazitaxel injection, which incorporates ethanol and polyethylene glycol into the formulation. Ethanol, as a solvent, improves the viscosity of the drug solution, facilitating filtration and filling. Polyethylene glycol, as a stabilizer, pre-dissolves cabazitaxel to form a protective film, preventing direct contact between the polysorbate 80 and the drug, thereby enhancing the stability of the cabazitaxel injection. While the patented cabazitaxel injection preparation process is feasible and the prepared samples are stable, from the perspective of generic drugs, the patent introduces other excipients, ethanol and polyethylene glycol, which have not been removed, increasing the need for clinical trials. Summary of the Invention

[0006] In order to solve the problems in the prior art, the present invention aims to provide a cabazitaxel injection and a preparation method thereof.

[0007] In order to achieve the above-mentioned purpose and the above-mentioned technical effect, the technical solution adopted by the present invention is: A cabazitaxel injection is provided. The raw materials for preparing the cabazitaxel injection include cabazitaxel, polysorbate 80 and a pH regulator. The pH of the cabazitaxel injection is adjusted to acidic by the pH regulator.

[0008] Furthermore, the pH adjuster is a phosphoric acid solution, which is used to adjust the pH of cabazitaxel injection to 3.0-4.0.

[0009] Furthermore, the molar concentration of the phosphoric acid solution is 0.05-0.15M.

[0010] Furthermore, each 1.5 ml of cabazitaxel injection contains 60 mg of cabazitaxel and 1.56 g of polysorbate 80.

[0011] The present invention also discloses a method for preparing cabazitaxel injection, comprising the following steps: Cabazitaxel and polysorbate 80 are mixed and stirred, and heated at 40-50°C to completely dissolve the cabazitaxel. A pH adjuster is then added to adjust the pH of the solution to 3.0-4.0. The mixture is then kept warm and sterilized and filtered to obtain the desired cabazitaxel injection.

[0012] Furthermore, the insulation temperature is 35~50℃.

[0013] Furthermore, a 0.22 μm PVDF filter element was used for sterilization filtration, and nitrogen pressure filtration was used.

[0014] Furthermore, after sterilization and filtration, nitrogen filling, stoppering, capping, light inspection and packaging are carried out to obtain the desired cabazitaxel injection.

[0015] Compared with the prior art, the present invention has the following beneficial effects: The preparation method provided by the present invention has the advantages of simplified preparation process and short preparation time, which are specifically reflected in the following aspects: (1) Due to the high viscosity of polysorbate 80 itself, cabazitaxel is difficult to disperse in it. If you want to dissolve cabazitaxel directly in it, ordinary stirring equipment may not be able to achieve the desired effect. In addition, the dissolution time of cabazitaxel is very long, and the risk of microbial invasion is high. The applicant innovatively discovered for the first time that cabazitaxel can be quickly dissolved in polysorbate 80 by heating, so that the dissolution temperature of cabazitaxel does not need to be too high, 40~50℃ is sufficient, so as to avoid high temperature instability and degradation of cabazitaxel. This innovative method not only effectively shortens the dissolution time of cabazitaxel, but also shortens the preparation time, and avoids the introduction of a large amount of cosolvents such as ethanol, reducing a process step of removing the cosolvent; (2) The present invention selects to adjust the pH of the system after the dissolution of cabazitaxel. Compared with the traditional method of adjusting the pH of polysorbate 80 first, the pH of the product can be adjusted to the target value more quickly and in one step; (3) Since polysorbate 80 is viscous, it is difficult to filter the liquid medicine. The applicant investigated the effect of temperature on the viscosity of polysorbate 80 and found that the higher the temperature, the lower the viscosity of polysorbate 80. To ensure the smooth progress of the filtration and filling processes, the present invention uses a method of keeping the liquid medicine warm to ensure the smooth progress of the filtration and filling. The temperature of the warming can be kept basically consistent with the temperature of the liquid preparation. This method can be operated in the workshop, is simple to implement, and the process is controllable throughout. Compared with room temperature filtration, the viscosity of the liquid medicine is reduced, the filtration resistance is reduced, and the filtration efficiency is improved. The viscosity of the liquid medicine filled at room temperature is high, and ceramic pump filling will cause dripping and leakage problems, resulting in poor filling accuracy. Compared with room temperature filling, the viscosity of the warming liquid medicine is reduced, which can avoid these problems, ensure the smooth progress of the filling process, reduce the manual cleaning process, and greatly shorten the product preparation time. DETAILED DESCRIPTION

[0016] The present invention is described in detail below so that the advantages and features of the present invention can be more easily understood by those skilled in the art, thereby making a clearer and more precise definition of the protection scope of the present invention.

[0017] The following is a brief summary of one or more aspects to provide a basic understanding of these aspects. This summary is not an exhaustive overview of all conceivable aspects and is neither intended to identify key or critical elements of all aspects nor to define the scope of any or all aspects. Its sole purpose is to present some concepts of one or more aspects in a simplified form as a prelude to the more detailed description that will be provided later.

[0018] The invention discloses a cabazitaxel injection. The preparation raw materials of the cabazitaxel injection include cabazitaxel, polysorbate 80 and a pH regulator. The pH of the cabazitaxel injection is adjusted to acidic by the pH regulator.

[0019] In some embodiments, the pH adjuster is a phosphoric acid solution, and the pH of the cabazitaxel injection is adjusted to 3.0-4.0 by the phosphoric acid solution.

[0020] In some embodiments, the molar concentration of the phosphoric acid solution is 0.05-0.15M.

[0021] In some embodiments, each 1.5 ml of cabazitaxel injection contains 60 mg of cabazitaxel and 1.56 g of polysorbate 80.

[0022] The present invention also discloses a method for preparing cabazitaxel injection, comprising the following steps: Cabazitaxel and polysorbate 80 are mixed and stirred, and heated at 40-50°C to completely dissolve the cabazitaxel. A pH adjuster is then added to adjust the pH of the solution to 3.0-4.0. The solution is then kept warm, sterilized and filtered, filled with nitrogen, stoppered, capped, inspected by light, and packaged to obtain the cabazitaxel injection.

[0023] In some embodiments, the holding temperature is 35-50°C.

[0024] In some embodiments, a 0.22 μm PVDF filter element is used for sterile filtration, and nitrogen pressure filtration is used.

[0025] Example 1 A method for preparing cabazitaxel injection comprises the following steps: Weigh 6 g of cabazitaxel and 156 g of polysorbate 80, mix, and place in a 40°C water bath with magnetic stirring for 30 minutes to completely dissolve the cabazitaxel. Then, add 0.1 M phosphoric acid solution and use the phosphoric acid solution to adjust the pH of the solution to 3.5. Keep the solution warm, sterilize and filter, fill with nitrogen, add a stopper, cap, inspect with light, and package to obtain the cabazitaxel injection.

[0026] Comparative Example 1 The difference between this comparative example and Example 1 is that this comparative example does not include the heating process in a 40° C. water bath.

[0027] The rest is the same as Example 1.

[0028] Comparative Example 2 The difference between this comparative example and Example 1 is that this comparative example uses ethanol, and the volume ratio of polysorbate 80 to ethanol is 1:1.

[0029] 6 g of cabazitaxel and 156 g of polysorbate 80 were weighed and added to ethanol in a volume ratio of polysorbate 80 to ethanol of 1:1. After mixing, the mixture was placed in a 40°C water bath with magnetic stirring for 30 minutes to completely dissolve the cabazitaxel. A phosphoric acid solution was then added and the pH of the solution was adjusted to 3.5 using the phosphoric acid solution. The ethanol was then evaporated under reduced pressure. The solution was kept warm, sterilized and filtered, and filled with nitrogen. The solution was stoppered and capped. The solution was then inspected by light and packaged to obtain the cabazitaxel injection.

[0030] The rest is the same as Example 1.

[0031] Comparative Example 3 Compared with Example 1, the water bath temperature of this comparative example is 20°C.

[0032] The rest is the same as Example 1.

[0033] The experimental results show that: Comparing Example 1 with Comparative Example 1, Comparative Example 1 failed to achieve complete dissolution of cabazitaxel, while Example 1 was able to achieve complete dissolution of cabazitaxel, indicating that heating at 40-50° C. and magnetic stirring are necessary conditions for achieving complete dissolution of cabazitaxel, and both are indispensable. Comparing Example 1 with Comparative Example 2, Comparative Example 2 uses ethanol, which requires a post-processing removal process, increasing costs, while Example 1 does not use ethanol, does not require any post-processing removal process, and can obtain a cabazitaxel injection that meets the requirements; Comparing Example 1 with Comparative Example 3, the viscosity of polysorbate 80 in Example 1 is 278.3 mPa∙s, while the viscosity of comparative example 3 is 578.1 mPa∙s, indicating that the lower the heating temperature, the higher the viscosity of polysorbate 80, and the higher the heating temperature, the lower the viscosity of polysorbate 80. Only under the heating condition of 40~50℃ can the filtration and filling processes be carried out smoothly.

[0034] The stability of the cabazitaxel injection of Example 1 was tested under the influence of high temperature and light at 50°C, long-term at 30°C, and accelerated at 40°C: (1) Full inspection of finished products, the results are shown in Table 1: Table 1 (2) 50℃ high temperature test: The finished product of Cabazitaxel injection of Example 1 was placed under high temperature conditions of 50°C for 30 days. Samples were taken on the 5th, 10th and 30th days to examine the changes in related substances. The test results are detailed in Table 2: Table 2 The results of the 30-day high temperature test at 50°C showed that the cabazitaxel injection prepared according to the present invention had little difference in related substances and similar change trends.

[0035] (3) Lighting test: Take the finished product of Cabazitaxel injection of Example 1, place the bare bottle under light 5000lμx+ultraviolet 90μw / cm 2 The samples were placed under the same conditions for 30 days, and samples were taken on the 5th, 10th and 30th days to investigate the changes in related substances. The carton packaging + light exposure was used as the control group. The test results are detailed in Table 3: Table 3 The results of the illumination test showed that the cabazitaxel injection prepared according to the present invention had no significant changes in related substances after being packaged in a carton and illuminated for 30 days.

[0036] (4) Long-term 30°C and accelerated 40°C stability test: The finished product of Cabazitaxel injection of Example 1 was placed under accelerated conditions of 40°C and long-term conditions of 30°C for 6 months. Samples were taken at the end of the 3rd and 6th months to examine the changes in related substances. The test results are detailed in Table 4: Table 4 The results of accelerated and long-term tests showed that the growth of related substances in the cabazitaxel injection prepared according to the present invention did not exceed the limit when stored at 40°C for 6 months, and the growth of related substances was small when stored at 30°C for 6 months.

[0037] Conclusion: The above test results show that the present invention can prepare cabazitaxel injection that meets the quality standards, and the prepared cabazitaxel injection shows good stability under high temperature of 50°C and light influence factors, long-term and accelerated conditions.

[0038] Parts or structures not specifically described in the present invention may adopt existing technologies or existing products and will not be described in detail here.

[0039] The above descriptions are merely embodiments of the present invention and are not intended to limit the patent scope of the present invention. Any equivalent structure or equivalent process transformation made using the contents of the present invention specification, or directly or indirectly applied in other related technical fields, are also included in the patent protection scope of the present invention.

Claims

1. A cabazitaxel injection, characterized in that: The raw materials for preparing the cabazitaxel injection include cabazitaxel, polysorbate 80 and a pH regulator, and the pH of the cabazitaxel injection is adjusted to acidic by the pH regulator.

2. The cabazitaxel injection according to claim 1, characterized in that: The pH regulator is a phosphoric acid solution, which is used to adjust the pH of cabazitaxel injection to 3.0-4.

0.

3. The cabazitaxel injection according to claim 2, characterized in that: The molar concentration of the phosphoric acid solution is 0.05-0.15M.

4. The cabazitaxel injection according to claim 1, characterized in that: Each 1.5 ml of cabazitaxel injection contains 60 mg of cabazitaxel and 1.56 g of polysorbate 80.

5. The method for preparing the cabazitaxel injection according to any one of claims 1 to 4, characterized in that: The following steps are involved: Cabazitaxel and polysorbate 80 are mixed and stirred, and heated at 40-50°C to completely dissolve the cabazitaxel. A pH adjuster is then added to adjust the pH of the solution to 3.0-4.

0. The mixture is then kept warm and sterilized and filtered to obtain the desired cabazitaxel injection.

6. The method for preparing cabazitaxel injection according to claim 5, characterized in that: The insulation temperature is 35~50℃.

7. The method for preparing cabazitaxel injection according to claim 5, characterized in that: A 0.22 μm PVDF filter element was used for sterilization filtration and nitrogen pressure filtration was used.

8. The method for preparing cabazitaxel injection according to claim 5, characterized in that: After sterilization and filtration, nitrogen filling, stoppering, capping, light inspection and packaging are carried out to obtain the required cabazitaxel injection.

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