Thetepib injection and production process thereof

Abstract

The invention relates to a thiotepa injection and a production process thereof, the thiotepa injection comprises 5-20 mg / ml of thiotepa, 0.05-0.5 mg / ml of edetate disodium and polyethylene glycol, and the pH value is 4.7-7.0, the production process comprises the following steps: filling and sealing a mixed liquid medicine containing thiotepa, edetate disodium and polyethylene glycol, introducing nitrogen to control the residual oxygen amount of headspace, and carrying out moist heat sterilization according to a sterilization process: F0 is greater than or equal to 8. The thiotepib injection can tolerate moist heat sterilization, avoids tedious operation of preparation before use, improves the sterile guarantee level of the preparation, improves the safety, and also can improve the stability of the product in the storage and transportation processes.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical production, and in particular relates to a thiotepa injection and a production process thereof. Background Art

[0002] Thiotepa, whose chemical name is triethylenethiophosphoramide, is a broad-spectrum anti-tumor drug with dual myeloablative and immunosuppressive effects. It can inhibit nucleic acid synthesis, cross-link with DNA, interfere with the function of DNA and RNA, and has a strong cytotoxic effect.

[0003] Thiotepa is an alkylating agent that is not cell cycle specific and is the only FDA-approved chemotherapy drug for the intravesical treatment of papillary bladder cancer. Adding thiotepa to the transplant conditioning regimen has been recommended by many authoritative guidelines and expert consensus at home and abroad, including the Chinese Society of Clinical Oncology (CSCO) Guidelines for Hematopoietic Stem Cell Transplantation for the Treatment of Hematological Diseases, CSCO Lymphoma Diagnosis and Treatment Guidelines, and the National Comprehensive Cancer Network (NCCN) Guidelines for Hematopoietic Stem Cell Transplantation.

[0004] Thiotepa has a low boiling point and poor stability. It is easy to produce impurities or degrade after storage, and it is difficult to withstand wet heat sterilization. Currently, the clinically approved thiotepa injections are in two forms: powder injection and solution. The powder injection is produced using a filtration sterilization process, and a diluent must be added before use to prepare a solution. The operation is cumbersome and the clinical use is not convenient enough.

[0005] In the prior art, for example, U.S. Patent No. US11975013B2 discloses a method for preparing a thiotepa solution, in which the solvent in the thiotepa injection is selected from dimethyl sulfoxide, polyethylene glycol, dimethylacetamide and N-methylpyrrolidone; Chinese patent application CN110840832A discloses an injection solvent of dimethyl sulfoxide, wherein each milliliter of dimethyl sulfoxide contains 5-15 mg of thiotepa injection; Chinese patent application CN115919784A discloses a method for preparing thiotepa for injection, and filtering and sterilization processes are used in the preparation or production.

[0006] However, the sterility assurance level of the products obtained through the filtration sterilization process is relatively low, and the safety of clinical use is not ideal. In addition, due to the poor stability of thiotepa, the transportation and storage of thiotepa injection and lyophilized powder injection must be carried out under refrigerated conditions of 2 to 8°C, which brings many inconveniences to the production, transportation and storage links. Summary of the invention

[0007] The object of the present invention is to provide a thiotepa injection and a production process thereof, which can withstand moist heat sterilization, has good long-term stability, avoids the cumbersome operation of preparation before use, improves the sterility assurance level of the preparation, improves safety, improves the stability of the product during storage and transportation, and can be stored and transported at room temperature.

[0008] In order to achieve the above object, the present invention provides the following technical solutions:

[0009] A thiotepa injection comprises 5-20 mg / ml of thiotepa, 0.05-0.5 mg / ml of edetate disodium and polyethylene glycol, and has a pH value of 4.7-7.0.

[0010] Preferably, the polyethylene glycol is selected from one or more of polyethylene glycol 300, polyethylene glycol 400 or polyethylene glycol 600.

[0011] Furthermore, the content of edetate disodium is 0.1-0.3 mg / ml.

[0012] Furthermore, the thiotepa injection is obtained through a wet heat sterilization process.

[0013] Preferably, in the moist heat sterilization process, F0≥8.

[0014] The present invention provides a production process of the thiotepa injection, comprising the following steps:

[0015] 1) According to the prescription amount of 5-20 mg / ml of thiotepa and 0.05-0.5 mg / ml of edetate disodium, edetate disodium and thiotepa are added to polyethylene glycol respectively, stirred until dissolved, and polyethylene glycol is added to the prescription volume to obtain a mixed solution;

[0016] 2) filtering the mixed drug solution prepared in step 1) through a filter membrane, filling, sealing or sealing with a rubber stopper after filtration, and performing moist heat sterilization to obtain the thiotepa injection.

[0017] Furthermore, in step 1), the amount of polyethylene glycol used during dissolution is 25 to 95% of the volume of the prescription.

[0018] Furthermore, in step 2), F0≥8 in the moist heat sterilization process.

[0019] Preferably, in step 2), the pore size of the filter membrane used for filtration is 0.22 μm or 0.45 μm, and the solution is filled into ampoules or vials after filtration; nitrogen is introduced before filling the solution, or nitrogen is introduced after filling the solution, or nitrogen is introduced before and after filling the solution, respectively, to control the residual oxygen content in the headspace to ≤5%.

[0020] The inventors unexpectedly discovered that by adding a very small amount of the metal ion chelating agent disodium edetate, the effect of metal ions on the stability of thiotepa during the preparation process can be greatly reduced, the stability of thiotepa can be improved, and the prepared thiotepa solution can withstand circulating steam, thereby achieving moist heat sterilization. Moreover, after moist heat sterilization, the thiotepa injection can remain stable for a long time during the subsequent stability placement process.

[0021] Compared with the prior art, the present invention has the following beneficial effects:

[0022] The invention improves the wet heat sterilization tolerance of thiotepa by introducing a very small amount of disodium edetate, so that the prepared thiotepa liquid can withstand circulating steam, thereby realizing wet heat sterilization production, having a simple production process, and being suitable for large-scale industrial production while ensuring product quality.

[0023] The thiotepa injection of the present invention reduces the degree of impurity degradation during the stability period after wet heat sterilization, has stable quality and low impurity content, does not require refrigerated storage and cold chain transportation, has a small increase in impurities after being placed under high temperature (60±2° C.) conditions for 30 days, meets the pH requirements, and has stable product quality.

[0024] For the thiotepa injection of the present invention, the product was fully inspected in accordance with the standards of the 2020 edition of the "Chinese Pharmacopoeia". After being placed at room temperature (25°C) for 12 months, the content, properties, pH, moisture and related substances still met the standard requirements. Among them, the thiotepa content was more than 99%, the chlorinated adduct ≤0.15%, the maximum single impurity ≤0.5%, and the total impurities ≤1.0%, which improved product quality and reduced product risks. DETAILED DESCRIPTION

[0025] The present invention is further described below by means of specific examples.

[0026] Examples 1 to 6 and Comparative Examples 1 to 4

[0027] 1. Prepare the liquid medicine according to the prescription composition in Table 1, and prepare the thiotepa injection according to the preparation process in Table 2.

[0028] First, take part of the solvent (polyethylene glycol 400, polyethylene glycol 600, water or ethanol) into the dispensing container, add edetate disodium and stir to dissolve, add thiotepa and stir to dissolve, add the corresponding solvent to the prescribed volume to obtain a mixed solution, filter the mixed solution through a 0.22 μm filter membrane, fill it into a borosilicate glass ampoule, pass nitrogen to control the residual oxygen in the headspace to ≤5%, seal it, and sterilize it with wet heat.

[0029] Table 1

[0030] Serial number Thiotepa Edetate Disodium Polyethylene glycol 400 Polyethylene glycol 600 water Ethanol Example 1 10mg 0.1mg Add to 1ml NA NA NA Example 2 10mg 0.05mg Add to 1ml NA NA NA Example 3 10mg 0.5mg Add to 1ml NA NA NA Example 4 5mg 0.1mg Add to 1ml NA NA NA Example 5 20mg 0.1mg Add to 1ml NA NA NA Example 6 10mg 0.1mg NA Add to 1ml NA NA Comparative Example 1 10mg NA Add to 1ml NA NA NA Comparative Example 2 10mg NA Add to 1ml NA NA NA Comparative Example 3 10mg 0.1mg NA NA Add to 1ml NA Comparative Example 4 10mg 0.1mg NA NA NA Add to 1ml

[0031] Note: NA means not included.

[0032] Table 2

[0033]

[0034] 2. Stability test

[0035] Samples were taken from Example 1 and Comparative Example 1 for long-term stability at 25°C, and samples were taken from Examples 1 to 3 and Comparative Examples 1 to 2 for high temperature (60°C) 30-day stability. Among them, Example 1 and Comparative Example 1 were also tested at 25°C for 6 to 12 months. The results are shown in Table 3.

[0036] Table 3 Stability test results of Examples 1 to 3 and Comparative Examples 1 to 2

[0037]

[0038] Note: ND means not detected; -- means no further investigation based on 6-month data at 25℃.

[0039] It can be seen from Comparative Example 1 and Comparative Example 2 that, compared with the sterilizing filtration process, adding a small amount of disodium edetate and adopting a wet heat sterilization process to prepare a sample can be stored for a long time at room temperature. It can be seen from Comparative Example 1, Example 2 and Example 3 that when the amount of disodium edetate added in the prescription is 0.1 mg / ml or 0.5 mg / ml, there is no significant difference in the sterilization resistance and stability of the prepared samples. When the amount of disodium edetate added is 0.05 mg / ml, the content of each impurity in the prepared sample is close to the limit after being placed at 60°C for 30 days.

[0040] It can be seen that the addition of edetate disodium in the prescription can significantly improve the stability of thiotepa injection during the sterilization process and the stability during storage.

[0041] Samples from Example 1, Example 4 and Example 5 were subjected to a high temperature 60° C., 30-day stability test. The results are shown in Table 4.

[0042] Table 4 Stability test results of Example 1 and Examples 4 and 5

[0043]

[0044] From the results in Table 4, it can be seen that the concentration of thiotepa in the prescription is in the range of 5 mg / ml to 20 mg / ml, and the samples have good tolerance and stability to wet heat sterilization.

[0045] Samples were taken from Example 1, Example 6 and Comparative Examples 3-4 for high temperature (60° C.) 30-day stability test. The results are shown in the following table.

[0046] Table 5 Stability test results of Example 1, Example 6 and Comparative Examples 3-4

[0047]

[0048] Note: ND means not detected; —— means not sampled and inspected.

[0049] From the results in Table 5, it can be seen that this product uses polyethylene glycol 400 and polyethylene glycol 600 as solvents to prepare samples. This product has good tolerance to wet heat sterilization. After high temperature stability inspection, the content of related substances and active ingredients meets the requirements of the pharmacopoeia. For samples prepared with water as the solvent, about 90% of the main components are degraded after sterilization, and for samples prepared with ethanol as the solvent, about 20% of the main components are degraded after sterilization.

Claims

1. A thiotepa injection, comprising 5-20 mg / ml of thiotepa, 0.05-0.5 mg / ml of edetate disodium and polyethylene glycol, with a pH value of 4.7-7.

0.

2. The thiotepa injection according to claim 1, characterized in that: The polyethylene glycol is selected from one or more of polyethylene glycol 300, polyethylene glycol 400 and polyethylene glycol 600.

3. The thiotepa injection according to claim 1, characterized in that: The content of the disodium edetate is 0.1-0.3 mg / ml.

4. The thiotepa injection according to any one of claims 1 to 3, characterized in that The thiotepa injection is obtained through a moist heat sterilization process.

5. The thiotepa injection according to claim 4, characterized in that: In the moist heat sterilization process, F0≥8.

6. The production process of thiotepa injection according to claim 1, comprising the following steps: 1) According to the prescription amount of 5-20 mg / ml of thiotepa and 0.05-0.5 mg / ml of edetate disodium, edetate disodium and thiotepa are added to polyethylene glycol respectively, stirred until dissolved, and polyethylene glycol is added to the prescription volume to obtain a mixed solution; 2) filtering the mixed drug solution prepared in step 1) through a filter membrane, filling, sealing or sealing with a rubber stopper after filtration, and performing moist heat sterilization to obtain the thiotepa injection.

7. The production process of thiotepa injection according to claim 6, characterized in that: In step 1), the initial addition amount of polyethylene glycol is 25 to 95% of the volume of the prescription amount.

8. The production process of thiotepa injection according to claim 7, characterized in that: In step 2), F0≥8 in the moist heat sterilization process.

9. The production process of thiotepa injection according to any one of claims 6 to 8, characterized in that: In the step 2), the pore size of the filter membrane used for filtration is 0.22 μm or 0.45 μm, and the solution is filled into an ampoule or a vial after filtration; nitrogen is introduced before filling the solution, or nitrogen is introduced after filling the solution, or nitrogen is introduced before and after filling the solution, respectively, to control the residual oxygen content in the headspace to be ≤5%.

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