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Preparation method of lolatrexex hydrochloride freeze-dried powder injection

A technology of lolatrexel hydrochloride and freeze-dried powder injection, which is applied in the field of preparation of lolatrexel hydrochloride freeze-dried powder injection, can solve the problems of impractical clinical application, unsatisfactory drug storage and transportation, and high content of related substances. Achieve the effect of facilitating industrial production, ensuring effectiveness and safety, and low content of related substances

Inactive Publication Date: 2018-03-09
BEIJING KONRUNS PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The clarification of the lolatrexex hydrochloride freeze-dried powder injection disclosed in this patent is higher than the No. 2 standard turbidimetric solution, so it cannot be practically used in clinical practice
The lolatrexex hydrochloride freeze-dried powder injection prepared according to the technology in this patent has a high content of related substances, and during storage, the related substances increase significantly, which cannot meet the requirements of drug storage and transportation

Method used

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  • Preparation method of lolatrexex hydrochloride freeze-dried powder injection
  • Preparation method of lolatrexex hydrochloride freeze-dried powder injection
  • Preparation method of lolatrexex hydrochloride freeze-dried powder injection

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] 1. Prescription of lolatrexel hydrochloride freeze-dried powder injection

[0033] Specification: 500mg / bottle

[0034]

[0035] 2. Preparation method

[0036] 1) Weigh the prescribed amount of lolatrexex hydrochloride and mannitol respectively, add about 80% of the prescribed amount of water for injection (80°C), stir and dissolve, add 1M sodium hydroxide solution to adjust the pH value to 2.0, add water for injection to 4000g.

[0037] 2) Filter and sterilize the drug solution obtained in step (1) with a microporous membrane to obtain a fine filtrate, which is subpackaged, filled with 4 g of the drug solution in each vial, and half-covered with a rubber stopper.

[0038] 3) Freeze-dry the fine filtrate contained in the vial:

[0039] Start the freeze dryer, and after pre-freezing at -30°C for 2 hours, start the vacuum pump, raise the shelf temperature to -15°C for sublimation drying for 20 hours, then raise the temperature to 5°C and dry for 4 hours; After the ...

Embodiment 2-5

[0054] The lolatrexex hydrochloride freeze-dried powder injection was prepared according to the method of Example 1, with the difference that the pH value in step 1) was adjusted to 1.8, 1.9, 2.1, and 2.2 with 1M hydrochloric acid and 1M sodium hydroxide solution, respectively.

[0055] The freeze-dried powder injections obtained in Examples 2-5 were subjected to a comparative study on appearance properties, reconstitution and clarity, and compared with Control Example 1 prepared by the prior art. The results are detailed in Table 3.

[0056] The detection result of table 3 embodiment 1-5 lyophilized powder injection

[0057]

[0058] When the pH range of the drug solution before freeze-drying is controlled between 1.8 and 2.2, the clarification values ​​of the prepared freeze-dried powder after reconstitution are all less than 1, which is almost clear and can meet the requirements of clinical use. When the pH value of the drug solution before freeze-drying is controlled b...

Embodiment 6-11

[0060] According to the method of Example 1, lolatrexex hydrochloride freeze-dried powder injection was prepared, the difference is that the freeze-drying process in step 3) adopts different freeze-drying curves respectively, and compares it with the control example 1 prepared by the prior art, and the results are shown in the table 4.

[0061] The detection result of table 4 embodiment 6-11 freeze-dried powder injection

[0062]

[0063] According to the appearance, reconstitution speed, clarity and test results of related substances, the freeze-drying process parameters of lolatrexex hydrochloride for injection are set as follows: -30~-20℃ for 2-4 hours, -15℃~-10 Sublimation at ℃ for 10-20 hours, followed by secondary drying at 5℃-15℃ for 0-4 hours, can obtain samples with good appearance, fast redissolving, clear liquid medicine and lower content of related substances.

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Abstract

The present invention relates to a preparation method of lolatrexex hydrochloride freeze-dried powder injection, specifically weighing the prescription amount of lolatrexil hydrochloride, adding water for injection to stir and dissolve, using a pH regulator to adjust the pH value, and preparing through a freeze-drying process Obtain freeze-dried powder. In the present invention, by adjusting the pH value of the intermediate solution in the preparation process within a certain range, and controlling the process parameters such as temperature and time during freeze-drying, the related substances of the freeze-dried powder of lolatrexex hydrochloride are effectively reduced, and the stability is enhanced. , significantly improved the reconstitution of the freeze-dried powder injection and the clarity of the solution after reconstitution, which can meet the requirements of clinical use and further ensure the effectiveness and safety of clinical use.

Description

technical field [0001] The invention relates to a preparation method of lolatrexex hydrochloride freeze-dried powder injection, belonging to the field of pharmaceutical preparations. Background technique [0002] Nolatrexed Dihydrochloride (Nolatrexed Dihydrochloride) is developed by the U.S. Agouron Pharmaceuticals company. According to the three-dimensional structural characteristics of the enzyme active center, the company has synthesized a series of thymidylate synthase inhibitors using computer simulation drug molecular technology. Nolatrexed Dihydrochloride is One of the compounds with the highest activity of inhibiting thymidylate synthase. On March 31, 1992, the company applied for a compound patent of lolatrexed hydrochloride in the United States. The results of clinical trials show that lolatrexel hydrochloride has a broad-spectrum anti-tumor effect, and has good curative effect on various solid tumors such as liver cancer, head and neck cancer, colon cancer, lung...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K9/19A61K31/517A61P35/00A61J3/00
Inventor 任广智陈东张燕曹相林王锡娟
Owner BEIJING KONRUNS PHARM CO LTD
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