Gemcitabine hydrochloride composition and preparation method thereof

A technique for gemcitabine hydrochloride and its composition, which is applied in the field of gemcitabine hydrochloride composition and preparation, and can solve the problems of poor stability of gemcitabine hydrochloride, troublesome storage and transportation of liquid reagents, and easy decomposition.

Active Publication Date: 2009-12-23
SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, gemcitabine hydrochloride has poor stability and is easily decomposed when stored in a solution state.
Moreover, liquid reagents are more troublesome to store and transport.

Method used

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  • Gemcitabine hydrochloride composition and preparation method thereof
  • Gemcitabine hydrochloride composition and preparation method thereof
  • Gemcitabine hydrochloride composition and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0093] Hydrolysis: Add 100 g (212.3 mmol, α / β=1.1) of 2'-deoxy-2', 2'-difluorocytidine-3', 5'-dibenzoate into methanol, cool down to 7-8 ℃, feed 30g of ammonia gas to react, after the completion of the reaction, the temperature is naturally raised to room temperature, stirred for 8h, and then concentrated to near dryness, the obtained product is dissolved in 2150ml of water, extracted by adding 2150ml of ethyl acetate after dissolution, the water layer is separated and then used with 2150ml of ethyl acetate Extract, combine ethyl acetate, extract with 2150ml of water, combine all the water layers, decolorize with activated carbon, filter the obtained aqueous solution and concentrate under reduced pressure (pressure 1330Pa, temperature 60°C) to nearly dry, add 2150ml of isopropanol to the concentrate, heat to 70 ℃, heat preservation for 0.5h, and then heat preservation at 30°C for 7.5h, then cool down to about 0°C, freeze for 2h, and filter to obtain 51.2g of white solid of form...

Embodiment 2

[0097] Hydrolysis: Add 200 g (424.6 mmol, α / β=1.05) of 2'-deoxy-2', 2'-difluorocytidine-3', 5'-dibenzoate into methanol, cool down to 8-10 ℃, feed 85.7g of ammonia gas to react, after the completion of the reaction, the temperature is naturally raised to room temperature, stirred for 8h, and then concentrated to near dryness, the obtained product is dissolved in 4300ml of water, and extracted by adding 4300ml of ethyl acetate after dissolution, the water layer is separated and then used with 4300ml of ethyl acetate Ester extraction, combined with ethyl acetate, extracted with 4300ml of water, combined all the water layers, decolorized with activated carbon, concentrated the aqueous solution obtained by filtration under reduced pressure (pressure 4030Pa, temperature 55°C) to near dryness, added 4300ml of isopropanol to the concentrate, and heated to 50°C, keep warm for 0.4h, then keep warm at 28°C for 7.5h, then cool down to about -5°C, freeze for 2h, filter to obtain 101.6g of ...

Embodiment 3

[0101] Hydrolysis: Add 50 g (106.15 mmol, α / β=1.03) of 2'-deoxy-2', 2'-difluorocytidine-3', 5'-dibenzoate into methanol, cool down to 5-7 ℃, feed 11.5g of ammonia gas to react, after the completion of the reaction, the temperature is naturally raised to room temperature, stirred for 10h, and then concentrated to nearly dryness, the obtained product is dissolved in 1075ml of water, extracted by adding 1075ml of ethyl acetate after dissolution, the water layer is separated and then used in 1075ml of ethyl acetate Ester extraction, combined ethyl acetate, extracted with 1075ml of water, combined all the water layers, decolorized with activated carbon, concentrated the aqueous solution obtained by filtration under reduced pressure (pressure 1000Pa, temperature 40°C) to nearly dryness, added 900ml of isopropanol to the concentrate, and heated To 90°C, keep warm for 0.6h, then keep warm at 33°C for 7.0h, then cool down to about -5~-2°C, freeze for 2h, filter to obtain 25.4g of white ...

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Abstract

The invention provides a gemcitabine hydrochloride composition which comprises the following components by weight portions: 57 portions of gemcitabine hydrochloride, 20 to 50 portions of mannitol and proper amount of sodium acetate. The gemcitabine hydrochloride is firstly recrystallized to improve the purity of the product after synthesizing gemcitabine, and the gemcitabine hydrochloride is prepared. The method has high yield and the obtained gemcitabine hydrochloride has high purity. Freeze-drying powder prepared by the gemcitabine hydrochloride synthesized by the method has good stability. The invention also provides a preparation of the gemcitabine hydrochloride composition, and the adopted freeze-drying method comprises the following steps of: reducing the temperature of a freeze-drying box to -42 to -38 DEG C, putting encapsulated medicines, keeping the temperature for 3 hours, starting a vacuum pump, keeping the vacuum degree in the drying box to 3 to 9Pa, raising the temperature slowly to minus 22 to minus 18 DEG C with the speed of raising the temperature of 0.3 DEG C / min, keeping the temperature for 2 hours, raising the temperature to 0 DEG C with the speed of 0.5 DEG C / min, keeping the temperature for 15 hours, raising the temperature of the drying box to 8 to 12 DEG C with the speed of 1 DEG C / min, keeping the temperature for 3 to 5 hours, raising the temperature to 34 to 36 DEG C with the speed of 2 DEG C / min and keeping the temperature for 10 hours.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a gemcitabine hydrochloride composition and a preparation method. Background technique [0002] Gemcitabine hydrochloride (formula IIb) was developed by U.S. Eli Lilly Company, and it was listed in countries such as Australia and Finland in 1995, and existing raw materials and preparations have been produced in my country. The listed dosage form of gemcitabine hydrochloride is an injection, and the specification is (1) 0.2g (in C 9 h 11 f 2 N 3 o 4 In terms of), (2) 1.0g (in C 9 h 11 f 2 N 3 o 4 ), and the indication is non-small cell lung cancer. Gemcitabine hydrochloride is a nucleoside homologue, which is a cell cycle-specific antineoplastic drug. It mainly kills cells in S phase (DNA synthesis), and also blocks the transition process of cell proliferation from G1 to S phase. This product is metabolized into active nucleoside diphosphate (dFdCDP) and nucleoside triphosphate...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/7068C07H19/06C07H1/00A61K9/19A61J3/02A61P35/00
Inventor 李明华高菲菲李志滨
Owner SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD
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