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Composition of Doripenem and amino acid

A technology of composition and amino acid, which is applied in the direction of drug delivery, medical preparations with non-active ingredients, medical preparations containing active ingredients, etc., which can solve problems such as darkening of color, poor fluidity of crystalline powder, and difficulty in ensuring the level of sterility , to achieve the effect of improving stability and storage stability

Active Publication Date: 2011-01-05
CHIA TAI TIANQING PHARMA GRP CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, carbapenems have poor stability in aqueous solution, especially at higher concentrations and temperatures, and the stability is worse, and side reactions such as darkening of color, product polymerization, and degradation often occur, which is unfavorable.
In addition, the applicant found in the test that the crystalline powder of doripenem has poor fluidity. In order to increase the fluidity of the powder, it needs to be micronized, but the aseptic control of the sterile powder is difficult when it is micronized. It is difficult to guarantee its sterility level

Method used

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  • Composition of Doripenem and amino acid
  • Composition of Doripenem and amino acid
  • Composition of Doripenem and amino acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Embodiment 1 (preparation of doripenem crude product)

[0042]

[0043] 100 grams of DN-8 (referring to document organic process research & development 2003, 7, 649-654 method preparation) is dissolved in water (450ml) and THF (800ml), adds 100 grams of Pd / C (water content 66%), heats to At 25°C, under the pressure of 20-24kg, react for 2 hours, heat is released during hydrogenation, and the reaction temperature is maintained at 30-40°C. After the reaction is completed, filter with suction and wash with 150ml (THF:water=2:1) Palladium carbon, wash the water layer with ethyl acetate (750ml×2), wash the water layer with n-butanol (500ml×2), cool the water layer to 0°C, a light yellow solid precipitates, keep warm at 0-5°C and stir overnight, pump Filter and dry under reduced pressure at 25°C for 15 hours to obtain crude doripenem (32 g, yield 65%, purity 96.2%).

Embodiment 2

[0045] Dissolve the crude product of doripenem (1.0g) in distilled aqueous solution (22ml), heat with stirring, and dissolve at 55°C, keep the solution at 50-55°C, add activated carbon (50mg) and stir for decolorization for 5min, filter, Remove the heat source, take the filtrate and cool it to 0-5°C and stir it. After about 10 hours, solids will precipitate out, and keep it at 0-5°C for aging for 2 hours. Depyrogenated ethanol (30ml) was dropped into it within about 1 hour, kept at 0-5°C for aging for 2 hours, and then the obtained crystals were filtered out. The obtained crystals were washed with 80% aqueous ethanol (5 ml), and then dried under reduced pressure at 30°C (20-30 mmHg) for 4 hours to obtain 0.62 g of doripenem (purity: 98.51%).

Embodiment 3

[0047] Crude doripenem (1.0g) and L-threonine (0.9g) were dissolved in distilled aqueous solution (15ml), heated with stirring, and dissolved at 50°C, the solution was maintained at 50°C, and activated carbon ( 50 mg) was stirred for 5 minutes to decolorize, filtered, and the heat source was removed, and the filtrate was cooled to 0-5°C and stirred. Solids precipitated within about 1 hour, and aged at 0-5°C for 2 hours. Depyrogenated ethanol (30ml) was dropped into it within about 1 hour, kept at 0-5°C for aging for 2 hours, and then the obtained crystals were filtered out. The obtained crystals were washed with 80% ethanol aqueous solution (5ml), and dried under reduced pressure at 30°C (20-30mmHg) for 4 hours to obtain 1.7g of the composition of doripenem and L-threonine (donipenem The purity is 99.68%, and the mass ratio of doripenem to L-threonine is 1:1).

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Abstract

The invention relates to a composition containing Doripenem, in particular to a composition containing the Doripenem and amino acid, wherein the amino acid is selected from one ore some of aminopropionic acid, phenylalanine, aminocaproic acid and threonine.

Description

technical field [0001] The present invention relates to a composition containing doripenem, in particular to a composition containing doripenem and amino acids. Background technique [0002] Doripenem (S-4661) is a broad-spectrum carbapenem antibiotic developed by Japan Shioyagi Company. It has a broad antibacterial spectrum, is stable to most β-lactamases, has strong affinity for PBPSs, and has antibacterial activity. High, stable to DHP-1 and so on. Its chemical name is (4R, 5S, 6S)-3-[((3S, 5S)-5-[[(sulfamoyl)amino]methyl]-3-pyrrolidinyl)mercapto]-6-[( 1R)-1-hydroxyethyl]4-methyl-7-oxyl-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, the structural formula is shown in formula I. [0003] [0004] Formula I [0005] The currently marketed product is a sterile crystalline powder of doripenem, which is administered intravenously in the form of a doripenem solution after dissolving. During preparation (eg patent document CN1432016A), doripenem is crystallized from an ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/407A61K47/18A61K9/08A61K9/14A61P31/04
Inventor 朱雪焱袁哲东俞雄张爱明董平
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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