Novel amoxicillin clavulanic acid composition

A technology of amoxicillin-clavulanic acid and clavulanic acid, which is applied in the field of new amoxicillin-clavulanic acid compositions, can solve the problems of easy deterioration of drugs, increase the economic burden of patients, and low encapsulation efficiency, so as to reduce production And treatment cost, reduce adverse reactions, reduce the effect of dosage

Active Publication Date: 2014-07-30
石药集团中诺药业(石家庄)有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Chinese patent CN1850074 discloses a method for preparing amoxicillin sodium and clavulanate potassium drug mixture by using carbon dioxide supercritical technology. This scheme improves the uniformity and fluidity of the drug mixture to a certain extent, but does not fundamentally improve The instability of amoxicillin sodium, in the later storage and transportation process, the drug is still easy to deteriorate
[0008] Chinese patents CN101804051 and CN101890007 respectively disclose a liposome injection and a microsphere injection of amoxicillin sodium clavulanate potassium pharmaceutical composition, which can improve the problem of poor stability of ordinary injections to a certain extent
These new injection preparations (liposome injections, microsphere injections) have certain advantages over traditional injections, but they also have low encapsulation efficiency, easy adhesion and aggregation, easy rupture, burst release effect, and possible cause immune response
In addition, the scale-up production of these new dosage forms in China is not mature enough, and the preparation process conditions are very strict, the production is difficult, the process reproducibility is poor, and the production cost is high, which virtually increases the financial burden of patients, so it does not not ideal

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  • Novel amoxicillin clavulanic acid composition
  • Novel amoxicillin clavulanic acid composition
  • Novel amoxicillin clavulanic acid composition

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Example 1 Amoxicillin-monomethoxypolyethylene glycol clavulanic acid composition

[0033] 1. Preparation of Amoxicillin-Monomethoxy Polyethylene Glycol

[0034] The reaction route of amoxicillin pegylation:

[0035]

[0036] (1) Preparation of aminated monomethoxy polyethylene glycol (mPEG-NH 2 )

[0037] Add 1.5L of 1M azide acid in dichloromethane to 10L of 896g (0.5mol) monomethoxypolyethylene glycol (mPEG) in tetrahydrofuran, then add 0.3L (1.5mol) of diisopropyl azodicarboxylate 2L of tetrahydrofuran solution of the ester (DIAD), add 5L of 787g (3.0mol) triphenylphosphine solution in tetrahydrofuran to the resulting mixture, stir at room temperature for 30min, heat at 65°C for 2h, and finally add 1L of 1M hydrochloric acid at 65°C After heating for another 2h, cooling to room temperature, filtering and vacuum drying, the yield was 99%.

[0038] (2) Preparation of amoxicillin-monomethoxy polyethylene glycol

[0039] Dissolve 365g (1mol) of amoxicillin in 3.3L of dimethylform...

Embodiment 2

[0046] Example 2 Amoxicillin sodium clavulanic acid-glucuronate composition

[0047] The composition involved in this example is composed of unmodified amoxicillin and modified clavulanic acid, wherein amoxicillin is used as the active ingredient, and the preparation method is as follows:

[0048] 1. Preparation of clavulanic acid-glucuronate

[0049] The choice to modify the hydroxyl group of clavulanic acid instead of the carboxyl group is mainly due to the steric hindrance of the isomerized carboxyl group. After the carboxyl group enters the body as an ester, it is not easy to decompose the active ingredient, thus failing to achieve good efficacy. , And the hydroxyl modified product can quickly release the active ingredient. In addition, in order to improve the esterification activity of the carboxyl group of glucuronic acid, the carboxylic acid is first converted into an acid chloride, and then esterified with the hydroxyl group in the clavulanic acid structure to obtain clavula...

Embodiment 3

[0065] Example 3 Preparation of amoxicillin-monomethoxy polyethylene glycol and clavulanic acid-glucuronate

[0066] Among the pharmaceutical ingredients involved in this embodiment, the active ingredients are amoxicillin and clavulanic acid in modified forms.

[0067] 1. Preparation of Amoxicillin-Monomethoxy Polyethylene Glycol

[0068] The method in Example 1 was used to complete the preparation of amoxicillin-monomethoxy polyethylene glycol.

[0069] 2. Preparation of clavulanic acid-glucuronic acid ester

[0070] The method in Example 2 was used to complete the preparation of clavulanic acid-glucuronic acid ester.

[0071] The reactions mentioned above are all carried out under anhydrous conditions, and the reagents used are also anhydrous treatment in advance.

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Abstract

The invention discloses a novel amoxicillin clavulanic acid composition. When pegylation is conducted on the amoxicillin, the medicine water-solubility is improved and at the same time good stability of the medicine is ensured; by modifying the clavulanic acid by using glucuronic acid, the original characteristic of strong hygroscopicity is changed, and problems that the clavulanic acid is poor in mobility, non-uniform when being mixed with the amoxicillin, easy to discolor, deteriorate and degrade and the like caused by the strong hygroscopicity are avoided, so that by carrying out molecular modification on the two active ingredients respectively, not only is the physiochemical property of the medicine changed, but also the stability is greatly improved, the effective content after entering human bodies is ensured, problems that the content is greatly reduced and related substances are increased after an ordinary preparation product in market is prepared into injection are solved, the problem of mass stability of the composition in the production, storage, preparation and injection process is substantially solved, and the use amount of the clavulanic acid is greatly reduced.

Description

Technical field [0001] The invention relates to an antibiotic medicine, in particular to a novel amoxicillin and clavulanic acid composition. Background technique [0002] Amoxicillin and clavulanic acid formed by the combination of clavulanic acid and amoxicillin belong to the β-lactam compound antibiotic. It was originally researched and developed by GlaxoSmithKline Pharmaceuticals and was approved by the FDA on August 6, 1984 for many years. It ranks among the world's best-selling drugs, ranking first in the world's anti-infective drugs, and has been included in the Chinese Pharmacopoeia. It can inhibit the β-lactamase pair produced by microorganisms such as Staphylococcus, Haemophilus influenzae, Catacoccus, Escherichia coli, Klebsiella, Proteus mirabilis, Proteus vulgaris, Neisseria gonorrhoeae, Legionella, Bacteroides fragilis and other microorganisms The destruction of amoxicillin is therefore effective against enzyme-producing or non-enzyme-producing strains of the afore...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/765A61K31/7056A61K47/48A61P31/04
Inventor 马慧丽王忠王荣端董朝蓬申翠美
Owner 石药集团中诺药业(石家庄)有限公司
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