Novel amoxicillin clavulanic acid composition

A technology of amoxicillin-clavulanic acid and clavulanic acid, which is applied in the field of novel amoxicillin-clavulanic acid compositions, can solve the problems of easy deterioration of drugs, low encapsulation rate, increased economic burden on patients, etc., and achieves reduction in production and the effect of treatment cost, dose reduction, and adverse reactions

Active Publication Date: 2013-04-17
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

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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] Embodiment 1 Amoxicillin-monomethoxy polyethylene glycol clavulanic acid composition

[0033] One, the preparation of amoxicillin-monomethoxypolyethylene glycol

[0034] The reaction scheme of pegylation of amoxicillin:

[0035]

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

[0037] Add 1.5L of 1M dichloromethane solution of azide acid into 10L of 896g (0.5mol) monomethoxy polyethylene glycol (mPEG) tetrahydrofuran solution, and then add 0.3L (1.5mol) diisopropyl azodicarboxylate 2 L of tetrahydrofuran solution of ester (DIAD), and 5 L of tetrahydrofuran solution of 787 g (3.0 mol) triphenylphosphine was added to the obtained mixture, stirred at room temperature for 30 min, heated at 65 °C for 2 h, and finally added with 1 L of 1M hydrochloric acid, and heated at 65 °C Heating for another 2 hours, cooling to room temperature, filtering, and vacuum drying, the yield was 99%.

[0038] (2) Preparation of amoxicillin-monomethoxypol...

Embodiment 2

[0046] Embodiment 2 amoxicillin sodium clavulanic acid-glucuronate composition

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

[0048] 1. Preparation of clavulanic acid-glucuronate

[0049] Choose to modify the hydroxyl group of clavulanic acid instead of the carboxyl group, mainly because the isomerized carboxyl group has a certain steric hindrance, and the carboxyl group is not easy to decompose the active ingredient after entering the body after forming an ester, so that it cannot achieve good drug effect. , and the product modified by the hydroxyl group can release the active ingredient rapidly. 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 hydro...

Embodiment 3

[0065] The preparation of embodiment 3 amoxicillin-monomethoxypolyethylene glycol and clavulanic acid-glucuronate

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

[0067] One, the preparation of amoxicillin-monomethoxypolyethylene glycol

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

[0069] 2. Preparation of clavulanic acid-glucuronate

[0070] The preparation of clavulanic acid-glucuronate was completed by the method in Example 2.

[0071] The reactions involved in the above are all carried out under anhydrous conditions, and the reagents used have also been anhydrous treated 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 drug, in particular to a novel amoxicillin-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 antibiotics. It was originally researched and developed by GlaxoSmithKline Pharmaceutical Company. It was approved by the FDA on August 6, 1984 and has been on the market for many years It ranks among the world's best-selling drugs, ranks first in the world's anti-infective drugs, and has been included in the Chinese Pharmacopoeia. It can inhibit the β-lactamase produced by Staphylococcus, Haemophilus influenzae, catarrhalis, 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 af...

Claims

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Application Information

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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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