A sustained-release microsphere preparation for injection of liraglutide

Abstract

The invention discloses a slow-release microsphere preparation for injection of liraglutide, which is composed of liraglutide, polyethylene lactide and polyvinyl alcohol, wherein liraglutide, polyethylene lactide and polyvinyl alcohol The weight ratio is 1:15:30. The preparation method adopts the double emulsion method, and the slow-release microspheres are obtained by centrifugation and then freeze-dried. The preparation of the invention has good stability, large drug loading capacity, high encapsulation efficiency, no degradation and aggregation under accelerated test conditions, and good safety in vivo.

Description

technical field [0001] The invention relates to a pharmaceutical preparation, in particular to a sustained-release microsphere preparation for injection of the polypeptide drug liraglutide. Background technique [0002] Liraglutide, commonly known as liraglutide in English, is a synthetic analogue of human glucagon-like peptide-1, consisting of 31 amino acid residues, and its amino acid sequence is: H-His-Ala-Glu- Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys(N-ε-(N-α-Palmitoyl-L-y-glutamyl)) -Glu-Phe-Ile-Ala-Trp-Leu-Val-Arg-Gly-Arg-Gly-OH. [0003] Liraglutide preparations currently available on the market are injections, and the route of administration is subcutaneous injection. Since polypeptide drugs are easily degraded in the body and have a short plasma half-life, they need to be administered three times a day, resulting in low patient compliance and easy to forget to administer, which is not conducive to self-administration by patients. [000...

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Problems solved by technology

However, the results of in vivo pharmacodynamic experiments given in the accompanying drawings of the document show that blood samples were taken on the 1st, 7th, 14th, and 28th days after the administration of the sustained-release microspheres to measure the blood sugar concentration, and the results showed significant blood sugar levels on the sampling day. The peak-to-valley phenomenon shows that there is an unstable burst release phenomenon in the drug release in the body, which leads to the problem of sudden high and low blood sugar. The above problems have not been found in the cumulative release test in vitro, and the in vivo safety of the above preparations has not yet been obtained. confirmed

For sustained-release preparations with a sustained-release effect of 28-30 days, it is beneficial to reduce the frequency of administration, but due to the excessive drug loading, once the drug is released suddenly, it will lead to a sharp drop in blood sugar and induce hypoglycemia coma and other problems , Therefore, the current slow-release dosage forms of polypeptide drugs for the treatment of diabetes or chemically modified slow-release polypeptides are usually designed to be administered once a day or once a week, and hypoglycemic drugs administered once a month, compared to their burst release risk However, the benefit of its sustained-release effect is no longer important, so such sustained-release preparations have yet to be approved for marketing

[0007] The present inventor has studied the sustained-release microsphere preparation of liraglutide, and found that the liraglutide sustained-release preparation prepared by the method in the prior art and the conventional method has instability, burst release, encapsulation efficiency and loading rate. However, there are many shortcomings such as unsatisfactory drug dosage, and in the current research on drug sustained-release microsphere preparations, although there is some experience to follow in solving technical problems such as drug loading and encapsulation efficiency of the microspheres according to the physical and chemical properties of the drug, but There is still a lack of experience and technical guidance that can be generally followed to improve the stability of microspheres and effectively avoid the problem of drug burst release

Especially for the risk of thyroid C-cell carcinoma caused by the human glucagon-like peptide-1 analogue polypeptide glycolide-lactide copolymer sustained-release microsphere preparation, there is no effective means to reduce its incidence

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