利拉鲁肽鼻用温敏原位凝胶的制备与体内外评价

Preparation and ex vivo evaluation of Liraglutide in-situ thermosensitive gel for nasal delivery

关键词:  利拉鲁肽  原位凝胶  鼻腔给药  药效学

Key words:  liraglutide  in situ gel  nasal administration  pharmacodynamics

摘要:

目的 制备鼻腔给药的利拉鲁肽温敏凝胶,改变皮下注射的给药方式,提高患者顺应性,提高药效。方法 以胶凝温度为主要指标,单因素考察不同温敏凝胶基质的用量比例,采用CCD响应面优化处方工艺,筛选出最佳处方。对温敏凝胶进行质量评价、稳定性试验和体外释药。SD大鼠构建2型糖尿病模型,皮下注射利拉鲁肽溶液为阳性对照,鼻腔给予生理盐水为阴性对照,研究温敏原位凝胶给药后血糖下降百分比,计算相对生物利用度,通过小鼠鼻腔成像观察鼻腔滞留及荧光强度。结果 利拉鲁肽温敏凝胶的制备：取处方量的P407、P188、PVP加入PBS溶液至10mL,4℃冷藏溶胀,再加入5%苯扎溴铵和处方量的利拉鲁肽,分散均匀即得。利拉鲁肽温敏凝胶的溶蚀与释放均符合零级动力学方程,大鼠药效学显示出了更高的生物利用度,鼻腔荧光显示利拉鲁肽经凝胶递送可以增强鼻腔滞留。结论 利拉鲁肽温敏凝胶制备工艺简单,其延长了药物在鼻腔的滞留时间,提高了顺应性,为利拉鲁肽鼻腔给药治疗2型糖尿病提供了新思路。

Abstract:

OBJECTIVE To prepare liraglutide thermosensitive gel for nasal administration, change the mode of administration of subcutaneous injection, improve patient compliance, and improve drug efficacy. METHODS Based on the main indicators of gel temperature, the proportion of usage of different temperature sensitive gel substrates was examined univariately. The optimization of prescribing process using CCD response surface was used to select the best prescription.Quality evaluation, stability testing, and in vitro release of thermosensitive gels were performed.A model of type 2 diabetes was constructed in SD rats, with positive controls treated with subcutaneous liraglutide solution and negative controls treated with nasal saline solution.We investigated the percentage of blood glucose loss after topical gel administration, calculated relative bioavailability, and visualized nasal retention and fluorescence intensity by nasal imaging in mice. RESULTS Preparation of liraglutide thermosensitive gel:P407, P188, and PVP were prescribed in PBS to 10 mL incubated at 4°C, followed by 5% benzalkonium bromide and prescribed liraglutide in a homogeneous dispersion.The solubilization and release of liraglutide temperature-sensitive gels were consistent with a zero-order kinetic equation, and rat pharmacodynamics demonstrated higher bioavailability.Rhinal fluorescence showed that gel delivery of liraglutide enhanced nasal retention. CONCLUSION The manufacturing process of liraglutide thermosensitive gel is simple, which prolongs the retention time of drug in the nasal cavity and improves compliance, providing a new approach for nasal administration of liraglutide to treat type 2 diabetes.