利拉鲁肽鼻用温敏原位凝胶的制备与体内外评价  

Preparation and in Vitro/in Vivo Evaluation of Thermosensitive in Situ Gel Loaded with Liraglutide for Nasal Delivery

作　　者：张红瑶 张静[1] 郭雨虹 张睿妮 彭金川 张颖[1] ZHANG Hongyao;ZHANG Jing;GUO Yuhong;ZHANG Ruini;PENG Jinchuan;ZHANG Ying(Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province,Sichuan Industrial Institute of Antibiotics,School of Pharmacy,Chengdu University,Chengdu 610052,China)

机构地区：[1]抗生素研究与再评价四川省重点实验室,四川抗菌素工业研究所,成都大学药学院,成都610052

出　　处：《中国现代应用药学》2025年第3期360-367,共8页Chinese Journal of Modern Applied Pharmacy

基　　金：国家留学基金委西部人才培养特别项目(202308510235)。

摘　　要：目的制备鼻腔给药的利拉鲁肽温敏凝胶(liraglutide temperature-sensitive in situ gel,Lrg-TS-ISG),改变皮下注射的给药方式,提高患者适应性,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,采用星点设计-响应面法优化处方工艺,筛选出最佳处方。对Lrg-TS-ISG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Lrg-TS-ISG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Lrg-TS-ISG制备的最佳处方:取处方量的P407、P188、PVP加入PBS溶液至10 mL,4℃冷藏溶胀,再加入苯扎溴铵和利拉鲁肽,分散均匀即得。Lrg-TSISG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相比Lrg溶液更高的生物利用度,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Lrg-TS-ISG制备工艺简单,其延长了药物在鼻腔的滞留时间,提高了鼻腔给药的生物利用度。鼻腔给药可改善患者的顺应性,为多肽药物的非注射传递系统的研发提供了新思路。OBJECTIVE To prepare liraglutide nasal thermosensitive in situ gel(Lrg-TS-ISG)which aims at altering the form of drug delivery from subcutaneous injection for nasal administration to enhance patient compliance and improve pharmacodynamics.METHODS Using gelation temperature as the primary criterion,the proportions of thermosensitive gel matrices were screened via single-factor analysis.The formulation was optimized via central composite design(CCD)response surface methodology.The quality,stability,and in vitro release of Lrg-TS-ISG were evaluated.A type 2 diabetes model was established in SD rats,with subcutaneous liraglutide solution as the positive control and nasal saline as the negative control.Blood glucose reduction percentages post-administration were measured,and relative bioavailability was calculated.Nasal retention and fluorescence intensity were assessed through murine nasal imaging.RESULTS The optimal formulation for the preparation of Lrg-TS-ISG:dissolving the prescribed amounts of P407,P188,PVP in PBS solution to 10 mL,swelling at 4°C,then adding benzalkonium chloride and liraglutide,followed by uniform dispersion.Both the dissolution and release profiles of Lrg-TS-ISG followed zero-order kinetics.Pharmacodynamic data indicated higher bioavailability of Lrg-TS-ISG compared to liraglutide solution.Nasal fluorescence demonstrated that gel delivery could enhance nasal retention of liraglutide.CONCLUSION Lrg-TSISG exhibites a simple preparation process,prolonges nasal retention,and superior bioavailability versus subcutaneous injection.Nasal delivery improves patient compliance,offering a novel approach for non-invasive peptide administration.

关 键 词：利拉鲁肽 原位凝胶 鼻腔给药 药效学 

分 类 号：R943[医药卫生—药剂学]