Wang Yingting, Jiang Shulong, Wang Hongli, Bie Haiyan
Jining No.1 People's Hospital, Jining, Shandong Province, China.
PLoS One. 2017 Dec 14;12(12):e0189478. doi: 10.1371/journal.pone.0189478. eCollection 2017.
Neurodegenerative diseases are becoming prevalent as the population ages. Geniposide could inhibit oxidative stress, reduce apoptosis, protect neuron, and has been used for therapy of the neurodegenerative diseases. The bioavailability of geniposide by nasal route is greater than that by oral administration. However, mucociliary clearance is a rate-limiting factor for nasal route administration. The objective of this study was to develop and evaluate a mucoadhesive, thermoreversible in situ nasal gel of geniposide. The poloxamers (P407, P188) and the hydroxypropyl methylcellulose were used as thermoreversible and mucoadhesive polymers, respectively. Borneol was used as a permeation enhancer. The hydrogel was prepared with the cold method and optimized by the response surface methodology-central composite design. Gelation temperature, pH, clarity, gel strength, mucoadhesive strength, in vitro and ex vivo release kinetics of formulations were evaluated. The optimized amounts of poloxamer407 (P407), poloxamer188 (P188) and hydroxypropyl methylcellulose were determined to be 19.4-20.5%, 1.1-4.0% and 0.3-0.6% respectively. The second-order polynomial equation in terms of actual factors indicated a satisfactory correlation between the independent variables and the response (R2 = 0.9760). An ANOVA of the empirical second-order polynomial model indicated the model was significant (P<0.01). P407, P188, P407×P188, P4072 and P1882 were significant model terms. The effects of P407 on gelation temperature were greater than those of other independent variables. The pH values of all the formulations were found to be within 6.3-6.5 which was in the nasal physiological pH range 4.5-6.5. The drug content, gel strength, mucoadhesive strength of the optimized formulations were 97-101%, 25-50 sec and 4000-6000 dyn/cm2 respectively. The in vitro release kinetics of cumulative release of geniposide was fitted to the zero-order model. The ex vivo cumulative release kinetics of geniposide was fitted to the Weibull model. This study concludes that the release of geniposide is controlled by gel corrosion, and that the permeation of geniposide is time-dependent. The more residence time, mucoadhesive, thermoreversible in situ nasal gel of geniposide for neurodegenerative diseases is of compliance and potential application.
随着人口老龄化，神经退行性疾病正变得越来越普遍。栀子苷可以抑制氧化应激、减少细胞凋亡、保护神经元，并且已被用于治疗神经退行性疾病。栀子苷经鼻给药的生物利用度高于口服给药。然而，黏液纤毛清除是经鼻给药的一个限速因素。本研究的目的是研制并评价一种栀子苷的黏膜黏附性、热可逆原位鼻用凝胶。泊洛沙姆（P407、P188）和羟丙基甲基纤维素分别用作热可逆和黏膜黏附聚合物。冰片用作渗透促进剂。采用冷法制备水凝胶，并通过响应面法-中心复合设计进行优化。评价了制剂的胶凝温度、pH值、澄清度、凝胶强度、黏膜黏附强度、体外和离体释放动力学。确定泊洛沙姆407（P407）、泊洛沙姆188（P188）和羟丙基甲基纤维素的优化用量分别为19.4 - 20.5%、1.1 - 4.0%和0.3 - 0.6%。根据实际因素的二阶多项式方程表明自变量与响应之间具有良好的相关性（R2 = 0.9760）。对经验二阶多项式模型的方差分析表明该模型具有显著性（P<0.01）。P407、P188、P407×P188、P4072和P1882是显著的模型项。P407对胶凝温度的影响大于其他自变量。发现所有制剂的pH值在6.3 - 6.5范围内，处于鼻生理pH值范围4.5 - 6.5内。优化制剂的药物含量、凝胶强度、黏膜黏附强度分别为97 - 101%、25 - 50秒和4000 - 6000达因/平方厘米。栀子苷累积释放的体外释放动力学符合零级模型。栀子苷的离体累积释放动力学符合威布尔模型。本研究得出结论，栀子苷的释放受凝胶溶蚀控制，且栀子苷的渗透具有时间依赖性。具有更长滞留时间、黏膜黏附性、热可逆原位的栀子苷鼻用凝胶对神经退行性疾病具有顺应性和潜在应用价值。
