Purpose

To overcome the problems of low bioavailability of the drug associated with the short pre-corneal residence time, a thermoresponsive in situ gel system containing poloxamer P407, hydroxypropyl methylcellulose, and chitosan was developed to prolong the pre-corneal residence time of the drug.

Methods

The central composite design was utilized to assess the effects of the concentration of poloxamer 407 hydroxypropyl methylcellulose and chitosan, the concentration of polymer, and the polymer type on the viscosity, pH, and gelation temperature, which were considered indicators of optimum formulations.

Results

After model selection for response analysis, the quadratic model was found to be the best-fitting model for the relationship between independent factors and response variables. As a result of the central composite design, the optimized formulation contained 15.17% poloxamer 407 and 2.141% chitosan. Viscosity 25 °C = 2199.4 ± 26.2, viscosity 35 °C = 15,487.2 ± 117.4, pH = 6.5 ± 0.01, and gelation temperature °C = 33.3 ± 0.47 were obtained. The ex-vivo study revealed that the BRN formulation containing flurbiprofen-cyclodextrin inclusion complex has higher corneal penetration (P < 0.01). The cytotoxicity of ARPE-19 cells and irritation studies, as measured by in situ gel, was found to be acceptable. In lipoxygenase studies, the effectiveness of the BRN formulation was found to be significantly higher than other formulations (P < 0.01).

Conclusions

It is thought that the BRN formulation may be an alternative to the treatment of ocular allergic disease.

中文翻译：

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使用析因设计开发双载药温敏眼部原位凝胶的配方

目的

为了克服与角膜前停留时间短相关的药物生物利用度低的问题，开发了一种含有泊洛沙姆P407、羟丙基甲基纤维素和壳聚糖的热响应性原位凝胶系统，以延长药物在角膜前的停留时间。

方法

利用中心复合设计来评估泊洛沙姆407羟丙基甲基纤维素和壳聚糖的浓度、聚合物的浓度以及聚合物类型对粘度、pH值和胶凝温度的影响，这些被认为是最佳配方的指标。

结果

经过模型选择进行响应分析后，发现二次模型是独立因素与响应变量之间关系的最佳拟合模型。根据中心复合设计，优化的配方含有 15.17% 泊洛沙姆 407 和 2.141% 壳聚糖。得到粘度25℃=2199.4±26.2，粘度35℃=15,487.2±117.4，pH=6.5±0.01，凝胶化温度℃=33.3±0.47。离体研究表明，含有氟比洛芬-环糊精包合物的 BRN 制剂具有更高的角膜渗透性（P < 0.01）。ARPE-19 细胞的细胞毒性和刺激研究（通过原位凝胶测量）被发现是可接受的。在脂氧合酶研究中，发现 BRN 制剂的有效性显着高于其他制剂（P  < 0.01）。

结论

人们认为 BRN 制剂可能是治疗眼部过敏性疾病的替代方案。