Adısanoğlu Pınar, Özgüney Işık
Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Ege, 35100 Bornova, İzmir, Türkiye.
Gels. 2024 Apr 15;10(4):267. doi: 10.3390/gels10040267.
In this study, we aimed to develop thermosensitive and bioadhesive in situ gelling systems containing solid dispersions of flurbiprofen (FB-SDs) using poloxamer 407 (P407) and 188 (P188) for ophthalmic delivery. FB-SDs were prepared with the melt method using P407, characterized by solubility, stability, SEM, DSC, TGA, and XRD analyses. Various formulations of poloxamer mixtures and FB-SDs were prepared using the cold method and P407/P188 (15/26.5%), which gels between 32 and 35 °C, was selected to develop an ophthalmic in situ gelling system. Bioadhesive polymers Carbopol 934P (CP) or carboxymethyl cellulose (CMC) were added in three concentrations (0.2, 0.4, and 0.6% (/)). Gelation temperature and time, mechanical properties, flow properties, and viscosity values were determined. The in vitro release rate, release kinetics, and the release mechanism of flurbiprofen (FB) from the ophthalmic formulations were analyzed. The results showed that FB-SDs' solubility in water increased 332-fold compared with FB. The oscillation study results indicated that increasing bioadhesive polymer concentrations decreased gelation temperature and time, and formulations containing CP gel at lower temperatures and in a shorter time. All formulations except F3 and F4 showed Newtonion flow under non-physiological conditions, while all formulations exhibited non-Newtonion pseudoplastic flow under physiological conditions. Viscosity values increased with an increase in bioadhesive polymer concertation at physiological conditions. Texture profile analysis (TPA) showed that CP-containing formulations had higher hardness, compressibility, and adhesiveness, and the gel structure of formulation F4, containing 0.6% CP, exhibited the greatest hardness, compressibility, and adhesiveness. In vitro drug release studies indicated that CP and CMC had no effect below 0.6% concentration. Kinetic evaluation favored first-order and Hixson-Crowell kinetic models. Release mechanism analysis showed that the values of the formulations were greater than 1 except for formulation F5, suggesting that FB might be released from the ophthalmic formulations by super case II type diffusion. When all the results of this study are evaluated, the in situ gelling formulations prepared with FB-SDs that contained P407/P188 (15/26.5%) and 0.2% CP or 0.2% CMC or 0.4 CMC% (F2, F5, and F6, respectively) could be promising formulations to prolong precorneal residence time and improve ocular bioavailability of FB.
在本研究中，我们旨在开发含氟比洛芬固体分散体（FB-SDs）的热敏性和生物黏附性原位凝胶系统，使用泊洛沙姆407（P407）和188（P188）用于眼部给药。采用熔融法用P407制备FB-SDs，并通过溶解度、稳定性、扫描电子显微镜（SEM）、差示扫描量热法（DSC）、热重分析法（TGA）和X射线衍射法（XRD）分析对其进行表征。采用冷法制备了各种泊洛沙姆混合物和FB-SDs配方，并选择在32至35℃之间凝胶化的P407/P188（15/26.5%）来开发眼部原位凝胶系统。添加了三种浓度（0.2%、0.4%和0.6%（/））的生物黏附性聚合物卡波姆934P（CP）或羧甲基纤维素（CMC）。测定了凝胶化温度和时间、机械性能、流动性能和黏度值。分析了氟比洛芬（FB）从眼部制剂中的体外释放速率、释放动力学和释放机制。结果表明，FB-SDs在水中的溶解度与FB相比提高了332倍。振荡研究结果表明，增加生物黏附性聚合物浓度会降低凝胶化温度和时间，含CP的配方在较低温度下且在较短时间内凝胶化。除F3和F4外，所有配方在非生理条件下均表现出牛顿流动，而所有配方在生理条件下均表现出非牛顿假塑性流动。在生理条件下，黏度值随生物黏附性聚合物浓度的增加而增加。质地剖面分析（TPA）表明，含CP的配方具有更高的硬度、可压缩性和黏附性，含0.6%CP的配方F4的凝胶结构表现出最大的硬度、可压缩性和黏附性。体外药物释放研究表明，CP和CMC在浓度低于0.6%时无影响。动力学评估支持一级和希克森-克劳威尔动力学模型。释放机制分析表明，除配方F5外，各配方的 值均大于1，这表明FB可能通过超Ⅱ型扩散从眼部制剂中释放。综合本研究的所有结果，用含有P407/P188（15/26.5%）和0.2%CP或0.2%CMC或0.4%CMC（分别为F2、F5和F6）的FB-SDs制备的原位凝胶制剂可能是延长角膜前滞留时间和提高FB眼部生物利用度的有前景的制剂。
