氢溴酸西酞普兰鼻用温敏凝胶的处方优化及体外性质评价

目的优化氢溴酸西酞普兰(citalopram hydrobromide,CTH)鼻用温敏凝胶的处方并对其体外性质进行评价。方法以泊洛沙姆407(F127)和卡波姆940(CP940)作为凝胶基质材料,胶凝温度与胶凝时间为观察指标,采用星点设计-效应面法和单因素实验法优化凝胶基质处方;同时,以离体羊鼻黏膜为模型,采用Franz透皮扩散池法筛选药物透皮吸收促渗剂,最后采用冷法制备CTH鼻用温敏凝胶并进行体外性质评价;采用无膜溶出法测定制剂的体外溶蚀率及体外释放率;采用透析膜法测定其体外释放度。同时,考察温度及pH对该制剂黏度的影响。结果CTH鼻用温敏凝胶最优处方组成为:CTH 8.0%、F12720.27%、CP9400.17%、DM-β-003.0%、尼泊金乙酯0.05%及适量水。该制剂的胶凝温度为32.5℃,胶凝时间为42s,PH值为5.0,55 min时体外累积溶蚀率与药物累积释放率均大于90%,且二者具有良好线性相关性(r^2=0.9986);该制剂在8 h内体外累积释药为92%,其释药过程符合Higuchi动力学方程。温度及pH对该制剂的黏度均有不同程度的影响。结论采用星点设计-效应面法和单因素法优化处方所制备CTH鼻用温敏凝胶其肢凝温度、胶凝时间及pH值适宜,符合鼻用制剂要求,其体外释药具明显缓释特征。

Formulation Optimization of Citalopram Hydrobromide Thermosensitive Nasal Gel and Its In Vitro Properties

OBJECTIVE To optimize the formulation of citalopram hydrobromide(CTH)thermosensitive nasal gel and further e-valuate its in vitro properties.METHODS With gelling temperature and gelling time as evaluating indexes,central composite design-response surface and single factor experimental design method were used to optimize the formulation of CTH thermosensitive nasal gel by using poloxamer 407(F127)and carbomer 940(CP940)as gel materials.Meanwhile,nasal mucosa permeation enhancer for CTH was then sieved by using Franz diffusion cell and ex vivo sheep nasal mucosa as experimental model.Finally,CTH thermosensitive nasal gel was prepared with cold method and then its in vitro properties was evaluated.In vitro cumulative erosion and cumulative release rate of the drug thermosensitive nasal gel were investigated by membrane-free dissolution method and dialysis membrane method,respectively.Moreover,the effect of temperature and pH on the viscosity of the drug nasal gel formulation was also evaluated.RESULTS The optimal formulation of the thermosensitive nasal gel consisted of CTH 8.0%,FI2720.27%,CP9400.17%,DM-β-CD 3.0%,eth-ylparaben 0.05%and distilled water.The gelling temperature,gelling time and pH of the drug thermosensitive nasal gel were found to be about 32.5℃,42 s and 5.0,respectively.The in vitro cumulative erosion and cumulative release percentage were both greater than 90%in 55 min and furthermore there was good linear correlation between these two parameters(r=0.9986).Additionally,in vitro cumulative release of the drug from the gel formulation was determined to be 92%within 8 h,which conformed to Higuchi kinetic equation.Furthermore,the viscosity of the drug nasal gel was influenced by temperature as well as pH in different extent.CONCLUSION The optimized formulation of the CTH thermosensitive nasal gel with central composite design-response surface method and single factor design method shows suitable gelling temperature,gelling time,pH value for nasal preparation and obvious in vitro drug sustained release characteristics.