Hsin Yong Kai, Thangarajoo Thaneswary, Choudhury Hira, Pandey Manisha, Meng Lim Wei, Gorain Bapi
School of Pharmacy, Faculty of Health and Medical Sciences, Taylor's University, Subang Jaya 47500 Selangor, Malaysia.
Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia.
J Pharm Sci. 2023 Feb;112(2):562-572. doi: 10.1016/j.xphs.2022.09.002. Epub 2022 Sep 9.
Vaginal candidiasis is a common form of infection in women caused by Candida species. Due to several drawbacks of conventional treatments, the current research is attempted to formulate and optimize a miconazole nitrate-loaded in situ spray gel for vaginal candidiasis. The stimuli-responsive (pH and thermo-responsive) polymers selected for the in situ gel were chitosan and poloxamer 407, respectively, whereas hydroxypropyl methylcellulose (HPMC) was introduced in the formulation to further improve the mucoadhesive property. The dispersion of each polymer was carried out using the cold method, whereas the optimization of the formulation was achieved using Box-Behnken statistical design considering viscosity and gelation temperature as dependent variables. Present design achieved the optimized outcome with HPMC, poloxamer and chitosan at 0.52% (w/v), 18.68% (w/v) and 0.41% (w/v), respectively. Evaluation of drug-excipients compatibility was performed using differential scanning calorimetry, Fourier transform infrared spectroscopy, and thermogravimetric analysis where the results showed the absence of any chemical interaction between the polymers and drug component. The optimized formulation showed gelation temperature at 31°C allowing in situ phase transition in a vaginal environment; pH of 4.21 is suitable for use in the vaginal cavity, and appropriate viscosity (290 cP) at storage temperature (below 30°C) would allow spraying at ease, whereas strong mucoadhesive force (22.4±0.513 g) would prevent leaking of the formulation after application. The drug release profile showed sustained release up to 24 h with a cumulative drug release of 81.72%, which is significantly better than the marketed miconazole nitrate cream. In addition, an improved antifungal activity could be correlated to the sustained release of the drug from the formulation. Finally, the safety of the formulation was established while tested on HaCaT cell lines. Based on our findings, it could be concluded that the in situ hydrogel formulation using stimuli-responsive polymers could be a viable alternative to the conventional dosage form that can help to reduce the frequency of administration with ease of application to the site of infection, thus will provide better patient compliance.
阴道念珠菌病是由念珠菌属引起的女性常见感染形式。由于传统治疗方法存在若干缺点，当前研究试图制备并优化一种用于治疗阴道念珠菌病的载硝酸咪康唑原位喷雾凝胶。原位凝胶选用的刺激响应性（pH和温度响应性）聚合物分别为壳聚糖和泊洛沙姆407，而在配方中引入羟丙基甲基纤维素（HPMC）以进一步改善粘膜粘附性能。每种聚合物的分散采用冷法进行，而配方的优化是使用Box-Behnken统计设计，将粘度和凝胶化温度作为因变量。当前设计分别使用0.52%（w/v）的HPMC、18.68%（w/v）的泊洛沙姆和0.41%（w/v）的壳聚糖实现了优化结果。使用差示扫描量热法、傅里叶变换红外光谱法和热重分析法对药物-辅料相容性进行评估，结果表明聚合物与药物成分之间不存在任何化学相互作用。优化后的配方在31°C显示凝胶化温度，可在阴道环境中实现原位相变；pH值为4.21适合在阴道腔使用，储存温度（低于30°C）下适当的粘度（290 cP）便于喷雾，而强大的粘膜粘附力（22.4±0.513 g）可防止制剂在应用后泄漏。药物释放曲线显示持续释放长达24小时，累积药物释放率为81.72%，明显优于市售硝酸咪康唑乳膏。此外，改善的抗真菌活性与药物从制剂中的持续释放相关。最后，在HaCaT细胞系上进行测试时确定了制剂的安全性。基于我们的研究结果，可以得出结论，使用刺激响应性聚合物的原位水凝胶制剂可能是传统剂型的可行替代方案，有助于减少给药频率，易于应用于感染部位，从而提供更好的患者依从性。
