氨甲环酸纳米乳凝胶的制备及其体外透皮行为研究

Research on preparation of tranexamic acid nanoemulsion gel and its transdermal performance in vitro

关键词:  氨甲环酸  纳米乳凝胶  Box-Behnken响应面设计  经皮渗透

Key words:  tranexamic acid  nanoemulsion gel  Box-Behnken response surface design  in vitro transdermal

摘要:

目的 以氨甲环酸（Tranexamic acid，TXA）为模型药物，构建TXA纳米乳凝胶并初步阐明其透皮作用机制。方法 采用剪切搅拌乳化法制备TXA纳米乳，以物理交联法制备TXA纳米乳凝胶，以粒径、Zeta电位、包封率、多分散性指数、外观为评价指标进行制剂工艺研究，通过平衡溶解度、伪三元相图及Box-Behnken响应面设计进行工艺优化。通过透射电镜、纳米乳染色对制剂进行表征，采用Franz扩散池法、全衰减反射傅里叶变换红外光谱法、HE染色法考察制剂体外透皮及对皮肤结构的影响。 结果 制备得到O/W型TXA纳米乳外观呈淡蓝色液体，粒径为68.29±0.11 nm，PDI为0.148±0.07，包封率为98.74±0.03%，pH值为6.95，且稳定性良好。纳米乳凝胶外观呈无色透明半固体状，均匀细腻。体外透皮结果表明，TXA纳米乳凝胶的累积透过量为199.74 μg/cm2且具缓释作用，皮内滞留量为97.6821μg/cm2。全衰减反射傅里叶变换红外光谱表明，TXA纳米乳凝胶通过增加角质层脂质双分子层流动相，降低皮肤屏障作用；HE染色法发现，正常组皮肤结构完整，TXA纳米乳和TXA纳米乳凝胶组结构均发生一定的变化，间隙增大；综合全衰减反射傅里叶变换红外光谱与HE染色结构，说明TXA纳米乳和TXA纳米乳凝胶通过改变皮肤角质层构象以发挥透皮作用。结论 制备的TXA纳米乳凝胶物理性质稳定，具有较好的释药和透皮性，为TXA的应用提供了新的参考和选择。

Abstract:

OBJECTIVE To construct TXA nanoemulsion gel and preliminarily elucidate its transdermal mechanism using Tranexamic acid (TXA) as a model drug. METHODS The TXA nanoemulsion was prepared by shear-stirring emulsification method, and TXA nanoemulsion gel was prepared by physical cross-linking method. The preparation process was evaluated based on particle size, Zeta potential, encapsulation efficiency, the polydispersion coefficient(PDI) and appearance. Process optimization was conducted through equilibrium solubility, pseudo-ternary phase diagram and Box-Behnken response surface design. The formulation was characterized by transmission electron microscopy (TEM) and nanoemulsion staining. In vitro transdermal permeation and its effects on skin structure were investigated using Franz diffusion cell method, attenuated total reflectance Fourier-transform infrared spectroscopy (ATR-FTIR), and HE staining. RESULTS The prepared O/W-type TXA nanoemulsion appeared as a light blue liquid with a particle size of 68.29 ± 0.11 nm, PDI of 0.148 ± 0.07, encapsulation efficiency of 98.74 ± 0.03%, pH of 6.95, and exhibited good stability..The nanoemulsion gel appeared as a colorless, transparent semi-solid with a uniform and fine texture. In vitro transdermal results showed that the cumulative permeation of the TXA nanoemulsion gel was 199.74 μg/cm2 with sustained-release properties, and the intradermal retention was 97.6821 μg/cm2. ATR-FTIR analysis indicated that the TXA nanoemulsion gel enhanced the fluidity of the lipid bilayers in the stratum corneum, thereby reducing the skin barrier function. HE staining revealed intact skin structure in the control group, while both the TXA nanoemulsion and TXA nanoemulsion gel groups exhibited structural changes with increased intercellular gaps. Combined ATR-FTIR and HE staining results demonstrated that the TXA nanoemulsion and TXA nanoemulsion gel facilitated transdermal delivery by altering the conformation of the stratum corneum. CONCLUSION The prepared TXA nanoemulsion gel exhibits stable physical properties, excellent drug release and transdermal performance, providing new reference and option for the application of TXA.