盐酸小檗碱对芍药苷的经皮促透规律及促透机制研究

目的 考察盐酸小檗碱对芍药苷体外经皮渗透行为的影响，筛选最佳促透条件并探索促透机制。方法 采用改良Franz扩散池法，选择适宜的供给液及接收液，探索盐酸小檗碱促进芍药苷经皮渗透的最佳促透条件及促透规律；利用扫描电子显微镜、激光扫描共聚焦显微镜、分子模拟探究促透机制。结果 选择20%乙醇-pH 7.4磷酸盐缓冲液（PBS）为接收液，盐酸小檗碱-芍药苷在pH 5.0的介质条件下透皮效果最佳，且在此条件下，高、中、低质量浓度的芍药苷与盐酸小檗碱配伍后，芍药苷的24 h累积透过量（Q₂₄）分别增加了78.03%、44.73%、35.63%，其中高质量浓度配伍组中芍药苷的Q₂₄与芍药苷单独给药组相比具有显著性差异（P<0.05），芍药苷透皮速率显著增加，促透比为1.74。促透机制研究结果显示，盐酸小檗碱可能使角质层整齐紧密堆积排列的叠瓦式结构松动，表面的褶皱明显增多加深；盐酸小檗碱可促进水溶性成分荧光素钠和脂溶性成分尼罗红在皮肤中的渗透，相应皮肤渗透量及渗透深度均有所增加。盐酸小檗碱可竞争性地与角质层脂质的头部结合，使芍药苷摆脱皮肤脂质氢键网络的束缚，进而促进芍药苷的经皮吸收。结论 芍药苷-盐酸小檗碱透皮的最佳pH值为5.0，盐酸小檗碱可促进芍药苷的经皮吸收，且具有浓度依赖性，促透机制可能为盐酸小檗碱通过调控角质层紧密连接易化皮肤转运阻力、影响皮肤通透性及竞争性与角质层脂质的极性头部结合进而促进芍药苷经皮渗透。

Transdermal permeation law and permeation mechanism of paeoniflorin by berberine hydrochloride

Objective To investigate the effect of berberine hydrochloride on transdermal permeation behavior of paeoniflorin in vitro, screen the best penetration promoting conditions and explore the penetration promoting mechanism.Methods A modified Franz diffusion cell method was used to select suitable supply and receiving solutions to explore the optimal permeation-promoting conditions and rules for berberine hydrochloride to promote transdermal permeation of paeoniflorin; Scanning electron microscopy, confocal laser scanning microscopy and molecular simulation were used to investigate the mechanism of permeation promotion. Results The 20% ethanol-pH 7.4 phosphate buffer solution (PBS) was selected as the receiving solution, and the best transdermal effect of berberine hydrochloride-paeoniflorin was achieved under the media condition of pH 5.0, and the 24 h cumulative permeation (Q₂₄) of paeoniflorin was increased by 78.03%, 44.73%, and 35.63% in the high, medium and low concentrations of paeoniflorin paired with berberine hydrochloride under this condition, respectively. The Q₂₄ of paeoniflorin in the high concentration combination group was significantly different (P < 0.05) compared with the paeoniflorin alone administration group, and the transdermal rate of paeoniflorin increased significantly with a pro-permeation ratio of 1.74. The results of the study onpermeation promoting mechanism showed that berberine hydrochloride could loosen the stacked tile structure of the neat and tightly stacked arrangement of the stratum corneum, and the surface folds were significantly increased and deepened; Berberine hydrochloride could promote the permeation of the water-soluble component sodium fluorescein and lipid-soluble nile red in the skin, and the amount and depth of skin permeation were increased. Berberine hydrochloride can competitively bind to the head of stratum corneum lipids, freeing paeoniflorin from the hydrogen bonding network with skin lipids, and thus promoting the transdermal absorption of paeoniflorin. Conclusion The optimal pH of paeoniflorin-berberine hydrochloride transdermal permeation is 5.0. Berberine hydrochloride can promote the transdermal absorption of paeoniflorin with concentration dependence, and the mechanism of promoting permeation may be that berberine hydrochloride promotes the transdermal permeation of paeoniflorin by modulating the tight junctions of stratum corneum to ease skin transport resistance, affecting skin permeability and competitively binding to the polar head of stratum corneum lipids.