特立氟胺经皮吸收贴剂的处方筛选和体内外相关性评价

Formulation and in vitro/in vivo correlation evaluation of a transdermal patch containing teriflunomide

目的制备特立氟胺经皮吸收贴剂,评价其体内外经皮透过行为。方法有机溶媒挥散法制备特立氟胺压敏胶分散型贴剂;采用水平双室扩散池,以离体兔皮为通透屏障,单因素考察法筛选贴剂系统中的压敏胶、载药量及促透剂;以家兔为实验动物,考察特立氟胺经皮吸收贴剂及注射液在体内的药动学行为,用HPLC法测定血药浓度,Win Nonlin软件求算药物动力学参数并进行体内外相关性评价。结果特立氟胺贴剂最优处方为DURO-TAK1压敏胶,质量分数为10%的氮酮和2.75%的特立氟胺。体内结果表明血药浓度在(12.92±3.95)h达到峰值,达峰质量浓度为(5.44±1.36)mg·L-1,MRT(mean retention time,MRT)达(16.30±3.70)h,血药浓度可长时间维持;体内外相关系数为0.9822。结论所制备的特立氟胺贴剂体内药物浓度平缓,体内外相关性良好。

Objective To prepare a transdermal patch for teriflunomide, and to evaluate the correlation between its in vitro penetration and in vivo absorption. Methods A drug-in-adhesive transdermal patch for teriflunomide was prepared using the organic solvent evaporation technique. The effects of adhesives, permeation enhancers and drug loadings on the penetration of teriflunomide through the rabbit skin were investigated in vitro using horizontal two-chamber diffusion cells. The pharmacokinetic parameters were determined after intravenous administration with teriflunomide solution and topical application of the developed patches. The in vitro and in vivo correlation was carried out by a deconvolution approach using the WinNonlin program. Results The optimized formulation contained DURO-TAK 1 as adhesive, 10% of azone as penetration en- hancer and 2.75% of teriflunomide. The maximal plasma teriflunomide concentration [Pmax = （5.44 ± 1. 36） mg· L - 1 ] was achieved at the time point of（ 12. 92 ±3.95 ） h, the MRT of teriflunomide was prolonged to（ 16. 30 ±3.70）h. Plasma concentration of teriflunomide can be maintained for a long time, and the correlation coefficient observed between in vitro and in vivo was 0. 982 2. Conclusions Teriflunomide trasdermal patch had sustained drug concentrations in plasma, and the in vivo result is in good correlation with that from the in vitro study.