基于皮肤-关节囊屏障特点的中药关节靶向性DDS的构建与评价

Arthritis is one of the refractory diseases for high rate of incidence, disability and teratogenesis. It is divided into different types, but all of which have the same symptom——inflammatory in articular cavity, which causes many other clinical symptoms. TCM has a unique advantage in the treatment of arthritis. However, for the barriers of skin and articular capsule, the concentration in the articular cavity is very low, which leads to poor effective on arthritis. How to improve the permeability of articular capsule and to achieve articular targeting are the two important factors to reduce toxicity and enhance efficacy for arthritic treatment. So, an articular targeting system of FA-TGP-E is prepared based on the characteristic of skin and articular capsule barrier: ① micro needle array is employed on the surface of the skin to form non-invasive penetration pores, which promote transdermal absorption and ensure the structural integrity of FA-TGP-E; ② FA-TGP-E break through the articular capsule to the articular cavity taking the advantage of flexible deformation; ③ FA on the surface of FA-TGP-E bind to β-FA receptors on those activated macrophages of synovial membrane, then a system targeted to inflammatory cells is prepared. The permeability and articular targeting of this system（micro needles mediated FA-TGP-E）are evaluated by transdermal experiment, vivo imaging, micro-dialysis, and et al. The feasibility and key questions of this dermal drug delivery and articular targeting system are also investigated and discussed, that will provide credible references to some other TCM articular targeting preparations.

关节炎发病率、致残致畸率高，是一种难治性疾病；尽管类型各异，但均存在关节腔的炎性反应，引发各种临床症状。中药治疗关节炎具有独特优势，但受到皮肤屏障及关节囊屏障的限制，常规给药途径难以满足关节腔内有效的药物浓度，影响了治疗效果。提高药物的关节囊渗透性，实现关节靶向，是增效减毒、提高关节炎治疗效果的核心。基于此，本课题以白芍总苷为模型，基于皮肤-关节囊屏障特点设计叶酸修饰醇质体经皮给药系统：①以微针阵列在皮肤表层形成非损伤性渗透微孔，为完整醇质体透皮吸收提供高效通道；②发挥完整醇质体的柔性变形特点，突破关节囊屏障，实现关节腔内转运；③通过醇质体表面修饰叶酸与滑膜活化巨噬细胞的特异性结合，实现炎性细胞主动靶向。通过体外透皮、活体成像、在体微透析等技术，对微针介导叶酸修饰白芍总苷醇质体透皮及关节靶向性能进行评价，探讨经皮-关节靶向给药系统的可行性及关键问题，为中药关节靶向制剂的研究提供参考。

外用给药是治疗关节炎的主要手段，但受到皮肤屏障及关节囊屏障的限制，常规给药无法使关节腔内达到有效的药物浓度，影响治疗效果。因此增强药物的皮肤渗透性、提高药物的深层渗透能力是提高关节炎治疗效果的关键。基于此，本项目选择对关节炎有明确效果的白芍总苷（TGP）为模型药物，将载体促渗、物理促渗与靶向技术相结合，设计了TGP醇质体（TGP-E）及叶酸修饰TGP醇质体（FA-TGP-E），并考察其微针作用下的渗透性；从体外透皮、体内药动学、药效学等角度对其深层渗透及靶向性进行评价。.1.经皮-关节靶向系统的制备. 以包封率和载药量为指标，在单因素考察的基础上通过正交设计试验对TGP-E的处方进行优化，最终得到最佳处方为：乙醇3 mL，磷脂浓度5%，药脂比1:10，PBS缓冲液7mL（pH 7.3）。用 FA-PEG-DSPE 替代处方中的部分磷脂（替代比10%），采用优选的制备方法制备FA-TGP-E。制备的三批样品在40天内形态、包封率、粒径分布和电位均能保持稳定。.2.微针介导TGP透皮条件的研究. 以累计渗透率（Qn）为指标，结合组织切片法和光学相干断层扫描法对微针的有效性和安全性条件进行筛选，得到最佳的微针施加条件为：500μm的滚轮微针，以3N的作用力，作用皮肤3 min。.3.微针介导TGP跨皮肤-关节囊屏障研究. 透皮评价：利用Franz扩散池法研究了微针介导下TGP的体外经皮渗透特性，发现微针能够最大程度上促进TGP的渗透，但纳米技术（醇质体）和物理技术（微针）并无协同作用。. 跨关节囊屏障及关节靶向性评价：利用在体微透析研究TGP在微针介导下皮下及关节腔内的药物浓度。药动学结果表明，TGP-E、FA-TGP-E可提高皮下及关节腔内峰浓度（Cmax）和药时曲线下面积（AUC），滞留时间（MRT）则处于更低水平，说明给药系统具有良好的关节靶向性。. 药效学评价：佐剂性关节炎大鼠的药效结果显示，FA-TGP-E可显著改善大鼠足趾肿胀度，降低大鼠血清IL-1β、PGE2、TNF-α的含量，体现出明显的治疗优势。. 本项目为多种方式联用促进药物吸收提供了参考，也为研制易用、安全、有效的白芍总苷新剂型和新的给药途径提供了参考。