A Study Of Triptolide-loaded Liposome Hydrogel Patch For Transdermal Delivery On CIA Model Under Micro-needle

Triptolide, a diterpenoid triepoxide compound, is isolated from Tripterygium wilfordii Hook.f.(TWHF). It is a major active component of TWHF, and has anti-inflammatory and immunosuppressive activity. However, it has serious toxicities on digestive, urogenital and blood circulatory system. In this study, a new formulation, named triptolide-loaded liposome hydrogel patch (TP-LHP), was prepared. Collagen induced arthritis (CIA) model is similar to rheumatoid arthritis (RA), so it was recognized as the best model for RA research. The optimal prescription was determined by orthogonal experiment. Rat with collagen induced arthritis was used as the carrier, and MEMS micro-needle was performed for enhancement. We studied the skin injure of TP-LHP in CIA rats under micro-needle, and evaluated the pharmacokinetics and pharmacodynamics. Based on these studies, we draw the following conclusions:(1) Both100μm and200μm MEMS micro-needles were safe for enhancement of transdermal delivery. The skin injury was observably relieved when triptolide was prepared as liposomes hydrogel patch which was a perfect formulation for transdermal delivery of triptolide.(2) A new HPLC method, using andrographolide as an internal standard, was established for the determination of triptolide in plasma. This method showed a good linear curve without any interference factors. The minimum detectable concentration was5ng/mL, which was enough to meet the demand for detection. Transdermal delivery of TP-LHP under micro-needle was fitted to the one-compartment open model. The relationship equation between plasma concentration and time was C=303.59X (e"0.064t-e-0.287t). Compared with i.g. administration, TP-LHP had a slower time-to-peak and longer stability of plasma concentration. There was a significant increase in the AUCoâ†'x, which indicated that TP-LHP improved the bioavailability of triptolide.(3) The degree of joint swelling was mitigated by TP-LHP which also suppressed the expressions of Flk-1, Flt-4and HIF-1α in synovium. Moreover, other indicators were reduced by TP-LHP, including hyperfunction of immune, IL-1β and IL-6levels in serum. We speculated that the therapeutic mechanism of TP-LHP might regulate the balance between Thl and Th2in organism, as well as inhibited the expression and biological effects of VEGF.This paper demonstrated that micro-needle technology can be efficiently and safely used in topical formulations for enhancement. When triptolide was preparated as TP-LHP, the hepatic first-pass metabolism and digestive toxicity were eliminated. The skin injure of rat was relieved as well. TP-LHP provided stable long-term release of triptolide, and had a significant efficacy in CIA model. Therefore, TP-LHP and micro-needle technology combine to treat rheumatoid arthritis, which develop the characteristic of external treatment of traditional Chinese medicine and have a great development prospect.