Experimental plan of central composite design.

Rheumatoid arthritis is considered a chronic systemic autoimmune disorder that may cause joint destruction. Triptolide, an active component isolated from Tripterygium wilfordii Hook.f., is considered to have promising potential for clinical use in treating rheumatoid arthritis. However, its clinical application has been limited by the narrow therapeutic window, side effects associated with plasma drug fluctuations, low oral bioavailability, and poor patient compliance with the long and frequent dosing regimen. An extended drug release preparation may address these limitations. The aim of this work was therefore to develop, formulate and optimize sustained release triptolide microspheres with poly (lactide-co-glycolide) (PLGA). Triptolide-loaded microspheres were prepared using PLGA as the matrix polymer, dichloromethane as the oil phase, and polyvinyl alcohol (PVA) as the matrix forming emulsifier. An oil-in-water (O/W) emulsion solvent evaporation technique was utilized to prepare the microspheres. Surface response methodology (RSM) coupled with central composite design (CCD) was used to optimize the formulation and a total of twenty formulations were prepared. PVA concentration (X1), PLGA concentration (X2), and theoretical drug content (X3) were selected as independent variables; and drug content (Y1), encapsulation efficiency (Y2), mean diameter (Y3) and the initial release during the first day (Y4) were taken as the response variables. The optimized formulation showed mean diameter of 42.36 μm, drug content of 7.96%, encapsulation efficiency of 80.16% and an initial release of 14.48%. The prepared microspheres exhibited a sustained release profile of triptolide in vitro over 4 weeks, which was wellfitted with a Korsmeyer-Peppas equation. However, the initial drug release (~14%) of triptolide-loaded microspheres was very high and should be specifically investigated in future studies. The results indicate that long-term sustained release microspheres of triptolide can be considered a strategy to overcome the low bioavailability and poor patient compliance with conventional triptolide tablets. The issue of initial burst release and in vivo evaluations should be specifically investigated in the future.

类风湿关节炎（Rheumatoid arthritis）被认为是一种可引发关节破坏的慢性全身性自身免疫性疾病。雷公藤内酯（triptolide）是从雷公藤（Tripterygium wilfordii Hook.f.）中分离得到的活性成分，在类风湿关节炎的临床治疗中展现出良好的应用潜力。然而，其临床应用受限于较窄的治疗窗、与血浆药物浓度波动相关的不良反应、较低的口服生物利用度，以及长期频繁给药方案导致的患者依从性不佳。缓控释制剂有望解决上述局限。本研究旨在开发、制备并优化以聚乳酸-羟基乙酸共聚物（poly (lactide-co-glycolide)，PLGA）为载体的雷公藤内酯缓释微球。采用聚乳酸-羟基乙酸共聚物作为载体聚合物、二氯甲烷作为油相、聚乙烯醇（polyvinyl alcohol，PVA）作为乳化基质，通过水包油（O/W）乳液溶剂挥发法制备载雷公藤内酯微球。采用响应面法（Surface response methodology，RSM）结合中心复合设计（central composite design，CCD）对处方进行优化，共制备20组处方。选取聚乙烯醇浓度（X₁）、聚乳酸-羟基乙酸共聚物浓度（X₂）与理论载药量（X₃）作为自变量，以实际载药量（Y₁）、包封率（Y₂）、平均粒径（Y₃）及首日初始释药量（Y₄）作为响应指标。优化后的处方平均粒径为42.36 μm，实际载药量为7.96%，包封率为80.16%，首日初始释药量为14.48%。所制备的微球在体外可实现长达4周的雷公藤内酯缓释行为，其释药过程与Korsmeyer-Peppas方程拟合度良好。但载药微球的初始药物突释（约14%）仍较高，需在后续研究中针对性开展深入探究。研究结果表明，雷公藤内酯长效缓释微球可作为解决传统雷公藤内酯片剂生物利用度低、患者依从性差问题的可行策略。未来仍需针对初始突释问题及体内评价开展专项研究。