PVP solid dispersions containing Poloxamer 407 or TPGS for the improvement of ursolic acid release

Abstract Solid dispersions (SDs) of ursolic acid (UA) were developed using polyvinylpyrrolidone K30 (PVP K30) in combination with non-ionic surfactants, such as D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) or poloxamer 407 (P407) with the aim of enhancing solubility and in vitro release of the UA. SDs were investigated using a 24 full factorial design, subsequently the selected formulations were characterized for water solubility, X-ray diffractometry (XRD), differential scanning calorimetry (DSC), particle diameter, scanning electron microscopy, drug content, physical-chemical stability and in vitro release profile. SDs showed higher UA water-solubility than physical mixtures (PMs), which was attributed by transition of the drug from crystalline to amorphous or molecular state in the SDs, as indicated by XRD and DSC analyses. SD1 (with P407) and SD2 (with TPGS) were chosen for further investigation because they had higher drug load. SD1 proved to be more stable than SD2, revealing that P407 contributed to ensure the stability of the UA. Furthermore, SD1 and SD2 increased UA release by diffusion and swelling-controlled transport, following the Weibull model. Thus, solid dispersions obtained with PVP k-30 and P407 proved to be advantageous to enhance aqueous solubility and stability of UA.摘要 本研究以聚乙烯吡咯烷酮K30（polyvinylpyrrolidone K30，PVP K30）联合非离子表面活性剂D-α-生育酚聚乙二醇1000琥珀酸酯（D-α-tocopherol polyethylene glycol 1000 succinate，TPGS）或泊洛沙姆407（poloxamer 407，P407）制备熊果酸（ursolic acid，UA）固体分散体（solid dispersions，SDs），旨在提升熊果酸的水溶性与体外释药性能。本研究采用24全因子设计对固体分散体进行系统考察，随后对筛选得到的制剂开展水溶性、X射线衍射法（X-ray diffractometry，XRD）、差示扫描量热法（differential scanning calorimetry，DSC）、粒径、扫描电子显微镜、药物含量、理化稳定性及体外释药曲线表征。结果表明，固体分散体的熊果酸水溶性显著优于物理混合物（physical mixtures，PMs），结合XRD与DSC分析结果可知，该现象源于固体分散体中药物由结晶态转变为无定形态或分子分散态。鉴于载药量更高，本研究选取SD1（含P407）与SD2（含TPGS）开展后续研究。稳定性测试结果显示，SD1的稳定性优于SD2，证实泊洛沙姆407可有效保障熊果酸的稳定性。此外，SD1与SD2均通过扩散与溶胀控释机制实现熊果酸的体外释放，其释药行为符合威布尔模型（Weibull model）。综上，采用PVP K30与P407制备的固体分散体可有效提升熊果酸的水溶性与稳定性，具备显著应用优势。