目的 基于“药辅合一”理念，探究油状活性成分油酸自身为油相构建自乳化递送系统（self-emulsifying drug delivery system，OA@SEDDS）过程中，无水乙醇、甘油、聚乙二醇（polyethylene glycol，PEG）400、1,2-丙二醇（1,2-propylene glycol，PG）4种助乳化剂对OA@SEDDS界面膜结构、乳化行为及环境耐受性的影响，为脂肪酸类活性成分的理性处方设计提供依据。方法 采用伪三元相图法筛选4种助乳化剂构建的OA@SEDDS处方，结合傅里叶变换红外光谱（Fourier transform infrared spectroscopy，FTIR）、¹H核磁共振（¹H nuclear magnetic resonance，¹H-NMR）、二维核磁共振（nuclear Overhauser effect spectroscopy，NOESY）及分子对接技术等，解析SEDDS界面分子间相互作用。通过动态光散射、流变学测试及加速稳定性实验，评估制剂的理化性质与应激稳定性。结果 无水乙醇体系展现出最宽的乳化区域与最佳的稀释稳定性。FTIR证实油酸羧基的去质子化是形成稳定离子对的关键，体现了油酸作为“药辅合一”组分在界面电荷调控中的核心作用。NOESY与分子对接结果证实，无水乙醇与聚山梨酯-80界面的结合能（-1.812 kJ/mol）相对最低，并与油酸羧酸根离子在界面形成高密度的氢键网络，显著提升了界面膜的均一性。流变学数据显示，无水乙醇体系表现出适宜的模量与剪切稀化行为，赋予制剂良好的流动性；而PEG400体系则因长链缠结表现出高弹性模量，不利于快速乳化。在应激稳定性方面，碱性条件（pH 9）通过破坏油酸离子对结构导致普遍破乳，而盐离子耐受性则体现了非离子表面活性剂的空间位阻优势。结论 助乳化剂通过调控界面氢键网络密度与离子对空间邻近度决定OA@SEDDS的性能。无水乙醇体系因构建了“适度流动性”兼具“适中相互作用强度”的界面膜，实现了综合性能的最佳平衡。揭示了以活性成分自身为油相的SEDDS界面动态非平衡特性的重要性，为开发耐受复杂生理环境的脂肪酸基自乳化制剂提供了理论指导。

Objective Guided by the “combination of medicine and adjuvant” concept, this study investigates the mechanisms by which four co-emulsifiers-anhydrous ethanol (EtOH), glycerol, polyethylene glycol (PEG) 400, and 1,2-propylene glycol (PG)-influence interfacial film structure, emulsification behavior, and environmental tolerance during the construction of a self-emulsifying drug delivery system (OA@SEDDS) using oleic acid (OA), an oily active ingredient, as the oil phase. The findings aim to provide a rationale for the rational formulation design of fatty acid-based active ingredients. Methods Pseudo-ternary phase diagrams were employed to screen OA@SEDDS formulations prepared with the four co-emulsifiers. Fourier transform infrared spectroscopy (FTIR), ¹H nuclear magnetic resonance (NMR), nuclear Overhauser effect spectroscopy (NOESY), and molecular docking were utilized to elucidate intermolecular interactions at the SEDDS interface. Physicochemical properties and stress stability were evaluated through dynamic light scattering, rheological measurements, and accelerated stability testing. Results The EtOH-based system exhibited the broadest emulsification region and optimal dilution stability. FTIR analysis confirmed that deprotonation of the OA carboxyl group was critical for forming stable ion pairs, underscoring OA’s central role as a “combination of medicine and adjuvant” component in modulating interfacial charge. NOESY and molecular docking revealed that EtOH possessed the lowest binding energy (-1.812 kJ/mol) at the Tween-80 interface and formed a high-density hydrogen-bonding network with OA carboxylate ions, significantly enhancing interfacial film homogeneity. Rheological data indicated that the EtOH system displayed suitable modulus values and shear-thinning behavior, conferring favorable flowability; in contrast, the PEG400 system exhibited high elastic modulus due to long-chain entanglement, hindering rapid emulsification. In terms of stress stability, alkaline conditions (pH 9) lead to universal emulsion breakdown occurred via disruption of OA ion-pair structures, whereas salt tolerance reflected the steric stabilization advantage of non-ionic surfactants. Conclusion Co-emulsifiers govern OA@SEDDS performance by modulating interfacial hydrogen-bonding network density and spatial proximity of ion pairs. The EtOH system achieved an optimal overall balance by forming an interfacial film characterized by “moderate fluidity” and “appropriate interaction strength”. This study highlights the importance of dynamic non-equilibrium interfacial properties in SEDDS where the active ingredient itself serves as the oil phase, offering theoretical guidance for developing fatty acid-based self-emulsifying formulations capable of withstanding complex physiological environments.

R283.6

国家自然科学基金资助项目（82660902）；国家自然科学基金资助项目（82260827）；贵州省科技计划项目黔科合基础项目（ZK[2022]380）；贵州省科技计划项目黔科合基础项目（MS[2025]564）；贵州省科技创新基地，黔科合中引地项目（[2023]003）；贵州省高层次创新型人才百层次人才黔科合平台人才项目（GCC[2023]048）；贵州省卫生健康委员会项目（Grant No.:126）；贵州医科大学高层次人才科研启动基金项目（校博合J字（2023）026号）；贵州医科大学高层次人才科研启动基金项目（校博合J字（2026）004号）