While flash nanoprecipitation (FNP) has proven to be an extremely rapid and highly efficient nanoparticle fabrication process for hydrophobic drugs, physical instability associated with nonequilibrium molecular orientation of amphiphilic stabilizers (ASs) in nanoparticles remains a major snag in the general application of this nanotechnology, particularly for a drug with ACDLog P in the range of ∼2–9. This study was aimed at elucidating the costabilizing role of cholesterol (CLT) in the FNP of AS-stabilized nanoparticles of itraconazole (ITZ), a model drug with an ACDLog P of 4.35 ± 1.22 and log P of 5.66. The presence of CLT was shown to reduce the initial particle size and markedly improve the short-term storage stability of ITZ nanoparticles. The stability-enhancement by CLT can be linked to its higher miscibility or stronger interaction with the AS hydrophobic moiety than with ITZ (as reflected by the absolute differences of their solubility parameter values). Surface analyses employing X-ray photoelectron spectroscopy (XPS) and atomic force microscopy (AFM) suggest that, through the coprecipitation of CLT with ITZ to form a mixed hydrophobic drug core, the CLT molecules that are exposed on the core surface serve to afford a stronger and more timely surface anchorage of the AS hydrophobic moieties, thereby facilitating the rearrangement of AS molecules toward the stable micelle-like structure. The present findings offer a mechanistic insight into the interplay between amphiphilic stabilizer and costabilizer in enhancing the physical stability of drug nanoparticles and may carry important implications for the development of more stable and efficacious nanoparticle therapeutics.

中文翻译：

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两性稳定剂与胆固醇在快速纳米沉淀法制备的伊曲康唑纳米粒子稳定中的相互作用

尽管闪速纳米沉淀（FNP）已被证明是疏水性药物的极其快速且高效的纳米颗粒制造工艺，但与纳米颗粒中两亲稳定剂（AS）的非平衡分子取向相关的物理不稳定性仍然是该纳米技术普遍应用的主要障碍，特别是对于ACDLog P在〜2–9范围内的药物。这项研究旨在阐明胆固醇（CLT）在伊曲康唑（ITZ）的AS稳定纳米颗粒的FNP中的协同作用，ACDLog P为4.35±1.22，log P为模型药物5.66。已显示CLT的存在可减小初始粒径，并显着提高ITZ纳米颗粒的短期储存稳定性。与ITZ相比，CLT增强的稳定性可以与它与AS疏水性部分的更高溶混性或更强的相互作用有关（如其溶解度参数值的绝对差异所反映）。使用X射线光电子能谱（XPS）和原子力显微镜（AFM）进行的表面分析表明，通过CLT与ITZ的共沉淀以形成混合的疏水性药物核心，暴露在核心表面上的CLT分子可提供AS疏水基团更强，更及时的表面锚定，从而促进AS分子向稳定的胶束状结构重新排列。