Puyathorn Napaphol, Tamdee Poomipat, Yodsin Nuttapon, Phaechamud Thawatchai, Sirirak Jitnapa
Department of Pharmaceutical Sciences, Faculty of Pharmacy, Chiang Mai University, Chiang Mai 50200, Thailand.
Center of Excellence in Pharmaceutical Nanotechnology, Chiang Mai University, Chiang Mai 50200, Thailand.
ACS Omega. 2025 May 21;10(21):21432-21449. doi: 10.1021/acsomega.5c00187. eCollection 2025 Jun 3.
In situ gels (ISGs) are well-known as smart drug delivery systems due to their inherent gel-forming ability and controlled drug release properties. This study presents comprehensive molecular-level insights into the physical properties and phase transformation processes of the formulation of 10 to 60% w/w myristic acid (MYR)-based ISGs using ethanol (EtOH), -methyl-2-pyrrolidone (NMP), and dimethyl sulfoxide (DMSO) as solvents, investigated using conventional experimental techniques, molecular dynamics (MD) simulations, and density functional theory (DFT). The results showed that 40% w/w myristic acid in NMP (NM40) exhibited swift gel formation with low water tolerance to induce phase inversion into the matrix. Scanning electron microscopy revealed that NM40 had multilayer, sheet-like structures, in which NM40 displayed a denser and less porous topography than 40% w/w myristic acid in DMSO (DM40). NM40 also had efficient antimicrobial efficacy against various microbes; thus, NM40 was the appropriate ISG as an antimicrobial drug delivery system. Moreover, MD simulation demonstrated that during the initial stage of gel formation, MYR began to agglomerate and arrange in an orderly manner, resembling crystallization. A higher concentration of MYR promoted a higher compactness of the MYR structure and the lower solvent exchange rate. Additionally, DFT calculations demonstrate that hydrogen bonding is the key interaction, contributing to the orderly arrangement of molecules. These significant findings pave the way for the tailoring and optimization of ISG formulations in drug delivery systems.
原位凝胶（ISGs）因其固有的凝胶形成能力和可控的药物释放特性而作为智能药物递送系统而闻名。本研究使用乙醇（EtOH）、N-甲基-2-吡咯烷酮（NMP）和二甲基亚砜（DMSO）作为溶剂，对基于10%至60% w/w肉豆蔻酸（MYR）的原位凝胶制剂的物理性质和相变过程进行了全面的分子水平洞察，采用传统实验技术、分子动力学（MD）模拟和密度泛函理论（DFT）进行研究。结果表明，NMP中40% w/w的肉豆蔻酸（NM40）表现出快速凝胶形成，且耐水性低，可诱导相转变为基质。扫描电子显微镜显示，NM40具有多层片状结构，其中NM40的形貌比DMSO中40% w/w的肉豆蔻酸（DM40）更致密且孔隙率更低。NM40对各种微生物也具有高效抗菌功效；因此，NM40是作为抗菌药物递送系统的合适原位凝胶。此外，MD模拟表明，在凝胶形成的初始阶段，MYR开始聚集并有序排列，类似于结晶。较高浓度的MYR促进了MYR结构更高的致密性和更低的溶剂交换率。此外，DFT计算表明氢键是关键相互作用，有助于分子的有序排列。这些重要发现为药物递送系统中原位凝胶制剂的定制和优化铺平了道路。
