Sakuma Fumie, Higashi Kenjirou, Ueda Keisuke, Morita Takeshi, Iohara Daisuke, Hirayama Fumitoshi, Moribe Kunikazu
Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8675, Japan.
Graduate School of Science, Chiba University, 1-33, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan.
Langmuir. 2024 Jul 16. doi: 10.1021/acs.langmuir.4c01362.
Poloxamer hydrogel possesses thermosensitive sol-gel transition characteristics and is widely used as a drug-controlled-release carrier for topical or injectable formulations. In this study, the effect of loading of a drug, acetaminophen (ACE), on the physical and structural properties of poloxamer 407 (P407) micelles and hydrogels was investigated. Differential scanning calorimetry measurements revealed that ACE reduced the critical micelle temperature and enthalpy of micellization of P407 solutions. The P407 micellization was promoted by ACE incorporation. Rheometry showed that ACE increased the sol-gel transition temperature and reduced the gel strength of P407. In situ small-angle X-ray scattering (SAXS) using synchrotron radiation revealed that ACE altered the structure of P407 micelles and their packing in the P407 gels. As ACE concentration increased, the P407 micelle packing changed from a face-centered cubic phase to a body-centered cubic phase. Furthermore, ACE disordered the micelle packing structure and induced the formation of an amorphous phase. Structural analysis of the P407 micelle packing indicated that ACE reduced the aggregation number () of P407 micelles in the gels. The SAXS study for diluted P407 solutions revealed that ACE reduced the P407 micelle size and its uniformity. The structural changes in P407 micelles by ACE loading (e.g., the reduction of , size, and size uniformity) would alter the micelle packing structure. It was found that these structural changes of micelle packing, especially the formation of an amorphous phase, could destabilize the P407 gel. As a result, the physical properties of P407 gels, such as gelation temperature and gel strength, were changed. This relationship between the structure and physical property of drug-loaded P407 gels was well-explained by correlating the micelle and gel structures. The mechanistic understanding of the change in the physical properties of P407 gels by drug loading is essential for the effective development of poloxamer gel formulations.
泊洛沙姆水凝胶具有热敏性的溶胶-凝胶转变特性，被广泛用作局部或注射制剂的药物控释载体。在本研究中，考察了药物对乙酰氨基酚（ACE）的负载量对泊洛沙姆407（P407）胶束和水凝胶的物理及结构性质的影响。差示扫描量热法测量结果表明，ACE降低了P407溶液的临界胶束温度和胶束化焓。ACE的加入促进了P407的胶束化。流变学研究表明，ACE提高了P407的溶胶-凝胶转变温度并降低了其凝胶强度。利用同步辐射进行的原位小角X射线散射（SAXS）表明，ACE改变了P407胶束的结构及其在P407凝胶中的堆积方式。随着ACE浓度的增加，P407胶束堆积从面心立方相转变为体心立方相。此外，ACE使胶束堆积结构无序化并诱导了非晶相的形成。对P407胶束堆积的结构分析表明，ACE降低了凝胶中P407胶束的聚集数（）。对稀释的P407溶液进行的SAXS研究表明，ACE减小了P407胶束的尺寸及其均匀性。ACE负载导致的P407胶束结构变化（如聚集数、尺寸和尺寸均匀性的降低）会改变胶束堆积结构。研究发现，这些胶束堆积的结构变化，尤其是非晶相的形成，会使P407凝胶不稳定。结果，P407凝胶的物理性质，如凝胶化温度和凝胶强度，发生了改变。通过关联胶束和凝胶结构，很好地解释了载药P407凝胶的结构与物理性质之间的这种关系。对药物负载导致P407凝胶物理性质变化的机理理解对于泊洛沙姆凝胶制剂的有效开发至关重要。
