2-ヒドロキシプロピル-β-シクロデキストリンを液体製剤で使用する際の注意点：物理的特性と界面活性剤適合性に関する系統的研究

This study explores the role of 2-hydroxypropyl-β-cyclodextrin (HPβCD) as an excipient in liquid formulations by evaluating its physical properties, thermal behavior, and compatibility with other excipients. Critical attributes for formulation development - including osmolality, viscosity, and glass transition temperature (Tg') - were systematically examined across varying degrees of substitution, pH conditions, and excipient combinations. To assess its interactions with surfactants, particularly polysorbates, we employed high-throughput UV-extinction measurements coupled with principal component analysis to generate heat maps as phase diagrams, comprehensively delineating phase separation regions at relevant concentration ranges within the formulation. The findings indicate that HPβCD exhibits practical ranges of osmolality and viscosity, and can be leveraged to elevate Tg', reinforcing its suitability for both liquid and lyophilized formulations. However, formulation stability can be significantly influenced by excipient compatibility, particularly with polysorbates. For the first time, we report phase separation in HPβCD/PS80 and HPβCD/PS20 solutions, manifesting as high turbidity at specific concentration ranges. The phase separation was more pronounced with PS80, possibly due to stronger molecular interactions between HPβCD and the longer hydrophobic chain in PS80. Conversely, P188 did not exhibit phase separation, suggesting a distinct interaction pattern between HPβCD and polysorbates. The heat maps developed herein provide a quantitative tool for rationally selecting excipients and optimizing their concentrations, thereby ensuring formulation clarity and physical stability. These results emphasize the importance of excipient compatibility assessments in sterile injectable formulations and highlight phase mapping as a practical approach to guide formulation scientists in mitigating phase-separation risks and improving the quality and reliability of liquid formulation development.