Development of drug-rich phase-forming solid dispersion formulations based on molecular-level characterization by NMR

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K16334
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47020:Pharmaceutical analytical chemistry and physicochemistry-related
• Research Institution: Chiba University
• Principal Investigator: Ueda Keisuke 千葉大学, 大学院薬学研究院, 助教 (40755972)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 非晶質固体分散体 / 過飽和 / 液-液相分離 / 薬物ナノ粒子 / NMR / 経口吸収改善

Outline of Final Research Achievements

The effect of pharmaceutical additives used in supersaturated formulations on liquid-liquid phase separation (LLPS) behavior of drugs was evaluated. It was revealed that HPMC-AS can stabilize the drug-rich phase formed by LLPS at nanosize. Solution NMR analysis showed that HPMC-AS distributed into the drug-rich phase formed in the supersaturated solution and suppressed drug crystallization and particle aggregation. On the other hand, excessive distribution of the polymer into the drug-rich phase reduces the amorphous solubility of the drug, suggesting that the absorption-improving ability of the supersaturated formulation can be diminished by polymer coexistence. The selection of pharmaceutical additives based on the molecular-level evaluation of drug-rich phase is essential for designing solid dispersion formulations with maximized drug absorption improvement.

Free Research Field

分子製剤学

Academic Significance and Societal Importance of the Research Achievements

本研究より、薬物濃縮相の安定性や薬物の最大過飽和溶解度を考慮した製剤添加剤選択が、過飽和製剤の開発には必要不可欠であることが示された。特に一部の製剤添加剤ポリマーは、薬物の非晶質溶解度を大きく低下させ、過飽和製剤による経口吸収改善能を低下させるリスクがあることが示された。本研究より見いだされた知見から、非晶質固体分散体による吸収改善能を最大限に引き出した製剤開発が可能となり、従来の固体分散体製剤では十分な薬効が得られない超難水溶性薬物の経口製剤化に寄与すると考えられる。加えて本研究が指針となり、各種NMR応用測定を用いた分子レベルでの物性評価に基づく製剤設計が可能となることが期待される。