Structure of supersaturated solution of poorly water-soluble drug indexed by mobility and diffusibility and the correlation with membrane permeability

• Project/Area Number: 24590045
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Physical pharmacy
• Research Institution: Chiba University
• Principal Investigator: MORIBE Kunikazu 千葉大学, 薬学研究科(研究院), 教授 (50266350)
• Co-Investigator(Kenkyū-buntansha): YAMAMOTO Keiji 千葉大学, 大学院薬学研究院, 名誉教授 (50110341) ; HIGASHI Kenjirou 千葉大学, 大学院薬学研究院, 助教 (40451760)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2014: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2013: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2012: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 固体分散体 / 過飽和 / 固体分散体過飽和

Outline of Final Research Achievements

The decrease of the substituent ratio of succinoyl group in HPMC-AS promoted the inhibition effect of drug crystallization. NMR measurements revealed that HPMC-AS suppressed the molecular mobility of drug and formed the hydrophobic interaction with drug. The molecular interaction between drug and HPMC-AS was strongest in acetyl group and weakest in succinoyl group of HPMC-AS, indicated by saturation transfer difference (STD)-NMR measurements. The molecular interaction between drug and HPMC-AS revealed by NMR measurement showed good correlation with the inhibitory effect of drug crystallization.

Research Products

• [Journal Article] The effect of HPMCAS functional groups on drug crystallization from the supersaturated state and dissolution improvement (2014)
  • Author(s): Ueda, K., Higashi, K., Yamamoto, K., Moribe, K
  • Journal Title: Int. J. Pharm. Volume: 464 (1-2) Issue: 1-2 Pages: 205-213
  • DOI: 10.1016/j.ijpharm.2014.01.005
  • Peer Reviewed
• [Journal Article] Inhibition mechanism of hydroxypropyl methylcellulose acetate succinate on drug crystallization in gastrointestinal fluid and drug permeability from a supersaturated solution (2014)
  • Author(s): Ueda, K., Higashi, K., Kataoka, M., Yamashita, S., Yamamoto, K., Moribe, K.
  • Journal Title: Eur. J. Pharm. Sci. Volume: 62 Pages: 293-300
  • DOI: 10.1016/j.ejps.2014.06.007
  • Peer Reviewed
• [Journal Article] Inhibitory effect of hydroxypropyl methylcellulose acetate succinate on drug recrystallization from a supersaturated solution assessed using nuclear magnetic resonance measurements (2013)
  • Author(s): K. Ueda, K. Higashi, K. Yamamoto
  • Journal Title: Mol. Pharm. Volume: 10 Issue: 1 Pages: 3801-3811
  • DOI: 10.1021/mp4005723
  • Peer Reviewed
• [Journal Article] Mechanistic differences in permeation behavior of supersaturated and solubilized solutions of carbamazepine revealed by nuclear magnetic resonance measurements. (2012)
  • Author(s): Ueda K, Higashi K, Limwikrant W, Sekine S, Horie T, Yamamoto K, Moribe K.
  • Journal Title: Mol. Pharm. Volume: 9 Issue: 11 Pages: 3023-3033
  • DOI: 10.1021/mp300083e
  • Peer Reviewed
• [Journal Article] Transglycosylated Rutin-Specific Non-Surface-Active Nanostructure Affects Absorption Enhancement of Flurbiprofen (2012)
  • Author(s): Yuichi Tozuka
  • Journal Title: European Journal of Pharmaceutics and Biopharmaceutics Volume: 82 Issue: 1 Pages: 120-126
  • DOI: 10.1016/j.ejpb.2012.05.005
  • Peer Reviewed
• [Presentation] HPMC-AS の薬物結晶化抑制作用に及ぼす胆汁酸及び脂質の影響 (2015)
  • Author(s): 植田 圭祐, 東 顕二郎, 片岡 誠, 山下 伸二, 山本 恵司, 森部 久仁一
  • Organizer: 日本薬学会第135年会
  • Place of Presentation: 神戸
  • Year and Date: 2015-03-26 – 2015-03-28
• [Presentation] HPMC及びPVPの薬物結晶化抑制機構の違いが膜透過性に及ぼす影響 (2014)
  • Author(s): 大塚 直哉, 植田 圭祐, 清水 梢, 片川 和明, 熊本 卓也, 東 顕二郎, 山本 恵司, 森部 久仁一
  • Organizer: 製剤機械技術学会第24回大会
  • Place of Presentation: 名古屋
  • Year and Date: 2014-10-08 – 2014-10-09
• [Presentation] 薬物結晶化抑制作用に及ぼすHPMC-AS置換基比率の影響：溶液NMRによる評価 (2013)
  • Author(s): 植田圭祐、東顕二郎、森部久仁一、山本恵司
  • Organizer: 製剤機械技術学会 第23回大会
  • Place of Presentation: 東京
• [Presentation] Solution NMR study of permeation mechanism of carbamazepine from supersaturated and solubilized solution (2013)
  • Author(s): K. Ueda, K. Moribe, K. Higashi, K. Yamamoto
  • Organizer: The 5th Asian Arden Conference
  • Place of Presentation: 名古屋
• [Presentation] 置換基比率の異なる各種HPMC-ASによる結晶化抑制作用の比較 (2013)
  • Author(s): 植田圭祐、東顕二郎、森部久仁一、山本恵司
  • Organizer: 第30回 製剤と粒子設計シンポジウム
  • Place of Presentation: 岐阜
• [Presentation] 過飽和溶液中におけるHPMC及びPVPによるフェニトイン誘導体結晶化抑制メカニズムの解明 (2013)
  • Author(s): 大塚直哉、植田圭祐、清水梢、片山和明、熊本卓哉、東顕二郎、森部久仁一、山本恵司
  • Organizer: 第30回 製剤と粒子設計シンポジウム
  • Place of Presentation: 岐阜
• [Presentation] 1H-NMRによるCarbamazepine/HPMC-AS過飽和溶液中の薬物分子状態の解明 (2012)
  • Author(s): 植田圭祐、Waree Limwikrant、東顕二郎、森部久仁一、山本恵司
  • Organizer: 日本薬剤学会第27年会
  • Place of Presentation: 神戸
• [Presentation] 過飽和溶液中でのHPMC-ASによるCarbamazepine結晶化抑制メカニズムの解明 (2012)
  • Author(s): 植田圭祐、東顕二郎、森部久仁一、山本恵司
  • Organizer: 第29回製剤と粒子設計シンポジウム
  • Place of Presentation: 豊橋
• [Presentation] 非晶質製剤及びナノ結晶製剤を利用した難溶性薬物の溶解性改善 (2012)
  • Author(s): 森部久仁一
  • Organizer: 第８回ナノ製剤技術研究会
  • Place of Presentation: 京都
• [Presentation] Phenytoin過飽和溶液のCaco-2細胞透過改善メカニズムの解明
  • Author(s): 大塚直哉、植田圭祐、清水梢、片山和明、熊本卓哉、東顕二郎、森部久仁一、山本恵司
  • Organizer: 第57回 日本薬学会関東支部大会
  • Place of Presentation: 東京
• [Presentation] Phenytoin/Eudragit S100 固体分散体の物性と溶出挙動との関連
  • Author(s): 林大基、東顕二郎、森部久仁一、山本恵司
  • Organizer: 第57回 日本薬学会関東支部大会
  • Place of Presentation: 東京
• [Book] 医薬ジャーナル：各種ポリマーによる難水溶性薬物の溶解性改善機構の解明と製剤化への応用 (特集 実用可能な新しい製剤技術の進歩と将来展望) (2014)
  • Author(s): 植田 圭祐, 東 顕二郎, 森部 久仁一
  • Total Pages: 256
  • Publisher: 医薬ジャーナル社
• [Remarks] 製剤工学
  • URL: http://www.p.chiba-u.ac.jp/lab/seizai/