Evaluation of molecular state of drug nanosuspensions by suspended-state NMR spectroscopy

• Project/Area Number: 15K07885
• 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: Higashi Kenjirou 千葉大学, 大学院薬学研究院, 准教授 (40451760)
• Co-Investigator(Kenkyū-buntansha): 森部 久仁一 千葉大学, 大学院薬学研究院, 教授 (50266350)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 薬物ナノ懸濁液 / NMR / 固液界面 / 運動性 / 分子間相互作用 / 結晶多形 / 非晶質 / 湿式粉砕 / Suspended state NMR / 薬物ナノ粒子 / 多形 / 難水溶性薬物 / indomethacin / piroxicam / poloxamer / ナノ懸濁液 / suspended state NMR / 表面構造 / 分散安定性 / Indometacin / Poloxamer / ナノ粒子 / Cryo-TEM

Outline of Final Research Achievements

Two species of drug nanosuspensions prepared by wet-milling were evaluated by suspended-state NMR spectroscopy. We succeeded in directly clarifying the molecular state of both drug and stabilizer of drug nanoparticle in suspended-state. The knowledge obtained in this study provides a new insight into the mechanism of formation and stabilization of drug nanosuspensions. This study also shows that suspended-state NMR spectroscopy is a useful analytical method for quality assessment of drug nanosuspension formulations. We expect that this study will become a new index in development for drug nanosuspension and will be a help to design a new drug nanosuspension formulations of high quality.

Research Products

• [Journal Article] Nano-scale and molecular-level understanding of wet-milled indomethacin/poloxamer 407 nanosuspension with TEM, suspended-state NMR, and Raman measurements (2018)
  • Author(s): Kuroiwa Yosuke、Higashi Kenjirou、Ueda Keisuke、Yamamoto Keiji、Moribe Kunikazu
  • Journal Title: International journal of pharmaceutics Volume: 537 Issue: 1-2 Pages: 30-39
  • DOI: 10.1016/j.ijpharm.2017.12.028
  • Peer Reviewed
• [Journal Article] Structural elucidation of a novel transglycosylated compound α-glucosyl rhoifolin and of α-glucosyl rutin by NMR spectroscopy (2017)
  • Author(s): Aoki Chisa、Takeuchi Yoshihiro、Higashi Kenjirou、Okamoto Yuta、Nakanishi Akihito、Tandia Mahamadou、Uzawa Jun、Ueda Keisuke、Moribe Kunikazu
  • Journal Title: Carbohydrate Research Volume: 443-444 Pages: 37-41
  • DOI: 10.1016/j.carres.2017.03.011
  • Peer Reviewed
• [Journal Article] Effect of guest drug character encapsulated in the cavity and intermolecular spaces of γ-cyclodextrins on the dissolution property of ternary γ-cyclodextrin complex (2017)
  • Author(s): Liu Nan、Higashi Kenjirou、Ueda Keisuke、Moribe Kunikazu
  • Journal Title: International journal of pharmaceutics Volume: 531 Issue: 2 Pages: 543-549
  • DOI: 10.1016/j.ijpharm.2017.04.049
  • Peer Reviewed
• [Journal Article] A solid-phase mediated methodology to incorporate drug into intermolecular spaces of CD columns in the PEG/CD-polypseudorotaxanes by cogrinding and subsequent heating (2017)
  • Author(s): Ogawa, M., Higashi, K., Namiki, S., Liu, N. Ueda, K., Limwikrant, W., Yamamoto, K., Moribe, K.
  • Journal Title: Cryst. Growth Des. Volume: 17(3) Issue: 3 Pages: 1055-1068
  • DOI: 10.1021/acs.cgd.6b01410
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Molecular-level understanding of the encapsulation and dissolution of poorly water-soluble ibuprofen by functionalized organic nanotubes using solid-state NMR spectroscopy. (2016)
  • Author(s): Liu, N., Higashi, K., Kikuchi, J., Ando, S., Kameta, N., Ding, W., Masuda, M., Shimizu, T., Ueda, K., Yamamoto, K., Moribe, K.
  • Journal Title: J. Phys. Chem B Volume: 120(19) Issue: 19 Pages: 4496-4507
  • DOI: 10.1021/acs.jpcb.6b00939
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Direct evaluation of molecular states of piroxicam/poloxamer nanosuspension by suspended-state NMR and Raman spectroscopies (2015)
  • Author(s): Hasegawa, Y., Higashi, K., Yamamoto, K., Moribe, K.
  • Journal Title: Molecular Pharmaceutics Volume: 12 (5) Issue: 5 Pages: 1564-1572
  • DOI: 10.1021/mp500872g
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Crystallization of probucol in nanoparticles revealed by AFM analysis in aqueous solution (2015)
  • Author(s): Egami, K., Higashi, K., Yamamoto, K., Moribe, K.
  • Journal Title: Molecular Pharmaceutics Volume: 12 (8) Issue: 8 Pages: 2972-2980
  • DOI: 10.1021/acs.molpharmaceut.5b00236
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] 分光法及び顕微鏡法を用いた薬物ナノ懸濁液の構造・分子状態の直接評価 (2017)
  • Author(s): 東 顕二郎, 植田 圭祐, 森部 久仁一
  • Organizer: 日本薬学会第137年会
  • Place of Presentation: 宮城
  • Year and Date: 2017-03-25
  • Invited
• [Presentation] Characterization of glibenclamide amorphous nanoparticles prepared by antisolvent method: Effect of hypromellose addition method (2017)
  • Author(s): Higashi, K., Yonashiro, H., Ueda K., Itoh, T., Itoh, Masataka, Masu, H., Noguchi, S., Moribe, K.
  • Organizer: Asian federation pharmaceutical sciences 2017
  • Int'l Joint Research / Invited
• [Presentation] Glibenclamide非晶質ナノ粒子の構造評価：HPMC添加方法の影響 (2017)
  • Author(s): 東 顕二郎, 與那城 葉月、 植田 圭祐, 森部 久仁一、伊藤 努武、桝飛雄真、伊藤雅隆、野口修治
  • Organizer: 第34回製剤と粒子設計シンポジウム計シンポジウム
• [Presentation] ナノ医薬品開発における 電子顕微鏡の応用 (2017)
  • Author(s): 東 顕二郎
  • Organizer: 第6回大学連携研究設備ネットワーク研究成果報告会
  • Invited
• [Presentation] 分子レベルからデザイン！超分子構造体を基盤とした固体医薬品製剤の開発 (2017)
  • Author(s): 東 顕二郎、植田 圭祐、森部 久仁一
  • Organizer: 日本薬学会第138年会
  • Invited
• [Presentation] Characterization of amorphous cyclosporin A nanosuspension prepared by wet bead milling with poloxamer 407 (2017)
  • Author(s): Ziqiao CHEN, Keisuke UEDA, Kenjirou HIGASHI, Kunikazu MORIBE
  • Organizer: 日本薬学会第138年会
• [Presentation] 製剤開発における固体NMRの活用：基礎から応用まで (2017)
  • Author(s): 東 顕二郎
  • Organizer: 日本薬学会東海支部 特別講演会
  • Place of Presentation: 愛知
  • Invited
• [Presentation] NMR法を用いた医薬品ナノ懸濁液の構造解明 (2016)
  • Author(s): 東 顕二郎
  • Organizer: 粉体工学会2016年度第１回粉体操作に伴う諸現象に関する勉強会
  • Place of Presentation: 愛知
  • Year and Date: 2016-07-28
  • Invited
• [Presentation] Characterization of the mechanism of drug dissolution enhancement by saccharin addition from phenytoin/Eudragit E PO solid dispersion (2016)
  • Author(s): Higashi, K., Ueda, K., Kanaya, H., Yamamoto, K., Moribe, K.
  • Organizer: 58th Annual International Industrial Pharmaceutical Research and Development Conference
  • Place of Presentation: Madison,USA
  • Year and Date: 2016-06-06
  • Invited
• [Presentation] 初期の薬物結晶形が湿式粉砕したナノ粒子の物性に及ぼす影響 (2016)
  • Author(s): 森部 久仁一, 黒岩 洋佑, 植田 圭祐, 東 顕二郎, 山本 恵司
  • Organizer: 日本薬学会第136年会
  • Place of Presentation: 横浜
  • Year and Date: 2016-03-26
• [Presentation] 医薬品開発に用いられる製剤化技術の現状と展望 (2016)
  • Author(s): 東 顕二郎
  • Organizer: エネルギー環境学域・JAXA宇宙環境利用WG合同講演会
  • Place of Presentation: 茨城
  • Invited
• [Presentation] 固体 NMR法による難水溶性薬物の溶解性を改善する特殊製剤の評価事例 (2015)
  • Author(s): 東 顕二郎
  • Organizer: 前臨床開発フォーカスグループ第1回合宿討論会
  • Place of Presentation: 逗子
  • Year and Date: 2015-12-10
• [Presentation] Aggregation and crystallization behavior of probucol from the ternary spray-dried sample solution evaluated by AFM (2015)
  • Author(s): Moribe, K., Egami, K., Higashi, K., Ueda, K., Yamamoto, K.
  • Organizer: 2015AAPS Annual Meeting and Exposition
  • Place of Presentation: Oralnd USA
  • Year and Date: 2015-10-25
  • Int'l Joint Research
• [Presentation] Indomethacinナノ懸濁液中における薬物結晶形の直接評価 (2015)
  • Author(s): 黒岩 洋佑, 植田 圭祐, 東 顕二郎, 山本 恵司, 森部 久仁一
  • Organizer: 第32回製剤と粒子設計シンポジウム
  • Place of Presentation: 豊橋
  • Year and Date: 2015-10-22
• [Presentation] NMRによる特殊製剤の物性評価 (2015)
  • Author(s): 東 顕二郎
  • Organizer: 日本薬剤学会 経口吸収フォーカスグループ第５回合宿討論会
  • Place of Presentation: 滋賀
  • Year and Date: 2015-10-10
  • Invited
• [Presentation] 懸濁ナノ粒子中のindomethacin結晶形の直接評価 (2015)
  • Author(s): 黒岩 洋佑, 東 顕二郎, 山本 恵司, 森部 久仁一
  • Organizer: 日本薬剤学会第30年会
  • Place of Presentation: 長崎
  • Year and Date: 2015-05-21
• [Book] 難水溶性薬物の経口製剤化技術最前線 (2016)
  • Author(s): 東 顕二郎, 森部 久仁一
  • Total Pages: 14
  • Publisher: シーエムシー出版