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Development of drug amorphous/nanocrystal hybrid formulation based on the molecular-level evaluation by solid-state NMR

Research Project

Project/Area Number 16K18859
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field Physical pharmacy
Research InstitutionChiba University

Principal Investigator

Ueda Keisuke  千葉大学, 大学院薬学研究院, 助教 (40755972)

Research Collaborator Moribe Kunikazu  
Higashi Kenjirou  
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywords混合粉砕 / 非晶質 / ナノ結晶 / 固体NMR / 緩和時間測定 / 難水溶性薬物 / ナノ粒子 / 製剤 / 薬物ナノ結晶
Outline of Final Research Achievements

The co-grinding of nifedipine (NIF) with polymers, including hydroxypropyl methylcellulose (HPMC) and polyvinylpyrrolidone (PVP), and sodium dodecyl sulfate (SDS) was performed to prepare the NIF nanoparticle formulations. Solid-state NMR measurements revealed that the crystal size of NIF was reduced to several tens of nm with amorphization of NIF by co-grinding with HPMC and SDS for 100 min. Similarly, the size of the NIF crystal was reduced to less than 90 nm in the 40-min ground mixture of NIF/PVP/SDS. Furthermore, 100-min grinding of NIF/PVP/SDS induced amorphization of almost all the NIF crystals followed by nano-sizing. Excess amorphization of the NIF crystals failed to efficiently prepare the NIF nanoparticles. In contrast, the efficient nano-sizing of the NIF crystal in the solid state, revealed by the solid-state NMR relaxation time measurements, enabled the formation of large amounts of NIF nanoparticles in water followed by the polymer dissolution.

Academic Significance and Societal Importance of the Research Achievements

分子レベルでの物性評価に基づく製剤設計により、非晶質化及びナノ結晶化の利点を最大限に引き出した製剤開発が可能となり、これまでトライ&エラーであった薬物の非晶質化及びナノ結晶化を利用した超難水溶性薬物の特殊製剤設計に新たな指針を示すことが出来る。さらには、本新規製剤開発により、従来の固体分散体製剤及びナノ結晶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吸収製剤開発の効率化が期待される。現在も技術革新によりNMRの感度は向上しており、将来本研究が指針となり、各種固体NMR応用測定を用いた製剤中の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。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (26 results)

All 2019 2018 2017 2016

All Journal Article (7 results) (of which Peer Reviewed: 7 results) Presentation (17 results) (of which Int'l Joint Research: 3 results,  Invited: 1 results) Book (2 results)

  • [Journal Article] Mechanistic elucidation of formation of drug-rich amorphous nanodroplets by dissolution of the solid dispersion formulation2019

    • Author(s)
      Ueda Keisuke、Higashi Kenjirou、Moribe Kunikazu
    • Journal Title

      International Journal of Pharmaceutics

      Volume: 561 Pages: 82-92

    • DOI

      10.1016/j.ijpharm.2019.02.034

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Effect of molecular weight of hypromellose on mucin diffusion and oral absorption behavior of fenofibrate nanocrystal2019

    • Author(s)
      Ueda Keisuke、Iwai Takaaki、Sunazuka Yushi、Chen Ziqiao、Kato Nao、Higashi Kenjirou、Moribe Kunikazu
    • Journal Title

      International Journal of Pharmaceutics

      Volume: 564 Pages: 39-47

    • DOI

      10.1016/j.ijpharm.2019.04.033

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Combined effects of the drug distribution and mucus diffusion properties of self-microemulsifying drug delivery systems on the oral absorption of fenofibrate2018

    • Author(s)
      Sunazuka Yushi、Ueda Keisuke、Higashi Kenjirou、Tanaka Yusuke、Moribe Kunikazu
    • Journal Title

      International Journal of Pharmaceutics

      Volume: 546 Issue: 1-2 Pages: 263-271

    • DOI

      10.1016/j.ijpharm.2018.05.031

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Mechanism of Enhanced Nifedipine Dissolution by Polymer-Blended Solid Dispersion through Molecular-Level Characterization2018

    • Author(s)
      Ueda Keisuke、Yamazoe Chisato、Yasuda Yuki、Higashi Kenjirou、Kawakami Kohsaku、Moribe Kunikazu
    • Journal Title

      Molecular Pharmaceutics

      Volume: 15 Issue: 9 Pages: 4099-4109

    • DOI

      10.1021/acs.molpharmaceut.8b00523

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Molecular-level elucidation of saccharin-assisted rapid dissolution and high supersaturation level of drug from Eudragit E solid dispersion2018

    • Author(s)
      Ueda Keisuke、Kanaya Harunobu、Higashi Kenjirou、Yamamoto Keiji、Moribe Kunikazu
    • Journal Title

      Int. J. Pharm.

      Volume: 538 Issue: 1-2 Pages: 57-64

    • DOI

      10.1016/j.ijpharm.2017.12.050

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Synergetic Role of Hypromellose and Methacrylic Acid Copolymer in the Dissolution Improvement of Amorphous Solid Dispersions2017

    • Author(s)
      Ohyagi N., Ueda K., Higashi K., Yamamoto K., Kawakami K., Moribe K.
    • Journal Title

      J. Pharm. Sci.

      Volume: 106 Issue: 4 Pages: 1042-1050

    • DOI

      10.1016/j.xphs.2016.12.005

    • Related Report
      2016 Research-status Report
    • Peer Reviewed
  • [Journal Article] Application of Solid-State NMR Relaxometry for Characterization and Formulation Optimization of Grinding-Induced Drug Nanoparticle2016

    • Author(s)
      Ueda K., Higashi K., Moribe K.
    • Journal Title

      Mol. Pharm.

      Volume: 13 Issue: 3 Pages: 852-862

    • DOI

      10.1021/acs.molpharmaceut.5b00781

    • Related Report
      2016 Research-status Report
    • Peer Reviewed
  • [Presentation] Quercetin配糖体による薬物濃縮相の安定化メカニズム解明2019

    • Author(s)
      髙橋 寿実, 植田 圭祐, 東 顕二郎, 森部 久仁一
    • Organizer
      第139年会日本薬学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Hypromellose/Eudragit S 100含有3成分固体分散体を用いたnifedipine溶出改善及びそのメカニズム解明2018

    • Author(s)
      植田 圭祐、山添 千里、東 顕二郎、川上 亘作、森部 久仁一
    • Organizer
      第33年会日本薬剤学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] SMEDDS製剤の物性がfenofibrate経口吸収性に及ぼす影響2018

    • Author(s)
      砂塚 祐志、植田 圭祐、東 顕二郎、森部 久仁一
    • Organizer
      第33年会日本薬剤学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 薬物-ポリマー分子間相互作用がカルバマゼピン非晶質固体分散体の物理的安定性に及ぼす影響2018

    • Author(s)
      石塚 優也、植田 圭祐、武田 順平、辛島 正俊、東 顕二郎、池田 幸弘、森部 久仁一
    • Organizer
      第33年会日本薬剤学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 難水溶性薬物の経口吸収改善を目的とした薬物濃縮相形成型固体分散体製剤の設計2018

    • Author(s)
      植田 圭祐
    • Organizer
      日本薬剤学会経口吸収フォーカスグループ 第 8 回合宿討論会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 加熱混練過程における薬物ナノ結晶形成メカニズムの解明2017

    • Author(s)
      植田 圭祐, 尾曲 克彦, 東 顕二郎, 井上 元基, 深水 啓朗, 森部 久仁一
    • Organizer
      日本薬剤学会第32年会
    • Related Report
      2017 Research-status Report
  • [Presentation] Nifedipine/Hypromellose/Eudragit S100三成分固体分散体の調製による薬物溶出性改善メカニズムの解明2017

    • Author(s)
      山添 千里, 植田 圭祐, 東 顕二郎, 森部 久仁一
    • Organizer
      第34回製剤と粒子設計シンポジウム
    • Related Report
      2017 Research-status Report
  • [Presentation] HPMCの分子量が薬物ナノ結晶製剤の経口吸収性に及ぼす影響2017

    • Author(s)
      岩井 隆暁, 植田 圭祐, 東 顕二郎, 森部 久仁一
    • Organizer
      新製剤技術とエンジニアリングを考える会第15回技術講演会
    • Related Report
      2017 Research-status Report
  • [Presentation] 難水溶性薬物の溶出性向上を目的としたポリマーブレンドの応用2017

    • Author(s)
      植田 圭祐, 大八木 直子, 東 顕二郎, 森部 久仁一
    • Organizer
      第33回日本DDS学会学術集会
    • Related Report
      2017 Research-status Report
  • [Presentation] 加熱溶融混錬により調製したnifedipine/HPMC-AS固体分散体の溶出性評価2017

    • Author(s)
      山添 千里, 植田 圭祐, 東 顕二郎, 川上 亘作, 森部 久仁一
    • Organizer
      日本薬剤学会第32年会
    • Related Report
      2017 Research-status Report
  • [Presentation] 薬物過飽和溶解量の限界値2016

    • Author(s)
      植田 圭祐
    • Organizer
      日本薬剤学会 第7 回経口吸収フォーカスグループ合宿討論会
    • Place of Presentation
      KKRホテル熊本(熊本県熊本市)
    • Year and Date
      2016-12-15
    • Related Report
      2016 Research-status Report
  • [Presentation] Characterization and formulation optimization of grinding-induced drug nanoparticle using solid-state NMR relaxometry2016

    • Author(s)
      Ueda K., Higashi K., Moribe K.
    • Organizer
      2016 AAPS Annual Meeting and Exposition
    • Place of Presentation
      Denver, CO (USA)
    • Year and Date
      2016-11-13
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] 固体NMRによる混合粉砕過程における薬物ナノ結晶及び非晶質形成評価2016

    • Author(s)
      植田 圭祐,東 顕二郎,森部 久仁一
    • Organizer
      第33回製剤と粒子設計シンポジウム
    • Place of Presentation
      ホテルメトロポリタン長野(長野県長野市)
    • Year and Date
      2016-10-27
    • Related Report
      2016 Research-status Report
  • [Presentation] Drug Supersaturation to Improve Oral Absorption of Poorly Water-Soluble Drugs2016

    • Author(s)
      Ueda K.
    • Organizer
      The 1st Workshop for Japan-Korea Young Scientists on Pharmaceutics
    • Place of Presentation
      京都教育文化センター(京都府京都市)
    • Year and Date
      2016-06-24
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] 固体NMRのよる混合粉砕物中の薬物ナノ結晶サイズ評価2016

    • Author(s)
      植田 圭祐,東 顕二郎,森部 久仁一
    • Organizer
      日本薬剤学会第31年会
    • Place of Presentation
      長良川国際会議場(岐阜県岐阜市)
    • Year and Date
      2016-05-19
    • Related Report
      2016 Research-status Report
  • [Presentation] Mechanistic study of drug crystallization inhibition by HPMC-AS using solution-state NMR measurements2016

    • Author(s)
      Ueda K., Higashi K., Moribe K.
    • Organizer
      51st AAPS Arden Conference: Contemporary Perspectives on Developing Amorphous Pharmaceuticals
    • Place of Presentation
      Baltimore, MD (USA)
    • Year and Date
      2016-04-18
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] 難溶解性薬物の吸収改善の現状と分子レベルでの考察2016

    • Author(s)
      植田 圭祐
    • Organizer
      創剤研究コンソーシアム2016年度第1回研究会
    • Place of Presentation
      立命館大学東京キャンパス(東京都千代田区)
    • Related Report
      2016 Research-status Report
    • Invited
  • [Book] 最新の薬剤学知見と世界の開発状況をふまえた 前臨床/臨床医薬品開発の展望と戦略2018

    • Author(s)
      植田 圭祐 他 (日本薬剤学会 前臨床開発フォーカスグループ・経口吸収フォーカスグループ)
    • Total Pages
      208
    • Publisher
      じほう
    • ISBN
      9784840750875
    • Related Report
      2018 Annual Research Report
  • [Book] 難水溶性薬物の経口製剤化技術最前線(固体分散体の過飽和溶解)2016

    • Author(s)
      植田 圭祐,森部 久仁一
    • Total Pages
      250
    • Publisher
      シーエムシー出版
    • Related Report
      2016 Research-status Report

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Published: 2016-04-21   Modified: 2020-03-30  

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