Formation of the Ternary Inclusion Complex of Limaprost with α- and β-Cyclodextrins in Aqueous Solution
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- Inoue Yasuo
- CMC Regulatory and Analytical R&D, Ono Pharmaceutical Co., Ltd.
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- Sekiya Noboru
- Pharmaceutical R&D, Ono Pharmaceutical Co., Ltd.
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- Yamamoto Masanobu
- Pharmaceutical R&D, Ono Pharmaceutical Co., Ltd.
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- Iohara Daisuke
- Faculty of Pharmaceutical Sciences, Sojo University
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- Hirayama Fumitoshi
- Faculty of Pharmaceutical Sciences, Sojo University
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- Uekama Kaneto
- DDS Research Institute, Sojo University
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The inclusion mode of Limaprost in the presence of α- and β-cyclodextrins (CDs) was investigated to gain insight into the stabilization mechanism of Limaprost-alfadex upon the addition of β-CD in the solid state. The inclusion sites of α- and β-CDs were studied by NMR spectroscopic and kinetic methods. With the addition of α- and β-CDs, displacements in 13C chemical shifts of prostaglandin F2α (PGF2α) were observed in the ω-chain and the five-membered ring, respectively, of the drug. Similar shift changes were observed with the addition of both α- and β-CDs. In two-dimensional (2D) 1H-NMR spectra, intermolecular correlation peaks were observed between protons of PGF2α and protons of both α- and β-CDs, suggesting that PGF2α interacts with α- and β-CDs to form a ternary complex by including the ω-chain with the former CD and the five-membered ring with the latter. In kinetic studies in aqueous solution, Limaprost was degraded to 17S,20-dimethyl-trans-Δ2-PGA1 (11-deoxy-Δ10) and 17S,20-dimethyl-trans-Δ2-8-iso-PGE1 (8-iso). The addition of α-CD promoted the dehydration to 11-deoxy-Δ10, while β-CD promoted the isomerization to 8-iso, under these conditions. In the presence of both α- and β-CDs, dehydration and isomerization were also accelerated, supporting the formation of the ternary Limaprost/α-CD/β-CD complex.
収録刊行物
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- CHEMICAL & PHARMACEUTICAL BULLETIN
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CHEMICAL & PHARMACEUTICAL BULLETIN 63 (5), 318-325, 2015
公益社団法人 日本薬学会
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詳細情報 詳細情報について
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- CRID
- 1390282679153269632
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- NII論文ID
- 130005067244
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- NII書誌ID
- AA00602100
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- ISSN
- 13475223
- 00092363
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- NDL書誌ID
- 026355160
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- PubMed
- 25948325
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- 本文言語コード
- en
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- データソース種別
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- JaLC
- NDL
- Crossref
- PubMed
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- 使用不可