title: Stabilizing effect of β-cyclodextrin on Limaprost, a PGE₁ derivative, in Limaprost alfadex tablets (Opalmon) in highly humid conditions.
abstract: Stabilization against humidity of Limaprost (a prostaglandin E₁ derivative), which is currently marketed as Opalmon, was undertaken using β-cyclodextrin (β-CD). Aqueous solutions of Limaprost alfadex/dextran 40 were lyophilized with and without β-CD. Limaprost alfadex lyophilized with β-CD was more chemically stable in humid conditions than that without β-CD. Moreover, the addition of β-CD as an excipient to tablets of these lyophilized composites remarkably improved the stability of Limaprost, and Limaprost in this moisture-resistant formulation was chemically stable for 19 weeks at 30°C, 75% relative humidity (R.H.). Chemical analysis of Limaprost and its degradation products indicated that degradation proceeded in the inclusion form (i.e., within the CD cavity). Solid (2)H-NMR spectroscopic studies showed that β-CD constrained the molecular mobility of water in the solid state. These results suggested that the stabilization of Limaprost by β-CD was at least partly due to the restricted molecular mobility of water, which acted as a catalytic species for the degradation, and also to the protection of the five-membered ring of Limaprost from water catalytic dehydration through inclusion complex formation with β-CD.
authors.affiliation: Pharmaceutical Development Laboratories, Ono Pharmaceutical Co., Ltd.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Inoue
authors.forename: Noboru
authors.initials: N
authors.lastname: Sekiya
authors.forename: Kazunori
authors.initials: K
authors.lastname: Katayama
authors.forename: Shoji
authors.initials: S
authors.lastname: Narutaki
authors.forename: Masanobu
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Daisuke
authors.initials: D
authors.lastname: Iohara
authors.forename: Fumitoshi
authors.initials: F
authors.lastname: Hirayama
authors.forename: Kaneto
authors.initials: K
authors.lastname: Uekama
mesh_terms: D000527:Alprostadil / Q000031:analogs & derivatives* / Q000737:chemistry; D003911:Dextrans / Q000737:chemistry; D004355:Drug Stability; D005079:Excipients / Q000737:chemistry*; D005612:Freeze Drying; D006813:Humidity; D013607:Tablets; D047391:alpha-Cyclodextrins / Q000737:chemistry*; D047392:beta-Cyclodextrins / Q000737:chemistry*
chemical_list: D003911:Dextrans; D005079:Excipients; D013607:Tablets; D047391:alpha-Cyclodextrins; D047392:beta-Cyclodextrins; C525749:limaprost-alfadex; D000527:Alprostadil; C031215:betadex; C059238:limaprost