Stabilizing Effect of β-Cyclodextrin on Limaprost, a PGE1 Derivative, in Limaprost Alfadex Tablets (Opalmon(R)) in Highly Humid Conditions

• Published in: Chemical and Pharmaceutical Bulletin Vol. 62; no. 8; pp. 786 - 792
• Main Authors: Yasuo Inouea, Noboru Sekiyaa, Kazunori Katayamaa, Shoji Narutakia, Masanobu Yamamotoa, Daisuke Ioharab, Fumitoshi Hirayamab, Kaneto Uekamac
• Format: Journal Article
• Language: Japanese
• Published: Pharmaceutical Society of Japan 01-08-2014
• ISSN: 0009-2363

Stabilization against humidity of Limaprost (a prostaglandin E1 derivative), which is currently marketed as Opalmon(R), 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℃, 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 2H-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.