Stabilization of Prostaglandin E1in Fatty Alcohol Propylene Glycol Ointment by Acidic Cyclodextrin Derivative, 0-Carboxymethyl-O-ethyl-/J-cycIodextrin

Abstract

To improve the instability of prostaglandin E1(PGEi) in ointments, potential use of 0-carboxymethyl-O-ethyl-/f-cyclodextrin (CME-/?-CyD) was examined, comparing with parent fi-CyD. Inclusion complexation of PGEj in aqueous solution and in solid state was investigated by circular dichroism and carbon-13 nuclear magnetic resonance spectroscopies, kinetic method, powder X-ray diffractometry and thermal analysis. The inclusion ability of CME-/f-CyD against PGEi was much higher than that of/J-Cyl), i.e., stability constants determined by the kinetic method were 880 and 290M-1 for the CME-j5-CyD and/?-CyD complexes, respectively. The chemical instability of PGEt in fatty alcohol propylene glycol (FAPG) ointment and in aqueous solution was significantly improved by the complexation with CME-/?-CyD, while parent/i-CyD accelerated the degradation in neutral and alkaline solutions. The stabilizing effect of CME-/J-CyD seemed to come from 1) the adjustment of microscopic and/or macroscopic pH to about 4 where PGEj was most stable, 2) the low hygroscopicity of CME-jP-CyD preventing access of water molecules to pgejl and 3) the inclusion of the reactive site, where the first effect contributed most significantly to the stabilization. The in vitro release of PGEi from FAPG ointments was enhanced by complexation with CME-/?-CyD, and its superior release characteristics were retained even after aging. The limited data obtained here suggest that CME-CyD is useful for improvements of not only the chemical instability of PGEt in ointments as well as in solution, but also the release rate from the ointment. © 1992, The Pharmaceutical Society of Japan. All rights reserved.