Stabilizing and solubilizing effects of sulfobutyl ether β-cyclodextrin on prostaglandin E1 analogue.

Uekama K, Hieda Y, Hirayama F, Arima H, Sudoh M, Yagi A, Terashima H.

Faculty of Pharmaceutical Sciences, Kumamoto University, Japan. uekama@gpo.kumamoto-u.ac.jp

Abstract

PURPOSE: Parent cyclodextrins are known to accelerate the degradations such as dehydration and isomerization of E-type prostaglandins in neutral and alkaline solutions. The objective of this study was to attempt the stabilization and solubilization of E1-type prostaglandin analogue in aqueous solution by biocompatible cyclodextrin derivatives. METHODS: The interaction of an E1-type prostaglandin, methyl 7-[(1R,2R,3R)-3-hydroxy-2-[(E)-(3S)-3-hydroxy-4-(m-methoxymethylphenyl)1-butenyl]-5-oxocyclopentyl]-5-thiaheptanoate (MEester) with cyclodextrins (CyDs) was studied by spectroscopies and the solubility method. The degradation of MEester was monitored by high-performance liquid chromatography. RESULTS: 1H-nuclear magnetic resonance spectroscopic studies indicated that MEester forms 1:1 inclusion complexes with β-, β-, and γ-CyDs in solutions, where β-CyD interacts with the a-side chain containing methyl ester moiety of the drug, whereas β- and γ-CyDs preferentially include around the five-membered ring and both side chains of the drug. Parent β-CyD and hydrophilic derivatives, such as 2-hydoxypropyl-β- and -β-CyDs, sulfobutyl ether β-CyD (SBE-β-CyD) and maltosyl β-CyD showed higher solubilizing abilities against MEester over parent β- and γ-CyDs. SBE-β-CyD and 2,6-dimethyl-β-CyD (DM-β-CyD) significantly decelerated the degradation of MEester, particularly the base-catalyzed dehydration, in neutral and alkaline solutions, whereas other CyDs accelerated the degradation. The acid-catalyzed degradation of MEester (pH < 3) was decelerated by the addition of CyDs, especially β-CyD. CONCLUSIONS: SBE-β-CyD with low hemolytic activity and low toxicity is useful as a pharmaceutical carrier for the preparation of injectable MEester, because of its higher stabilizing and solubilizing effects on MEester. Furthermore, SBE-β-CyD can be useful as a stabilizing agent for drugs, that are subject to base-catalyzed degradations, probably because of the electric repulsion between anionic charges of the sulfobutylmoiety and catalytic anionic species such as hydroxide ion.