Formation of the Ternary Inclusion Complex of Limaprost with α- and β-Cyclodextrins in Aqueous Solution

Abstract

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 13 C chemical shifts of prostaglandin F 2α (PGF 2α ) 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) 1 H-NMR spectra, intermolecular correlation peaks were observed between protons of PGF 2α and protons of both α-and β-CDs, suggesting that PGF 2α 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-Δ 2 -PGA 1 (11-deoxy-Δ 10 ) and 17S,20-dimethyl-trans-Δ 2 -8-iso-PGE 1 (8-iso). The addition of α-CD promoted the dehydration to 11-deoxy-Δ 10 , 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.Key words Limaprost alfadex; α-cyclodextrin; β-cyclodextrin; ternary inclusion complex; NMR spectroscopy; kinetics α-, β-and γ-Cyclodextrins (CDs) are cyclic oligosaccharides in which six, seven and eight D-glucose units, respectively, are linked by α-1,4 glycosidic bonds.

Ternary inclusion complex formation and stabilization of limaprost, a prostaglandin E 1 derivative, in the presence of α- and β-cyclodextrins in the solid state

“…The peak at 16.7 ppm was higher than that at 19.2 ppm in the a-CD complex and the peak at 213 ppm was higher than that of 215 ppm in the b-CD complex, which may be due to the partial crystallization of limaprost in the CD complexes by heat during the NMR measurement. These inclusion modes of the a-CD and b-CD complexes were consistent with those in aqueous solution, reported previously (Inoue et al, 2015). In the a-/b-CD complex, both peaks of the alkyl and five-membered ring carbons changed significantly: the 16.7 ppm peak shifted to 19.2 ppm, accompanied by a small broadened peak at 16.7 ppm, and the 213 ppm peak shifted to 215 ppm concomitant with marked broadening.…”

“…5B and D). The initial amount (about 1%) of 11-deoxy-D 10 in the complex was produced during the freeze-drying process, because the dehydration of limaprost in aqueous solution was accelerated by the addition of b-CD, and the accelerating effect of a-/b-CD was larger than that of b-CD alone, as reported previously (Inoue et al, 2015). The stabilization of limaprost by the combination of a-/b-CD is due to the formation of the stable amorphous complex, which prevents the dissociation of the complex, the crystallization of b-CD, and the liberation of free limaprost (Fig.…”

“…Due to the presence of dextran in the composite, the stabilization mechanism has not been elucidated in detail. However, based on 1 H-and 13 C NMR spectroscopy and kinetics of degradation, we demonstrated that limaprost and a-and b-CDs form a ternary inclusion complex in aqueous solution (Inoue et al, 2015). Therefore, we investigated the degradation profile and interaction of limaprost with the two CDs in a simpler, two-or three-component system, i.e., the drug/CD or drug/a-CD/b-CD system without dextran.…”

Potential Use of Cyclodextrins as Drug Carriers and Active Pharmaceutical Ingredients

“…25) The stabilization of limaprost by both α-and β-CyDs could be ascribed to a formation of a ternary inclusion complex 26) (Fig. 1).…”

“…Namely, the interaction between limaprost and the two CyDs was protected by inclusion of different moieties of limaprost: α-CyD predominantly included the alkyl ω-chain, whereas β-CyD included the fivemembered ring. 26) Henceforth, it is expected that use of ternary complexes of drugs with two types of CyDs will present a new trends in stabilizing and solubilizing methods.…”