Amorphous spironolactone-hydroxypropylated cyclodextrin complexes with superior dissolution and oral bioavailability

Abstract

Inclusion complex formations of spironolactone (SP) with four cyclodextrins (parent β- and γ-CyDs and hydroxypropylated β- and γ-CyDs) in aqueous solution and in the solid state were investigated by the solubility method, spectroscopic methods, thermal analysis, powder X-ray diffractometry, and cross polarization/magic angle spinning 13C-nuclear magnetic resonance spectroscopy. Although the stability constant of the parent CyD complexes was larger than that of the corresponding hydroxypropylated CyD complexes, the solubilizing effect of hydroxypropyl CyDs was greater than that of parent CyDs. The solid complexes of SP were prepared by the spray-drying method in molar ratios of 1:2 and 2:3 (guest/host) with β-CyDs and γ-CyDs, respectively. The CyD complexes maintained an amorphous state for lengthy time periods (over 2 months at 75% relative humidity and 60°C), with the exception of the β-CyD complex which was converted to a crystalline complex after 1 month storage. The dissolution rate of hydroxypropyl CyD complexes was much faster than that of the parent CyD complexes, the rate being in the order of hydroxypropyl-β-CyD ⪢ hydroxypropyl-γ-CyD > γ-CyD > β-CyD > metastable SP forms > stable SP form. Plasma levels of canrenone, a major effective metabolite of SP, were monitored to estimate the absorption-enhancing effect of hydroxypropyl CyDs. The area under the plasma concentration-time curve after oral administration of the hydroxypropyl-β-CyD complex in dogs was 3.6 times that of SP alone, and this enhancement was higher than those of the parent CyD complexes reported previously (Seo, H., Tsuruoka, M., Hashimoto, T., Fujinaga, T., Otagiri, M. and Uekama, K., Enhancement of oral bioavailability of spironolactone by β- and γ-cyclodextrin complexations. Chem. Pharm. Bull., 31 (1983) 286–291).