Improving the solubility of vorinostat using cyclodextrin inclusion complexes: The physicochemical characteristics, corneal permeability and ocular pharmacokinetics of the drug after topical application

Abstract

Vorinostat (suberoylanilide hydroxamic acid, SAHA), an FDA-approved drug for cutaneous T cell lymphoma, has antiangiogenic and anti-inflammatory activity and thus has therapeutic potential for inflammatory corneal neovascularization (CNV). However, its practical administration is limited due to its poor aqueous solubility and permeability. This study aimed to enhance the corneal permeability of SAHA by promoting its inclusion into a complex with hydroxypropyl-β-CD (HPβCD) for topical application. In phase-solubility studies, the solubility of SAHA with HPβCD and sulfobutyl ether-β-CD (SEβCD) was assessed at different temperatures, and complexation efficiencies (K) were calculated. The inclusion complexes (ICs) were prepared and characterized by differential scanning calorimetry (DSC), infrared spectrometry (IR), scanning electron microscopy (SEM), and X-ray diffraction (XRD) after freeze-drying. The phase-solubility study showed that the complexation efficiencies of SAHA were higher in HPβCD solutions (297.35 M^-1, 115.28 M^-1 and 122.75 M^-1) than in SEβCD solutions (169.75 M^-1, 91.33 M^-1 and 96.49 M^-1) at 4 °C, 25 °C and 37 °C. HPβCD was selected for SAHA-IC preparation, and characterization revealed IC formation. SAHA existed in an amorphous state in the ICs. The ex vivo corneal permeability of SAHA was also evaluated and found to be greater when formulated as an HPβCD solution than as a suspension. Irritation assays in rabbit eyes showed that the SAHA-IC solution was not irritating after topical application. The ocular pharmacokinetics of SAHA in New Zealand White rabbits were assessed following topical administration (0.2%), and a 0.2% SAHA suspension was used as the control. Compared to its formulation as a suspension, the formulation of SAHA as an HPβCD solution increased its corneal bioavailability by more than 3-fold and its conjunctival bioavailability by more than 2-fold. Thus, IC formation was effective at improving the ocular bioavailability of SAHA. This study provides an important alternative approach for developing liquid pharmaceutical formulations of SAHA for topical ocular applications.

Keywords: Corneal neovascularization; Corneal permeation; Hydroxypropyl-β-CD; Ocular pharmacokinetics; Vorinostat.