Delivery of Fenofibrate to Ocular Tissues using 2-Hydroxypropyl-β-cyclodextrin-Based Micelles

Abstract

Age-related macular degeneration and diabetic retinopathy are the main diseases that cause vision impairment. The standard treatment for this condition is the intravitreal injection of anti-vascular endothelial growth factor agents, which cause several side effects to the eye after injection. Topical administration would be a more effective method, but the ocular layers act as barriers to drug diffusion. In this research, we presented the preparation and characterization of poly(pseudo)rotaxanes (PPRs) containing 2-hydroxypropyl-β-cyclodextrin (2-HPβCD), Pluronic® F127 (PF127) and Soluplus® to enhance the solubility of fenofibrate (FEB), a poorly water-soluble drug, for potential application in ocular drug delivery. The FEB-loaded micelles and PPRs were investigated using DLS, 1H NMR and XRD techniques, which demonstrated that FEB could be encapsulated into both micelles and PPRs with small particle sizes (7–67 nm). The inclusion complex between FEB and 2-HPβCD was observed, as evidenced by a high stability constant (K1:1) and the shift in proton positions (1H NMR) within the hydrophobic cavity of 2-HPβCD in the FEB-loaded PPR formulations. Moreover, 1H NMR demonstrated structural modifications involving the PF127/ Soluplus® copolymers and proton shifts at the exterior wall of 2-HPβCD in the FEB-loaded PPR formulations, supporting the interactions between the copolymers and 2-HPβCD. The XRD pattern of free FEB compound, indicating its crystalline structure, whereas the drug-loaded PPRs (PF127/Soluplus®/2-HPβCD) showed an amorphous phase with a single broadband without a sharp diffraction peak, suggesting the transformation of the FEB drug from the crystalline to the amorphous state. Subsequently, the solubility enhancement of FEB in the prepared formulations was evaluated and found that the addition of 2-HPβCD to the mixed PF127/Soluplus® micelles had a 910-fold increase in FEB solubility compared to the intrinsic solubility of the FEB (0.34 ± 0.0011 μg/mL), indicating a synergistic effect of 2-HPβCD in drug solubility enhancement. Ex vivo permeation across porcine eyes revealed that FEB-loaded PPRs helped FEB to cross the scleral tissue with FEB permeation levels varying from 0.27 to 4.25 μg/cm2. Mathematical modelling based on Fick's law was employed to explain the transportation of FEB-loaded micelles or PPRs across the scleral tissue and to calculate effective diffusivity (Deff). Thus, this study highlights the potential application of PPRs as an effective drug delivery system for eye disease treatments and the importance of mathematical modelling in understanding drug permeation mechanisms.