Chitosan grafted methoxy poly(ethylene glycol)-poly(ε-caprolactone) nanosuspension for ocular delivery of hydrophobic diclofenac

Abstract

This study aimed to develop a cationic nanosuspension of chitosan (CS) and methoxy poly(ethylene glycol)-poly(Îμ -caprolactone) (MPEG-PCL) for ocular delivery of diclofenac (DIC). MPEG-PCL-CS block polymer was synthesized by covalent coupling of MPEG-PCL with CS. The critical micelle concentration of the MPEG-PCL-CS block polymer was 0.000692â €‰g/L. DIC/MPEG-PCL-CS nanosuspension (mean particle sizeâ €‰=â €‰105â €‰nm, zeta potentialâ €‰=â €‰8â €‰mV) was prepared and characterized by Fourier transform infrared spectroscopy, X-ray diffraction, and differential scanning calorimetry. The nanosuspension was very stable without apparent physical property changes after storage at 4â €‰°C or 25â €‰°C for 20 days, but it was unstable in the aqueous humor solution after 24â €‰h incubation. Sustained release of the encapsulated DIC from the nanosuspension occurred over 8â €‰h. Neither a blank MPEG-PCL-CS nanosuspension nor a 0.1% (mass fraction) DIC/MPEG-PCL-CS nanosuspension caused ocular irritation after 24â €‰h of instillation. Enhanced penetration and retention in corneal tissue was achieved with a Nile red/MPEG-PCL-CS nanosuspension compared with a Nile red aqueous solution. In vivo pharmacokinetics studies showed enhanced pre-corneal retention and penetration of the DIC/MPEG-PCL-CS nanosuspension, which resulted in a higher concentration of DIC (C max) in the aqueous humor and better bioavailability compared with commercial DIC eye drops (Pâ €‰