Preparation and Characterization of a Low-Molecular-Weight Chitosan Nanoparticle-Based Ocular Formulation for Enhanced Permeation of Timolol Maleate.
TL;DR
The TM-based nanoparticle formulation enhanced corneal permeation and sustained TM release, offering a promising approach to improve ocular bioavailability and therapeutic efficacy.
Abstract
INTRODUCTION/
Objective
Timolol Maleate (TM) is primarily used to treat glaucoma by reducing intraocular pressure. However, its efficacy is limited by poor ocular bioavailability (<5%) and systemic side effects. This study aimed to develop and evaluate Low-Molecular-Weight Chitosan (LMWC)-based complexes in an eye formulation to sustain TM release and enhance its corneal permeability.
Methods
TM-LMWC Polyelectrolyte Complexes (PECs) were prepared by ionic interactions between TM and LMWC and characterized for particle size, polydispersity, surface charge, and physicochemical properties. TM Liquid Medicated Nanoparticle Formulations (LMFs) were prepared by the solvent diffusion method, and their dissolution behaviors, release kinetics in simulated tear fluid, and ex vivo permeation through sheep corneas were evaluated.
Results
The prepared TM nanoparticles showed a uniform particle size (185-258 nm) and a positive zeta potential exceeding +26 mV, with encapsulation efficiency ranging from 28 to 35%. The formation of a polycationic complex was confirmed by the thermal and structural analyses. The LMFs showed a reduced particle size (65-130 nm). Moreover, the TEM image of LMF 4 revealed a spherical nanoparticle with a smooth surface. Sustained drug release was observed over 24 hours and best fitted to the Korsmeyer-Peppas model, indicating a Fickian diffusion (n < 0.45). Ex vivo studies showed LMF1 increased flux (2.54 ± 0.04 μg cm-2 h-1) and permeation coefficient (0.00987 cm·h⁻¹), representing a 2.62-fold increase in TM permeation.
Discussion
Chitosan molecular weight influenced PEC particle size due to differences in polymer chain length and viscosity. A sustained release of TM from LMFs was observed as TM was entrapped within the chitosan matrix and had to diffuse through the polymer or be released by matrix erosion. The enhanced corneal permeability was attributed to the mucoadhesive properties of the nanoparticles and their interaction with the corneal epithelium.
Conclusion
The TM-based nanoparticle formulation enhanced corneal permeation and sustained TM release, offering a promising approach to improve ocular bioavailability and therapeutic efficacy.