Optimization of Nanostructured Lipid Carrier Using Central Composite Design for Ocular Delivery of Pirfenidone

Purpose: Pirfenidone (PFD) possesses significant anti-inflammatory and anti-fibrotic properties, making it a promising therapeutic agent for ocular fibrotic conditions. However, its clinical application is limited due to a short half-life (< 19 minutes) in corneal tissue and poor ocular bioavailability. This study aimed to develop and characterize a nanostructured lipid carrier (NLC) based in situ gel formulation for enhancing the ocular delivery and therapeutic efficacy of PFD. Methods: NLCs were prepared via hot melt emulsification followed by probe sonication and incorporated into a gellan gum-based in situ gel system. A central composite design was used for formulation optimization. The optimized NLC formulation included Compritol® 888 ATO (1.64%), Capmul® MCM (0.32%), Poloxamer 188 (0.5%), and Tween 80 (0.5%). The formulation was characterized for particle size, polydispersity index (PDI), zeta potential, entrapment efficiency, in vitro drug release, ex vivo permeation, cytotoxicity, bioadhesion, and biocompatibility using HET-CAM assay. Stability studies were also conducted. Results: The optimized PFD-loaded NLCs showed a particle size of 90.15 ± 10.2 nm, PDI of 0.155 ± 0.014, zeta potential of -11.4 ± 1.2 mV, and entrapment efficiency of 90.43 ± 2.14%. In vitro release studies demonstrated sustained drug release (84.39 ± 3.41% over 12 hours). Ex vivo corneal and scleral permeation were 82.97 ± 3.01% and 77.01 ± 1.98%, respectively. Biocompatibility, cytotoxicity, and stability assessments confirmed the safety and robustness of the formulation. Conclusion: The developed NLC-based in situ gel offers a promising strategy for enhancing the ocular bioavailability and therapeutic potential of PFD, potentially overcoming the limitations of conventional topical administration.