Dual Asymmetric Centrifugation Efficiently Produces a Poloxamer-Based Nanoemulsion Gel for Topical Delivery of Pirfenidone
Eugene P. Chung, Adrienne R. Wells, Mia Mae Kiamco, Kai P. Leung
Abstract
Abstract This study used dual asymmetric centrifugation (DAC) to produce a topical vehicle for Pirfenidone (Pf; 5-methyl-1-phenyl-2[1H]-pyridone)—a Food and Drug Administration-approved antifibrotic drug indicated for idiopathic fibrosis treatment. Pf was loaded (8 wt%) in a poloxamer nanoemulsion gel (PNG) formulation consisting of water (47.8 wt%), triacetin (27.6 wt%), poloxamer 407 (P407, 13.8 wt%), polysorbate 80 (1.8 wt%), and benzyl alcohol (0.9 wt%). To our knowledge, poloxamer gels are typically processed with either high-shear methods or temperature regulation and have not been emulsified using DAC. Using a single-step emulsification process, 2 min mixed at 2500 RPM resulted in the lowest Pf loading variability with a relative standard deviation (RSD) of 0.96% for a 1.5 g batch size. Batch sizes of 15 g and 100 g yield higher RSD of 4.18% and 3.05%, respectively, but still in compliance with USP guidelines. Ex vivo permeation in full thickness porcine skin after 24 h showed total Pf permeation of 404.90 ± 67.07 μg/cm 2 . Tested in vitro on human dermal fibroblasts stimulated with transforming growth factor-beta 1 (TGF-β1), Pf-PNG resulted in a > 2 fold decrease in α-SMA expression over vehicle control demonstrating that formulated Pf retained its biological activity. One-month stability testing at 25°C/60% relative humidity (RH) and 40°C/75% RH showed that % drug content, release kinetics, and biological activity were largely unchanged for both conditions; however, pH decreased from 6.7 to 5.5 (25°C/60% RH) and 4.5 (40°C/75% RH) after 1 month. Overall, these data demonstrate the utility of DAC to rapidly and reproducibly prepare lab-scale batches of emulsified gels for pharmaceutical formulation development.