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/cm2. 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.
Highlights
Dual asymmetric centrifugation (DAC) is a bladeless mixing process that is efficient at blending viscous materials [1]
poloxamer 407 (P407), triacetin, propylene glycol, polyethylene glycol (PEG) 400, oleyl alcohol, octyldodecanol, medium chain triglyercides, isopropyl myristate, cocoyl caprylocaprate, decyl oleate, and pyrrolidone were kindly provided by BASF (Florham Park, NJ, USA)
Normal human dermal fibroblasts (NHDF) were seeded in complete media at 8 × 104 cells per well in 6-well tissue culture plates and grown to 70% confluence before 24 h serum starvation and subsequent treatment
Summary
Dual asymmetric centrifugation (DAC) is a bladeless mixing process that is efficient at blending viscous materials (e.g., silicone adhesives) [1]. Through a combination of centrifugal motion on a primary axis and rotational motion on a secondary axis, the wall of a DAC mixing vessel essentially acts as a shearing blade. DAC is generally reproducible and has several advantages over traditional mixing methods [2,3]. DAC excels in processing lab-scale volumes (< 1 g) [5] enabling high sample number, and low sample volume formulation screening studies [6,7,8]. DAC utilization in the pharmaceutical space seems relatively novel still, but notable applications include siRNA-loaded liposomes [5], vesicular phospholipid gels [9,10,11], and fat emulsions [12]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
