Development of 4-phenylbutyric acid microsponge gel formulations for the treatment of lewisite-mediated skin injury.

Abstract

Lewisite, a chemical warfare agent, causes skin blisters, erythema, edema, and inflammation, requiring mitigation strategies in case of accidental or deliberate exposure. 4-phenyl butyric acid (4-PBA), a chemical chaperone, reduces endoplasmic reticulum stress and skin inflammation. The study aimed to encapsulate 4-PBA in microsponges for effective, sustained delivery against lewisite injury. Porous microsponges in a topical gel would potentially sustain delivery and improve residence time on the skin. Microsponges were developed using the quasi-emulsion solvent diffusion method with Eudragit RS100. Optimized formulation showed 10.58%w/w drug loading was incorporated in a carboxymethylcellulose (CMC) and Carbopol gel for in vitro release and permeation testing using dermatomed human skin. A sustained release was obtained from all vehicles in the release study, and IVPT results showed that compared to the control (41.52 ± 2.54 µg/sq.cm), a sustained permeation profile with a reduced delivery was observed for microsponges in PBS (14.16 ± 1.23 µg/sq.cm) along with Carbopol 980 gel (12.55 ± 1.41 µg/sq.cm), and CMC gel (10.09 ± 1.23 µg/sq.cm) at 24 h. Optimized formulation showed significant protection against lewisite surrogate phenyl arsine oxide (PAO) challenged skin injury in Ptch1^+/-/SKH-1 hairless mice at gross and molecular levels. A reduction in Draize score by 29%, a reduction in skin bifold thickness by 8%, a significant reduction in levels of IL-1β, IL6, and GM-CSF by 54%, 30%, and 55%, respectively, and a reduction in apoptosis by 31% was observed. Thus, the translational feasibility of 4-PBA microsponges for effective, sustained delivery against lewisite skin injury is demonstrated.