(T1430-12-67) Development of Topical Foam Formulation for Decontamination Post Exposure to Lewisite and Extended Antidote Delivery upon Reapplication

Purpose: Chemical warfare agents, including lewisite are highly toxic agents capable of causing acute and chronic tissue damage even in low concentration. Lewisite are arsenic based chemical warfare agents with high permeability across skin¹. Thus, mass exposure of such lewisite needs an effective strategy to treat exposed population. As these agents are highly permeable, their removal from surface of the body and immediate treatment for systemic toxicity is a necessity. Thus, selection of suitable easy to apply and generate formulation is key to effective management in case of lewisite exposure. Amongst different formulations, a foam formulation containing surfactant can help decontaminate the surface of skin. Considering the ease of application, reuse of same formulation for extended delivery of antidotes can increase patient compliance. Thus, our study aimed at developing a dual-purpose topical foam formulation to simultaneously decontaminate the simulated lewisite – phenylarsine oxide (PAO) and delivery of 4-phenylbutyric acid (4-PBA) and N-acetylcysteine (NAC) as antidotes². We further evaluated, the extended delivery of these antidotes via reapplication of same foam formulation post decontamination for 24 hours.

Methods: The development of topical foam formulation involved selection of appropriate excipients such as foaming agent, vehicle, and chemical enhancer. We screened various foaming agents such as sodium lauryl ether sulfate (SLES), Tween 20, Tween 80, and poloxamer 407 and vehicles [propylene glycol (PG), polyethylene glycol, and deionized water] for foam formulation. Based on initial screening studies oleic acid (5%), oleyl alcohol (10%), and isopropyl myristate (15%) were selected as chemical enhancers to be incorporated for increased delivery of 4-PBA and NAC. Lastly, ethanol was also added due to its ability to increase delivery of drugs and ability to dissolve PAO which could be beneficial for decontamination. These combinations provided a matrix of total 34 formulations which were tested for their foamability and appearance. Based on foamability and composition having minimum amount of penetration enhancer, a lead formulation F30 loaded with 4-PBA and NAC (15.96% w/v each) was selected to be evaluated for in vitro testing to determine their decontaminating power and extended delivery for 24 hours after reapplication and compared to passive diffusion from PG. In vitro permeation studies were conducted using vertical Franz diffusion cells across dermatomed human skin. The protocol involved first, dosing of PAO solution in ethanol (100 µL; 100 mg/mL) for 30 minutes to simulate lewisite exposure followed by application of foam formulation for 5 minutes to allow decontamination. After 5 minutes, the donor compartment was washed by soaking up the solution with cotton swabs and rinsing three times with phosphate buffered saline. Finally, 100 µL of same foam formulation was reapplied and tested for delivery of 4-PBA and NAC till 24 hours. Receptor and skin samples were analyzed using developed and validated RP-HPLC method to determine amount of 4-PBA and NAC delivered into and across skin.

Results: Amongst the 34 formulations, only 8 formulations were clear solutions with capacity to create foam. Isopropyl myristate being immiscible with other excipients turned the formulation hazy and hence was not selected for further studies. Amongst the surfactants, tween 20 and SLES were able to form a clear solution with foaming properties. Foam F30 was selected as lead formulation based on its foamability and nature of foam to collapse quickly. The selected formulation showed over 99% decontamination efficacy for removal of PAO from skin. The formulated foam F30 significantly enhanced delivery of both 4-PBA and NAC with over 3.7-fold increase for 4-PBA with a total delivery of 14629.44 ± 2327.95 µg/cm² and over 40-fold increase for NAC with a total delivery of 19355.79 ± 643.2 µg/cm² as compared to their passive diffusion from PG where the total delivery of 4-PBA and NAC was 3949.38 ± 809.79 µg/cm² and 474.78 ± 123.55 µg/cm².

Conclusion: We successfully screened various excipients and developed a topical foam formulation for simultaneous decontamination of PAO and delivery of antidotes. The selected lead formulation showed high decontamination efficacy with enhanced delivery of both 4-PBA and NAC after reapplication. This study establishes the novel strategy to use a foam formulation to decontaminate chemical warfare agent and reapplication of same formulation for extended delivery of antidotes.

References: 1. Srivastava RK, Li C, Weng Z, Agarwal A, Elmets CA, Afaq F, et al. Defining cutaneous molecular pathobiology of arsenicals using phenylarsine oxide as a prototype. Sci Rep 2016;6:1–15. https://doi.org/10.1038/srep34865.
2. Li C, Srivastava RK, Weng Z, Croutch CR, Agarwal A, Elmets CA, et al. Molecular Mechanism Underlying Pathogenesis of Lewisite-Induced Cutaneous Blistering and Inflammation: Chemical Chaperones as Potential Novel Antidotes. Am J Pathol 2016;186:2637–49. https://doi.org/10.1016/j.ajpath.2016.06.012.

Acknowledgements: This project was funded by NIH/NIAMS 1U01AR078544-01 titled “Optimization of Novel Molecular Target-based Drugs for Arsenical Skin Injury”.


Formulation development of topical foam formulation for decontamination post exposure to lewisite and extended antidote delivery upon reapplication


Delivery of 4-PBA and NAC from PG and foam F30 a) permeation profile b) total delivery into and across skin


Matrix of foam formulations