(M1430-01-03) Topical/Transdermal Strategies for Decontamination of Chemical Warfare Agents and Delivery of Antidotes

Purpose: Chemical warfare agents, including lewisite, are potent, highly toxic agents. Lewisite is an arsenic-based blistering agent capable of causing pain, inflammation, and blistering even in small quantities. Thus, an early and effective decontamination strategy and rapid administration of antidote are crucial in the event of chemical warfare agent exposure. Administration of antidotes via skin can be beneficial in treating both local and systemic effects. Thus, in this study, we developed an in vitro skin model to investigate various topical/transdermal strategies to decontaminate warfare agents and to co-administer the developed antidotes: 4-PBA (MW: 164.2 g/mol; logP:2.4) and NAC (MW: 163.1; logP: -0.71). The model was tested for decontamination using phenyl arsine oxide (PAO) as a surrogate model for lewisite and other warfare agents. We explored various formulation strategies such as chemical enhancers, topical foam, and microneedles to enhance topical and transdermal delivery of these antidotes.

Methods: In vitro permeation studies were conducted using vertical Franz diffusion cells across dermatomed porcine and human skin. The amount of 4-PBA, NAC, and PAO delivered into and across skin was quantified using the validated UV-HPLC method. Firstly, various chemical enhancers, namely 5% oleic acid, 10% oleyl alcohol, 15% isopropyl myristate, and 10% ethanol in propylene glycol (PG) as the vehicle, were tested for enhanced delivery of 4-PBA and NAC individually (15.96 w/v drug loading) and compared to passive diffusion from propylene glycol (PG). Based on these observations, a topical foam formulation (5% oleic acid, 10% ethanol, 20% SLES, and 65% PG) was developed and tested for decontamination of PAO and delivery of 4-PBA and NAC. A quick-breaking foam formulation would collapse upon application to skin and result in a decrease in the volume of resultant solution on skin. To address this, we conducted a study to compare the effect of donor volume of foam formulation (7.5, 17.6, and 100 µL) on delivery of 4-PBA and NAC. Lastly, microporation as a physical enhancement strategy for needle-free, rapid antidote delivery was investigated. Dissolving maltose microneedles were used to create microchannels in the skin. Microneedle-assisted delivery of 4-PBA (0.3% w/v) and NAC (15.96% w/v) in PBS as the vehicle was evaluated and compared with its passive delivery.

Results: Passive diffusion of 4-PBA alone from PG was 1745.76 ± 443.51 µg/cm². There was no passive diffusion of NAC (0 ± 0 µg/cm²) from PG when administered alone. Except for ethanol, all the other chemical enhancers resulted in increased delivery of both 4-PBA and NAC into and across skin. These screening studies using different chemical enhancers demonstrated the feasibility of administration of these antidotes via skin. The developed foam formulation (blank as well as loaded with antidotes) showed more than 75% decontamination efficacy in porcine skin, demonstrating the use of topical foam formulation for decontamination. The foam loaded with both 4-PBA and NAC resulted in enhanced delivery of both 4-PBA and NAC from all the three donor volumes tested. The total delivery of 4-PBA from 7.5, 17.6, and 100 µL of donor volume was 1267.61 ± 27.77, 2746.98 ± 143.63, 11826.10 ± 11477.31 µg/sq.cm respectively, while total delivery of NAC was 1349.13 ± 116.12, 2928.14 ± 118.45, 4990.78 ± 579.30 µg/sq.cm respectively. This established the feasibility of using topical foam formulation for antidote delivery. Next, the microneedle-mediated delivery of 4-PBA and NAC was tested. There was no significant difference in passive and microneedle-mediated delivery of 4-PBA with a total delivery of 350.61 ± 7.72 µg/sq.cm and 339.26 ± 2.64 µg/sq.cm. However, microporation significantly enhanced the delivery of NAC with a total delivery of 2292.34 ± 268.83 µg/sq.cm as compared to passive delivery (479.61 ± 195.28 µg/sq.cm). Microporation also resulted in reduction in lag time to 0.29 ± 0.03 h as compared to passive diffusion (3.18 ± 0.73 h) for permeation of NAC.

Conclusion: Chemical enhancers were successfully used for increased delivery of antidotes into and across skin. The developed foam formulation demonstrated high decontamination efficacy along with the ability to deliver the antidotes into and across skin. In addition, microporation showed significant enhancement in the delivery of NAC with a reduced lag time suggesting possibility of rapid delivery. These studies establish that various topical/transdermal strategies can be used for decontamination of chemical warfare agents and rapid as well as sustained delivery of antidotes.

Acknowledgments: This project was funded by NIH/NIAMS 1U01AR078544

Figure 1: Average amount of 4-PBA and NAC delivered using different donor volumes of the developed foam formulation



Figure 2: Average amount of 4-PBA and NAC delivered via passive diffusion and microneedle-mediated delivery