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Enhanced Transdermal Delivery of N-Acetylcysteine and 4-Phenylbutyric Acid for Potential Use as Antidotes to Lewisite

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Abstract

Lewisite is a highly toxic chemical warfare agent that leads to cutaneous and systemic damage. N-acetylcysteine (NAC) and 4-phenylbutryic acid (4-PBA) are two novel antidotes developed to treat toxicity caused by lewisite and similar arsenicals. Our in vivo studies demonstrated safety and effectiveness of these agents against skin injury caused by surrogate lewisite (Phenylarsine oxide) proving their potential for the treatment of lewisite injury. We further focused on exploring various enhancement strategies for an enhanced delivery of these agents via skin. NAC did not permeate passively from propylene glycol (PG). Iontophoresis as a physical enhancement technique and chemical enhancers were investigated for transdermal delivery of NAC. Application of cathodal and anodal iontophoresis with the current density of 0.2 mA/cm2 for 4 h followed by passive diffusion till 24 h significantly enhanced the delivery of NAC with a total delivery of 65.16 ± 1.95 µg/cm2 and 87.23 ± 7.02 µg/cm2, respectively. Amongst chemical enhancers, screened oleic acid, oleyl alcohol, sodium lauryl ether sulfate, and dimethyl sulfoxide (DMSO) showed significantly enhanced delivery of NAC with DMSO showing highest delivery of 28,370.2 ± 2355.4 µg/cm2 in 24 h. Furthermore, 4-PBA permeated passively from PG with total delivery of 1745.8 ± 443.5 µg/cm2 in 24 h. Amongst the chemical enhancers screened for 4-PBA, oleic acid, oleyl alcohol, and isopropyl myristate showed significantly enhanced delivery with isopropyl myristate showing highest total delivery of 17,788.7 ± 790.2 µg/cm2. These studies demonstrate feasibility of delivering these antidotes via skin and will aid in selection of excipients for the development of topical/transdermal delivery systems of these agents.

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Data Availability

The data generated during the study is contained in the manuscript.

Abbreviations

4-PBA:

4-Phenylbutyric acid

NAC:

N-Acetylcysteine

SLES:

Sodium lauryl ether sulfate

DMSO:

Dimethyl sulfoxide

BAL:

British anti-lewisite

PG:

Propylene glycol

PBS:

Phosphate-buffered saline

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Funding

This project was funded by NIH/NIAMS 1U01AR078544 to M.A. The study sponsors had no involvement in the study design, collection, analysis and interpretation of data, the writing of the manuscript or the decision to publish the manuscript.

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Authors and Affiliations

  1. Center for Drug Delivery Research, Department of Pharmaceutical Sciences, College of Pharmacy, Mercer University, Atlanta, Georgia, 30341, USA

    Amruta A. Dandekar, Deepal Vora, Jihee Stephanie Yeh & Ajay K. Banga

  2. Department of Dermatology, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, 35233, USA

    Ritesh Kumar Srivastava & Mohammad Athar

Authors
  1. Amruta A. Dandekar
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  2. Deepal Vora
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  3. Jihee Stephanie Yeh
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  4. Ritesh Kumar Srivastava
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  5. Mohammad Athar
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  6. Ajay K. Banga
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Contributions

Amruta Dandekar: conceptualization, methodology, formal analysis, original draft preparation, writing—review and editing. Deepal Vora: conceptualization, methodology, formal analysis, original draft preparation, writing—review and editing. Jihee Stephanie Yeh: methodology, formal analysis, original draft preparation. Ritesh Kumar Srivastava: writing—review and editing. Mohammad Athar: writing—reviewing and editing, funding acquisition. Ajay K. Banga: conceptualization, writing—reviewing and editing.

Corresponding authors

Correspondence to Mohammad Athar or Ajay K. Banga.

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Ethics Approval

All studies involving animals were reviewed and approved by Institutional Animal Care and Use Committee of University of Alabama at Birmingham (IACUC number: 22077).

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The authors declare no competing interests.

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Dandekar, A.A., Vora, D., Yeh, J.S. et al. Enhanced Transdermal Delivery of N-Acetylcysteine and 4-Phenylbutyric Acid for Potential Use as Antidotes to Lewisite. AAPS PharmSciTech 24, 71 (2023). https://doi.org/10.1208/s12249-023-02527-6

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