Center for Drug Delivery Research, Department of Pharmaceutical Sciences, College of Pharmacy, Mercer University, Atlanta, GA 30341, USA.
UAB Research Center of Excellence in Arsenicals, Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Int J Pharm. 2024 Nov 15;665:124661. doi: 10.1016/j.ijpharm.2024.124661. Epub 2024 Sep 6.
Chemical warfare agents, particularly vesicants like lewisite, pose a threat due to their ability to cause skin damage through accidental exposure or deliberate attacks. Lewisite rapidly penetrates the skin, causing inflammation and blistering. This study focuses on developing a cream formulation of a therapeutic agent, called integrated stress response inhibitor (ISRIB), to treat lewisite-induced injuries. Moreover, animal studies demonstrate a molecular target engagement (ISR) and significant efficacy of ISRIB against lewisite-induced cutaneous injury. The goal of this formulation is to enhance the delivery of ISRIB directly to affected skin areas using an oil-in-water cream emulsion system. We investigated various excipients, including oils, surfactants, emollients, and permeation enhancers, to optimize ISRIB's solubility and penetration through the skin. The result of this study indicated that the optimal formulation includes 30 % w/w of N-Methyl-2-pyrrolidone, dimethyl sulfoxide and Azone® at a pH of 5. 5. It delivered the highest amount of ISRIB into the skin, demonstrating highest skin absorption with no detectable systemic exposure. Additionally, characterization of the cream, including texture analysis, emulsion type, and content uniformity, confirmed its' suitability for topical application. These findings suggest that ISRIB cream formulation is a promising approach for the localized treatment of skin injuries caused by lewisite.
化学战剂，特别是路易氏剂等糜烂性毒剂，由于其能够通过意外暴露或蓄意攻击造成皮肤损伤，因此构成威胁。路易氏剂迅速穿透皮肤，引起炎症和起疱。本研究专注于开发一种治疗剂（称为整合应激反应抑制剂，ISRIB）的乳膏制剂，以治疗路易氏剂引起的损伤。此外，动物研究表明 ISRIB 对路易氏剂诱导的皮肤损伤具有分子靶标结合（ISR）和显著疗效。该制剂的目标是使用油包水乳膏乳液系统，将 ISRIB 直接递送至受影响的皮肤区域，从而增强其递送。我们研究了各种赋形剂，包括油、表面活性剂、润肤剂和渗透增强剂，以优化 ISRIB 的溶解度和穿透皮肤的能力。这项研究的结果表明，最佳配方包括 30%w/w 的 N-甲基-2-吡咯烷酮、二甲基亚砜和 Azone®，pH 值为 5.5。它将最多量的 ISRIB 递送至皮肤，显示出最高的皮肤吸收，而没有可检测到的全身暴露。此外，对乳膏的特性进行了表征，包括质地分析、乳剂类型和含量均匀性，证实其适合局部应用。这些发现表明，ISRIB 乳膏制剂是治疗路易氏剂引起的皮肤损伤的局部治疗的有前途的方法。
