Collaborative Research: GOALI: High-Impact Multiscale Physicochemical Advancements for the Prediction of Transient Dermal Absorption

合作研究：GOALI：预测瞬时真皮吸收的高影响力多尺度物理化学进展

• 批准号: 2124542
• 负责人: Johannes Nitsche
• 金额: $ 11.43万
• 依托单位: SUNY at Buffalo
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2124542&HistoricalAwards=false
• 关键词: Collaborative; Research; GOALI; Impact; Multiscale

This GOALI project will advance the science of skin penetration and, in particular, the prediction of transient dermal absorption for human exposure to chemical agents, whether they are beneficial or hazardous. The former case includes topical drugs and cosmetic benefit agents; the latter includes aerosolized pesticides encountered by farm workers, airborne pollutants encountered by residents in city environments, and trace chemicals encountered by workers in settings such as concrete and metal working. Modeling and simulation has recently become a component of the US FDA’s approval process for generic drug products, which reduces cost and accelerates approval of these products. Global regulatory agencies including US NIOSH have increasingly included modeling as part of their dermal risk assessment process. This project will address two vexing issues plaguing predictions of transient skin absorption: (1) slowly reversible binding of chemicals to skin proteins (especially keratin) complicates the uptake and release profiles of many commonly-encountered chemicals including topical steroids; and (2) gradual dissolution of solid particles deposited on the skin surface or within hair follicles affects absorption of drugs from gels and ointments and dermal absorption of heavy metals leached from airborne pollutants. Results from the project will be incorporated into a publicly available, spreadsheet-based skin penetration program and also a state-of-the-art simulation code for dermal absorption maintained by the GOALI industrial partner, Procter & Gamble. Parts of the research will be incorporated into undergraduate and graduate training in the cosmetic science area at the University of Cincinnati. The educational plan also specifically targets undergraduate research experiences for undergraduate women and underrepresented minority students.This project entails: (1) experimental measurement and broad parameterization of rate constants for keratin binding in the outer skin barrier cells (corneocytes) supported by a rigorous theoretical framework; and (2) development and implementation of interfacial mass transport relationships capable of representing absorption of precipitated solids on the skin. Intellectual merit lies in the identification and resolution of important strategic gaps in the current understanding of dermal absorption, which block progress in these two areas involving multiphase and multiscale transport. A central element of the project is multiscale modeling based on two stages of rigorous coarse graining - from ultrastructural (intracellular) to microscopic (intercellular) to macroscopic (tissue) scales - in resolving slow reversible binding of permeating molecules to stratum corneum keratin, which dramatically affects transport rates. The project will define the reservoir capacity of the skin barrier in theoretically rigorous and pragmatically useful terms, which will open the way to a broad-spectrum ability to accurately predict transient dermal absorption outcomes. The detailed treatment of dissolution-limited absorption will finally resolve dramatically different absorption rates observed for ostensibly similar molecules that have long baffled pharmaceutical and consumer product development efforts and risk assessments related to chemical exposures.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

这一目标项目将推动皮肤渗透科学的发展，特别是对人体接触化学制剂的瞬时皮肤吸收的预测，无论它们是有益的还是有害的。前者包括外用药物和美容美容剂；后者包括农场工人遇到的雾化农药，城市环境中居民遇到的空气污染物，以及工人在混凝土和金属加工等环境中遇到的微量化学品。建模和模拟最近已成为美国FDA仿制药产品审批流程的一个组成部分，这降低了成本并加快了这些产品的审批速度。包括美国NIOSH在内的全球监管机构越来越多地将建模作为其皮肤风险评估过程的一部分。该项目将解决两个困扰暂时性皮肤吸收预测的棘手问题：(1)化学品与皮肤蛋白质(尤其是角蛋白)的缓慢可逆结合使许多常见化学品的吸收和释放谱复杂化，包括局部类固醇；(2)沉积在皮肤表面或毛囊内的固体颗粒逐渐溶解，影响从凝胶和软膏中吸收药物，并影响从空气污染物中滤出的重金属的真皮吸收。该项目的结果将被纳入一个公开的、基于电子表格的皮肤渗透计划，以及由Goali工业合作伙伴宝洁公司维护的最先进的皮肤吸收模拟代码。部分研究将纳入辛辛那提大学化妆品科学领域的本科生和研究生培训。该教育计划还专门针对本科生女性和代表性不足的少数族裔学生的本科生研究经验。该项目包括：(1)在严格的理论框架支持下，对外层皮肤屏障细胞(角质细胞)中角蛋白结合的速率常数进行实验测量和广泛的参数化；(2)开发和实施能够代表沉淀固体在皮肤上的吸收的界面质量传输关系。知识的价值在于识别和解决目前对皮肤吸收的理解中的重要战略差距，这些差距阻碍了这两个涉及多阶段和多尺度转运的领域的进展。该项目的一个核心要素是基于严格粗粒化的两个阶段的多尺度建模，从超微结构(细胞内)到微观(细胞间)再到宏观(组织)尺度，以解决渗透分子与角质层的缓慢可逆结合，这将显著影响传输速率。该项目将以理论上严格和实用的术语定义皮肤屏障的储存量，这将为获得准确预测瞬时皮肤吸收结果的广谱能力铺平道路。溶解限制吸收的详细处理最终将解决对表面上相似的分子观察到的截然不同的吸收速率，这些分子长期以来一直困扰着药品和消费品开发努力以及与化学品暴露相关的风险评估。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

Impact of solvent dry down, vehicle pH and slowly reversible keratin binding on skin penetration of cosmetic relevant compounds: I. Liquids

溶剂干燥、载体 pH 值和缓慢可逆角蛋白结合对化妆品相关化合物皮肤渗透的影响： I. 液体

• DOI: 10.1016/j.ijpharm.2022.122030
• 发表时间: 2022
• 期刊: International Journal of Pharmaceutics
• 影响因子: 5.8
• 作者: Tonnis, Kevin;Nitsche, Johannes M.;Xu, Lijing;Haley, Alison;Jaworska, Joanna;Kasting, Gerald B.
• 通讯作者: Kasting, Gerald B.

A Framework for Incorporating Transient Solute-Keratin Binding Into Dermal Absorption Models

将瞬时溶质-角蛋白结合纳入真皮吸收模型的框架

• DOI: 10.1016/j.xphs.2021.11.026
• 发表时间: 2022
• 期刊: Journal of Pharmaceutical Sciences
• 影响因子: 3.8
• 作者: Nitsche, Johannes M.;Kasting, Gerald B.
• 通讯作者: Kasting, Gerald B.