A translational approach to predicting small molecule drug permeation through microneedle-treated skin

预测小分子药物通过微针处理的皮肤渗透的转化方法

• 批准号: 10623967
• 负责人: Nicole K Brogden
• 金额: $ 39.91万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-10 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10623967
• 关键词: Affect; Age; Age Years; Animals; Area; Biological; Cavia; Characteristics; Charge; Development; Dosage Forms; Dose; Drug Compounding; Drug Delivery Systems; Drug Kinetics; Enrollment; Environment; Formulation; Goals; Health; Human; Hydrophobicity; In Vitro; Kinetics; Knowledge; Laboratories; Length; Medical; Methods; Mission; National Institute of General Medical Sciences; Needles; Oral; Pathway interactions; Patients; Permeability; Pharmaceutical Preparations; Pharmacologic Substance; Plasma; Property; Research; Route; Skin; Structure; Testing; Time; Transdermal substance administration; Work; absorption; age related; chemical property; clinical application; clinically relevant; cohort; cost effective; human subject; hydrophilicity; improved; in vivo; innovation; ionization; micropore; programs; small molecule; translational approach

PROJECT SUMMARY / ABSTRACT Transdermal drug delivery has many benefits including ease of product application for patients and more consistent plasma drug concentrations compared to oral or IV dosing. However, many active pharmaceutical ingredients (APIs) do not meet the strict physicochemical properties needed to permeate through the hydrophobic outer skin layer. For APIs that cannot adequately absorb through skin, microneedles (MNs) temporarily increase skin permeability through formation of epidermal micropores. There are two major routes of API transport to consider with MN treatment: micropores (a hydrophilic environment), and intact skin around the micropores (a hydrophobic environment). Effects of API properties and formulation are well understood for delivery through intact skin, but they need to be systematically considered for MN delivery because of the introduction of the second parallel transport pathway (micropores). In vivo micropore closure time and human skin characteristics also impact API delivery with MNs, and these variables cannot be well simulated in vitro. The long-term goal of this work is to improve API delivery and treatment options for a wide range of health conditions through development of innovative MN dosage forms. The goal for the next 5 years is to determine significant in vitro and in vivo factors impacting absorption of small molecule APIs through MN-treated skin. We will use in vitro permeation tests and in vivo pharmacokinetics studies (in animals and humans) to answer key questions about how API properties, formulation, and in vivo skin characteristics impact permeability and flux through micropore vs. intact skin pathways. The main physicochemical characteristics we will initially investigate include ionization/charge, logP, and pKa. Permeation will be examined in vitro under heated vs non-heated conditions (heat can synergistically enhance skin API permeation), and MN properties (length, number) will be examined for effects on permeation. This will give a mechanistic understanding of the API and MN properties having the greatest impact on micropore permeation. Pharmacokinetics studies in guinea pigs will be completed so that in vivo factors impacting permeation can be assessed and compared to in vitro predictions. A second major area of study will involve pharmacokinetics studies in healthy human subjects. We will enroll a cohort of subjects >50 years of age, along with younger (<50 yrs) control subjects so we can 1) correlate age-related micropore closure estimates with API absorption, and 2) study age-related skin changes on MN API delivery. The combined in vitro and in vivo studies will maintain the high clinical relevance of the work. We expect to identify key physicochemical properties and increase our understanding of structure-permeability relationships and biological aspects impacting API permeability with MNs. This will generate fundamental knowledge that can result in direct clinical applications and supports the NIGMS mission in the areas of drug delivery, absorption, transport, and kinetics.

项目摘要 /摘要 透皮药物输送具有许多好处 与口服或IV剂量相比，血浆药物浓度一致。但是，许多活跃的药物 成分（API）不符合渗透到渗透所需的严格理化特性 疏水外皮层。对于无法充分吸收皮肤的API，微针（MN） 通过形成表皮微孔来暂时增加皮肤渗透率。有两条主要路线 API传输以进行MN处理：微孔（一种亲水环境）和周围完整的皮肤 微孔（疏水环境）。 API性质的影响和配方的效果已充分了解 通过完整的皮肤递送，但由于需要系统地考虑MN 引入第二平行传输途径（微孔）。体内微孔闭合时间和人类 皮肤特征还会影响使用MNS的API递送，并且这些变量在体外不能很好地模拟。这 这项工作的长期目标是改善各种健康状况的API交付和治疗选择 通过开发创新的MN剂型。接下来5年的目标是确定 体外和体内因素因MN处理的皮肤影响小分子API的吸收。我们将使用 体外渗透测试和体内药代动力学研究（在动物和人类中）回答关键问题 关于API性质，配方和体内皮肤特性如何影响渗透性和通量 微孔与完整的皮肤途径。我们最初将研究的主要理化特征包括 电离/电荷，LOGP和PKA。在加热与非加热条件下，将在体外检查渗透率 （热量可以协同增强皮肤API渗透），并检查MN特性（长度，数字） 为渗透的影响。这将对具有的API和MN属性有一个机械理解 对微孔渗透的影响最大。豚鼠的药代动力学研究将完成，以便 可以评估影响渗透的体内因子，并将其与体外预测进行比较。第二个主要区域 研究将涉及健康人类受试者的药代动力学研究。我们将注册一系列受试者> 50 年龄，以及年轻的（<50年）对照对象，因此我们可以1）与年龄相关的微孔闭合相关 API吸收的估计值和2）研究MN API递送的与年龄相关的皮肤变化。体外合并 体内研究将保持工作的高临床相关性。我们希望确定关键的物理化学 性质并增加我们对结构 - 渗透性关系和生物学方面的理解 用MNS影响API渗透性。这将产生基本知识，可以导致直接临床 应用和支持在药物输送，吸收，运输和动力学领域的NIGMS任务。