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.

项目总结/摘要 经皮给药具有许多优点，包括易于患者应用产品等。 与口服或IV给药相比，血药浓度一致。然而，许多活性药物 原料药（API）不符合渗透所需的严格物理化学性质。 疏水性外皮层。对于不能通过皮肤充分吸收的原料药，微针（MN） 通过形成表皮微孔暂时增加皮肤渗透性。有两条主要路线 MN治疗中需要考虑的API转运：微孔（亲水环境）和周围完整的皮肤 微孔（疏水环境）。API性质和配方的影响是众所周知的， 通过完整的皮肤递送，但由于MN递送需要系统地考虑， 引入第二平行运输途径（微孔）。体内血管闭合时间和人体 皮肤特征也影响MN的API递送，并且这些变量不能在体外很好地模拟。的 这项工作的长期目标是改善API的输送和治疗方案，以应对各种健康状况 通过开发创新的MN剂型。未来5年的目标是确定重大 影响小分子API通过MN处理的皮肤吸收的体外和体内因素。我们将在 体外渗透试验和体内药代动力学研究（动物和人体），以回答关键问题 关于API性质、配方和体内皮肤特征如何影响渗透性和通量， 皮肤通路与完整皮肤通路。我们将初步研究的主要物理化学特性包括 电离/电荷、logP和pKa。将在体外加热与非加热条件下检查渗透 (heat可以协同地增强皮肤API渗透），并且将检查MN性质（长度、数目 对渗透的影响。这将给出对具有以下性质的API和MN性质的机械理解： 对渗透率影响最大。将完成豚鼠的药代动力学研究， 可以评估影响渗透的体内因素并与体外预测进行比较。第二大领域 本研究将涉及健康人类受试者的药代动力学研究。我们将招募一组>50名受试者 沿着的年轻（<50岁）对照受试者，因此我们可以1）将年龄相关性血管闭合 估计API吸收，和2）研究MN API递送时与年龄相关的皮肤变化。联合体外 并且体内研究将保持该工作的高度临床相关性。我们希望能找出关键的物理化学 增加我们对结构-渗透性关系和生物学方面的理解 用MN影响API渗透率。这将产生基础知识，可以导致直接的临床 在药物递送、吸收、运输和动力学领域，为NIGMS的使命提供支持。