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 经皮给药有许多好处，包括患者使用产品的简便性等 与口服或静脉给药相比，血浆药物浓度保持一致。然而，许多活性药物 配料(原料药)不符合渗透所需的严格物理化学性质 疏水外层皮肤。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，暂时增加皮肤的渗透性。有两条主要路线 MN治疗时要考虑的原料药传输：微孔(亲水性环境)和周围完整的皮肤 微孔(疏水环境)。原料药性质和配方的影响对于 通过完整的皮肤递送，但需要系统地考虑MN递送，因为 引入第二个平行运输途径(微孔)。体内微孔闭合时间与人体 皮肤特性也影响MNS的原料药释放，这些变量在体外不能很好地模拟。这个 这项工作的长期目标是改进原料药的交付和针对各种健康状况的治疗选择 通过开发创新的MN剂型。未来5年的目标是确定重要的 影响小分子原料药经MN皮肤吸收的体内外因素。我们将在 体外渗透试验和体内药代动力学研究(在动物和人类中)以回答关键问题 关于原料药的性质、配方和体内皮肤特性如何通过 微孔VS完整的皮肤路径。我们将初步调查的主要物理化学特征包括 电离/电荷、logP和pKA。体外透皮试验将在加热和非加热条件下进行。 (热可以协同增强皮肤原料药的渗透性)，并将检查MN属性(长度、数量) 对渗透的影响。这将提供对API和MN属性的机械理解，这些属性具有 对微孔渗透性的影响最大。在豚鼠身上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素，并将其与体外预测进行比较。第二个主要领域 这项研究将涉及健康受试者的药代动力学研究。我们将招收一批科目&50 年龄，以及年龄较小(50岁)的对照受试者，因此我们可以1)关联年龄相关的微孔闭合 使用API吸收的估计，以及2)研究MN API递送的年龄相关皮肤变化。体外联合应用 体内研究将保持这项工作的高度临床相关性。我们希望确定关键的物理化学 属性，增加我们对结构-渗透性关系和生物学方面的理解 MNS对原料药渗透性的影响这将产生基础知识，可以导致直接的临床 在药物输送、吸收、转运和动力学领域，应用和支持NIGMS任务。