The effects of pharmacologic and physiologic variables on the pharmacokinetics of microneedle drug delivery

药理学和生理变量对微针药物输送药代动力学的影响

• 批准号: 9704900
• 负责人: Nicole K Brogden
• 金额: $ 16.04万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9704900
• 关键词: Acute Disease; Affect; Anatomy; Applied Research; Biological; Chronic Disease; Clinical; Clinical Research; Data; Diffusion; Disease; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Epidermis; Ethnic Origin; Formulation; Future; Gender; Goals; Human; Human Volunteers; In Vitro; Knowledge; Length; Methods; Pathway interactions; Patients; Permeability; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Physiological; Race; Recovery; Research; Site; Skin; System; Systemic disease; Thick; Variant; absorption; aqueous; fundamental research; improved; in vivo; macromolecule; micropore; minimally invasive; patient population; patient subsets; pre-clinical; programs; response; sex; small molecule; tool

PROJECT SUMMARY/ABSTRACT Microneedles are a minimally invasive method for enhancing skin permeability through the creation of micropores in the epidermis. The micropores are aqueous pathways that allow an otherwise skin-impermeable drug to pass through the skin and be delivered systemically. This has important implications for the treatment of many diseases in diverse patient populations. Drug delivery parameters (drug formulation, microneedle length/number) and in vivo considerations (rate of closure of the micropores) both contribute to the pharmacokinetics and drug disposition. Despite extensive study of microneedles in humans, there is a large paucity of data describing how physiologic factors such as sex/gender and race/ethnicity affect the drug delivery profile. Many significant differences are present in the skin of subjects of differing sex/gender and race/ethnicity, including variations in epidermal thickness, reactivity, and recovery from insult. Epidermal thickness also varies dramatically between different sites of the body. In order to achieve widespread use of microneedles for drug delivery, it is necessary to understand the variability in drug delivery profiles between diverse patient subgroups. The effect of physiologic factors on the drug delivery profile cannot be predicted from in vitro diffusion studies, which makes it critical to study the in vitro and in vivo settings together. The long- term goal of this research is to develop advanced microneedle delivery platforms that will improve pharmacotherapy and treatment for diverse patient populations with a variety of acute and chronic diseases. The strategy of this 5 year MIRA research program is to make correlations between preclinical drug delivery studies and clinical human microneedle studies by combining fundamental and applied research. In vitro studies will aim to maximize percutaneous flux of macromolecules and small molecules by optimizing formulation and microneedle delivery parameters. We will study micropore closure rates and drug absorption profiles from numerous anatomical sites in healthy human volunteers of differing sex/gender and race/ethnicity. Microneedle length and number, and drug formulation will be studied as additional factors that may contribute to in vivo variability. In the clinical studies we will calculate micropore closure half-lives under various conditions and validate the predictions with pharmacokinetic studies. Correlations will be made between in vitro percutaneous flux studies and in vivo pharmacokinetic studies for each patient population. This MIRA program will expand our understanding of how physiologic variables affect microneedle drug delivery in healthy subjects, and in the future we will expand upon these results and perform micropore closure and pharmacokinetic studies in patients with systemic diseases. This will enable us to understand how diseases further contribute to variation in response to microneedles. We then will have the necessary tools to optimize microneedle delivery in distinct patient subsets for treatment of disease.

项目摘要/摘要 微针是一种通过创建来增强皮肤渗透性的微创方法 表皮中的微孔。微孔是水途径，允许原本具有皮肤的途径 药物可以通过皮肤并系统地递送。这对治疗具有重要意义 在多种患者人群中的许多疾病中。药物输送参数（药物配方，微针 长度/数字）和体内考虑（微孔的闭合率）都有助于 药代动力学和药物处置。尽管对人类微针的广泛研究，但仍有大量 描述性别/性别和种族/种族等生理因素如何影响药物的数据的匮乏 交货资料。不同性别/性别的受试者的皮肤中存在许多显着差异， 种族/民族，包括表皮厚度，反应性和侮辱中恢复的变化。表皮 厚度在身体的不同部位之间也有很大变化。为了广泛使用 用于药物输送的微针，有必要了解药物输送概况的变异性 多样化的患者亚组。生理因素对药物输送概况的影响无法预测 从体外扩散研究中，研究体外和体内环境至关重要。长期 这项研究的术语目标是开发高级微针交付平台，以改善 患有多种急性和慢性疾病的不同患者人群的药物治疗和治疗。 这项5年MIRA研究计划的策略是在临床前药物交付之间建立相关性 研究和临床人类微针研究通过结合基础和应用研究。体外 研究的目的是通过优化大分子和小分子的经皮通量。 公式和微针输送参数。我们将研究微孔闭合率和吸收药物 来自健康的性别/性别和种族/种族的健康人类志愿者的众多解剖场所的概况。 微针的长度和数量和数量，并将药物配方作为可能有助于的其他因素 体内变异性。在临床研究中，我们将计算各种小孔闭合半衰期 条件并通过药代动力学研究验证预测。体外将建立相关性 每个患者人群的经皮通量研究和体内药代动力学研究。这个Mira计划 将扩大我们对生理变量如何影响微针药物在健康中的理解 受试者，将来我们将扩展这些结果并执行微孔关闭，并 全身性疾病患者的药代动力学研究。这将使我们能够了解疾病如何 进一步有助于对微针的响应变化。然后，我们将有必要的工具来优化 在不同的患者子集中的微针递送以治疗疾病。