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

项目摘要/摘要 微针是一种微创的方法，通过创建 表皮中的微孔。微孔是水通道，允许皮肤在其他情况下不透水 药物通过皮肤并有系统地给药。这对治疗有重要的意义。 在不同的患者群体中发现了许多疾病。药物输送参数(药物配方、微针 长度/数量)和体内考虑因素(微孔闭合率)都有助于 药物动力学和药物处置。尽管对人类的微针进行了广泛的研究，但仍有大量的 缺乏描述性别/性别和种族/民族等生理因素如何影响药物的数据 交付配置文件。不同性别和性别的受试者的皮肤存在许多显著差异 种族/民族，包括表皮厚度、反应性和从侮辱中恢复的差异。表皮层 身体不同部位的厚度也有很大差异。为了实现广泛使用 对于药物输送的微针，有必要了解药物输送曲线之间的变异性 不同的患者亚群。生理因素对药物传递曲线的影响是无法预测的 来自体外扩散研究，这使得同时研究体外和体内环境变得至关重要。长的- 这项研究的长期目标是开发先进的微针输送平台，将改善 为不同的急慢性疾病患者群体提供药物治疗和治疗。 这项为期5年的Mira研究计划的策略是将临床前药物释放之间的相关性 基础研究和应用研究相结合的人体微针研究和临床研究。离体 研究的目标将是通过优化优化来最大化大分子和小分子的经皮渗透 配方和微针给药参数。我们将研究微孔闭合率和药物吸收。 不同性别/性别和种族/民族的健康人类志愿者的多个解剖部位的概况。 微针的长度和数量，以及药物配方，将作为可能影响的其他因素进行研究 到体内的可变性。在临床研究中，我们将计算不同条件下的微孔闭合半衰期。 条件，并用药代动力学研究验证预测。将在体外建立相关关系 每个患者群体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健康人微针给药的理解 在未来，我们将在这些结果的基础上扩展，并进行微孔关闭和 系统性疾病患者的药代动力学研究。这将使我们能够了解疾病是如何 进一步导致对微针反应的差异。然后，我们将拥有必要的工具来优化 在不同的患者亚群中应用微针治疗疾病。

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.