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

项目总结/摘要 刺针是一种微创方法，通过创建 表皮上的微孔微孔是水通道，其允许皮肤不可渗透的水通道。 药物通过皮肤并全身递送。这对治疗有重要意义 在不同的患者群体中的许多疾病。药物递送参数（药物制剂、微针 长度/数量）和体内考虑（微孔的闭合速率）都有助于 药代动力学和药物处置。尽管对人体微针进行了广泛的研究，但仍有大量的 缺乏描述生理因素（如性别和人种）如何影响药物的数据 交付配置文件。在不同性别/性别的受试者的皮肤中存在许多显著差异， 人种/种族，包括表皮厚度、反应性和损伤恢复的变化。表皮 厚度在身体的不同部位之间也有显著变化。为了实现广泛使用 为了使用用于药物递送的微针，有必要了解药物递送曲线在 不同的患者亚组。生理因素对药物释放曲线的影响无法预测 从体外扩散研究中，这使得体外和体内环境一起研究至关重要。很长的- 这项研究的长期目标是开发先进的微针输送平台， 药物疗法和治疗用于患有各种急性和慢性疾病的不同患者群体。 这项为期5年的MIRA研究计划的战略是使临床前药物输送之间的相关性 研究和临床人体微针研究相结合的基础和应用研究。体外 研究的目的是通过优化大分子和小分子的经皮通量， 制剂和微针递送参数。我们将研究直肠癌的闭合率和药物吸收 来自不同性别/性别和种族/民族的健康人类志愿者的许多解剖部位的图谱。 将研究针头长度和数量以及药物制剂作为可能影响的其他因素 到体内变异性。在临床研究中，我们将计算在各种条件下的药物闭合半衰期。 条件，并验证预测与药代动力学研究。将在体外进行相关性分析 经皮流量研究和体内药代动力学研究。MIRA计划 将扩大我们对生理变量如何影响微针药物递送的理解， 受试者，并在未来，我们将扩大这些结果，并执行关闭， 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是如何 进一步有助于响应于微针的变化。然后我们将有必要的工具来优化 在不同的患者亚群中进行微针递送以治疗疾病。

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.