Pharmacokinetic Tomography for the Measurement of Topical Drug Product Bioequivalence

项目摘要 缺乏准确和可靠的技术，以可视化和量化的交付和吸收 小分子进入皮肤的药物动力学（药代动力学）一直是开发新的 和非专利外用药。在生物等效性的测量中尤其如此，其中仿制药 候选药物必须与参考品牌标签药物进行比较。目前的方法，依赖于昂贵的， 破坏性的，和批量测量不提供必要的空间或时间分辨率提取 药物代谢动力学曲线，以确定药物在人皮肤中随时间在细胞水平上的等效性。新 需要一种能够直接、实时、无创地定量人体药代动力学的工具 推动局部用药领域的创新。 药代动力学断层扫描（PKT）是一种生成各种药物的三维实时图的方法。 使用光谱成像技术测量组织中的分子种类，例如脂质、水、蛋白质和药物。 这些成像技术利用药物分子的固有分子振动来跟踪它们的吸收 而不需要标记或改变分子结构。该提案将开发新的 相干拉曼成像工具，以创建用于量化药物在离体人类皮肤中的行为的平台。 这个基于PKT的平台将能够测量药物的摄取，如抗生素，激酶抑制剂， 类固醇，维甲酸和非甾体抗炎药在皮肤亚细胞和亚秒的时间分辨率，以收集关键 药物开发和生物等效性测量所需的药代动力学参数。比较PKT 根据FDA认可的标准，这些PKT成像将与真皮开放流一起进行 微灌注（dOFM），一种测量药物浓度随时间变化的皮肤液体采样技术。的 多模式PKT平台建成后，将能够原位测量各种药物的生物等效性 在人类实验对象中。 这项研究计划将专门开发新的成像工具包，结合联合收割机先进的显微镜， 最先进的计算机视觉和机器学习分析技术来收集和提取药代动力学 数据利用一种新型的多功能激光器，我们将建立一种用于药物检测的理想的相干拉曼技术 含有独特化学结构的分子。为了将平台的适用性拓宽到更远的地方 更广泛的潜在药物分子，我们将开发一种稀疏采样相干拉曼成像方法 通过分子结构的独特组合来量化分子。

Project Summary The lack of accurate and reliable techniques for visualizing and quantifying the delivery and uptake (pharmacokinetics) of small molecules into the skin has been a major challenge in the development of both new and generic topical drugs. This is particularly true in the measurement of bioequivalence, where a generic drug candidate must be compared against a reference brand-label drug. Current methods, which rely on expensive, destructive, and bulk measurements do not provide the spatial or temporal resolution necessary to extract pharmacokinetic profiles to determine equivalence of drugs at the cellular level over time in human skin. New tools, which allow for direct, real-time quantification of pharmacokinetics non-invasively in humans are needed to drive innovation in the topical drug space. Pharmacokinetic Tomography (PKT) is a method of generated three-dimensional, real-time maps of various molecular species such as lipids, water, proteins and drugs in tissue using spectroscopic imaging techniques. These imaging techniques make use of the intrinsic molecular vibrations of drug molecules to track their uptake quantitatively without the need for labels or alterations to molecular structure. This proposal will develop new coherent Raman imaging tools to create a platform for quantifying the behavior of drugs in ex vivo human skin. This PKT-based platform will be able to measure the uptake of drugs such as antibiotics, kinase inhibitors, steroids, retinoids and NSAIDs in the skin with sub-cellular and sub-second time resolution to glean critical pharmacokinetic parameters needed for drug development and bioequivalence measurements. To compare PKT to an FDA-recognized standard, these PKT imaging will be carried out alongside dermal open flow microperfusion (dOFM), a skin fluid sampling technique that measures the concentration of drugs over time. The multimodal PKT platform, when completed, will be able to measure the bioequivalence of various drugs in situ in human subjects. This research program will specifically develop new imaging toolkits that combine advanced microscopy with state-of-the-art computer vision and machine learning analysis techniques to collect and extract pharmacokinetic data. Using a new type of versatile laser, we will create a coherent Raman technique ideal for detection of drug molecules which contain unique chemical structures. In order to broaden the applicability of the platform to a far wider range of potential drug molecules, we will develop a sparse sampling coherent Raman imaging approach that will quantify molecules by their unique combinations of molecular structures.