A new high-throughput gastrointestinal tract explant platform for drug formulation discovery and metabolic disease modulation

项目摘要/摘要 我们的长期目标是开发系统，提供广泛的受控药物输送 治疗学，包括仅限于非肠外途径的治疗学。在本提案中，我们在先前工作的基础上 重点关注胃肠道(GI)障碍，并专门提出支持高吞吐量GI的平台 运输评估的新配方迅速。开发与口服相容的治疗方法 给药，需要重要的制剂和体外和体内评价，以实现最大的口服生物利用度 在人类身上。目前胃肠道吸收的体外模型受到它们的吞吐量和近似的 生理状态。因此，我们建议：1)开发能够长期培养的系统 完整的哺乳动物胃肠道组织与2)高通量机器人相连，以改变配方开发和 胃肠道的研究。这些调查得到了强有力的初步数据的支持，这些数据表明：1)文化 在体外维持广泛的细胞标志物和药物转运体存在的条件 猪胃肠道组织，2)能够高通量询问的原型系统的制造，3)演示 对一大批药物的药物吸收预测能力，4)近几个数量级的演示 大规模赋形剂筛选后模型分子摄取的幅度增强。目前， 通过口服途径吸收较差的有希望的治疗药物可以在药物开发中体现出来。 拖延数年，并多次找不到配方解决方案。拟议的工作将针对 通过提供工具来快速确定能够实现：最大药物的配方，从而满足关键的未得到满足的临床需求 溶解和吸收能力强，局部毒性最小。此外，拟议的系统将使审问 以及对胃肠道肠道内分泌系统的研究，使发现新陈代谢疗法成为可能 精神错乱。通过这项提议，我们将开发一套新的配方和新的材料-药物 能够口服以前仅限于非肠外途径的药物的组合。此外，我们还将 开发新的肠道内分泌系统调节剂，为代谢性疾病提供新的解决方案 流行病。总而言之，这项提议旨在提供一个类似于芯片上的肠的平台，具有以下能力 转化配方学和对具有转化治疗潜力的胃肠道的研究 代谢性疾病和其他胃肠道疾病。

Project Summary/Abstract Our long-term goal is the development of systems providing controlled drug delivery of a broad set of therapeutics including those that are limited to parenteral routes. In this proposal, we build on our prior work to focus on the gastrointestinal (GI) barrier and specifically propose a platform enabling the high-throughput GI transport evaluation of novel formulations rapidly. Developing therapies which are compatible with oral administration, requires significant formulation and in vitro and in vivo evaluation for maximal oral bioavailability in humans. Current in vitro models of GI absorption are limited by their throughput and approximation of the physiologic state. Consequently, we propose: 1) the development of systems enabling prolonged culturing of intact mammalian GI tissue coupled to 2) high-throughput robotics to transform formulation development and study of the GI tract. These investigations are supported by strong preliminary data demonstrating: 1) culture conditions which maintain the presence of a broad set of cellular markers and drug transporters ex vivo in porcine GI tissue, 2) fabrication of prototype systems enabling high-throughput interrogation, 3) demonstration of predictive capacity of drug absorption for a large panel of drugs, 4) demonstration of near order of magnitude enhancement of uptake of a model molecule following a large-scale excipient screen. Currently, promising therapeutics which are poorly absorbed through the oral route can manifest in drug development delays on the order of years and many times no formulation solution is identified. The proposed work will target a critical unmet clinical need by providing tools to rapidly identify formulations that enable: maximal drug solubility and absorption and minimal local toxicity. Moreover, the proposed system will enable interrogation and study of the GI tract entero-endocrine system enabling the discovery of new therapies for metabolic disorders. Through this proposal we will develop a novel set of formulations and novel material-drug combinations enabling the oral delivery of drugs previously restricted to parenteral routes. Moreover, we will develop novel modulators of the enteroendocrine system providing novel solutions to the metabolic disease epidemic. In sum, this proposal aims to provide a platform akin to an ‘intestine-on-a-chip’ with the capacity to transform formulation science and the study of the GI tract with the potential to transform treatments for metabolic disease and other diseases of the GI tract.