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

项目总结/摘要 我们的长期目标是开发一种系统，提供广泛的药物控制递送。 治疗剂，包括限于肠胃外途径的那些。在本提案中，我们在先前工作的基础上， 专注于胃肠道（GI）屏障，并特别提出了一个平台，使高通量GI 新制剂的运输评估迅速。开发与口服药物相容的治疗方法 给药，需要大量的制剂和体外和体内评价，以获得最大的口服生物利用度 在人类身上。目前的胃肠道吸收体外模型受到其通量和胃肠道吸收的近似值的限制。 生理状态因此，我们建议：1）开发能够延长培养的系统， 完整的哺乳动物胃肠道组织与2）高通量机器人技术相结合，以改变制剂开发， 研究胃肠道。这些调查得到了强有力的初步数据的支持，表明：1）文化 在体外维持一组广泛的细胞标记物和药物转运蛋白存在的条件下， 猪胃肠道组织，2）制造原型系统，实现高通量询问，3）演示 的预测能力的药物吸收的一个大的面板的药物，4）演示的近顺序， 在大规模赋形剂筛选后模型分子摄取的幅度增强。目前， 通过口服途径吸收差的有希望的治疗剂可以在药物开发中显现 数年的延迟和许多时候没有确定配方解决方案。拟议工作将针对 通过提供快速鉴定制剂的工具来满足关键的未满足的临床需求， 溶解性和吸收性以及最小的局部毒性。此外，拟议的系统将使审讯 研究胃肠道肠道内分泌系统，发现代谢性疾病的新疗法。 紊乱通过这一建议，我们将开发一套新的配方和新的材料-药物 能够口服递送以前限于肠胃外途径的药物的组合。而且还要 开发新的肠内分泌系统调节剂，为代谢疾病提供新的解决方案 疫情总而言之，这项建议旨在提供一个类似于“芯片上的计算机”的平台， 改变配方科学和胃肠道研究，有可能改变治疗方法， 代谢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.