Sustained 3-Month Delivery of Stabilized Exenatide Through Nanopore Membranes for

描述（由申请人提供）：预计到2050年，2型糖尿病的患病率将达到20%-30%。在过去的8年中，一类新的药物，称为肠促胰岛素模拟物，已成功地用于治疗这种疾病。肠促胰岛素模拟物（包括艾塞那肽）的半衰期非常短，需要频繁皮下自我注射。这种递送可能是侵入性的、痛苦的、存在安全问题，并且影响患者对药物依从性的态度。维持肽稳定性和使艾塞那肽能够持续长期递送预期将改善依从性、便利性、安全性、成本和治疗成功。目前的长效艾塞那肽制剂仅为1周，并且不允许在需要时将药物移除。拟定项目的目标是开发一种小型非机械（无源）皮下植入物（储药器），能够在至少3个月的时间内提供一致的治疗水平的稳定exenetrine。植入物主体由钛制成，通过套管针皮下植入上臂或腹部，在简单的15分钟诊室手术中使用局部麻醉，无需任何外科缝合。植入的储库在一端装配有纳米孔膜，该纳米孔膜被制造成含有直径比所选药物分子的流体动力学直径大大约两倍的孔;这种膜结构已被证明导致零级释放动力学。拟议的输送方法将消除每天或每周自我注射的需要。益处包括药物依从性、患者便利性、改善的安全性和有效性以及具有成本效益的维持治疗。此外，该系统将允许医疗保健提供者在需要时快速移除药物，这是一个重要的考虑因素，因为这类药物与急性胰腺炎有关。该计划的主要I期目标是开发一种稳定的艾塞那肽制剂，并验证所选纳米孔膜在暴露于体内条件时不会发生生物污染，并且足够稳健以推进临床前研究、产品开发和临床测试。我们提出的工作将建立在现有的数据上，关于生物制剂的稳定性，因为我们尝试两种方法来开发一种在体温下稳定的艾塞那肽制剂。除了监测药物的稳定性和效力作为我们的输出测定的一部分之外，我们还将选择适合于以零级方式递送肽的纳米孔膜，并测试这种膜的体内性能。该公司已经在IND前会议上收到了FDA对其另一种分子纳米孔技术的反馈。在成功完成拟议的研究后，该公司将准备提交II期申请，这将进一步推进拟议的产品进入IND阶段。第一阶段的成功完成还将使我们能够潜在地减小设备的尺寸，延长其持续时间，并探索使用相同的技术来输送其他生物制剂。

DESCRIPTION (provided by applicant): The prevalence of Type 2 diabetes is expected to reach 20%-30% by 2050. In the last 8 years, a new class of drugs, called incretin mimetics, has been used successfully for the treatment of the disease. Incretin mimetics (including exenatide) have a very short half-life requiring frequent subcutaneous self-injections. Such delivery can be invasive, painful, present safety issues, and impact the patient's attitude towards medication adherence. Maintaining peptide stability and enabling the sustained long-term delivery of exenatide are expected to improve compliance, convenience, safety, cost, and treatment success. The current long acting formulation of exenatide is for only 1 week and does not allow for the medication to be removed if needed. The goal of the proposed program is to develop a small non-mechanical (passive) subcutaneous implant (reservoir) which will be able to deliver consistent, therapeutic levels of stable exenatide over a period of at least 3 months. The implant body is made of titanium and it is implanted subcutaneously in the upper arm or abdomen via a trocar, with local anesthetic during a simple 15-minute in-office procedure, and without the need for any surgical sutures. The implanted reservoir is fitted at one end with a Nanopore membrane fabricated to contain pores with diameters that are approximately twofold larger than the hydrodynamic diameter of the selected drug molecule; such membrane architecture has been shown to result in zero-order release kinetics. The proposed delivery method will eliminate the need for daily or weekly self-injections. Benefits include medication adherence, patient convenience, improved safety and efficacy, and cost effective maintenance therapy. Furthermore, the system will allow healthcare providers to quickly remove the medication if needed, an important consideration, as this class of drugs has been associated with acute pancreatitis. The primary Phase I objectives of this program are to develop a stable formulation of exenatide, and validate that the selected nanopore membrane is not subject to biofouling when exposed to in-vivo conditions and is robust enough to advance into preclinical studies, product development, and clinical testing. Our proposed work will build on existing data regarding the stabilization of biologics as we attempt two approaches in developing a stable formulation of exenatide at body temperature. In addition to monitoring the stability and potency of the drug as part of our output assay, we will also select a Nanopore membrane suitable for the delivery of peptides in a zero-order fashion and test the performance of such membrane in vivo. The company has already received feedback from the FDA on its Nanopore technology for another molecule during a pre-IND meeting. Upon successful completion of the proposed study, the company will be ready to submit a Phase II application which will further advance the proposed product into the IND phase. Successful completion of Phase I will also allow us to potentially reduce the size of the device, extend its duration, and explore using the same technology for the delivery of other biologics.