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年里，一种叫做促肠促胰岛素的新药已经被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）的半衰期很短，需要经常皮下自我注射。这种分娩可能是侵入性的，痛苦的，存在安全问题，并影响患者对药物依从性的态度。维持肽的稳定性和使艾塞那肽的持续长期递送有望提高依从性、便利性、安全性、成本和治疗成功率。目前的长效制剂艾塞那肽仅为1周，如果需要，不允许将药物移除。该计划的目标是开发一种小型的非机械（被动）皮下植入物（储存库），能够在至少3个月的时间内提供稳定的治疗水平的艾塞那肽。植入体由钛制成，通过套管针将其皮下植入上臂或腹部，在15分钟的简单手术过程中进行局部麻醉，不需要任何手术缝合。所述植入的储液器一端装有纳米孔膜，该纳米孔膜被制造成包含直径约为所选药物分子的流体动力学直径的两倍的孔；这种膜结构已被证明导致零级释放动力学。拟议的给药方法将消除每天或每周自我注射的需要。好处包括药物依从性、患者便利性、安全性和有效性的提高以及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。该项目的主要I期目标是开发一种稳定的艾塞那肽配方，并验证所选择的纳米孔膜在暴露于体内条件下不会受到生物污染，并且足够坚固，可以推进临床前研究、产品开发和临床测试。我们提出的工作将建立在关于生物制剂稳定性的现有数据的基础上，因为我们尝试了两种方法来开发一种稳定的艾塞那肽在体温下的配方。除了监测药物的稳定性和效力作为输出试验的一部分外，我们还将选择一种纳米孔膜，适合于以零阶方式输送肽，并在体内测试这种膜的性能。在ind之前的一次会议上，该公司已经收到了FDA关于另一种分子的纳米孔技术的反馈。在成功完成拟议研究后，公司将准备提交II期申请，这将进一步推进拟议产品进入IND阶段。第一阶段的成功完成也将使我们有可能减小设备的尺寸，延长其持续时间，并探索将相同的技术用于其他生物制剂的输送。

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.