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

通过纳米孔膜持续 3 个月递送稳定的艾塞那肽

• 批准号: 8781687
• 负责人: FRANCIS JOSEPH MARTIN
• 金额: $ 22.25万
• 依托单位: DELPOR, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-22 至 2016-08-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8781687
• 关键词: Abdomen; Accounting; Achievement; Acute; Adult; Aging; Architecture; Attitude; Bicarbonates; Binding; Biological Assay; Biological Products; Blood Glucose; Body Temperature; Buffers; Caliber; Carbon Dioxide; Caring; Centers for Disease Control and Prevention (U.S.); Chronic Disease; Clinical; Data; Development; Devices; Diabetes Mellitus; Disease; Disease Management; Drug Formulations; Enzyme-Linked Immunosorbent Assay; Feedback; Goals; Half-Life; Health Care Costs; Health Personnel; High Pressure Liquid Chromatography; Hormones; Implant; In Vitro; Industry; Injection of therapeutic agent; Insulin; Kinetics; Local Anesthetics; Maintenance; Maintenance Therapy; Measures; Membrane; Methods; Modification; Molecular Probes; Monitor; Non-Insulin-Dependent Diabetes Mellitus; Operative Surgical Procedures; Output; Overweight; Pain; Pancreas; Patients; Peptides; Pharmaceutical Preparations; Phase; Plasma Proteins; Prevalence; Procedures; Protein Binding; Proteins; Pump; Relative (related person); Risk; Safety; Staging; Structure; Surface; Surgical sutures; Suspension substance; Suspensions; System; Technology; Therapeutic; Titania; Titanium; Treatment Cost; Treatment outcome; Trocars; Upper arm; Validation; Withdrawal; Withholding Treatment; Work; acute pancreatitis; analog; aqueous; base; cost; cost effective; disorder prevention; exenatide; glucagon-like peptide 1; improved; in vivo; medication compliance; meetings; mimetics; nanopore; patient population; performance tests; preclinical study; product development; programs; prototype; public health relevance; research and development; research clinical testing; subcutaneous; success; trend

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.

描述（由申请人提供）：到 2050 年，2 型糖尿病的患病率预计将达到 20%-30%。在过去 8 年中，一类称为肠促胰岛素模拟物的新药物已成功用于治疗糖尿病疾病。肠促胰素模拟物（包括艾塞那肽）的半衰期非常短，需要频繁皮下自我注射。这种输送可能是侵入性的、痛苦的、存在安全问题，并且影响患者对药物依从性的态度。维持肽稳定性并实现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。目前艾塞那肽的长效制剂有效期仅为 1 周，并且不允许在需要时停药。该计划的目标是开发一种小型非机械（被动）皮下植入物（储库），能够在至少 3 个月的时间内提供稳定的治疗水平的稳定艾塞那肽。植入体主体由钛制成，通过套管针将其植入上臂或腹部皮下，在15分钟的简单诊室手术中使用局部麻醉剂，无需任何手术缝合。植入的储库一端装有纳米孔膜，纳米孔膜的孔径大约是所选药物分子流体动力学直径的两倍；这种膜结构已被证明可以产生零级释放动力学。所提出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维持治疗的成本效益。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，因为此类药物与急性胰腺炎有关。该项目第一阶段的主要目标是开发艾塞那肽的稳定制剂，并验证所选纳米孔膜在暴露于体内条件时不会受到生物污染，并且足够坚固，可以进入临床前研究、产品开发和临床测试。我们提出的工作将建立在有关生物制剂稳定性的现有数据的基础上，因为我们尝试两种方法来开发体温下稳定的艾塞那肽制剂。除了作为我们输出测定的一部分监测药物的稳定性和效力之外，我们还将选择适合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 前会议期间收到了 FDA 对其另一种分子的 Nanopore 技术的反馈。成功完成拟议研究后，公司将准备提交第二阶段申请，这将进一步将拟议产品推进到 IND 阶段。第一阶段的成功完成还将使我们能够缩小设备的尺寸，延长其使用寿命，并探索使用相同的技术来输送其他生物制剂。