Multi-Orifice Continuous Subcutaneous Insulin Infusion Catheter with Reduced Pharmacokinetic Variability and Rapid On-Off Pharmacodynamic Actions

项目总结/摘要 超过400，000名美国患者接受持续皮下胰岛素输注（CSII）泵治疗 需要每2-3天更换一次输液部位。许多患者试图使用他们的 输注导管持续时间较长，导致血糖控制较差的第3天后， 研究中心使用和因输注失败导致的高血糖风险增加。不幸的是，胰岛素 周围皮下组织的吸收因每日和剂量而异 并且可能在导管使用的任何一天暂时或永久受损。 我们的目标是开发一种优化的CSII导管， 胰岛素吸收（药代动力学或PK），具有快速开启和快速关闭作用 （药效学或PD）。更可预测和一致的胰岛素吸收将使 患者通过延长每个输注部位的使用时间来改善血糖控制。 我们假设，沿导管轴沿着具有多个孔口的CSII导管将输送 胰岛素以圆柱形进入皮下组织，提供更大的表面积 与传统单孔注射器产生的扁平球形胰岛素储库相比， 导尿管更大的表面积进入更多的毛细血管和淋巴管， 胰岛素快速均匀地吸收到循环中。此外，导管的设计和 插入方法将减少组织创伤和炎症。最大限度地减少组织损伤， 免疫应答将进一步降低胰岛素吸收的可变性。这种可行性的成功 研究将支持进一步开发由钢制成的多孔CSII导管， 软质聚合物（例如聚四氟乙烯），采用自动插入方法。 在这项SBIR第1阶段研究中，我们将通过激光钻孔构建CSII导管原型， 一种小直径不锈钢脊椎穿刺针，具有无创伤的针尖。的 将在6项研究中比较该原型导管与市售导管的性能 猪七天我们将评估胰岛素通过原型导管的孔流入 使用胰岛素/X射线造影剂进行微CT成像， 胰岛素染色组织的组织学和葡萄糖钳夹胰岛素PK-PD研究。组织学 数据和微CT成像数据将用于将胰岛素在体内的分布相关联。 皮下组织（3D形状、体积和表面积），具有PK-PD作用， 赖脯胰岛素该中试动物数据将证明该器械的分布情况 胰岛素可以释放到更大体积的组织中并减少组织创伤。后续SBIR第2阶段 资金将用于支持人体研究，以证明胰岛素吸收的改善功效。

PROJECT SUMMARY / ABSTRACT  Over 400,000 US patients on continuous subcutaneous insulin infusion (CSII) pump therapy are required to change their infusion site every 2–3 days. Many patients attempt to use their infusion catheters for longer durations, resulting in poorer blood glucose control after day 3 of site use and an increased risk for hyperglycemia due to infusion failure. Unfortunately, insulin absorption by the surrounding subcutaneous tissue varies from day-to-day and dose-to-dose and may become temporarily or permanently impaired on any day of catheter use. We aim to develop an optimized CSII catheter that will allow for more consistent and reliable insulin absorption (pharmacokinetics or PK) with rapid on and rapid off actions (pharmacodynamics or PD). More predictable and consistent insulin absorption will enable patients to achieve improved blood glucose control with longer use of each infusion site. We hypothesize that a CSII catheter with multiple orifices along the catheter's shaft will deliver insulin into the subcutaneous tissue in a cylinder-shape, providing a much larger surface area than the flattened sphere shape of insulin depots produced by conventional, single-orifice catheters. The larger surface area accesses more capillary and lymph vessels, allowing for more rapid and uniform insulin uptake into the circulation. Furthermore, the catheter's design and insertion method will reduce tissue trauma and inflammation. Minimizing tissue damage and the immune response will further reduce insulin absorption variability. Success of this feasibility study will support further development of multiple-orifice CSII catheters made of both steel and soft polymers (e.g. Teflon) with automated insertion methods. In this SBIR Phase 1 study, we will construct prototype CSII catheters by laser drilling holes into a small diameter stainless steel spinal needle with an atraumatic pencil-point tip. The performance of this prototype catheter will be compared to a commercial catheter in a study of 6 swine for 7 days. We will evaluate the flow of insulin through the prototype catheter's holes into the adjacent vascular tissue using micro-CT imaging with an insulin/x-ray contrast agent, histology of tissue stained for insulin, and glucose-clamp insulin PK-PD studies. The histology data and the micro-CT imaging data will be used to correlate the distribution of insulin within the subcutaneous tissue (3D shape, volume, and surface area) with the PK-PD actions of a insulin lispro bolus. This pilot animal data will demonstrate how well the device distributes insulin to a larger volume of tissue and reduces tissue trauma. Subsequent SBIR Phase 2 funding will support human studies demonstrating the improved efficacy of insulin absorption.