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

项目摘要：//摘要： 超过40万名美国患者接受持续皮下胰岛素输注(CSII)泵治疗 要求每2-3天更换一次输液部位。许多患者试图用他们的 输液导管持续时间较长，导致第三天后血糖控制较差 场地使用和输液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天和剂量不同而不同 并且在使用导管的任何一天都可能变得暂时或永久受损。 我们的目标是开发一种优化的CSII导管，使其更加一致和可靠 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 改善患者的血糖控制，延长每个输液部位的使用时间。 我们假设一个沿导管轴部有多个孔的CSII导管将提供 胰岛素以圆柱形进入皮下组织，提供更大的表面积 而不是由传统的单孔胰岛素库生产的扁平球形胰岛素库 导尿管。更大的表面积可以接触到更多的毛细血管和淋巴管，从而允许更多 快速、均匀地将胰岛素吸收到循环中。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和 免疫反应将进一步降低胰岛素吸收的可变性。这一可行性的成功 研究将支持进一步开发钢制和钢制多孔CSII导管 具有自动插入方法的软聚合物(例如特氟龙)。 在这项SBIR第一阶段研究中，我们将通过激光打孔来建造CSII原型导管 一种小直径的不锈钢脊椎针，有无损伤的铅笔尖。这个 在一项为期6年的研究中，该原型导管的性能将与商业导管进行比较。 养猪7天。我们将评估胰岛素通过原型导管的孔进入 使用带有胰岛素/X射线造影剂的微型CT成像对邻近血管组织进行成像， 组织学胰岛素染色和葡萄糖钳夹胰岛素PK-PD研究。组织学 数据和Micro-CT成像数据将被用来关联胰岛素在 具有PK-PD作用的皮下组织(3D形状、体积和表面积) 利斯普罗胰岛素丸剂。这一实验动物数据将证明该设备分布得有多好 胰岛素使组织体积更大，减少组织创伤。后续SBIR阶段2 资金将支持证明胰岛素吸收效率提高的人体研究。

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.