A novel inline platform provides an advanced drug delivery device foroptimized diabetes therapy

皮下胰岛素给药（SIA）技术的重大进展已经实现， 过去二十年尽管如此，SIA技术失败和胰岛素引起的潜在组织损伤 所有商业胰岛素制剂中存在的酚类防腐剂（IPP）可能会阻碍 SIA技术。有限的佩戴时间伴随着SIA设备部位轮换是目前的解决方案， 使组织损伤最小化并保持输注或注射部位随时间的完整性。这些做法， 虽然最终是有益的，但将不允许药物输送装置的性能超过当前的 建议佩戴时间为三天。扩展SIA技术，以符合当前的连续 被批准佩戴10-14天的葡萄糖监测传感器是一个显著未满足的需求。挑战 延长输注泵或注射端口的寿命涉及克服IPP诱导的组织损伤 在这些装置的位置处的炎症和纤维化反应。胰岛素制剂也易受 机械和化学应激导致非功能性胰岛素分子， 胰岛素原纤维形成（IDF）是指即使在存在IPP的情况下，胰岛素原纤维的聚合也会发生。我们的出版 初步数据表明，IPP和IDF都是促炎性的。这种促炎剂 反应导致累积的细胞/组织毒性、炎症和适应不良的伤口愈合。到 克服这一挑战，我们认为，最佳的IPP减少和IDF去除时，胰岛素 给药，在线和及时，而不是专注于制备新的胰岛素制剂 提供了一个更优雅的解决方案。因此，本提案的目的是设计、制造和 验证一个在线的基于β-环糊精的吸附剂平台，该平台1）可以降低 商业胰岛素制剂，以及2）在线并以“及时”模式去除任何IDF形成， 也就是说，在SIA之前。通过该平台的商业胰岛素制剂能够减轻 血糖水平，而不会引发急性和慢性SIA诱导的炎症和纤维化。这 将实现生理学上的健康，同时保持SIA部位的长期组织完整性。到 为了实现这些目标，我们制定了以下三个具体目标：1）设计和评估生物多样性- 胰岛素酚类防腐剂去除平台中的环糊精基吸附剂，2）设计和评估 微/超滤膜（MFM）作为IDF去除平台，以及3）长期保存组织 通过使用基于β-环糊精的吸附剂（珠和MFM）在SIA期间的完整性和生物活性 过滤）平台。最终，成功完成这一任务 该项目可能会改变目前的糖尿病管理实践， 增加胰岛素输注装置的使用寿命，最重要的是， 用于将来的反复胰岛素给药。

Significant progress in subcutaneous insulin administration (SIA) technology has been realized over the past two decades. Nonetheless, SIA technology failure and underlying tissue damage caused by insulin phenolic preservatives (IPP) present in all commercial insulin formulations could impede the progress of SIA technology. Limited wear time accompanied by SIA device site rotation are the current solutions to minimizing tissue damage and maintaining infusion or injection site integrity over time. These practices, while ultimately beneficial, will not allow for drug delivery devices to perform beyond the current recommended wear time of three days. Extending SIA technology to align with current continuous glucose monitoring sensors, approved for 10-14 days of wear, is a significant unmet need. Challenges to extending the lifespan of infusion pumps or injection ports involve surmounting the IPP-induced tissue reactions of inflammation and fibrosis at these devices’ location. Insulin formulations are also susceptible to mechanical and chemical stressors that lead to non-functional insulin molecules through polymerization designated as insulin fibril formation (IDF), even in the presence of IPP. Our published and preliminary data indicate that both, IPP and IDF, are pro-inflammatory. This pro-inflammatory response leads to cumulative cell/tissue toxicity, inflammation, and maladaptive wound healing. To overcome this challenge, we opine that optimum IPP reduction and IDF removal at the time of insulin dosing, in-line and just in time, rather than focusing on the preparation of new insulin formulations provides a more elegant solution. Thus, the objective of this proposal is to design, fabricate and validate an in-line ß-cyclodextrin-based adsorbents platform that 1) can reduce IPP levels in commercial insulin formulations, and 2) remove any IDF formation in-line and in a “just in time” mode, i.e., just before SIA. Commercial insulin formulations passed through this platform are able to mitigate blood glucose levels without triggering acute and chronic SIA-induced inflammation and fibrosis. This would achieve physiological euglycemia, while preserving long-term tissue integrity at SIA site. To achieve these goals, we have developed the following three specific aims: 1) Design and evaluate ß- cyclodextrin-based adsorbents in insulin phenolic preservative removal platforms, 2) Design and evaluate micro/ultrafiltration-based membranes (MFM) as IDF removal platforms, and 3) Preserve long-term tissue integrity and bioactivity during SIA through usage of ß-cyclodextrin-based adsorbent (beads and MFM filtration) platforms in a pre-clinical porcine model. Ultimately, the successful accomplishment of this project could result in transforming current diabetes management practices that would achieve the goals of increasing the lifespan of insulin infusion devices and most importantly, sustaining tissue site viability for future recurrent insulin administrations.