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

皮下胰岛素给药(SIA)技术在过去几年中取得了重大进展 过去的二十年。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。有限的磨损时间伴随着SIA器件位置的旋转是当前的解决方案 最大限度地减少组织损伤，并在一段时间内保持输液或注射部位的完整性。这些做法， 虽然最终是有益的，但不会允许药物输送设备的性能超过当前 建议佩戴时间为三天。扩展SIA技术以与当前的连续 血糖监测传感器，获准佩戴10-14天，是一个重要的未得到满足的需求。挑战 为了延长输液泵或输液口的寿命，需要克服IPP诱导的组织 这些装置部位的炎症和纤维化反应。胰岛素制剂也易受影响。 机械和化学应激源通过以下途径导致非功能性胰岛素分子 聚合称为胰岛素原纤维形成(IDF)，即使在IPP存在下也是如此。我们出版的 初步数据表明，IPP和IDF都是促炎的。这是一种促炎 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。至 克服这一挑战，我们认为最佳的IPP减少和IDF清除时，胰岛素 剂量、在线和及时，而不是专注于新胰岛素配方的准备 提供了更优雅的解决方案。因此，这项提案的目标是设计、制造和 验证基于环糊精的在线吸附平台：1)可以降低IPP水平 商业胰岛素制剂，以及2)以“及时”的方式去除任何IDF形成， 也就是说，就在SIA之前。通过这个平台的商业胰岛素配方能够减轻 在不触发急慢性SIA引起的炎症和纤维化的情况下降低血糖水平。这 将实现生理上的正常血糖，同时保持SIA部位的长期组织完整性。至 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？ 用于胰岛素酚类防腐剂去除平台的环糊精基吸附剂，2)设计与评价 作为IDF去除平台的微/超滤膜(MFM)；3)保存长期组织 在SIA过程中通过使用基于β-环糊精的吸附剂(珠子和MFM)的完整性和生物活性 临床前猪模型中的过滤)平台。归根结底，成功实现这一点 该项目可以改变目前的糖尿病管理做法，从而实现这些目标 延长胰岛素输注器的寿命，最重要的是，维持组织部位的生存能力 用于未来的经常性胰岛素给药。

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.