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

新型在线平台提供先进的药物输送装置，用于优化糖尿病治疗

• 批准号: 10736126
• 负责人: DON KREUTZER
• 金额: $ 68.79万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10736126
• 关键词: Achievement; Acute; Advanced Development; Air; Architecture; Binding; Binding Sites; Biological; Blood Glucose; Cell Line; Cell-Mediated Cytolysis; Cells; Characteristics; Chemicals; Chronic; Continuous Glucose Monitor; Cresol; Cyclodextrins; Data; Dermal; Devices; Dose; Drug Delivery Systems; Excision; Failure; Family suidae; Fibrosis; Filtration; Food Processing; Formulation; Future; Glucose; Goals; Human; Hydrophobicity; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Infusion Pumps; Infusion procedures; Injections; Insulin; Insulin-Dependent Diabetes Mellitus; Legal patent; Life; Literature; Location; Longevity; Macrophage; Mechanics; Membrane; Molecular Conformation; Mus; Pathology; Pharmaceutical Solutions; Phenols; Physiological; Plant Resins; Polymers; Practice Management; Predisposition; Preparation; Proteins; Publishing; Reaction; Recommendation; Recurrence; Reporting; Rotation; Serum; Site; Skin; Solvents; Sterility; Structure; Subcutaneous Tissue; System; Technology; Testing; Time; Tissue Preservation; Tissues; Toxic effect; Ultrafiltration; Zeolites; absorption; beta-Cyclodextrins; blood glucose regulation; clinically relevant; cytotoxic; cytotoxicity; cytotoxicity test; design; diabetes management; diabetes mellitus therapy; drinking water; euglycemia; in vivo; manufacture; mouse model; novel; pharmacokinetics and pharmacodynamics; polymerization; porcine model; pre-clinical; preservation; pressure; sensor; stressor; subcutaneous; wasting; water treatment; wound healing

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.

皮下胰岛素注射（SIA）技术在过去几年中取得了重大进展 尽管如此，SIA技术的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。有限的磨损时间以及 SIA 设备位置轮换是当前的解决方案。 随着时间的推移，组织损伤和保持输注或注射部位的完整性最小化。 虽然最终是有益的，但不允许药物输送装置的性能超出目前的水平 建议佩戴时间为三天。延长 SIA 技术以符合当前的连续佩戴时间。 批准佩戴 10-14 天的葡萄糖传感器监测是一项尚未满足的重大挑战。 延长输液泵或注射端口的使用寿命，涉及克服 IPP 诱导的组织 这些装置所在位置的炎症和纤维化反应也很容易受到影响。 机械和化学应激源导致胰岛素分子无功能 即使在我们发表的 IPP 存在下，聚合也被称为胰岛素原纤维形成 (IDF)。 初步数据表明，IPP 和 IDF 均具有促炎作用。 反应会导致累积的细胞/组织毒性、炎症和适应不良的伤口愈合。 克服这一挑战，我们认为在胰岛素治疗时最佳的 IPP 减少和 IDF 去除 在线、及时给药，而不是专注于新胰岛素配方的制备 因此，该提案的目标是设计、制造和。 验证基于 ß-环糊精的在线吸附剂平台，该平台 1) 可以降低 IPP 水平 商业胰岛素制剂，以及 2) 以“及时”模式在线消除任何 IDF 形成， 即，就在 SIA 之前，通过该平台的商业胰岛素制剂能够缓解。 血糖水平不会引发急性和慢性 SIA 引起的炎症和纤维化。 将实现生理正常血糖，同时保持 SIA 部位的长期组织完整性。 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 ß- 胰岛素酚类防腐剂去除平台中基于环糊精的吸附剂，2) 设计和评估 基于微滤/超滤的膜 (MFM) 作为 IDF 去除平台，以及 3) 保存长期组织 通过使用基于 ß-环糊精的吸附剂（珠子和 MFM）在 SIA 期间提高完整性和生物活性 最终，在临床前猪模型中成功实现了这一目标。 该项目可能会改变当前的糖尿病管理实践，从而实现目标 延长胰岛素输注装置的使用寿命，最重要的是维持组织部位的活力 用于未来的反复胰岛素给药。