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; 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.

皮下胰岛素给药（SIA）技术的重大进展已在 过去二十年。尽管如此，SIA技术故障和胰岛素造成的潜在组织损害 所有商业胰岛素配方中存在的酚类防腐剂（IPP）可能阻碍 SIA技术。 SIA设备站点旋转完成的磨损时间有限是目前的解决方案 随着时间的推移，最大程度地减少组织损伤并保持输注或注射部位的完整性。这些做法， 虽然最终有益，但不允许药物输送设备超出当前 建议磨损时间为三天。扩展SIA技术以与当前连续 葡萄糖监测传感器批准了10-14天的磨损，这是一个很大的未满足需求。挑战 延长输液泵或注入端口的寿命涉及覆盖IPP诱导的组织 这些设备位置的炎症和纤维化的反应。胰岛素配方也易感 通过机械和化学应激源，导致非功能性胰岛素分子通过 即使在IPP存在下，聚合被指定为胰岛素原纤维形成（IDF）。我们出版了 并且初步数据表明IPP和IDF都是促炎性的。这种亲炎 反应导致累积细胞/组织毒性，感染和适应不良的伤口愈合。到 克服这一挑战，我们在胰岛素时选择最佳的IPP减少和IDF去除 剂量，在线和及时，而不是专注于准备新胰岛素配方的准备 提供更优雅的解决方案。这是该提议的目的是设计，捏造和 验证一个基于ß-Cyclodextrin的内在吸附剂平台，1）可以降低IPP水平 商业胰岛素公式，以及2）在线删除任何IDF编队，以“及时”模式删除 即，在SIA之前。通过该平台通过的商业胰岛素公式能够减轻 血糖水平没有触发急性和慢性SIA诱导的注射和纤维化。这 可以在SIA部位保留长期组织完整性的同时，达到物理优化。到 实现这些目标，我们已经开发了以下三个特定目标：1）设计和评估ß- 胰岛素酚类防腐剂清除平台中的基于环糊精的吸附剂，2）设计和评估 作为IDF拆卸平台，基于微/超滤的机制（MFM），3）保留长期组织 SIA期间通过使用基于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。最终，成功的成就 项目可能会导致当前的糖尿病管理实践，以实现目标 增加胰岛素输注装置的寿命，最重要的是，维持组织位点的生存能力 用于将来的经常性胰岛素管理。