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

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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.