Objective
The project aims to improve blood glucose control performance of automated insulin delivery (AID) systems by developing a new generation of ultrafast-acting insulin (UFI) and ultra-concentrated insulin (UCI) formulations. The delayed action of insulin after subcutaneous infusion followed by a long duration of activity is the main cause of the spike in glucose level after a meal and the subsequent post-meal hypoglycemia. The project seeks to tackle the challenge by introducing a new generation of UFI, taking advantage of its unique monomeric status in the formulation. The monomeric UFI would display faster absorption and shorter duration action compared with commercially available rapid-acting insulins, which take an extra dissociation step into monomeric insulin, before being active in bloodstream absorption. In addition to portable insulin pumps, the more physiological intraperitoneal insulin delivery via implanted insulin pumps (IIPs) has enormous glycemic control potential over subcutaneous insulin delivery. Nonetheless, frequent clinic visits for insulin refill (every ~6-12 weeks) and flushing (every ~6-9 months), greatly prevent the accessibility of IIPs to large T1D populations, despite their large clinical benefits. Thus, another objective is to fulfill an unmet need for stable UCI, which can provide potential benefits to the optimal long-term performance of insulin delivery devices, especially the next-generation IIPs.
Background Rationale
Currently, automated insulin delivery (AID) systems provide advanced glycemic control to relieve the burden of T1D patients, but the high occurrence of out-of-range post-prandial glucose fluctuation is not negligible. Clinical results indicated the patients with closed-loop insulin pumps had an average 63% of the time spent in the normal range of 72-144 mg/dL, still far from what a healthy pancreas can provide (99.2% time <140 mg/dL). The challenge for tight blood glucose control, even with the assistance of AID, is due to the delays of insulin absorption and the long duration of action in subcutaneous tissue after injections. To address this issue, two approaches are worth highlighting. The first focus is on developing ultrafast-acting insulin (UFI) formulations, with faster onset and shorter duration of action, to enhance compliance with mealtime insulin administration. Several fast-acting insulin formulations (e.g., Novolog®, Fiasp®, Humalog®, Lyumjev®) have already been introduced and applied to AID systems as meal bolus, but the outcomes are modest. Even with the introduction of current fast-acting formulations, the greatest postprandial glucose reduction is obtained when administering these insulin products 15 min before a meal, which is far behind that of endogenous insulin in non-diabetic individuals. Previous research found that the rate-limiting step for this insulin absorption into the bloodstream is the dissociation of highly-associated insulin molecules into monomeric insulin. As such, it is beneficial to develop a novel UFI with stable monomeric insulin in formulation, which will be able to diffuse into the bloodstream instantly without an extra dissociation step. In addition to UFI, the second focus is on the much faster insulin absorption via the intraperitoneal route over the subcutaneous one, which leads to the exploration of implanted insulin pumps (IIPs) that are able to deliver insulin directly into the abdominal space. IIPs are able to exhibit a more physiological insulin secretion activity and have been demonstrated with superior clinical performance on blood glucose control. However, the clinical benefit of IIPs is hindered by the burden of frequent doctor visit for pump refills. The only IIPs model that was commercially available is Medtronic MiniMed™ Insulin Pump. The insulin reservoir can hold 2- to 3- month supply of concentrated U-400 insulin (400 U/ml) and need percutaneous refills under strict aseptic conditions by physicians. Moreover, systematically rinsing the pump every 6–9 months is recommended for the concern of precipitates formed by insulin aggregation. Therefore, to promote the translation of IIPs into the wide type 1 diabetes population, there is an urgent need for stable ultra-concentrated insulin (UCI) formulation to reduce the frequency of clinic visits and concern for insulin aggregation. However, the most concentrated insulin formulation approved by FDA currently is Humulin R U-500 (500 U/ml). To address these above-mentioned challenges, this project aims to develop novel UFI and UCI formulations for applications in AID as well as the future use of IIPs, ultimately promoting type 1 diabetes management with tight blood glucose control.
Description of Project
Automated insulin delivery (AID) system (i.e., artificial pancreas) has a great potential to improve glucose control and reduce the burden of type 1 diabetes management. In addition to the insulin pump, continuous glucose monitor, and control algorithm, insulin formulation is a key component required for the development of effective full closed-loop AID systems. However, the delays in insulin absorption bring up a critical challenge for realizing tight blood glucose control without the need for a carefully-timed pre-meal announcement. Even the most fast-acting insulin formulations available for mealtime boluses exhibit a delayed onset of action and an extended duration of action, which is far from endogenous insulin secretion and can increase the risk of hypoglycemia as insulin may remain on board even after the mealtime glucose load passes. These delayed actions are an outcome of the mixed association states of insulin in formulation, which must dissociate into monomers to reach the bloodstream. Therefore, to improve glucose control in AID systems, design of novel ultrafast-acting insulin (UFI) formulation, or circumvent the subcutaneous delay by delivering insulin via a more physiological intraperitoneal route (i.e., implanted insulin pumps that deliver insulin directly into the abdominal space) should be considered. In this context, this project is constructed on developing novel insulin formulations that are able to address these challenges. A monomeric UFI formulation that is able to achieve faster onset and tighter duration action will be developed to integrate with subcutaneous AID systems. A much-needed stable ultra-concentrated insulin (UCI) formulation that allows future use of implanted insulin pumps (IIPs) will also be established, with potential benefits to reduce the insulin aggregation problem and extend the usage time between clinic visits for pump refill. The availability of UFI and UCI formulations proposed in this project would be promising for developing the next-generation AID systems and further increase the quality of life for people with type 1 diabetes.
Anticipated Outcome
The project is anticipated to develop two novel insulin formulations for the application in automated insulin delivery (AID). An ultrafast-acting insulin (UFI) will be developed based on novel monomeric insulin. The UFI is expected to exhibit more rapid onset action and a shorter duration of action compared with the fast-acting insulins on the market (e.g., Novolog, Fiasp). Such UFI will be able to be administrated with a meal (or within 5 minutes before) to get optimal postprandial glucose control, rather than 15-30 minutes before a meal as required when using other fast-acting insulins on the market. In addition, an ultra-concentrated insulin (UCI) formulation will be established (at least 1000 U/ml) to achieve long-term stability, and maintain bioactivity without insulin precipitation after months of carriage in insulin pumps. The availability of the UCI would allow future use of implanted insulin pumps (IIPs), which would further increase the quality of life for people with diabetes. The project is expected to provide ideal therapeutic formulation options for improving the glucose control performance of insulin pumps with AID systems.
Relevance to T1D
Intensive insulin therapy is critical for people with type 1 diabetes (T1D) to regulate blood glucose levels in the normal range. Research advances in automated insulin delivery (AID) systems (i.e., artificial pancreas) have great potential to improve glucose control and reduce the burden of T1D management. However, owing to limitations of onset speed and action duration of the most rapid-acting subcutaneous insulins currently available, the glucose control is challenging even with the assistance of AID, and the fear of hypoglycemia after meal bolus is a major concern for people with T1D. This project intends to tackle the challenge of implementing AID application, by developing novel insulin formulations that enable a tighter insulin onset action and duration, for reducing blood glucose variability and optimizing T1D management.