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DANBURY, CT, United States

Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 582.76K | Year: 2012

DESCRIPTION (provided by applicant): A device system which automatically maintain blood glucose concentrations in the normal range by dosing insulin in response to continuously sensed glucose concentration data represents a modern attempt to mechanically simulate normal beta cell physiology and solve many of the problems associated with intensive insulin therapy today, including improving the quality of life for patients with diabetes and improving glucose control. The development of such a closed loopartificial pancreas algorithmically linking continuous glucose sensors with insulin infusion pumps is an active area of research. Most studies with experimental artificial pancreas (AP) systems which have used insulin only have shown that hypoglycemia requiring carbohydrate administrations has not been eliminated using multiple experimental algorithms. The insulin- only approach to the artificial pancreas does not fully mimic normal physiology in that there is no ability to abort impending hypoglycemia through the use of counter-regulatory hormones. The only way for such insulin only AP system to react to declining glucose concentrations is to reduce or stop infusing subcutaneous insulin. This will not guarantee prompt termination of insulin effect in part because of residual depots of insulin in the subcutaneous space. In normal physiology, pancreatic alpha cells secrete glucagon to counter the glucose lowering effect of insulin. One of these counter-regulatory hormones is glucagon, a 29 amino acid peptide which stimulates the conversion of glycogen stored in the liver into glucose (glycogenolysis). Recent closed loop insulin studies in which glucagon is also used algorithmically to prevent impeding hypoglycemia have shown excellent glucose control with verylow rates of hypoglycemia. Glucagon in its currently marketed form however is chemically and physically unstable in solution and therefore not practical for clinical development in bi-hormonal artificial pancreas systems. Biodel scientist have prepared labformulations of aqueous glucagon at pH 7 that remain stable in solution. In this application, Biodel proposes to optimize multiple pH 7 aqueous formulations of glucagon to provide a minimum of 18 month stability under refrigerated and if possible, room temperature (25C) conditions for long-term storage requirements. We will assess whether all current US Pharmacopeia (USP) compendia methods are applicable to these formulations and we will develop suitable methods if required. We will demonstrate biologicalactivity in a swine model and we will demonstrate that our formulation is compatible with a marketed insulin pump system at elevated temperatures for at least 9 days. PUBLIC HEALTH RELEVANCE: The full benefits of intensive insulin therapy for patients with diabetes have yet to be realized in large part because it is extremely difficult to optimize continuously variable insulin dose requirements using current technology and because of the inability to eliminate hypoglycemia. The development of closed loop artificial pancreas systems is an active area of research which promises to address the first problem; however initial studies of insulin-only systems have not shown elimination of hypoglycemia. The addition of algorithmically delivered glucagon aspart of a bi-hormonal closed loop system has been shown to result in very low hypoglycemia rates. However, currently marketed formulations of glucagon are chemically and physically unstable at high temperatures and are not likely to be practical for continuous infusion through insulin pumps. In this application, Biodel proposes a strategy to develop a stable glucagon formulation suitable for continuous pump delivery.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 582.47K | Year: 2012

DESCRIPTION (provided by applicant): Extreme insulin resistance in patients with diabetes is defined as insulin dose requirement of greater than 200 units daily. Currently, U-500 regular insulin is frequently used to treat these patients, however, the slowabsorption and prolonged duration of action associated with this formulation does not lend itself to effective closed loop insulin pump therapy. A more rapidly absorbed formulation of concentrated insulin would be desirable in this scenario and would provide the additional benefit of taking up less volume than current insulin preparations. Biodel has studied formulations of recombinant human insulin designed for ultra-rapid absorption at meal time. These formulations use EDTA to chelate zinc atoms, destabilizing recombinant human insulin hexamers. Citric acid is also used to mask surface charges on the insulin molecules inhibiting re-aggregation of monomers and directly facilitating absorption. Experiments to date have shown that EDTA/citrate based formulations at concentrations of up to 400 units/ml remain soluble and stable at 5 C. In this application, Biodel proposes to optimize multiple pH 7 aqueous formulations of concentrated recombinant human insulin together with excipients which in U-100 formulations have been shown to be ultra-rapid acting, to provide a minimum of 18 month stability under refrigerated conditions. We will ensure that all current US Pharmacopeia (USP) compendia methods are applicable to these formulations and will develop suitable methods if required. We will demonstrate biological activity in a diabetic swine model and will demonstrate that our formulation is compatible with a marketed insulin pump system for at least 14 days. PUBLIC HEALTH RELEVANCE: Severe insulin resistance in patients with diabetes is defined as insulin dose requirement of greater than 200 units daily. This is usually treated with U-500 regular insulin, the use of which has nearly doubled since 2008. U-500 is associated with long period to peak effect anda prolonged duration of action, both of which make it not desirable for use in pumps, particularly in the setting of closed loop insulin systems. A more rapidly absorbed formulation of concentrated insulin would be desirable in this setting and would provide the additional benefit of taking up less space than current insulin preparations. In this application, Biodel proposes a strategy to develop concentrated insulin with more rapid absorption properties for use in insulin pumps.

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