Ultra‐Fast Insulin–Pramlintide Co‐Formulation for Improved Glucose Management in Diabetic Rats
Open Access
- 9 September 2021
- journal article
- research article
- Published by Wiley in Advanced Science
- Vol. 8 (21), 2101575
- https://doi.org/10.1002/advs.202101575
Abstract
Dual-hormone replacement therapy with insulin and amylin in patients with type 1 diabetes has the potential to improve glucose management. Unfortunately, currently available formulations require burdensome separate injections at mealtimes and have disparate pharmacokinetics that do not mimic endogenous co-secretion. Here, amphiphilic acrylamide copolymers are used to create a stable co-formulation of monomeric insulin and amylin analogues (lispro and pramlintide) with synchronous pharmacokinetics and ultra-rapid action. The co-formulation is stable for over 16 h under stressed aging conditions, whereas commercial insulin lispro (Humalog) aggregates in 8 h. The faster pharmacokinetics of monomeric insulin in this co-formulation result in increased insulin–pramlintide overlap of 75 ± 6% compared to only 47 ± 7% for separate injections. The co-formulation results in similar delay in gastric emptying compared to pramlintide delivered separately. In a glucose challenge, in rats, the co-formulation reduces deviation from baseline glucose compared to insulin only, or separate insulin and pramlintide administrations. Further, comparison of interspecies pharmacokinetics of monomeric pramlintide suggests that pharmacokinetics observed for the co-formulation will be well preserved in future translation to humans. Together these results suggest that the co-formulation has the potential to improve mealtime glucose management and reduce patient burden in the treatment of diabetes.Funding Information
- Stanford Diabetes Research Center (NIDDK #P30DK116074)
- Pharmaceutical Research and Manufacturers of America Foundation
This publication has 46 references indexed in Scilit:
- Streptozotocin‐Induced Diabetic Models in Mice and RatsCurrent Protocols in Pharmacology, 2008
- A Double-Blind, Placebo-Controlled Trial Assessing Pramlintide Treatment in the Setting of Intensive Insulin Therapy in Type 1 DiabetesDiabetes Care, 2006
- Advantage of Premeal-Injected Insulin Glulisine Compared With Regular Human Insulin in Subjects With Type 1 DiabetesDiabetes Care, 2006
- The Physiology of Amylin and Insulin: Maintaining the Balance Between Glucose Secretion and Glucose UptakeThe Diabetes Educator, 2006
- Pramlintide in the treatment of type 1 and type 2 diabetes mellitusClinical Therapeutics, 2005
- Adjunctive Therapy with Pramlintide Lowers HbA1c without Concomitant Weight Gain and Increased Risk of Severe Hypoglycemia in Patients with Type 1 Diabetes Approaching Glycemic TargetsExperimental and Clinical Endocrinology & Diabetes, 2005
- Amylin replacement with pramlintide as an adjunct to insulin therapy improves long‐term glycaemic and weight control in Type 1 diabetes mellitus: a 1‐year, randomized controlled trialDiabetic Medicine, 2004
- Insulin LisproThe New England Journal of Medicine, 1997
- Mechanism of insulin aggregation and stabilization in agitated aqueous solutionsBiotechnology & Bioengineering, 1992
- Amylin concentrations and glucose controlThe Lancet, 1992