2. Academic Validation
  3. A co-formulation of supramolecularly stabilized insulin and pramlintide enhances mealtime glucagon suppression in diabetic pigs

A co-formulation of supramolecularly stabilized insulin and pramlintide enhances mealtime glucagon suppression in diabetic pigs

  • Nat Biomed Eng. 2020 May;4(5):507-517. doi: 10.1038/s41551-020-0555-4.
Caitlin L Maikawa 1,  Anton A A Smith 2 3,  Lei Zou 4,  Gillie A Roth 1,  Emily C Gale 5,  Lyndsay M Stapleton 1,  Sam W Baker 6,  Joseph L Mann 2,  Anthony C Yu 2,  Santiago Correa 2,  Abigail K Grosskopf 7,  Celine S Liong 1,  Catherine M Meis 2,  Doreen Chan 8,  Megan Troxell 9,  David M Maahs 10 11,  Bruce A Buckingham 10 11,  Matthew J Webber 4,  Eric A Appel 12 13 14 15
Affiliations

Affiliations

  • 1 Department of Bioengineering, Stanford University, Stanford, CA, USA.
  • 2 Department of Materials Science and Engineering, Stanford University, Stanford, CA, USA.
  • 3 Department of Science and Technology, Aarhus University, Aarhus, Denmark.
  • 4 Department of Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, IN, USA.
  • 5 Department of Biochemistry, Stanford University, Stanford, CA, USA.
  • 6 Department of Comparative Medicine, Stanford University, Stanford, CA, USA.
  • 7 Department of Chemical Engineering, Stanford University, Stanford, CA, USA.
  • 8 Department of Chemistry, Stanford University, Stanford, CA, USA.
  • 9 Department of Pathology, Stanford University, Stanford, CA, USA.
  • 10 Department of Pediatrics (Endocrinology), Stanford University, Stanford, CA, USA.
  • 11 Diabetes Research Center, Stanford University, Stanford, CA, USA.
  • 12 Department of Bioengineering, Stanford University, Stanford, CA, USA. eappel@stanford.edu.
  • 13 Department of Materials Science and Engineering, Stanford University, Stanford, CA, USA. eappel@stanford.edu.
  • 14 Department of Pediatrics (Endocrinology), Stanford University, Stanford, CA, USA. eappel@stanford.edu.
  • 15 Diabetes Research Center, Stanford University, Stanford, CA, USA. eappel@stanford.edu.
PMID: 32393892 DOI: 10.1038/s41551-020-0555-4
Abstract

Treatment of patients with diabetes with Insulin and pramlintide (an amylin analogue) is more effective than treatment with Insulin only. However, because mixtures of Insulin and pramlintide are unstable and have to be injected separately, amylin analogues are only used by 1.5% of people with diabetes needing rapid-acting Insulin. Here, we show that the supramolecular modification of Insulin and pramlintide with cucurbit[7]uril-conjugated polyethylene glycol improves the pharmacokinetics of the dual-hormone therapy and enhances postprandial glucagon suppression in diabetic pigs. The co-formulation is stable for over 100 h at 37 °C under continuous agitation, whereas commercial formulations of Insulin analogues aggregate after 10 h under similar conditions. In diabetic rats, the administration of the stabilized co-formulation increased the area-of-overlap ratio of the pharmacokinetic curves of pramlintide and Insulin from 0.4 ± 0.2 to 0.7 ± 0.1 (mean ± s.d.) for the separate administration of the Hormones. The co-administration of supramolecularly stabilized Insulin and pramlintide better mimics the endogenous kinetics of co-secreted Insulin and amylin, and holds promise as a dual-hormone replacement therapy.

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