Stabilized Glucagon Formulation for Bihormonal Pump Use

Steiner, Solomon S.; Li, Ming; Hauser, Robert G.; Pohl, Roderike

doi:10.1177/193229681000400606

Cited by 37 publications

(26 citation statements)

References 23 publications

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“…There are several research groups addressing alternative formulations of glucagon to achieve stability, some of which involve creation of glucagon analogs [6]. Other approaches include the use of non-aqueous solvents (Xeris Pharmaceuticals) and the use of surfactants to increase solubility in the neutral pH range [30]. …”

Section: Discussionmentioning

confidence: 99%

Mechanisms of glucagon degradation at alkaline pH

et al. 2013

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Glucagon is unstable and undergoes degradation and aggregation in aqueous solution. For this reason, its use in portable pumps for closed loop management of diabetes is limited to very short periods. In this study, we sought to identify the degradation mechanisms and the bioactivity of specific degradation products. We studied degradation in the alkaline range, a range at which aggregation is minimized. Native glucagon and analogs identical to glucagon degradation products were synthesized. To quantify biological activity in glucagon and in the degradation peptides, a protein kinase A-based bioassay was used. Aged, fresh, and modified peptides were analyzed by liquid chromatography with mass spectrometry (LCMS). Oxidation of glucagon at the Met residue was common but did not reduce bioactivity. Deamidation and isomerization were also common and were more prevalent at pH 10 than 9. The biological effects of deamidation and isomerization were unpredictable; deamidation at some sites did not reduce bioactivity. Deamidation of Gln 3, isomerization of Asp 9, and deamidation with isomerization at Asn 28 all caused marked potency loss. Studies with molecular-weight-cutoff membranes and LCMS revealed much greater fibrillation at pH 9 than 10. Further work is necessary to determine formulations of glucagon that minimize degradation and fibrillation.

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Section: Discussionmentioning

confidence: 99%

Mechanisms of glucagon degradation at alkaline pH

et al. 2013

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“…11 The chemical degradation of glucagon was quantitated by UPLC over a 10-day period. Samples that gelled were not quantifiable, thus Lilly glucagon at pH 4 past 3 days and Lilly glucagon at pH 2 after 6 days have no data (Figure 4).…”

Section: Biod-903-stability Profile Of the Prototype Lmpc-based Glucamentioning

confidence: 99%

Development of Stable Liquid Glucagon Formulations for Use in Artificial Pancreas

Pohl

Krasner

et al. 2014

J Diabetes Sci Technol

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A promising approach to treat diabetes is the development of fully automated artificial/bionic pancreas systems that use both insulin and glucagon to maintain euglycemia. A physically and chemically stable liquid formulation of glucagon does not currently exist. Our goal is to develop a glucagon formulation that is stable as a clear and gel-free solution, free of fibrils and that has the requisite long-term shelf life for storage in the supply chain, short-term stability for at least 7 days at 37°C, and pump compatibility for use in a bihormonal pump. We report the development of two distinct families of stable liquid glucagon formulations which utilize surfactant or surfactant-like excipients (LMPC and DDM) to "immobilize" the glucagon in solution potentially through the formation of micelles and prevention of interaction between glucagon molecules. Data are presented that demonstrate long-term physical and chemical stability (~2 years) at 5°C, short-term stability (up to 1 month) under accelerated 37°C testing conditions, pump compatibility for up to 9 days, and adequate glucose responses in dogs and diabetic swine. These stable glucagon formulations show utility and promise for further development in artificial pancreas systems.

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“…Like the alkaline preparation discussed above and the other approaches discussed below, the formulation has not been approved by the FDA. The Biodel formulation was found to be reasonably stable by reverse-phase HPLC over several weeks [17]. For more details regarding the Biodel approach, the reader is referred to a published patent application [18].…”

Section: Degradation Of Glucagonmentioning

confidence: 99%

Stable Liquid Glucagon Formulations for Rescue Treatment and Bi-Hormonal Closed-Loop Pancreas

et al. 2012

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Small doses of glucagon given subcutaneously in the research setting by an automated system prevent most cases of hypoglycemia in persons with diabetes. However, glucagon is very unstable and cannot be kept in a portable pump. Glucagon rapidly forms amyloid fibrils, even within the first day after reconstitution. Aggregation eventually leads to insoluble gels, which occlude pump catheters. Fibrillation occurs rapidly at acid pH, but is absent or minimal at alkaline pH values of ~10. Glucagon also degrades over time; this problem is greater at alkaline pH. Several studies suggest that its primary degradative pathway is deamidation, which results in a conversion of asparagine to aspartic acid. A cell-based assay for glucagon bioactivity that assesses glucagon receptor (GluR) activation can screen promising glucagon formulations. However, mammalian hepatocytes are usually problematic as they can lose GluR expression during culture. Assays for cyclic AMP (cAMP) or its downstream effector, protein kinase A (PKA), in engineered cell systems, are more reliable and suitable for inexpensive, high-throughput assessment of bioactivity.

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Stabilized Glucagon Formulation for Bihormonal Pump Use

Abstract: Biodel glucagon is a stabilized formulation at physiological pH and remains chemically and physically stable beyond 7 days at 37 °C, suggesting its utility for use in a bihormonal pump.

Cited by 37 publications

References 23 publications

Mechanisms of glucagon degradation at alkaline pH

Mechanisms of glucagon degradation at alkaline pH

Development of Stable Liquid Glucagon Formulations for Use in Artificial Pancreas

Stable Liquid Glucagon Formulations for Rescue Treatment and Bi-Hormonal Closed-Loop Pancreas

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