Effects of Excipients on the Chemical and Physical Stability of Glucagon during Freeze-Drying and Storage in Dried Formulations

Fang, Wei-Jie; Wei, Qi; Kinzell, John H.; Prestrelski, Steven J.; Carpenter, John F.

doi:10.1007/s11095-012-0820-7

Cited by 26 publications

(23 citation statements)

References 37 publications

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“…11 There remains an unmet need for a stable glucagon formulation. Xeris Pharmaceuticals is developing a bodytemperature stable, soluble liquid glucagon formulation, G-Pump™ glucagon, that can be administered with an infusion pump, 12,13 and it has been safely administered to adults with type 1 diabetes via syringes.…”

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confidence: 99%

Comparative Pharmacokinetic/Pharmacodynamic Study of Liquid Stable Glucagon Versus Lyophilized Glucagon in Type 1 Diabetes Subjects

Castle

Youssef

Branigan

et al. 2016

J Diabetes Sci Technol

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Background: There is currently no stable liquid form of glucagon commercially available. The aim of this study is to assess the speed of absorption and onset of action of G-Pump™ glucagon at 3 doses as compared to GlucaGen®, all delivered subcutaneously via an OmniPod®. Methods: Nineteen adult subjects with type 1 diabetes participated in this Phase 2, randomized, double-blind, cross-over, pharmacokinetic/pharmacodynamic study. Subjects were given 0.3, 1.2, and 2.0 µg/kg each of G-Pump glucagon and GlucaGen via an OmniPod. Results: G-Pump glucagon effectively increased blood glucose levels in a dose-dependent fashion with a glucose Cmax of 183, 200, and 210 mg/dL at doses of 0.3, 1.2, and 2.0 µg/kg, respectively ( P = ns vs GlucaGen). Mean increases in blood glucose from baseline were 29.2, 52.9, and 77.7 mg/dL for G-Pump doses of 0.3, 1.2, and 2.0 µg/kg, respectively. There were no statistically significant differences between treatments in the glucose T50%-early or glucagon T50%-early with one exception. The glucagon T50%-early was greater following G-Pump treatment at the 2.0 μg/kg dose (13.9 ± 4.7 min) compared with GlucaGen treatment at the 2.0 μg/kg dose (11.0 ± 3.1 min, P = .018). There was more pain and erythema at the infusion site with G-Pump as compared to GlucaGen. No serious adverse events were reported, and no unexpected safety issues were observed. Conclusions: G-Pump glucagon is a novel, stable glucagon formulation with similar PK/PD properties as GlucaGen, but was associated with more pain and infusion site reactions as the dose increased, as compared to GlucaGen.

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confidence: 99%

Comparative Pharmacokinetic/Pharmacodynamic Study of Liquid Stable Glucagon Versus Lyophilized Glucagon in Type 1 Diabetes Subjects

Castle

Youssef

Branigan

et al. 2016

J Diabetes Sci Technol

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“…Also, empty pans are often used on the reference surface. Calibration of the instruments before use is often done using Indium as a standard [30,34], which displays a consistent melting onset temperature and heat of fusion. As described above, scan rates are typically much faster in solid DSC instruments than solution instruments to increase the sensitivity to small signal changes.…”

Section: Solid-dsc Operational Considerationsmentioning

confidence: 99%

Differential Scanning Calorimetry in the Biopharmaceutical Sciences

Demarest

Frasca²

2015

Biophysical Characterization of Proteins in Developing Biopharmaceuticals

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“…However, in order to ensure long term stability of protein pharmaceutical preparations, the moisture level shouldn't exceed 9% which is enough to J U S T A C C E P T E D hydrate the active site cleft of the proteins (16). Some excipients has cryoprotective and lyoprotective properties accordingly used to stabilise proteins in freeze drying process (see for examples; hydroxyethyl cellulose used with lactate dehydrogenase (17), polysorbate 20, trehalose, β-cyclodextrin and hydroxylethyl starch with glucagon (18), trehalose with insulin (19), pluronic F68 with calcitonin (20) and maltotriitol, trehalose, maltitol, and lactitol with L-lactate dehydrogenase and bovine serum albumin (21).…”

Section: Introductionmentioning

confidence: 99%

Influences of copolymers (Copovidone, Eudragit RL PO and Kollicoat MAE 30 DP) on stability and bioactivity of spray-dried and freeze-dried lysozyme

Haj-Ahmad

Mamayusupov

Elkordy

et al. 2016

Drug Development and Industrial Pharmacy

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Protein stability is the most crucial factor in protein pharmaceutical preparations. Various techniques were applied for producing stable protein formulations such as spray-drying and freeze-drying. However, heating and freezing stresses are disadvantages for proteins using these methods, respectively. Accordingly, excipients have been used to preserve therapeutic effects of proteins during processing and for long period of time. Therefore, influences of Copovidone, Eudragit® RL-PO and Kollicoat® MAE-30 DP (as excipients) on stability and integrity of lysozyme (as a model protein) in spray-dried and freeze-dried forms were investigated. Protein formulations in both dried forms were prepared without and with the addition of mentioned excipients at different concentrations. Protein formulations were characterised for yield determination, morphology using scanning electron microscopic (SEM), thermal analysis by Differential Scanning Calorimetry (DSC), secondary structure stability using Fourier transform infrared (FT-IR) spectroscopy and biological activity. All protein formulations were subjected to a stability study as solid protein formulations for 3 weeks at 24 °C/76% relative humidity and aqueous protein samples were stored at 50°C for 30 minutes in a water bath. Results showed that Copovidone successfully preserved integrity and biological activity of lysozyme before and after storage in both spray-dried and freezedried forms with more advantage for using higher concentration of the same excipient.Smooth spheres of spray-dried lysozyme formulations with Copovidone were smaller than spray-dried lysozyme without and with Kollicoat® MAE-30 DP, which affected %yield produced. Copovidone has demonstrated valuable protection ability for lysozyme.

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Effects of Excipients on the Chemical and Physical Stability of Glucagon during Freeze-Drying and Storage in Dried Formulations

Abstract: The formulation lessons learned from studies of freeze-dried formulations of proteins can be applied successfully to development of stable formulations of glucagon. However, peptides may behave differently than proteins due to their small molecule size and less ordered structure.

Cited by 26 publications

References 37 publications

Comparative Pharmacokinetic/Pharmacodynamic Study of Liquid Stable Glucagon Versus Lyophilized Glucagon in Type 1 Diabetes Subjects

Comparative Pharmacokinetic/Pharmacodynamic Study of Liquid Stable Glucagon Versus Lyophilized Glucagon in Type 1 Diabetes Subjects

Differential Scanning Calorimetry in the Biopharmaceutical Sciences

Influences of copolymers (Copovidone, Eudragit RL PO and Kollicoat MAE 30 DP) on stability and bioactivity of spray-dried and freeze-dried lysozyme

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