Nonclinical safety and pharmacokinetics of Miglyol 812: A medium chain triglyceride in exenatide once weekly suspension

Abstract

Exenatide, a glucagon-like peptide-1 receptor agonist was originally developed as either a twice daily or once weekly injectable therapeutic for patients with type 2 diabetes. Exenatide QW suspension was developed for use with an autoinjector device, in which the microspheres are suspended in Miglyol 812, a mixture of medium chain triglycerides (MCTs). MCTs are a class of lipids whose fatty acid chains contain from six to 12 carbon atoms (medium chain fatty acids or MCFAs). While MCTs are edible oils present in many foods, including foodstuffs containing coconut and palm kernel oils, limited information is available regarding the oral and subcutaneous bioavailability of MCTs as well as safety following subcutaneous injection. These studies were designed to investigate the non-clinical pharmacokinetics and safety of MCTs. In a single dose pharmacokinetic study, MCFAs were rapidly detected in the plasma of rats following oral administration of either Miglyol 812 or tricaprylin at doses of 10 or 9.48 g kg , respectively. Following subcutaneous dosing with Miglyol 812, MCFAs were rapidly absorbed with a similar profile to that following oral dosing. Furthermore, the toxicity of Miglyol 812 alone was evaluated in a 3 month repeat dose toxicology studies in cynomolgus monkeys. In this study, weekly subcutaneous doses of 0.15 g kg did not elicit any treatment-related effects in cynomolgus monkeys. In conclusion, these studies alongside the available literature data show that Miglyol 812 is a safe excipient for use in subcutaneously administered therapeutics.

Translational Significance of GMF-β Inhibition by Indazole-4-yl-methanol in Enteric Glial Cells for Treating Multiple Sclerosis

“…In fact, Miglyol is a biocompatible carrier of choice for prolonged drug delivery of compounds via s.c./p.o. with higher retention time due to its low viscosity …”

“…with higher retention time due to its low viscosity. 26 In silico toxicological analysis of the GMFBI.1 compound suggested its increased safety compared to FDA-approved current MS small-molecule therapeutics (Table S2 and Figure. S3).…”

How an organogelator can gelate water: gelation transfer from oil to water induced by a nanoemulsion

“…The oil phase was Miglyol s 812, a biocompatible mediumchain triglyceride used in toxicology studies. 36 As organogelator we selected 12-hydroxyoctadecanoic acid (12-HOA), also biocompatible and used in pharmaceutical applications. 37 Another point of interest of 12-HOA lies in its gelling power, allowing the gelation of many oils and organics solvents, even at very low concentrations.…”

“…PIT emulsification is based on the changes in the solubility (curvature) of surfactants depending on the temperature. [33][34][35][36][37] For example, nonionic surfactants of the polyoxyethylene kinds are hydrophilic and soluble in water at low temperatures. 30 When the temperature is raised, they turn lipophilic and become more soluble in the oil phase.…”