Comparative research of effects of permeability enhancers on the effectiveness of model protein (insulin) administered via the inhalation route

Abstract

Relevance.Inhalation administration of compounds with peptide and protein structure may be promising in provision of emergency medical assistance in emergency situations, including radiation injuries. The development of inhalation dosage forms for compounds with peptide and protein structure requires the selection of excipients to increase their bioavailability.Intention.To assess effects of permeability enhancers on the effectiveness of a model biologically active substance of protein nature (insulin) by inhalation.Methods.The experiments were carried out in outbred white male rats with initial weight of 180–220 g. To assess the effectiveness of insulin and permeability enhancers, they were administered via intranasal and intratracheal routes using a MicroSprayer® IA-2B instillation probe (Penn Century, USA). The list of biological membrane permeability enhancers under investigation (Sigma-Aldrich, USA) includes the following substances: methyl-β-cyclodextrin, dimethyl-β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, Tween-80, sodium methyl oleate, oleic acid, sodium taurocholate, sodium glycocholate, Pluronic F-68, tesit, Brij-35, saponin, cetylpyridine.Results and Discussion. Insulin bioavailability without permeability enhancers does not exceed 0.5% when administered intranasally. When assessing effects of multiple doses of permeability enhancers on food and water consumption in animals over time, decreased parameters under study were observed in the control and experimental groups compared to intact animals. Multiple intratracheal administration of solutions to rats can lead to some infectious complications.Conclusion. Such excipients as sodium taurocholate, dimethyl-β-cyclodextrin and Тween-80 in a concentration of 5 % increase bioavailability and intensity of biological effects of insulin when administered intranasally. The surfactants Brij-35, Тween-80 and sodium taurocholate in a concentration of 0.25 % increase the duration of biological effects of insulin when administered intratracheally. Sodium taurocholate and Tween-80 in a concentration of 0.25 % have the lowest toxicity during multiple intratracheal administration.