The Horizontal Ussing Chamber Method in Studies of Nasal Drug Delivery : Method Development and Applications Using Different Formulations

Abstract: The results from this thesis leads to the following conclusions; HUM is a useful tool that fills a gap in the in vitro methods previously available to study nasal drug delivery. Using HUM, the pig respiratory nasal mucosa can obtain acceptable viability and retain it longer than the period of time needed for a transport experiment. HUM has proven to be an appropriate tool for the study of liquids in low volume, gels, both unmodified and with controlled release properties, and particle suspensions. The potential local toxicity of formulations such as controlled release gels and surfactants could be evaluated and graded using HUM. The estimation of the apparent permeability can be corrected on a mathematical basis, for substances that bind to the chamber material. As seen using HUM, unmodified gels from Carbopol 934 (C934) are well tolerated by the nasal mucosa and may consequently be suitable for nasal administration. The release rate of testostenone, dihydroalprenolol and hydrocortisone from C934 gels can be successfully sustained. Protein-conjugated starch microparticles, intended to function as a vaccine carrier system, were taken up by non-ciliated epithelial cells of the pig respiratory nasal mucosa after incubation using HUM. The concentration-dependent effects on permeability and transepithelial electrical resistance on Caco-2 cells, of a series of nonionic polyoxyethylene surfactants, correlated with surfactant structure. Similar effects were seen on pig nasal mucosa using HUM, but the nasal mucosa appeared to be more tolerant to the surfactants than the intestinal cell model.The nasal route has advantages for several classes of drugs e.g. involved in migrain treatment, nicotine substitution therapy and mucosal vaccination. The increased development of a variety of substances, in a variety of formulation types, has increased the demand for suitable investigational tools. It is in this context that the horizontal Ussing chamber method (HUM) was developed. Using HUM, the studied formulation can be applied on the mucosa without additional buffer, giving an in vivo-like situation and the possibility to study solid and semi-solid formulations. Furthermore, the influence of gravity will not result in uneven distribution of the formulation.