Molecular associations and transport properties of amphiphiles and gastrointestinal mucin in aqueous solution

Sammanfattning: An effective uptake/absorption of drug formulations involve many processes; one being the transport of the active molecule through the mucus layer. The mucus layer is a complex mixture of biological molecules. Among them, mucin is the molecule that mainly provides the gel properties of the layer. Thus, the in-vivo physico-chemical properties of the mucus can to a first approximation be mimicked by an in-vitro mucin gel. Since most of the active molecules contained in drug formulations are hydrophobic, the aqueous environment in the gastrointestinal tract frequently requires solubilization in appropriate drug delivery carriers. Surfactants are one of the most common excipient used to form these carriers. Recently, studies have shown that inclusion of cationic amphiphiles may improve the bioavailability of active molecules. Therefore, in this work, the molecular associations between nonionic/cationic model drug carriers and mucin are studied by Pulse field gradient nuclear magnetic resonance (PFG-NMR). The drug carriers investigated are formed by Polysorbate 80 (PS-80), which is a common excipient, and quaternary ammonium chloride molecule, or dodecylbetaine ester which is a cleavable surfactant. These molecules are able to formed mixed micelles in solution. It appears that the binding of the micelles with mucin is highly dependent on the charge density. Indeed, strong binding with mucin molecules are observed for highly charged micelles. However, the interactions of nonionic model drug carriers are limited due to strong steric hindrance from the mucin molecules and the nonionic surfactant. The structure of a mucin gel also shows strong pH-dependence. Indeed, a loose network of expanded fully charged mucin molecules with considerable mobility is formed pH 7.4. At intermediate pH (pH 4), a three-dimensional expanded network is favoured. At pH 1, the predominant hydrophobic associations lead to the formation of clusters concentrated in the mucin molecules separated by water-rich domains. These structures are due to an equilibrium between electrostatic repulsions and hydrophobic associations between the mucin molecules. These different structures may explain why the transport properties of cationic drug vehicle is dependent on the pH as observed by magnetic resonance imaging with chemical shift resolution (MRI-CS). The transport properties of nonionic/cationic micelles are also dependent on the length of the aliphatic chain of the cationic molecules. The results obtained by MRI-CS lead to the conclusion that the bioavailability of drug carriers may be improved by the use of cationic surfactants. Therefore, the formulation of such carriers requires that the charge density of the carrier, the choice of the surfactant as well as the site of adsorption be taken into account.