Development of drug carrier systems with improved microadhesive properties

Research project P 13820 Drug carrier systems with improved mucoadhesive properties Andreas BERNKOP- SCHNÜRCH 28.06.1999 The aim of this project is to improve the mucoadhesive properties of various drug delivery systems. It should make a prolonged residence time at the site of drug action or absorption (I), an intensified contact to the mucosa, (II), as well as the localization at a given target site (III) feasible. In order to reach this goal, thiol groups, which are capable I of forming disulfide bonds with mucus gycoproteins of the mucosa, will be immobilized on well-known mucoadhesive polymers as well as on micro- and nanoparticles. The covalent attachment of sulthydryl compounds to sodium carboxymethycellulose, poly(acrylic acid), chitosan and carboxylated particles will be mediated by a carbodiimide in aqueous solutions. Whereas the adhesion so far was only based on non-covalent bonds, adhesion of delivery systems described here should be achieved for the first time by covalent bonds. The functionality of such systems should be verified by according in vitro and in vivo studies.

Since the early 80s the concept of mucoadhesion has gained considerable interest in the pharmaceutical technology. Mucoadhesion is defined as the ability of synthetic or biological materials to adhere to mucosal tissues, such as the mucosa of the small intestine, the nasal mucosa or the mucosa of the oral cavity. This ability leads to new strategies for the development of potential delivery systems. Mucoadhesive drug delivery systems have several advantages compared to commonly used pharmaceutical excipients. They show a prolonged adherence to the absorption membrane, followed by an increase in the concentration gradient of the drug. The intensive contact to the membrane makes interactions between the polymer and the mucosa, like a permeation enhancing effect or the inhibition of membrane bound enzymes, possible. The aim of this project was to develop new mucoadhesive drug carrier systems. The main focus was thereby on the development of thiomers (polymers with thiol moieties), which show significantly increased mucoadhesive and permeation enhancing properties. Based on these new polymers drug delivery systems for the vaginal application of clotrimazole and progesterone, respectively, were generated. Moreover a drug delivery system for the peroral administration of low molecular weight heparin was developed. These delivery systems were extensively tested in vitro and in the case of heparin also in vivo in rats. A bioavailability of at least 26% for 24 hours was achieved for the first time. Studies concerning the retention period of tablets made of polycarbophil-cysteine in pigs were also carried out.