UPTAKE AND TRANSPORT OF POLY(N-VINYLPYRROLIDONE-CO-MALEIC ACID) BY THE ADULT-RAT SMALL-INTESTINE CULTURED IN-VITRO - EFFECT OF CHEMICAL-STRUCTURE

To study the structure-activity relationships of polymer uptake and tr ansfer across the gastrointestinal mucosa, poly(N-vinylpyrrolidone-co- maleic acid) (NVP MA) polymers of standardised molecular mass (20 000 Da) were synthesised to contain side-chains of different charge or hyd rophobicity. All polymers additionally contained tyrosinamide residues to permit radioiodination. Using an improved everted gut sac prepared from adult rat small intestine, the tissue accumulation and serosal t ransport of the polymers was measured in vitro over a 2 h incubation p eriod. All polymers were captured by the tissue linearly with time (en docytic indices between 1.6 and 16 mu l/mg protein per h), and then tr ansferred slowly to the serosal fluid (endocytic indices between 0.18 and 2 mu l/mg protein per h). The neutral NVP MA polymer showed the lo west rate of tissue association, but this was increased 5-fold by the presence of either negatively or positively charged groups. The maximu m rate of transport across the mucosa was seen for the most negatively charged polymer derivative, this being equivalent to approx. 26% its rate of tissue accumulation. Increasing hydrophobicity of the polymer derivatives had a more pronounced effect on the rate of tissue capture , increasing it by up to 10-fold for the most hydrophobic derivative. However, in this case, the serosal transfer was only 10-15% the rate o f tissue uptake. The data presented indicate that NVP MA polymers can be tailor-made for use in oral delivery systems. Substituent groups ca n be incorporated to promote tissue uptake or translocation across the gastrointestinal mucosa, or a combination of the two.