Enhanced intestinal absorption of a hydrophobic polymer-conjugated protein drug, smancs, in an oily formulation

Abstract

Intestinal absorption of neocarzinostatin (NCS) and smancs (copolystyrene maleic acid-conjugated NCS), in aqueous and oily formulations, was investigated after oral administration in mice. Blood concentrations of NCS and smancs were determined with a cytotoxicity assay employing the highly sensitive Epstein-Barr (EB) virus-transformed B-lymphoblastoid cell line, TK/B. Smancs was more efficiently absorbed from a medium-chain triglyceride solution (oily smancs) than from an aqueous solution in phosphate-buffered saline (PBS). The maximum blood concentration and the area under the concentration curve versus time course (AUC) of oily smancs were 9 and 11 times greater than those of the aqueous form of smancs, respectively. At 5 hr after administration of oily smancs, 0.044% of the total smancs dose was found in blood, whereas the parent compound NCS was not detectable at any time. When oily smancs was administered orally to sarcoma 180 tumor-bearing mice, a selective accumulation of smancs in tumor tissue was observed. These results indicated that a biologically active protein, which cannot be used orally, may be rendered orally active drug by conjugation with a hydrophobic polymer in combination with an oily formulation.