IN-VITRO DRUG-RELEASE FROM HYC-141, A CORTICOSTEROID ESTER OF HIGH-MOLECULAR-WEIGHT HYALURONAN

The use of steroid drugs bound covalently to hyaluronate through ester linkages has been proposed for local treatment of arthritic diseases. The in vitro release profile of HYC 141, formed by linking covalently methylprednisolone to a soluble high molecular weight hyaluronate mat rix, was studied. First, the influence of various parameters (temperat ure, pH, protein content, viscosity), in the range of the physiopathol ogical values, was investigated in buffer medium. The release of methy lprednisolone was five-fold slower at 20 degrees C than at 37 degrees C and diminished further when the HYC 141 concentration was increased. The HYC 141 was more stable below neutral pH than above it, and this was not dependent on the protein content of the medium. Secondly, the release of methylprednisolone was studied in plasma and synovial fluid from patients with inflammatory arthritides. The T50% was similar in both samples and ranged from 3.2 to 5.9 h, but was faster than in phos phate buffer of corresponding pH (22-39 h). These results suggest that the release profile of HYC 141 depends on the physico-chemical parame ters of the medium and possibly on the chemical conformation of hyalur onate. In human samples, hydrolysis seems to be controlled by an ester ase activity. This hypothesis was strengthened by using an acylating i nhibitor that reduces the hydrolysis rate of ester linkages.