Novel sustained-release dosage forms of proteins using polyglycerol estersof fatty acids

In order to develop a novel delivery system for proteins based on polyglyce rol esters of fatty acids (PGEFs), we studied a model system using interfer on-alpha (IFN-alpha) as the test protein. A cylindrical matrix was prepared by a heat extrusion technique using a lyophilized powder of the protein an d ii different types of synthetic PGEFs, which varied in degree of glycerol polymerization (di- and tetra-), chain length of fatty acids (myristate, p almitate and stearate) and degree of fatty acid esterification (mono-, di- and tri-). In an in-vitro release study using an enzyme-linked immunosorben t assay (ELISA) as a detection method, the matrices prepared from a monogly ceride (used for comparison) and from diglycerol esters exhibited a biphasi c release pattern with a large initial burst followed by slow release. In c ontrast, the matrices prepared from tetraglycerol esters showed a steady ra te of release without a large initial burst. In an in vivo release study, i nitial bursts of IFN-alpha release were, also, dramatically reduced when th e matrices were prepared from the tetraglycerol esters of palmitate and ste arate, and the mean residence time (MRT) of IFN-alpha was prolonged, wherea s the matrices prepared from monoglyceride and from diglycerol esters showe d large initial bursts of IFN-alpha release. Since the release rates from t he matrices prepared from the tetraglycerol esters of palmitate and stearat e were governed by Jander's equation modified for a cylindrical matrix, the release from those matrices was concluded to be a diffusion-controlled pro cess. The bioavailability of IFN-alpha after implantation of the matrix for mulation prepared using all types of PGEFs, except for tetraglycerol triest ers, was almost equivalent to that after injection of IFN-alpha solution; c onsequently, IFN-alpha in these matrices appears to remain stable during th e release period. (C) 2000 Elsevier Science B.V. All rights reserved.