Novel sustained-release dosage forms of proteins using polyglycerol esters of fatty acids.
In order to develop a novel delivery system for proteins based on polyglycerol esters of fatty acids (PGEFs), we studied a model system using interferon-alpha (IFN-alpha) as the test protein. A cylindrical matrix was prepared by a heat extrusion technique using a lyophilized powder of the protein and 11 different types of synthetic PGEFs, which varied in degree of glycerol polymerization (di- and tetra-), chain length of fatty acids (myristate, palmitate and stearate) and degree of fatty acid esterification (mono-, di- and tri-). In an in-vitro release study using an enzyme-linked immunosorbent assay (ELISA) as a detection method, the matrices prepared from a monoglyceride (used for comparison) and from diglycerol esters exhibited a biphasic release pattern with a large initial burst followed by slow release. In contrast, the matrices prepared from tetraglycerol esters showed a steady rate of release without a large initial burst. In an in vivo release study, initial bursts of IFN-alpha release were, also, dramatically reduced when the matrices were prepared from the tetraglycerol esters of palmitate and stearate, and the mean residence time (MRT) of IFN-alpha was prolonged, whereas the matrices prepared from monoglyceride and from diglycerol esters showed large initial bursts of IFN-alpha release. Since the release rates from the matrices prepared from the tetraglycerol esters of palmitate and stearate were governed by Jander's equation modified for a cylindrical matrix, the release from those matrices was concluded to be a diffusion-controlled process. The bioavailability of IFN-alpha after implantation of the matrix formulation prepared using all types of PGEFs, except for tetraglycerol triesters, was almost equivalent to that after injection of IFN-alpha solution; consequently, IFN-alpha in these matrices appears to remain stable during the release period.
Yamagata
Y
Y
DDS Research Laboratories, Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., 17-85 Jusohonmachi 2-chome, Yodogawa-ku, Osaka, Japan. Yamagata_Yutaka@takeda.co.jp
Iga
K
K
Ogawa
Y
Y
D000818:Animals; D003692:Delayed-Action Preparations; D004355:Drug Stability; D005227:Fatty Acids / Q000008:administration & dosage*; D005990:Glycerol / Q000008:administration & dosage*; D016898:Interferon-alpha / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D008297:Male; D011108:Polymers / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley
D003692:Delayed-Action Preparations; D005227:Fatty Acids; D016898:Interferon-alpha; D011108:Polymers; C043941:polyglycerol; D005990:Glycerol