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Factors Affecting The In Vitro Release Of Recombinant Human Interferon‐γ (rhIFN‐γ) From PLGA Microspheres

J. Yang, J. Cleland
Published 1997 · Chemistry

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A long-acting depot formulation of recombinant human interferon-γ (rhIFN-γ) was achieved by microencapsulation of rhIFN-γ in polylactic-coglycolic acid (PLGA) microspheres by a water-in-oil-in-water technique. The release of protein was assessed with different release devices and buffer systems. The quality of the released protein was quantitated by sodium dodecyl sulfate-size exclusion chromatography, ELISA, and bioactivity assays. The microencapsulation process resulted in an encapsulation efficiency of 100% and the initial release of bioactive, native protein with no subsequent release. Further investigation suggested that the protein did not bind to the PLGA, but a constant and small amount of protein adsorbed to the filter device used for the release studies. The composition of the release media (pH, buffer species, salt concentration, ionic strength, and type and concentration of surfactants) had a profound effect on the in vitro release rate. The effect was mainly due to the differential solubility, stability, and aggregation of rhIFN-γ in the various systems for protein inside the microspheres or released into the bulk solution. The quality of the protein released from the microspheres was also affected by the buffer media upon storage at 5 °C, which, in turn, affected the quantification of released protein. The bicinchoninic acid method typically used to quantitate protein release underestimated protein release because of aggregation. Protein released after several days was less active than the starting material and had lost activity as a result of the inherent instability of rhIFN-γ at 37 °C. The release device, buffer species, pH, and excipients must be assessed in release studies of proteins from polymer matrices because the protein stability and release is dependent on these variables. These studies also indicated that rhIFN-γ was encapsulated and released from PLGA in a bioactive form, but its stability at 37 °C, which was greatly affected by the release conditions, limits the duration of release of native, bioactive protein to 7 days or less.
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