期刊
JOURNAL OF PHARMACEUTICAL SCIENCES
卷 90, 期 9, 页码 1356-1365出版社
JOHN WILEY & SONS INC
DOI: 10.1002/jps.1088
关键词
nerve growth factor; microspheres; microencapsulation; sustained-release; poly(lactic-co-glycolic) acid; PLGA; zinc acetate; zinc carbonate
The development of a stable sustained-release formulation of recombinant human nerve growth factor (rhNGF) for the treatment of neuronal diseases is described. The protein was encapsulated into poly(lactic-co-glycolic) acid (PLGA) microspheres using a spray freeze drying technique. Liquid nitrogen and cold ethanol were used to spray-freeze-dry solid rhNGF that had been suspended in a solution of PLGA dissolved in ethyl acetate. When excipients such as sugar (trehalose), surfactant (pluronic F68), and poly(ethylene glycol) (PEG) were added to the PLGA formulation to protect rhbNGF from degradation during spray freeze drying, the protein degraded via aggregation during in vitro release. The formation of an insoluble rhNGF-zinc complex prior to encapsulation into PLGA microspheres stabilized the protein during both microencapsulation and release. In this study, we have demonstrated that the addition of zinc acetate in a 1:12 rhNGF-to-zinc acetate molar ratio in a solid rhNGF formulation (4 nim sodium bicarbonate at pH 7.4) improves stability of rhNGF during release at 37 degreesC (physiological temperature). The stabilization may be due to rhNGF complexation with zinc to form stable aggregates. The PLGA formulation consisting of 10% rhNGF encapsulated in 12 kDa PLGA (50:50 lactide/glycolide) provided a continuous release of 14 days. The low initial burst (similar to1%) and controlled-release rate were achieved by the addition of 3 or 6% solid zinc carbonate to the polymer phase during microencapsulation. (C) 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association.
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