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Characterizing Release Mechanisms of Leuprolide Acetate-Loaded PLGA Microspheres for IVIVC Development I: In Vitro Evaluation

Characterizing Release Mechanisms of Leuprolide Acetate-Loaded PLGA Microspheres for IVIVC Development I: In Vitro Evaluation

Keiji Hirota, Amy C Doty, Rose Ackermann, Jia Zhou, Karl F Olsen, Meihua R Feng, Yan Wang, Stephanie Choi, Wen Qu, Anna S Schwendeman, Steven P Schwendeman

J Control Release. 2016 Dec 28;244(Pt B):302-313.

PMID: 27565212

Abstract:

Release testing of parental controlled release microspheres is an essential step in controlling quality and predicting the duration of efficacy. In the first of a two-part study, we examined the effect of various incubation media on release from leuprolide-loaded PLGA microspheres to understand the influence of external pH, plasticization, and buffer type on mechanism of accelerated release. PLGA 50/50 microspheres encapsulating ~5% w/w leuprolide were prepared by the double emulsion-solvent evaporation method with or without gelatin or by the self-healing encapsulation method. The microspheres were incubated at 37°C up to 56days in various media: pH5.5, 6.5, and 7.4 phosphate buffered-saline (PBS) containing 0.02% Tween 80; pH7.4 PBS containing 1.0% triethyl citrate (PBStc); and pH7.4 HEPES buffered-saline containing 0.02% Tween 80 (all media contained 0.02% sodium azide). The recovered release media and microspheres were examined for released drug, polymer molecular weight (Mw), water uptake, mass loss, and BODIPY (green-fluorescent dye) diffusion coefficient in PLGA. After the initial burst release, release of leuprolide from acid-capped PLGA microspheres appeared to be controlled initially by erosion and then by a second mechanism after day 21, which likely consists of a combination of peptide desorption and/or water-mediated breakage of pore connections. PBStc and acidic buffers accelerated degradation of PLGA and pore-network development and increased BODIPY diffusion coefficient, resulting in faster release. Release of leuprolide from the end-capped PLGA showed similar trends as found with acid capped PLGA but with a longer lag time before release. These data provide a baseline mechanistic signature of in vitro release of leuprolide for future comparison with corresponding in vivo performance, and in turn could lead to future development of rational in vitro-in vivo correlations.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
LS743138	Green Fluorescent PLGA microspheres			Price

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