Characterizing release mechanisms of leuprolide acetate-loaded PLGA microspheres for IVIVC development I: In vitro evaluation

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• 作者：Keiji Hirota^a ; ¹ ; Amy C. Doty^a ; ² ; Rose Ackermann^a ; Jia Zhou^a ; Karl F. Olsen^a ; Meihua R. Feng^a ; Yan Wang^b ; Stephanie Choi^b ; Wen Qu^c ; Anna S. Schwendeman^a ; Steven P. Schwendeman^a ; ^d ; ^{schwende@med.umich.edu}
• 关键词：PLGA ; Leuprolide ; Microspheres ; Release mechanisms ; IVIVC
• 刊名：Journal of Controlled Release
• 出版年：2016
• 出版时间：28 December 2016
• 年：2016
• 卷：244
• 期：part_PB
• 页码：302-313
• 全文大小：941 K
• 卷排序：244

文摘

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 56 days in various media: pH 5.5, 6.5, and 7.4 phosphate buffered-saline (PBS) containing 0.02% Tween 80; pH 7.4 PBS containing 1.0% triethyl citrate (PBStc); and pH 7.4 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.