title: Characterizing release mechanisms of leuprolide acetate-loaded PLGA microspheres for IVIVC development I: In vitro evaluation.
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.
authors: Department of Pharmaceutical Sciences, The Biointerfaces Institute, University of Michigan, 2800 Plymouth Rd., Ann Arbor, MI 48109, USA.
authors: Keiji
authors: K
authors: Hirota
authors: Department of Pharmaceutical Sciences, The Biointerfaces Institute, University of Michigan, 2800 Plymouth Rd., Ann Arbor, MI 48109, USA.
authors: Amy C
authors: AC
authors: Doty
authors: Department of Pharmaceutical Sciences, The Biointerfaces Institute, University of Michigan, 2800 Plymouth Rd., Ann Arbor, MI 48109, USA.
authors: Rose
authors: R
authors: Ackermann
authors: Department of Pharmaceutical Sciences, The Biointerfaces Institute, University of Michigan, 2800 Plymouth Rd., Ann Arbor, MI 48109, USA.
authors: Jia
authors: J
authors: Zhou
authors: Department of Pharmaceutical Sciences, The Biointerfaces Institute, University of Michigan, 2800 Plymouth Rd., Ann Arbor, MI 48109, USA.
authors: Karl F
authors: KF
authors: Olsen
authors: Department of Pharmaceutical Sciences, The Biointerfaces Institute, University of Michigan, 2800 Plymouth Rd., Ann Arbor, MI 48109, USA.
authors: Meihua R
authors: MR
authors: Feng
authors: Office of Generic Drugs, U.S. Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993, USA.
authors: Yan
authors: Y
authors: Wang
authors: Office of Generic Drugs, U.S. Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993, USA.
authors: Stephanie
authors: S
authors: Choi
authors: Office of Pharmaceutical Quality, U.S. Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993, USA.
authors: Wen
authors: W
authors: Qu
authors: Department of Pharmaceutical Sciences, The Biointerfaces Institute, University of Michigan, 2800 Plymouth Rd., Ann Arbor, MI 48109, USA.
authors: Anna S
authors: AS
authors: Schwendeman
authors: Department of Pharmaceutical Sciences, The Biointerfaces Institute, University of Michigan, 2800 Plymouth Rd., Ann Arbor, MI 48109, USA; Department of Biomedical Engineering, University of Michigan, 2800 Plymouth Rd., Ann Arbor, MI 48109, USA. Electronic address: schwende@med.umich.edu.
authors: Steven P
authors: SP
authors: Schwendeman
mesh_terms: D001896:Boron Compounds / Q000737:chemistry; D065546:Drug Liberation; D019344:Lactic Acid / Q000737:chemistry*; D016729:Leuprolide / Q000737:chemistry*; D008863:Microspheres; D008970:Molecular Weight; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D044366:Transition Temperature
chemical_list: C095489:4,4-difluoro-4-bora-3a,4a-diaza-s-indacene; D001896:Boron Compounds; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D016729:Leuprolide
keywords: IVIVC; Leuprolide; Microspheres; PLGA; Release mechanisms