title: Hot Melt Extrusion for Sustained Protein Release: Matrix Erosion and In Vitro Release of PLGA-Based Implants.
abstract: The design of biodegradable implants for sustained release of proteins is a complex challenge optimizing protein polymer interaction in combination with a mini-scale process which is predictive for production. The process of hot melt extrusion (HME) was therefore conducted on 5- and 9-mm mini-scale twin screw extruders. Poly(lactic-co-glycolic acid) (PLGA) implants were characterized for their erosion properties and the in vitro release of the embedded protein (bovine serum albumin, BSA). The release of acidic monomers as well as other parameters (pH value, mass loss) during 16 weeks indicated a delayed onset of matrix erosion in week 3. BSA-loaded implants released 17.0% glycolic and 5.9% lactic acid after a 2-week lag time. Following a low burst release (3.7% BSA), sustained protein release started in week 4. Storage under stress conditions (30°C, 75% rH) revealed a shift of erosion onset of 1 week (BSA-loaded implants: 26.9% glycolic and 9.3% lactic acid). Coherent with the changed erosion profiles, an influence on the protein release was observed. Confocal laser scanning and Raman microscopy showed a homogenous protein distribution throughout the matrix after extrusion and during release studies. Raman spectra indicated a conformational change of the protein structure which could be one reason for incomplete protein release. The study underlined the suitability of the HME process to obtain a solid dispersion of protein inside a polymeric matrix providing sustained protein release. However, the incomplete protein release and the impact by storage conditions require thorough characterization and understanding of erosion and release mechanisms.
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Straße 65, 88397, Biberach, Germany.|Department of Pharmaceutics, Rheinische Friedrich-Wilhelms-Universität Bonn, Gerhard-Domagk-Str. 3, 53121, Bonn, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Cossé
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Straße 65, 88397, Biberach, Germany.
authors.forename: Corinna
authors.initials: C
authors.lastname: König
authors.affiliation: Department of Pharmaceutics, Rheinische Friedrich-Wilhelms-Universität Bonn, Gerhard-Domagk-Str. 3, 53121, Bonn, Germany.
authors.forename: Alf
authors.initials: A
authors.lastname: Lamprecht
authors.affiliation: Department of Pharmaceutics, Rheinische Friedrich-Wilhelms-Universität Bonn, Gerhard-Domagk-Str. 3, 53121, Bonn, Germany. kgwagner@uni-bonn.de.
authors.forename: Karl G
authors.initials: KG
authors.lastname: Wagner
mesh_terms: D020341:Absorbable Implants; D001672:Biocompatible Materials / Q000737:chemistry; D003692:Delayed-Action Preparations / Q000737:chemistry*; D004339:Drug Compounding / Q000379:methods; D006358:Hot Temperature; D019344:Lactic Acid / Q000737:chemistry*; D018613:Microscopy, Confocal / Q000379:methods; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011506:Proteins / Q000737:chemistry*; D012710:Serum Albumin, Bovine / Q000737:chemistry; D013059:Spectrum Analysis, Raman / Q000379:methods
chemical_list: D001672:Biocompatible Materials; D003692:Delayed-Action Preparations; D011506:Proteins; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D012710:Serum Albumin, Bovine; D019344:Lactic Acid
keywords: BSA; hot melt extrusion; poly(lactic-co-glycolic acid) (PLGA); polyester erosion; sustained protein release