Developing biodegradable excipient systems for the delivery of protein therapeutics remains a hurdle in the field of biopharmaceuticals. Polymeric delivery systems for parenteral use have been growing in interest due to their ability to protect proteins from degradation and provide a constant release profile. Poly(lactide-co-glycolide) (PLGA) is a biodegradable polymer that is widely researched and used in pharmaceutical applications. PLGA excipients are typically manufactured through microencapsulation techniques that involve exposing the protein to a destabilizing aqueous/organic interface (1). Hot-melt extrusion (HME) is a viable alternative due to the lack of solvent during formulation and can lead to higher protein conformational stability with lower hydration states. Proteins have been successfully incorporated into PLGA scaffolds via HME, however the high temperatures and shear result in loss of activity[JP1] (2). Covalent attachment of poly(ethylene glycol) (PEG) to the surface of proteins has been shown to increase the thermal stability of proteins and increase circulation lifetime once in the body (3). The aim of this work was to examine the effect of PEG attachment and PEG length on the stability of proteins during HME. PEG lengths of 5 and 20 kDa were covalently attached to lysine residues on lysozyme and the PEGylated products were processed with PLGA using a self-built syringe extruder. Protein secondary structure, activity, release rates, and dispersion in the PLGA matrix were assayed and compared to native lysozyme processed with or without non-covalent PEG additive. The results indicate that PEGylation, using lysozyme as a model protein, increases retention of protein activity during melt processing, less aggregation within the matrix, and a constant release profile under biological conditions. (1) Jain, R.A. The manufacturing techniques of various drug loaded biodegradable poly(lactide-co-glycolide) (PLGA) devices. Biomaterials. 2000, 21, 2475–2490. (2) Ghalanbor, Z.; Korber, M.; Bodmeier, R. Improved lysozyme stability and release properties of poly(lactide-co-glycolide) implants prepared by hot-melt extrusion. Pharm. Res. 2009, 27 (2), 371-379. (3) Veronese, F. M.; Pasut, G. PEGylation, successful approach to drug delivery. Drug Discovery Today. 2005, 10 (21), 1451-1458. [JP1]References outside the period

Effect of PEGylation on protein stability and release from melt-processed biodegradable poly(lactic-co-glycolic acid) implants

249th National Meeting (2015)

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