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Purpose: Pulsatile delivery of proteins, in which release occurs over a short time after a period of little or no release, is desirable for many applications. This paper investigates the effect of biodegradable polymer shell thickness on pulsatile protein release from biodegradable polymer microcapsules. Methods: Using precision particle fabrication (PPF) technology, monodisperse microcapsules were fabricated encapsulating bovine serum albumin (BSA) in a liquid core surrounded by a drug-free poly(lactide- co-glycolide) (PLG) shell of uniform, controlled thickness from 14 to 19 μm. Results: When using high molecular weight PLG (Mw 88 kDa), microparticles exhibited the desired core-shell structure with high BSA loading and encapsulation efficiency (55-65%). These particles exhibited very slow release of BSA for several weeks followed by rapid release of 80-90% of the encapsulated BSA within 7 days. Importantly, with increasing shell thickness the starting time of the pulsatile release could be controlled from 25 to 35 days. Conclusions: Biodegradable polymer microcapsules with precisely controlled shell thickness provide pulsatile release with enhanced control of release profiles. [ABSTRACT FROM AUTHOR]

Abstract: Biodegradable polymer microparticles are promising delivery depots for protein therapeutics due to their relatively simple fabrication and facile administration. Double-wall microspheres (DWMS) comprising a core and shell made of two distinct polymers may provide enhanced control of the drug release profiles. Using precision particle fabrication (PPF) technology, monodisperse DWMS were fabricated with model protein bovine serum albumin (BSA)-loaded poly(lactide-co-glycolide) (PLG) core and drug-free poly(d,l-lactic acid) (PDLL) shell of uniform thickness. Monolithic single-wall microspheres were also fabricated to mimic the BSA-loaded PLG core. Using ethyl acetate and dichloromethane as shell- and core-phase solvents, respectively, BSA was encapsulated selectively in the core region within DWMS with higher loading and encapsulation efficiency compared to using dichloromethane as core and shell solvents. BSA in vitro release rates were retarded by the presence of the drug-free PDLL shell. Moreover, increasing PDLL shell thickness resulted in decreasing BSA release rate. With a 14-μm thick PDLL shell, an extended period of constant-rate release was achieved. [Copyright &y& Elsevier]

Biodegradable polymer double-wall microspheres (DWMS) are promising vehicles for macromolecular therapeutics such as proteins and peptides. Using precision particle fabrication (PPF) technology, uniform DWMS with outer diameter approximately 55 μm were fabricated comprising poly(lactide- co-glycolide) cores encapsulating bovine serum albumin (BSA) and approximately 10 μm thick, drug-free, poly(lactic acid) (PLA) shells of varying PLA molecular weight. Also, monolithic single-wall microspheres (SWMS) were fabricated to mimic the BSA-loaded core. The use of relatively fast-extracting ethyl acetate and slowly extracting dichloromethane as shell- and core-phase solvents, respectively, was found to produce DWMS with well-defined core-shell structure, high BSA encapsulation efficiency, and the desired localization of protein in the particle core. Initial protein distribution, particle erosion, and in vitro protein release from DWMS and SWMS were examined. The presence of a BSA-free shell in DWMS decreased the protein release rate and extended the duration of release from approximately 50 days to 70-80 days, demonstrating the capacity of such DWMS to provide enhanced control of protein delivery rates. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:1601-1609, 2013 [ABSTRACT FROM AUTHOR]