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Title:Uniform biodegradable microparticle systems for protein delivery
Author(s):Xia, Yujie
Director of Research:Pack, Daniel W.
Doctoral Committee Chair(s):Pack, Daniel W.
Doctoral Committee Member(s):Harley, Brendan A.; Leckband, Deborah E.; Wheeler, Matthew B.
Department / Program:Chemical & Biomolecular Engr
Discipline:Chemical Engineering
Degree Granting Institution:University of Illinois at Urbana-Champaign
Subject(s):Biodegradable Polymer
Poly(lactic acid)
Double-wall Microspheres
Protein Delivery
Abstract:Therapeutic protein drugs are receiving increasing attention in pharmaceutical industry due to the fast development of biotechnology and genomics. Because of their low oral and transdermal bioavailabilities, fragility and short half-lives in vivo, novel and effective alternatives to deliver protein therapeutics are an important issue for protein therapeutics’ application. Biodegradable polymer devices have been utilized as a means to deliver drugs in a controlled and less invasive manner. Poly(lactide-co-glycolide) (PLG) and poly(lactic acid) (PLA) microparticles such as double-wall/monolithic microspheres and microcapsules have been heavily investigated for controlled delivery of small-molecule drugs as well as peptides, proteins and DNA. The size distribution of protein-loaded biodegradable polymer microparticles is a crucial factor for allowable routes of administration. Also, geometric structure of microparticles can influence the resulted release profile. In this project, by using the Precision Particle Fabrication (PPF) method, we produced uniform double-wall microspheres (DWMS) with a bovine serum albumin (BSA)-loaded PLG core and a drug-free PLA shell. Different PLG and PLA molecular weight and organic solvent combination to dissolve core and shell polymers (organic solvent configuration) were used to produce uniform DWMS with average size around 55 µm and ~10 µm shell thickness. By studying the in vitro release profiles, intraparticle protein distribution and particle morphology, we found using fast extracting shell solvent ethyl acetate, lower molecular weight PLG (Mw 4.2 kDa) core and relatively lower molecular weight PLA (Mw 43 kDa) shell resulted in spherical double-wall microspheres with higher protein loading, better core entrapment and postponed protein release compared to monolithic microsphere controls. Subsequently, using the optimized polymer and organic solvent configuration and increasing the shell PLA/core PLG mass ratio from 1.09 to 3.04, we were able to fabricate DWMS with drug-free shell thickness varied from ~6 to ~14 µm and an extended period of “zero-order” or constant-rate protein release was achieved for five months when drug free shell thickness increased to ~14 µm. In addition to uniform double-wall microspheres, we fabricated microcapsules comprising a protein-loaded liquid-core (emulsion of aqueous BSA solution and canola oil) surrounded by a PLG shell. By increasing PLG shell flow rate from 30 to 50 mL/h while keeping liquid-core flow rate constant at 1 mL/h using PPF, uniform liquid-core microcapsules with different PLG shell thickness from ~14 to ~19 µm were obtained. The release profiles showed pulsatile release of encapsulated protein with thicker PLG shell resulting in detained starting time of protein pulsatile release. In summary, PPF was employed to produce uniform biodegradable microparticle systems for protein delivery. For double-wall microspheres as well as liquid-core microcapsules, organic solvent configuration, polymer molecular weight and particle geometric structure such as overall diameter and shell thickness can be crucial factor for protein intraparticle distribution, particle degradation/erosion rate, and thus protein release profile.
Issue Date:2014-01-16
Rights Information:Copyright 2013 Yujie Xia
Date Available in IDEALS:2014-01-16
Date Deposited:2013-12

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