Developing Print Dry Powders for Pulmonary Protein Delivery Public Deposited

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Last Modified
  • March 21, 2019
Creator
  • Wilson, Erin
    • Affiliation: Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics
Abstract
  • Pulmonary delivery is an attractive route of administration that can be used for the local delivery of therapeutics for respiratory conditions or to non-invasively deliver sufficiently low molecular weight therapeutics to systemic circulation. There is a particular interest in protein delivery, however, many respirable formulations are inefficient at delivering therapeutics to the desired region of the lungs, which precludes the development of costly biologics for inhalation. Particle engineering, a strategy that aims to rationally and precisely control particle size, shape, density, and composition, has been utilized to design high-performance dry powder aerosols that deposit efficiently and precisely in the desired area of the lungs. However, current fabrication methods offer limited control of particle geometry and impose unfavorable stresses on proteins during manufacturing. The overall goals of this dissertation were to fabricate and characterize protein-based microparticles with Particle Replication In Non-wetting Templates (PRINT) technology and engineer these particles into high-performance protein dry powder aerosols. We hypothesized that the precise control of particle geometry afforded by PRINT along with the low physical stress imparted by the process would allow for the stable incorporation of proteins into precisely engineered particles, resulting in high-performance protein dry powder aerosols. A generalizable formulation strategy to micromold a variety of proteins into precisely engineered PRINT particles was developed, and the incorporated proteins were found to retain their native structure and function. Following lyophilization into dry powders, these formulations were found to fluidize, aerosolize, and deposit with high efficiency and precision. We then expanded the formulation strategy to fabricate multiple PRINT particle shapes, which were used to explore the impact of particle shape on dry powder performance in an effort to inform and improve particle engineering strategies. Informed by the formulation development and particle shape studies, dry powder formulations of two therapeutic proteins were developed and the delivery of one formulation was demonstrated in vivo. Overall, we have demonstrated the utility of PRINT as a platform to manufacture high-performance protein dry powders and we have furthered understanding of the impact of particle shape on aerosol performance, both of which contribute to the advancement of particle engineering strategies for inhalable formulations.
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Rights statement
  • In Copyright
Advisor
  • Miley, Michael
  • DeSimone, Joseph M.
  • Henke, David
  • Smith, Philip
  • Jay, Michael
  • Luft, James Christopher
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill
Graduation year
  • 2017
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