ii To my loving wife and wonderful parents.iii ACKNOWLEDGMENTS First and foremost I would like to thank my research advisor Dr. Eric Nuxoll for his support, brilliant advice, professionalism and endless patience. He has been a great mentor throughout my doctoral studies at the University of Iowa since I became his first graduate student. Besides overall research skills, I learned much more including how to address a problem in a practical way, determine priorities and most importantly how to express and defend ideas. I have had the privilege to work with very talented undergrad students Matthew Gosse and Derek Baerenwald, who directly contributed to this project. I am also grateful to Yasuhiro Nishii, a visiting scholar from Japan, for his partial contributions to this work and continued work forward with this project. Guiding and mentoring these bright individuals was an exciting opportunity and also a great experience for me. Others who have helped me along the way include my fellow research group members Ann O'Toole, Joel Coffel, Erica Bader and Bryce Hundley. iv I am incredibly grateful to my parents who have always supported me. I have been blessed to be born in a loving family that has fully encouraged and enabled me to achieve my dreams. Finally, no words can express my thankfulness to Khushbu, my wife, who always stood by me throughout this journey. Without her encouragement and motivation I would not have pursued the education to the length I have.v ABSTRACT Solutes are often most efficiently deployed in discrete pulses, for example in the delivery of herbicides or drugs. Manual application of each pulse can be labor-intensive, automated application of each pulse can be capital intensive, and both are often costly and impractical. Barrier-Mediated Pulsatile Release (BMPR) systems offer a materialsbased alternative for automated pulsatile drug delivery, without pumps, power supplies, or complex circuitry. While earlier materials-based approaches such as delayed-release microcapsules are limited to two or three pulses due to the independent nature of each pulse's timing control, BMPR systems link the timing of each pulse to the previous pulse.Each dose of drug is sequestered in its own stimuli-sensitive depot, releasing only upon contact with the stimulant. These depots are stacked with sacrificial barriers in between, each of which block the stimulant for a predetermined time. For instance, layers of soluble drug may be separated by degradable polymer layers. Water, as the stimulant, will erode the polymer layer over a fixed period of time, followed by quick dissolution and release of the underlying drug and the start of degradation for the next polymer layer.This example, however, is quickly limited by irregular polymer erosion, a single stimulant (water), and difficulty in scaling delay times.The research work presented in this thesis reports the development of a generalized BMPR system which overcomes those limitations. Model drugs (methylene blue and methyl orange) were immobilized in a pH-sensitive ...
By stacking individual drug layers between degradable polymer membranes, unique individual drug doses may be delivered in pulsatile fashion from a simple polymer laminate. This strategy may be limited, however, by the bulk-eroding nature of most hydrolytically degradable polymer membranes. Current models classify polymer films as either bulk-or surface-eroding and are not suited for modeling intermediate erosion behaviors, though many polymer coatings demonstrate erosion behavior between these extremes. Moreover, no metric exists for quantifying the bulk-vs. surface-eroding behavior of a membrane. This paper introduces a stochastic, Monte-Carlo style model which calculates the erosion profile of a degradable polymer membrane based on its moisture diffusion coefficient, membrane thickness, and a modified degradation rate constant, generating erosion profiles spanning the continuum from strongly bulk-eroding to strongly surface eroding based on the membrane's Damköhler number. The nature of this erosion is quantified by the Bulk Erosion Factor (BEF), the factor by which the polymer's mean erosion time exceeds the surface-eroding ideal. The model is compared against experimental examples of intermediate erosion behavior and used to correlate the Damköhler number to BEF, the relative membrane percolation time, and the resulting pulsatility of drug release.
By sequestering individual doses of chemical in stimuli-sensitive depot membranes and stacking them between stimulant barriers, automated pulsatile chemical release can be obtained from a simple polymer laminate. By using non-degrading hydrogel depots, this approach has been demonstrated releasing multiple chemicals in up to ten pulses, with each depot membrane delaminating and releasing its payload at a preprogrammed time. This paper reports the first experimental demonstration of a non-delaminating, non-degrading pulsatile release composite, for applications where delamination may be unsuitable. Non-delaminating systems not only require significantly larger development resources, they have an inherent periodicity limit which increases with the number of pulses desired. This limit is not analytically tractable, prompting the development of a computational model to predict the complete release profile. This model is validated against experimental delaminating systems, then adapted to nondelaminating systems to correlate the system's pulsatility with the physical parameters of the system, including diffusion coefficients, stimulant concentration, solute loading, scavenger loading and membrane thicknesses. These correlations facilitate rapid feasibility assessment of proposed non-delaminating pulsatile release applications prior to development of physical systems.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.