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Mechanistic Analysis of in Vitro and in Vivo Drug Release from Plga Microspheres

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Mechanistic Analysis of in Vitro and in Vivo Drug Release from Plga Microspheres MECHANISTIC ANALYSIS OF IN VITRO AND IN VIVO DRUG RELEASE FROM PLGA MICROSPHERES by Amy Christine Doty A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Pharmaceutical Sciences) in the University of Michigan 2015 Doctoral Committee: Professor Steven P. Schwendeman, Chair Professor Gordon L. Amidon Research Professor Gregory E. Amidon Professor Joerg Lahann © Amy Christine Doty 2015 Dedication To my parents with my love and gratitude. ii Acknowledgements I would like to thank my graduate research advisor Dr. Steven Schwendeman for his guidance and support since I joined his lab 4 years ago. He has encouraged me to think critically and to become a strong and independent scientist, for which I will always be thankful. While in his lab, Dr. Schwendeman offered me many wonderful opportunities to present and discuss my research with other scientists, and that has enabled me to develop a confidence that will continue to help me throughout the rest of my career. I am also very thankful to Dr. Anna Schwendeman for all of her invaluable advice and encouragement. I would also like to thank the rest of my committee; Dr. Gregory Amidon, Dr. Gordon Amidon, and Dr. Joerg Lahann for their time and helpful insights and comments they offered during the course of my research. I cannot thank my parents, Mark and Linda Doty, enough for their constant love and encouragement. I always know that no matter where I am, your comforting words of assurance are only a phone call away. I truly cannot thank you enough for everything you’ve done for me. I must also thank my sister Casey. I cannot imagine going through anything without your support, especially not the long journey of graduate school. Having the love of my entire family has only made this accomplishment easier and I feel lucky to have such amazing people in my life. Next, I would like to thank the FDA for the support of the research for the last 2+ years. The insight of the team there, especially Yan Wang and Stephanie Choi, has helped this project and my own scientific growth tremendously. The questions and comments posed during monthly discussions made this research stronger, and made me a stronger scientist. Working closely with the FDA was a unique experience and one that I am very grateful to have had. iii Working in such a great lab with such wonderful labmates, past and present, has really made my time in graduate school enjoyable. There have been many people in the lab over the last several years but I would like to specifically thank Karl Olsen for his help with my animal studies, Rose Ackermann for her technical help and expertise, and Dr. Keiji Hirota for his collaboration and help with this project. My fellow graduate students in the Schwendeman group always made the lab a place I wanted to be, making even the most challenging days seem like fun: J. Maxwell Mazzara, Brittany Bailey, Kellisa Hansen, Rae Sung Chang, Karthik Pisupati, Morgan Giles, Jia Zhou, Dan Li, Kari Nieto, and Dan Li. Thank you all for creating a wonderful work environment that I will miss very much. I would now like to thank everyone who has been by my side over the past 5 years and has made my time in Ann Arbor truly special and memorable. I am grateful to my wonderful boyfriend Ricky who has supported me and encouraged me since the day I met him. Thank you for believing in me and pushing me to reach and even surpass my own goals; your love and support has made the last year so much easier. Finally, I don’t know how it would be possible to go through graduate school without the amazing friends I have been lucky enough to make in Michigan. There are too many to name individually, but I would like to especially thank Dr. Maya Lipert, Dr. Maria Posada, Dr. Jamie Connarn, Kellisa Hansen, Morgan Giles, Max Mazzara, and Karthik Pisupati. Thank you all for making this experience so enjoyable and memorable. I am blessed to have met you all and I’m looking forward to staying connected with you all as we progress in our careers. GO BLUE! iv Table of Contents Dedication ................................................................................................................................... ii Acknowledgements ...................................................................................................................... iii List of Figures ............................................................................................................................. viii List of Tables .............................................................................................................................. xiii List of Appendices ...................................................................................................................... xiv Abstract ................................................................................................................................ xvi : Introduction .............................................................................................................. 1 1.1 Controlled Release Drug Products ............................................................................... 1 1.2 PLGA Controlled Release Formulations ..................................................................... 1 1.3 Mechanisms of Controlled Release ............................................................................... 3 Osmosis and osmotic-induced drug release mechanisms ......................................... 4 Diffusion through Polymer Phase ............................................................................. 5 Diffusion through Pores ............................................................................................ 5 Water Uptake ............................................................................................................ 6 Hydrolysis and Erosion............................................................................................. 7 1.4 In vitro and In vivo Controlled Release from PLGA ................................................... 7 Accepted In vitro Release Conditions ....................................................................... 7 Release Methods ................................................................................................ 8 Release Media .................................................................................................... 8 Drug Release from PLGA Microparticles in vitro ............................................ 9 Drug Release from PLGA Microparticles in vivo..................................................... 9 Factors Affecting in vivo Drug Release .................................................................. 11 Biological factors ............................................................................................ 12 Physical-chemical factors................................................................................ 15 1.5 Research Scope and Impact ........................................................................................ 17 1.6 Thesis Overview............................................................................................................ 18 1.7 References ..................................................................................................................... 21 v : Mechanistic Analysis of Triamcinolone Acetonide Release from PLGA Microspheres as a Function of Varying in vitro Release Conditions...................................... 26 2.1 Abstract ......................................................................................................................... 26 2.2 Introduction .................................................................................................................. 27 2.3 Materials ....................................................................................................................... 29 2.4 Methods ......................................................................................................................... 29 Microsphere Preparation........................................................................................ 29 Scanning Electron Microscopy ............................................................................... 30 Determination of Tr-A Loading and Encapsulation Efficiency .............................. 30 Tr-A Quantification by UPLC ................................................................................. 30 Assessment of Drug Release in vitro ....................................................................... 31 Mass Loss and Water Uptake of Microspheres: ..................................................... 31 Molecular Weight of PLGA .................................................................................... 32 BODIPY uptake and Laser Scanning Confocal Microscopy (LSCM): ................... 32 Modelling Tr-A diffusion-controlled release .......................................................... 33 Statistical and Regression Analysis ........................................................................ 33 2.5 Results and Discussion ................................................................................................. 33 2.6 Conclusions ................................................................................................................... 45 2.7 References ..................................................................................................................... 46 2.8 Supplementary Information .......................................................................................
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