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GALA-DISSERTATION-2019.Pdf (6.752Mb) Copyright by Urvi Hasmukhlal Gala 2019 The Dissertation Committee for Urvi Hasmukhlal Gala Certifies that this is the approved version of the following Dissertation: IMPROVED PROSTATE CANCER THERAPEUTICS THROUGH KINETISOL® ENABLED AMORPHOUS SOLID DISPERSIONS OF ABIRATERONE Committee: Robert O. Williams III, Supervisor Dave A. Miller Hugh D. Smyth Feng Zhang IMPROVED PROSTATE CANCER THERAPEUTICS THROUGH KINETISOL® ENABLED AMORPHOUS SOLID DISPERSIONS OF ABIRATERONE by Urvi Hasmukhlal Gala Dissertation Presented to the Faculty of the Graduate School of The University of Texas at Austin in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy The University of Texas at Austin December 2019 Dedication To my family. Acknowledgements I would like to thank my supervisor, Dr. Robert O. Williams III, for his encouragement, support and invaluable guidance during the entire course of the program. I would like to express my earnest gratefulness to Dr. Dave A. Miller, for encouraging and supporting me to pursue doctoral studies. I am also thankful to Dr. Miller for his mentorship and constant guidance throughout the process. I would also like to thank Dr. Ed Rudnic, Dr. Dave Miller, Dr. Chris Brough, Mr. Raj Sheel and Dr. Justin Keen of DisperSol Technologies for financial support for my research and helping guide my research objectives. I would like to extend my gratitude to my dissertation committee members, Dr. Hugh Smyth, Dr. Feng Zhang and Dr. Dave Miller for their valuable suggestions. I am also thankful to the entire faculty of College of Pharmacy including Dr. Salomon Stavchansky, Dr. Feng Zhang, Dr. Maria Croyle, Dr. Zhengrong Cui, Dr. Janet Walkow and Dr. Kelly Revels for providing enriching courses and encouraging thoughtful discussions. My sincere thanks to College of Pharmacy staff Char Burke, Yolanda Abasta and Jay Hammam for always being helpful. I would also like to thank all my fellow graduate students and lab members at College of Pharmacy for their support and friendship. My sincere thanks to Mr. Marshall Cisneros and Ms. Vy Nguyen of DisperSol Technologies for their invaluable help. I would also like to thank the entire team of DisperSol Technologies including Devon MacDonald, Marshall Cisneros, Sandra Kucera, Angela Spangenberg and Jackie Jury for supporting and cheering me up during my low times. I would also like to acknowledge and thank Dr. Harsh Chauhan, my supervisor during Master’s program at Creighton University for his encouragement. I am forever grateful to v my faculty at Institute of Chemical Technology, Mumbai, who laid the foundation of scientific rationalizing in me. Most importantly I thank God and my family and I owe all my achievements to them. My father Mr. Hasmukhlal Gala and my mother Mrs. Ranjanben Gala have instilled values and ethics in me, which have helped me reach this point. My sister Dr. Mita Gala and Mrs. Kanan Chheda have been my pillars of strength. I am lucky to have a second set of parents in form of my in-laws Mr. Narendra Savla and Mrs. Nisha Savla who constantly encourage me to achieve the best. I am also thankful to my brother in laws Mr. Dhiren Chheda and Mihir for boosting me up during my hard times. My nieces Prisha and Freya deserve a big thanks for adding that extra happiness in my life. Finally, I thank my husband Romil Savla, the very reason I moved to Austin and all the great things happened in my life. Romil’s love, care, immense sacrifices and unwavering support has helped me sail happily through this process and I will be forever grateful. vi Abstract IMPROVED PROSTATE CANCER THERAPEUTICS THROUGH KINETISOL® ENABLED AMORPHOUS SOLID DISPERSIONS OF ABIRATERONE Urvi Hasmukhlal Gala, Ph.D. The University of Texas at Austin, 2019 Supervisor: Robert O. Williams III A majority of anticancer drugs have inherently poor water solubility, which limits their oral bioavailability and therapeutic potential. In Chapter one, the ability of amorphous solid dispersions (ASDs), to improve the dissolution, pharmacokinetics, efficacy and safety of anticancer drugs is demonstrated. Abiraterone is a poorly water soluble drug used in treatment of prostate cancer. Its commercial formulation Zytiga®, contains slightly more soluble prodrug, abiraterone acetate. Zytiga has poor oral bioavailability, high pharmacokinetic variability and high food effect, which limits its therapeutic potential. Abiraterone has a high melting point and limited solubility in organic solvents, which makes its ASD development difficult with conventional technologies. In Chapter two, KinetiSol® technology, which is a solvent free thermokinetic process, is utilized and an abiraterone ASD is developed for the first time. In addition to contemporary long- chain polymers, a short-chain oligomer is explored for development of binary and ternary KinetiSol processed ASDs (KSD) of abiraterone. Hydroxy propyl beta cyclodextrin (HPBCD) is identified as a suitable carrier for abiraterone KSD. In Chapter three, the impact of drug loading on abiraterone-HPBCD KSD properties is investigated. 10 to 50 % w/w drug loaded abiraterone KSDs are developed. The solid-state interaction studies revealed that abiraterone forms a complex with HPBCD in the KSD. Overall, as drug vii loading increased, the stability, in-vitro and in-vivo performance decreased. Thus, 10% drug loading is found to be optimum. In Chapter four, an optimal KSD of the prodrug abiraterone acetate is developed and compared with abiraterone KSD. A physicochemical stability study revealed, that the abiraterone acetate KSD is chemically unstable, while abiraterone KSD is both physically and chemically stable. Both KSDs have similar in- vitro and in-vivo performance. Thus, it is concluded that the active drug abiraterone’s KSD is more ideal and overcomes the issues associated with the prodrug use. In Chapter five, a preclinical prostate cancer xenograft model is developed to investigate the pharmacokinetic and pharmacodynamic performance of abiraterone KSD. This study demonstrated a statistically significant tumor growth inhibition of 33.1% by the abiraterone KSD. Thus, these studies suggest the potential for the abiraterone KSD formulation to improve therapeutic outcomes for prostate cancer patients. viii Table of Contents List of Tables .................................................................................................................. xvii List of Figures .................................................................................................................. xix Chapter One: Harnessing The Therapeutic Potential Of Anticancer Drugs Through Amorphous Solid Dispersions .......................................................................................1 1. Abstract: ................................................................................................................1 2. Graphical Abstract: ...............................................................................................2 3. Introduction:..........................................................................................................2 4. Poor Water Solubility Of Anticancer Drugs: ........................................................5 5. Application Of ASDs To Anticancer Drugs: ........................................................7 6. Benefits Of Oral Administration Of Anticancer Drugs And Current Market Scenario: .............................................................................................................12 6.1. Benefits of Oral Administration of Anticancer Drugs: ..................12 6.2. Current Market Scenario for Oncology Drug Products: ................15 7. Challenges And Consequences Associated With Oral Administration Of Poorly Water-Soluble Anticancer Drugs: ...........................................................17 7.1. Drug-Related Challenges: ..............................................................18 7.1.1. Solid State: ..............................................................................18 7.1.2. Ionization:................................................................................20 7.1.3. Stability: ..................................................................................21 7.1.4. Drug–drug interaction: ............................................................22 7.2. Physiology-Related Challenges: ....................................................25 7.2.1. Transmembrane efflux of drugs: .............................................25 7.2.2. Pre-systemic metabolism: .......................................................28 ix 7.2.3. Transporter saturation: ............................................................29 7.3. Other Challenges:...........................................................................30 7.3.1. Prandial state: ..........................................................................30 7.3.2. Patient/Oncologist Related Challenges: ..................................33 8. Alleviating The Consequences Through ASDs: .................................................35 8.1. Enhancing Oral Bioavailability: ....................................................37 8.2. Reducing Pharmacokinetic Variability: .........................................43 8.3. Enhancing Pharmacokinetic Linearity: ..........................................46 8.4. Enhancing Efficacy: .......................................................................48 8.5. Reducing Toxicity:.........................................................................50 9. Case Studies Of Commercial
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