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Microneedle-Assisted Transdermal Delivery of Naltrexone Species: in Vitro Permeation and in Vivo Pharmacokinetic Studies

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Microneedle-Assisted Transdermal Delivery of Naltrexone Species: in Vitro Permeation and in Vivo Pharmacokinetic Studies University of Kentucky UKnowledge University of Kentucky Doctoral Dissertations Graduate School 2011 MICRONEEDLE-ASSISTED TRANSDERMAL DELIVERY OF NALTREXONE SPECIES: IN VITRO PERMEATION AND IN VIVO PHARMACOKINETIC STUDIES Mikolaj Milewski University of Kentucky, [email protected] Right click to open a feedback form in a new tab to let us know how this document benefits ou.y Recommended Citation Milewski, Mikolaj, "MICRONEEDLE-ASSISTED TRANSDERMAL DELIVERY OF NALTREXONE SPECIES: IN VITRO PERMEATION AND IN VIVO PHARMACOKINETIC STUDIES" (2011). University of Kentucky Doctoral Dissertations. 160. https://uknowledge.uky.edu/gradschool_diss/160 This Dissertation is brought to you for free and open access by the Graduate School at UKnowledge. It has been accepted for inclusion in University of Kentucky Doctoral Dissertations by an authorized administrator of UKnowledge. For more information, please contact [email protected]. ABSTRACT OF DISSERTATION Mikolaj Milewski The Graduate School University of Kentucky 2011 MICRONEEDLE-ASSISTED TRANSDERMAL DELIVERY OF NALTREXONE SPECIES: IN VITRO PERMEATION AND IN VIVO PHARMACOKINETIC STUDIES ABSTRACT OF DISSERTATION A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the College of Pharmacy at the University of Kentucky By Mikolaj Milewski Lexington, Kentucky Director: Dr. Audra L. Stinchcomb, Associate Professor of Pharmaceutical Sciences Lexington, Kentucky 2011 Copyright © Mikolaj Milewski 2011 ABSTRACT OF DISSERTATION MICRONEEDLE-ASSISTED TRANSDERMAL DELIVERY OF NALTREXONE SPECIES: IN VITRO PERMEATION AND IN VIVO PHARMACOKINETIC STUDIES Naltrexone (NTX) is a drug used primarily in the management of alcohol dependence and opioid dependence. Based on several drawbacks associated with the oral and injectable intramuscular dosage forms of naltrexone currently available on the market, there is substantial interest in delivering naltrexone transdermally. Although naltrexone does not permeate skin at the rate sufficient to reach therapeutic plasma concentrations in humans, novel flux enhancement methods such as microneedles help address this challenge. Earlier work in humans has demonstrated that the use of microneedles achieves plasma concentrations in the lower end of expected therapeutic values. Further flux enhancement is desired to decrease the patch area while increasing drug transport rates. In the present work, several strategies aiming at in vitro flux maximization were employed including: formulation optimization, naltrexone salt screening, and naltrexone prodrug design. While naltrexone prodrugs did not reveal any improved permeation characteristics formulation optimization through decrease in vehicle microviscosity allowed a 5-fold increase in the percutaneous transport rates, and naltrexone glycolate salt selection provided an additional 1.5-fold enhancement in flux. One of the key observations was a good correlation (R2 = 0.99) between vehicle microviscosity and drug transport rates across the microchannel pathway. This finding alone allowed for formulation optimization and, at the same time, provided a potential explanation for the low permeation of high-concentration naltrexone salts and prodrugs. In vivo studies were carried out in Yucatan minipigs using a ―poke and patch‖ microneedle method to deliver NTX•HCl. These studies demonstrated that initial plasma concentrations spiked to 2.5 ng/ml but rapidly dropped to a plateau of below 1 ng/ml. This pharmacokinetic profile could be explained by the use of a mathematical model which identified the importance of microchannel closure kinetics on drug transport. Also, an estimate of diffusional resistance of the viable tissue associated with percutaneous NTX•HCl delivery through microchannels was obtained. Its relatively large value suggests that the effect of diffusional resistance of the dermis in vivo should not be ignored and must be accounted for in order to obtain a good in vitro-in vivo correlation. KEYWORDS: Transdermal drug delivery, naltrexone, microneedles, prodrugs, mathematical modeling Mikolaj Milewski Student‘s signature March 23rd, 2011 Date MICRONEEDLE-ASSISTED TRANSDERMAL DELIVERY OF NALTREXONE SPECIES: IN VITRO PERMEATION AND IN VIVO PHARMACOKINETIC STUDIES By Mikolaj Milewski Dr. Audra L Stinchcomb Director of Dissertation Dr. Jim Pauly Director of Graduate Studies March 23rd, 2011 Date RULES FOR THE USE OF DISSERTATIONS Unpublished dissertations submitted for the Doctor‘s degree and deposited in the University of Kentucky Library are as a rule open for inspection, but are to be used only with due regard to the rights of the authors. Bibliographical references may be noted, but quotations or summaries of the parts may be published only with permission of the author, and with the usual scholarly acknowledgements. Extensive copying or publication of the dissertation in whole or in part also requires the consent of the Dean of the Graduate School of the University of Kentucky A library that borrows this dissertation for use by its patrons is expected to secure the signature of each user. Name Date DISSERTATION Mikolaj Milewski The Graduate School University of Kentucky 2011 MICRONEEDLE-ASSISTED TRANSDERMAL DELIVERY OF NALTREXONE SPECIES: IN VITRO PERMEATION AND IN VIVO PHARMACOKINETIC STUDIES DISSERTATION A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the College of Pharmacy at the University of Kentucky By Mikolaj Milewski Lexington, Kentucky Director: Dr. Audra L. Stinchcomb, Associate Professor of Pharmaceutical Sciences Lexington, Kentucky 2011 Copyright © Mikolaj Milewski 2011 DEDICATION To my wife and parents whose enormous support, patience and understanding allowed me to complete my dissertation ACKNOWLEDGEMENTS The following dissertation, while an individual work, benefited from the insights and direction of several people. First, my dissertation chair, Dr. Audra Stinchcomb, exemplifies the high quality scholarship to which I aspire. Dr. Stinchcomb provided timely and instructive comments and evaluation at every stage of the dissertation process, allowing me to complete this project on schedule. Next, I wish to thank the complete dissertation committee, and outside examiner, respectively: Dr. Leslie Crofford, Dr. Peter Crooks, Dr. Markos Leggas, and Dr. Jiayou Zhang. Each individual provided insight that guided and challenged my thinking, substantially improving the finished product. In addition to the technical and instrumental assistance above, I received equally important assistance from family and friends. My wife, Marta Milewska, provided on-going support throughout the dissertation process critical for completing the project in a timely manner. My parents, Krystyna and Marek Milewscy, instilled in me, from an early age, the desire and skills to obtain the Ph.D. Also, I wish to thank all my labmates: Dr. Kalpana Paudel, Dr. Reddy Pinninti, Dr. Stan Banks, Dr. Caroline Strasinger, Dr. Courtney Swadley, Priyanka Ghosh, Nicole Brogden, Jessica Wehle and Dana Hammell - their help, comments and insight created an informative and interesting project with opportunities for future work. Finally, I would like to thank Josh Eldridge and Dr. Reddy Thirupathi for diligent synthetic chemistry work, as well as, Dr. Mark Prausnitz and Dr. Vladimir Zarnitsyn from Georgia Institute of Technology for providing microneedles and expert advice. Without the support of all the aforementioned people this thesis could not have been completed. iii TABLE OF CONTENTS Acknowledgements .......................................................................................................... .iii List of tables ................................................................................................................. …vii List of figures .................................................................................................................... ix List of abbreviations ........................................................................................................ xiv Chapter 1: Statement of the problem ................................................................................ 1 Chapter 2: Research hypotheses ...................................................................................... 6 Chapter 3: Research plan ................................................................................................. 9 3.1. Development of a mathematical model for in vitro microneedle-assisted drug delivery ........................................................................................................ 9 3.2. Characterization of the formulation physicochemical property effects on the flux of naltrexone hydrochloride across microneedle-enhanced Yucatan minipig skin ...................................................................................................................... 9 3.3. Characterization of the physicochemical properties and determination of in vitro microneedle-enhanced transdermal flux of naltrexone prodrugs across Yucatan minipig skin .......................................................................................... 10 3.4. Characterization of the physicochemical properties and determination of in vitro microneedle-enhanced transdermal flux of naltrexone salts across Yucatan minipig skin ........................................................................................................ 11 3.5. Development of a mathematical model for
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