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Enhanced Delivery of Actives Through Skin from Patches

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Enhanced Delivery of Actives Through Skin from Patches ENHANCED DELIVERY OF ACTIVES THROUGH SKIN FROM PATCHES AND FORMULATIONS, AND DISTRIBUTION WITHIN AND ACROSS SKIN by ASHANA PURI A Dissertation Submitted to the Graduate Faculty of Mercer University College of Pharmacy in Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY Atlanta, GA 2018 ENHANCED DELIVERY OF ACTIVES THROUGH SKIN FROM PATCHES AND FORMULATIONS, AND DISTRIBUTION WITHIN AND ACROSS SKIN by ASHANA PURI Approved: ……………………………………………………………………………………………… Dr. Ajay K. Banga, Ph.D. Date Thesis Advisor ……………………………………………………………………………………………… Dr. Martin J. D'souza, Ph.D. Date Dissertation Committee Member ……………………………………………………………………………………………… Dr. Ravi Palaniappan, Ph.D. Date Dissertation Committee Member ................................................................................................................................................ Dr. J. Grady Strom, Ph.D. Date Dissertation Committee Member ……………………………………………………………………………………………… Dr. Vishal Sachdeva, Ph.D. Date Dissertation Committee Member ……………………………………………………………………………………………… Dr. Brian L. Crabtree, Pharm.D. Date Dean, College of Pharmacy DEDICATION In memory of my father, Ramesh Kumar Puri To my mother, Chanchal Puri With Love and Eternal Appreciation iii ACKNOWLEDGEMENT It is always a tough job to express gratitude in words, for the “beautiful minds” that accompany in each and every step of the entire journey of carrying out the research work. The same perplexity haunts me in penning down sincere thanks to all those to whom this present work owes its existence. First and foremost, I offer my humble obeisance to Almighty God for giving me enough courage, strength, and mental tenacity to accomplish this endeavor. At this juncture, I think of my parents, whose selfless sacrificial life and great efforts with pain and unceasing prayers enabled me to reach the present position in my life. Unfortunately, my father could not witness the completion of my PhD, but I owe it all to him as it would not have been possible without his loving support, patience, understanding, timely guidance, constant motivation, and blessings. His confidence in me was my greatest strength that enabled me to get through the difficult stages during my research. I also owe special thanks to my uncle, aunt, brother, sister-in-law, brother-in- law, and all my cousins for being extremely supportive during my journey of pursuing PhD. My heartiest gratitude, especially to my sister, Vanita Puri Gakhar, who persistently motivated me to pursue research in Mercer University and was always with me, through thick and thin. At this moment of accomplishment, it gives me immense pleasure to express my sincere thanks to my advisor, Dr. Ajay K. Banga, who guided me and gave me the iv confidence to go on and never hesitated to help me throughout my research. I deem it as my privilege to have got the opportunity to work under his able guidance. This work would not have been possible without his support, guidance, and valuable suggestions. Under his guidance, I successfully overcame many difficulties and learnt a lot. His kind and humble words of appreciation always motivated me to work harder and perform to the best of my abilities. I would like to express my gratitude to Mrs. Saveta Banga, Manisha, and Anshul for all the cordiality and affection. I would like to express my heartfelt thanks to my committee members: Dr. J. Grady Strom, Dr. Martin D’Souza, Dr. Ravi Palaniappan, and Dr. Vishal Sachdeva for guiding me through my research and also helping in my professional development. I am also very thankful to my collaborators, Dr. Wei Zhang, Dr. Kevin Murnane, Dr. Onkar Singh for their valuable suggestions and guidance. A special note of thanks to Dean Hewitt William Matthews and Dean Brian L. Crabtree for their encouragement and support. My sincere thanks to all my colleagues and friends, Dr. Pooja Bakshi, Dr. Yamini Gorantla, Dr. Amruta Indapurkar, Dr. Sindhu Sunkara Ganti, Dr. Mahima Manian, Dr. Arunprasad Sivaraman, Nne Emmanuel Uko, Dr. Xinyi Gao, Behnam Dasht Bozorg, Sonalika Arup Bhattaccharjee, Ying Jiang, Yujin Kim, Dr. Yang Song, Jessica Anne Scott, Dr. Hiep Nguyen, Dr. Sucheta D’Sa, Dr. Kimberly Braz Gomes, Dr. Grace Lovia Allotey-Babington, Trang Nguyen, Ipshita Jayaprakash Menon, Mohammad Shajid Ashraf Junaid, and Madhura Kale for their timely help, guidance, company, and support. v More than a word of appreciation is recorded for my friends in India: Arshjyoti, Navjot, Anjali, Jayati, Ankita ma’am, and Dr. Neeraj Kumar, who selflessly supported me from distance, whenever I needed them. I would like to specially thank Ms. Vivienne Brown, Ms. Mary Catherine, Ms. Brenda Austrie-Cannaday, Ms. Cherilyn D’Souza, and Mr. Terry Mernard for all their help and assistance in administrative matters. Finally, I would like to thank all those whose direct and indirect support helped me in completing my dissertation. vi TABLE OF CONTENTS Page ACKNOWLEDGEMENT ............................................................................................... iv LIST OF FIGURES ....................................................................................................... xiv LIST OF TABLES ........................................................................................................ xvii CHAPTER 1 ...................................................................................................................... 1 Introduction ........................................................................................................................ 1 CHAPTER 2 ...................................................................................................................... 9 Review of literature ............................................................................................................ 9 Transdermal and Topical Drug Delivery ............................................................ 9 Skin Structure.................................................................................................... 10 Crossing the Stratum Corneum ......................................................................... 11 Permeation of Actives across Skin ................................................................... 12 Permeation Enhancement Strategies ................................................................. 13 Chemical Penetration Enhancers ...................................................................... 14 Microneedles ..................................................................................................... 18 Laser Microporation.......................................................................................... 20 Iontophoresis ..................................................................................................... 22 Lateral Diffusion of Drugs in Skin ................................................................... 25 Microdialysis..................................................................................................... 27 HIV prophylaxis................................................................................................ 29 Transdermal Delivery for HIV Prophylactic Agents ........................................ 36 Transdermal Patches ......................................................................................... 37 CHAPTER 3 .................................................................................................................... 43 Formulation of epigallocatechin-3-gallate hydrogel and evaluation of its intradermal delivery with the aid of microneedles .............................................................................. 43 Abstract ............................................................................................................ 43 Introduction ..................................................................................................... 44 Materials .......................................................................................................... 48 Methods ............................................................................................................ 48 vii TABLE OF CONTENTS (Continued) Photodegradation studies .............................................................................. 48 Formulation of hydrogels .............................................................................. 49 Rheological evaluation.................................................................................. 50 Flow curves. .............................................................................................. 50 Amplitude sweep. ...................................................................................... 51 Frequency sweep. ...................................................................................... 51 Thixotropy shear and oscillation tests. ..................................................... 51 Preparation of skin samples .......................................................................... 52 Microneedle insertion and visualization of microchannels .......................... 52 Pore uniformity. ........................................................................................ 52 Transepidermal water loss measurement. ................................................ 53 Skin resistance evaluation......................................................................... 53 In vitro skin permeation studies .................................................................... 54 Extraction recovery
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