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Biopharmaceutical Approaches for Improved Drug Delivery Across Ocular Barriers

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Biopharmaceutical Approaches for Improved Drug Delivery Across Ocular Barriers University of Mississippi eGrove Electronic Theses and Dissertations Graduate School 1-1-2011 Biopharmaceutical approaches for improved drug delivery across ocular barriers Ketan Hippalgaonkar University of Mississippi Follow this and additional works at: https://egrove.olemiss.edu/etd Part of the Pharmacy and Pharmaceutical Sciences Commons Recommended Citation Hippalgaonkar, Ketan, "Biopharmaceutical approaches for improved drug delivery across ocular barriers" (2011). Electronic Theses and Dissertations. 1484. https://egrove.olemiss.edu/etd/1484 This Dissertation is brought to you for free and open access by the Graduate School at eGrove. It has been accepted for inclusion in Electronic Theses and Dissertations by an authorized administrator of eGrove. For more information, please contact [email protected]. BIOPHARMACEUTICAL APPROACHES FOR IMPROVED DRUG DELIVERY ACROSS OCULAR BARRIERS A Dissertation presented in partial fulfillment of requirements for the degree of Doctor of Philosophy in the Department of Pharmaceutics The University of Mississippi by KETAN HIPPALGAONKAR July 2011 Copyright Ketan Hippalgaonkar 2011 ALL RIGHTS RESERVED ABSTRACT The eye is protected from the external environment by various physiological and anatomical barriers. These barriers through there protective actions drastically diminish the ocular bioavailability of drugs. The corneal epithelium acts as a major barrier towards the permeation of hydrophilic agents, whereas poor aqueous solubility presents a formulation challenge for lipophilic compounds. Additionally, P-glycoprotein (P-gp) expressed on the retinal pigmented epithelium (RPE P-gp) limits the penetration of substrates, in therapeutically relevant concentrations, into the back-of-the-eye. In the present research, use of penetration enhancers (chitosan, benzalkonium chloride (BAK) and ethylenediaminetetraacetic acid (EDTA)) and formulation approaches (cyclodextrins and solid lipid nanoparticles (SLNs)) were evaluated in terms of their ability to improve the ocular bioavailability of hydrophilic and lipophilic compounds, respectively. A novel approach, localized modulation of RPE P-gp using topically co-administered P-gp inhibitors, was investigated to improve the back-of-the eye delivery of P-gp substrates. In vitro transcorneal permeation results demonstrated that chitosan brought about a dose dependent increase in the permeability of acyclovir, a model hydrophilic compound. Combination of chitosan, BAK and EDTA resulted in a synergistic effect on the permeation of acyclovir. Dramatic increase in aqueous solubility, stability and in vitro transcorneal permeability of delta-8-tetrahydrocannabinol, a model lipophilic agent, was observed in the presence of 2-Hydroxypropyl-β-cyclodextrin (HP βCD), randomly methylated-β-cyclodextrin and ii sulfobutylether-β-cyclodextrin. The indomethacin loaded SLN (IN-SLNs) formulation was physically stable following sterilization and on storage. The IN-SLNs formulation increase stability and in vitro corneal permeability of indomethacin in comparison to the solution formulations (cosolvent and HP βCD based) tested. Furthermore, for the first time, studies in anesthetized male New Zealand rabbits demonstrate that topically applied P-gp inhibitors can diffuse to the RPE and alter the elimination kinetics of a systemically or intravtireally administered P-gp substrate, probably through inhibition of the basolateral RPE P-gp. The degree of inhibition was found to be dependent on the physicochemical characteristics of the inhibitor and its affinity for P-gp and the concentration of the therapeutic agent in the plasma or in the vitreous humor. Formulation factors such as inclusion of permeation enhancers may play a major role in yielding effective levels of the inhibitor at the RPE. iii DEDICATION This dissertation is dedicated to my parents Uday Kumar Hippalgaonkar and Sanjivani Hippalgaonkar. I would not have reached this milestone without their unending encouragement, patience, support, understanding and love. This dissertation is also dedicated to my lovely wife Swetha Mahalaxmi for being my oxygen and strength. iv ACKNOWLEDGMENTS Obtaining a Ph.D. degree could not be realized without my advisor Dr. Soumyajit Majumdar. His expertise, intellectual support and professional guidance were imperative for this work. I thank him dearly for his encouragement, patience, understanding and support throughout my graduate studies. I am truly grateful and indebted to him for his help and attention towards my academic and personal requests. Thank you for being my advisor! I express my heartfelt gratitude to my dissertation committee members Dr. Michael A. Repka, Dr. John S. Williamson and Dr. Walter G. Chambliss for their valuable time, guidance, suggestions and help during the evaluation of this dissertation. I extend my thanks to Dr. S. Narasimha Murthy, Dr. Bonnie A. Avery, Dr. Seongbong Jo and Dr. Christy M. Wyandt for making the experience at Ole Miss worthwhile, Ms. Deborah King for her help, patience and affection. I also thank the support and technical help extended by Dr. Harry Fyke and Ms. Penni Bolton during animal experiments. I thank all graduate students at Department of Pharmaceutics for their support and for making my stay at Ole Miss memorable. I profusely thank my colleagues and friends, especially Ramesh Srirangam and Tushar Hingorani for being such a great support and fun to work with. I also thank them for their help during experimental work and during my stay at Ole Miss. Special thanks to my lovely little sister and colleague Kanchan Hippalgaonkar for her love, moral v support, and encouragement. Working with her during this dissertation was special, fun and memorable. My warmest thanks to my wife Swetha Mahalaxmi, the support, encouragement, inspiration, love and strength that she has provided me is priceless. The years I spent pursuing my Ph.D. degree would have been more strenuous, less delightful and unsatisfactory without her. Thank you so much! I specially fall short of words to thank my brother Bipin Hippalgaonkar. He has been my inspiration, strength and moral support. Without his support, encouragement and sacrifices I would not have attended Ole Miss. Thank you for everything! Most importantly I thank my parents Uday Kumar Hippalgaonkar and Sanjivani Hippalgaonkar for their unyielding encouragement, patience, moral support and guidance. Thank you Aai and Baba! vi TABLE OF CONTENTS Chapter Page 1. Review of Literature _____________________________________________________ 1 2. Aims of the Study ______________________________________________________ 55 3. Effect of Chitosan, Benzalkonium Chloride and Ethylenediaminetetraacetic acid on Transcorneal Permeation of Acyclovir ______________________________________ 57 4. Effect of Modified Cyclodextrins on Solubility, Stability and Transcorneal Permeability of Delta-8-Tetrahydrocannabinol __________________________________________ 76 5. Indomethacin Loaded Solid Lipid Nanoparticles for Ocular Delivery: Development, Optimization and in vitro evaluation ______________________________________ 102 6. Effect of Topically Co-administered P-gp Substrates/Modulators on Vitreal Kinetics of intravitreally administered Quinidine in Rabbits _____________________________ 171 7. Interaction between Topically and Systemically Co-administered P-glycoprotein Substrates/Inhibitors: Effect on Vitreal Kinetics _____________________________ 204 8. References ___________________________________________________________ 237 9. Vita ________________________________________________________________ 253 vii LIST OF TABLES Table Page 1-1: Site of Application of Transscleral Injections. ...................................................................... 30 1-2: Trade name, manufacturer and physiochemical description of some of the solid lipids used in the present study .............................................................................................................. 46 4-1: Container types, capacity and approximate nominal and fill volumes in the binding studies……………………………………………………………………………………...81 4-2: Loss of ∆8 THC in different containers at two different concentrations. .............................. 87 4-3: Effect of pH on the degradation of ∆8-THC in the absence or in the presence of CDs. ...... 89 2 4-4: Slope, apparent stability constant (K 1:1 ) and correlation coefficient (R ) determined from the ∆8-THC: HP βCD, ∆8-THC: RM βCD and ∆8-THC: S βCD aqueous phase solubility diagrams. .............................................................................................................................. 94 5-1: Coded and actual values of factors used in Face Centered central composite design (FCCD). ............................................................................................................................................ 112 5-2: Experimental runs generated by Design Expert software and the observed responses in face centered central composite design for optimization of IN-SLNs. ..................................... 113 5-3: Analysis of variance results of different models for each response. ................................... 128 5-4: Fitted Quadratic model equations for particle size (Y 1), entrapment efficiency (Y 2), and zeta potential (Y 3) as the responses. .......................................................................................... 128 viii 5-5: Analysis of variance results of fitted quadratic model for particle size response (Y 1) ...... 129 5-6: Analysis of
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