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Biopharmaceutic and Pharmacokinetic Evaluation of Hesperidin and Hesperetin for Ocular Delivery

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Biopharmaceutic and Pharmacokinetic Evaluation of Hesperidin and Hesperetin for Ocular Delivery University of Mississippi eGrove Electronic Theses and Dissertations Graduate School 2011 Biopharmaceutic and Pharmacokinetic Evaluation of Hesperidin and Hesperetin for Ocular Delivery Ramesh Srirangam Follow this and additional works at: https://egrove.olemiss.edu/etd Part of the Pharmacy and Pharmaceutical Sciences Commons Recommended Citation Srirangam, Ramesh, "Biopharmaceutic and Pharmacokinetic Evaluation of Hesperidin and Hesperetin for Ocular Delivery" (2011). Electronic Theses and Dissertations. 271. https://egrove.olemiss.edu/etd/271 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]. BIOPHARMACEUTIC AND PHARMACOKINETIC EVALUATION OF HESPERIDIN AND HESPERETIN FOR OCULAR DELIVERY A Dissertation presented for the partial fulfillment of requirements for the degree of Doctor of Philosophy in Pharmaceutical Sciences in the Department of Pharmaceutics The University of Mississippi by RAMESH SRIRANGAM September 2011 Copyright © Ramesh Srirangam 2011 ALL RIGHTS RESERVED ABSTRACT The bioflavonoid hesperidin and its aglycone hesperetin are promising candidates for the treatment of diabetic retinopathy and diabetic macular edema because of their pharmacological properties. The objective of this project was to characterize the biopharmaceutic and pharmacokinetic characteristics of hesperidin and hesperetin for ocular delivery, especially with respect to the distribution of these compounds to the posterior segment of the eye. Hesperidin and hesperetin were found to be water insoluble compounds. Although they demonstrated good permeability across the ocular tissues, hesperetin’s permeability was found to be higher than that of hesperidin. Hesperidin demonstrated symmetrical transcorneal and transretinal permeation whereas hesperetin exhibited asymmetrical transcorneal and symmetrical transretinal transport. However, none of the influx or efflux transporters, expressed on the cornea, were involved in hesperetin’s corneal transport. It was concluded that hesperetin’s physicochemical properties, ultrastructure of the cornea and components of the diffusion media play a major role in the passive asymmetric transport. Results from the intravitreal kinetic studies of hesperidin, hesperetin and glucosyl- hesperidin (a water soluble derivative of hesperidin), following intravitreal injection, revealed that all three compounds have relatively short half-lives (< 8h) in the vitreous humor. Hesperetin demonstrated the shortest half-life, consistent with its physiochemical characteristics. All three compounds exhibited linear pharmacokinetics, within the dose range tested. This information will be critical in the design of ocular drug delivery systems for these compounds. ii The ocular bioavailability studies following systemic administration suggested that vitreal bioavailability is negligible because of rapid conversion of both hesperidin and hesperetin into their hydrophilic metabolite, hesperetin-glucuronide, in the plasma. In contrast, topical instillation produced significant concentrations of hesperidin and hesperetin in the ocular tissues. Hesperetin’s diffusion into the ocular tissues, in vivo, was high compared to hesperidin; however, very low levels were observed in the vitreous humor. Inclusion of benzalkonium chloride, as a penetration enhancer/preservative, significantly improved the vitreal levels of hesperetin. In conclusion, topical administration would be ideal for the delivery of hesperetin to the deeper ocular tissues. Development of a controlled release drug delivery system and specialized ophthalmic formulations will reduce the frequency of administration needed to sustain the levels at the target site. iii THIS DISSERTATION IS DEDICATED TO MY PARENTS AND MY WIFE iv ACKNOWLEDGMENTS I wish to express my deepest appreciation to those who have supported to make this dissertation a reality. Particularly, I would acknowledge my debt to the following people. Foremost, I would like to express my sincere gratitude to my advisor Dr. Soumyajit Majumdar for his immense patience, motivation, dedication, enthusiasm and endless support. He is an inspirational person and I could not have imagined a better advisor and mentor for my graduate study. I thank him for his unyielding support in every possible way during my stay at Ole Miss. I would also like to thank the other members of my dissertation committee: Dr. Michael A. Repka, Dr. S. Narasimha Murthy and Dr. John S. Williamson for their encouragement, support and diligent evaluation of my dissertation and the constructive criticism provided. I would like to extend my sincere thanks to Dr. Walt Chambliss, Dr. Christy Wyandt, Dr. Bonnie Avery and Dr. Seongbong Jo for their guidance and support and Ms. Deborah King for her help, patience and affection. I would like to acknowledge the support and technical help extended by Ms. Penni Bolton and Dr. Harry Fyke in conducting animal experiments and Dr. Bharathi Avula and Dr. Ikhlas A. Khan for extending their help with the analysis of samples. I thank all my fellow graduate students for their friendship and moral support during my stay at Ole Miss. In particular, I would like to thank Ketan Hippalgaonkar and Tushar Hingorani for their moral support and gratuitous help in conducting my research work. I really enjoyed working with them. v Finally, I would like to thank my parents Mr. Madanaiah Srirangam and Mrs. Laxmikanthamma Srirangam. There is no doubt in my mind that without their love, support, understanding and principles of life and character, I would have not been what I am today. I extend sincere thanks to my dear loving wife Mrs. Kranthi Srirangam, who did more than her share and for her untiring support and encouragement. I recall with gratitude the affectionate help, endless encouragement and support of all my other family members, without whose support and co-operation I would have not been attending Ole Miss and completing Ph.D. This work was supported in part by NIH grant numbers P20RR021929, from the National Center for Research Resources, and EY018426-01 from the National Eye Institute. vi TABLE OF CONTENTS ABSTRACT……………………………………………………………………………………...ii ACKNOWLEDGEMENT...………….…………………………………………………………v CHAPTER 1 : OVERVIEW OF THE RESEARCH PROJECT ............................................. 1 INTRODUCTION ....................................................................................................................... 1 STATEMENT OF THE PROBLEM ........................................................................................... 5 SPECIFIC OBJECTIVES ........................................................................................................... 7 CHAPTER 2 : LITERATURE REVIEW .................................................................................. 8 ANATOMY OF THE EYE ......................................................................................................... 8 OCULAR DRUG DELIVERY ................................................................................................. 14 MICRODIALYSIS.................................................................................................................... 18 OCULAR DISEASES/DISORDERS ........................................................................................ 21 MANAGEMENT AND PREVENTION OF DR/DME: CURRENT APPROACHES ............. 23 HESPERIDIN AND HESPERETIN ......................................................................................... 26 CHAPTER 3 : SOLUBILITY, STABILITY, PHYSICOCHEMICAL CHARACTERISTICS AND IN VITRO OCULAR TISSUE PERMEABILITY OF HESPERIDIN .............................................................................................................................. 35 ABSTRACT .............................................................................................................................. 35 INTRODUCTION ..................................................................................................................... 36 MATERIALS AND METHODS .............................................................................................. 37 RESULTS AND DISCUSSION ................................................................................................ 44 CONCLUSION ......................................................................................................................... 56 vii CHAPTER 4 : SOLUBILITY, STABILITY, PHYSICOCHEMICAL CHARACTERISTICS AND IN VITRO OCULAR TISSUE PERMEABILITY OF HESPERETIN ............................................................................................................................. 57 ABSTRACT .............................................................................................................................. 57 INTRODUCTION ..................................................................................................................... 58 MATERIALS AND METHODS .............................................................................................. 59 RESULTS.................................................................................................................................. 65 DISCUSSION ........................................................................................................................... 74 CONCLUSION ........................................................................................................................
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