University of Tennessee Health Science Center UTHSC Digital Commons Theses and Dissertations (ETD) College of Graduate Health Sciences 5-2017 Biodegradable Polymeric Biomaterials in Different Forms for Long-acting Contraception and Drug Delivery to the Eye and Brain Dileep Reddy Janagam University of Tennessee Health Science Center Follow this and additional works at: https://dc.uthsc.edu/dissertations Part of the Pharmaceutics and Drug Design Commons Recommended Citation Janagam, Dileep Reddy (http://orcid.org/0000-0002-7235-7709), "Biodegradable Polymeric Biomaterials in Different Forms for Long-acting Contraception and Drug Delivery to the Eye and Brain" (2017). Theses and Dissertations (ETD). Paper 425. http://dx.doi.org/10.21007/etd.cghs.2017.0429. This Dissertation is brought to you for free and open access by the College of Graduate Health Sciences at UTHSC Digital Commons. It has been accepted for inclusion in Theses and Dissertations (ETD) by an authorized administrator of UTHSC Digital Commons. For more information, please contact [email protected]. Biodegradable Polymeric Biomaterials in Different Forms for Long-acting Contraception and Drug Delivery to the Eye and Brain Document Type Dissertation Degree Name Doctor of Philosophy (PhD) Program Pharmaceutical Sciences Track Pharmaceutics Research Advisor Tao L. Lowe, Ph.D. Committee Joel Bumgardner, Ph.D. James R. Johnson, Ph.D. Bernd Meibohm, Ph.D. Duane D. Miller, Ph.D. ORCID http://orcid.org/0000-0002-7235-7709 DOI 10.21007/etd.cghs.2017.0429 Comments Two year embargo expires February 2019. This dissertation is available at UTHSC Digital Commons: https://dc.uthsc.edu/dissertations/425 Biodegradable Polymeric Biomaterials in Different Forms for Long-acting Contraception and Drug Delivery to the Eye and Brain A Dissertation Presented for The Graduate Studies Council The University of Tennessee Health Science Center In Partial Fulfillment Of the Requirements for the Degree Doctor of Philosophy From The University of Tennessee By Dileep Reddy Janagam May 2017 Portions of Chapter 2 © 2015 by Springer and Elsevier. Portions of Chapter 3 © 2013 by Springer. Portions of the Appendix © 2015 by Elsevier. All other material © 2017 by Dileep Reddy Janagam. All rights reserved. ii DEDICATION Dedicated to my loving family. iii ACKNOWLEDGEMENTS I would like to take this opportunity to express my heartfelt thanks to all those people who have been involved either directly or indirectly, at various stages of my journey at University of Tennessee Health Science Center (UTHSC). I may not be able to list all the names here, but I sincerely appreciate all the unforgettable help, support, advice, and encouragement I have received at UTHSC. First and foremost, I would like to express my sincerest thanks with a great gratitude to my advisor, Dr. Tao Lowe, for her continuous support, encouragement and guidance throughout the span of my graduate studies. She was always available to discuss my research plans, results, and manuscript; I truly appreciate her time, patience, and understanding. Her guidance helped me in all the time of my research, writing manuscripts, and dissertation, and also helped me to advance in my educational and personal growth. Apart from the academic and research skills, she has constantly encouraged and supported me to take up the leadership roles and improve my skills set in all other aspects that would help me in making a successful career. I am very grateful to her, and it has been an honor to work with her. I express my deep gratitude to all the graduate committee members Dr. James R. Johnson, Dr. Bernd Meibohm, Dr. James R. Johnson, and Dr. Joel Bumgardner for their time, support, useful suggestions, and insightful comments. I am thankful for the kindness and academic support they have offered me. I sincerely thank our collaborator Dr. James Johnson for his insight and expertise in injectable in situ depot formulations that helped guide my work as it progressed. I would like to thank Dr. Bernd Meibohm for allowing to use his lab facilities. I thank our collaborator Dr. Timothy Mandrell, and Ms. Stacey L Barnett for their help and support in animal studies. Thanks to Dr. Randy Buddington and his group (University of Memphis), Dr. Charles W. Leffler, Mr. Alexander Fedine, Dr. Dianna for providing the porcine eyeball samples for the permeability studies. I thank Dr. Lichong Xu for his support with the AFM studies of the nanogles. I thank our collaborator Dr. Francesca- Fang Liao, and her group member Dr. Bin Wang for their assistance in in vivo studies with cyclodextrin-based nanoparticles for brain delivery. I also extend my sincere thanks to our collaborator Dr. Anthony Guiseppi-Elie (Texas A&M University) and his group members (Dr. Kotanen and others) for their assistance related to the poly(HEMA)-based hydrogel characterization project. My thanks to all my past and present lab members Dr. Linfeng Wu, Dr. Kamaljit Kaur, Dr. Seshulatha Jamalapuram, Dr. Suryatheja Ananthula, Dr. Lizhu Wang, Dr. Xiaoxun Li, Dr. Misra, Keegan Compton, Chandana Damera for their help and support at various stages of the work, and even more, for creating a friendly atmosphere. I am grateful to the assistance received from various lab personnel outside my research groups from our department. iv I would like to thank all the faculty members of the Department of Pharmaceutical Sciences for their invaluable academic support. I thank our staff members Brenda Thornton, Corliss Finlay, Shelley Cannioto, Caroll Taylor, Lisa Schaffer, and Mary Newell for their support. My gratitude also extends to University of Tennessee Health Science Center, College of Pharmacy, and College of Graduate Health Sciences for the facilities, equipment, and financial support. I thank all the funding agencies that supported my research. Many thanks to all my friends at UT and in Memphis who has made my graduate study a memorable one. They all have been a valuable source of friendship and advice over the past years. Last but not the least, I am very much grateful to my wife Sri Chandana Damera, my mom, my dad and my brother, this is the culmination of all of their love and effort, and without them I could not have made it this far. Finally, I need to thank God for giving all these opportunities to learn new things and meet great people. v ABSTRACT Efficacy of many of the new and existing therapeutics is often hampered by the lack of an effective and compliant method of delivery. Typically, drugs have poor water solubility, short half-lives, and low permeability across the biological membranes. The result is low bioavailability of the drugs at the target site and can cause toxicity and side effects at high doses. Often the conventional dosage forms fail to overcome these limitations. In the recent decades, biodegradable polymeric drug delivery systems have emerged as promising candidates to solve the challenges of poor solubility, low permeability and sustained release owing to the advantages of biocompatibility, versatility, and tunable drug release. Polyesters and polysaccharides are the most common polymers that were explored for drug delivery applications because of their unique advantages including non-toxic nature, wide availability, relatively low cost, and flexibility in chemistry. Although a major progress has been in the field of drug delivery, still there are unmet medical needs which require new materials for delivering drugs such as, injectable systems that can achieve long-term contraception (five months or longer) at low cost, and drug delivery systems that can enhance the permeability of drugs across ocular/blood-brain barriers and sustain release as well for treating chronic diseases such as diabetic retinopathy in the eye and Alzheimer’s disease in the brain. Therefore, this research has evaluated the potential of different biodegradable polymeric biomaterials based on polyesters or polysaccharides for long-acting contraception and drug delivery to the eye and brain to resolve the issues such as poor compliance and adherence to the existing contraceptive dosage forms or poor solubility and permeability of the drugs across ocular/blood-brain barriers. The first system includes polyester-based injectable in situ forming depot systems (ISD) for long-acting contraception. The aim of this project was to develop injectable ISD system containing levonorgestrel (LNG) for contraceptive effect for five months or longer after single shot that helps to reduce unintended pregnancies with high patient compliance and low cost. A series of LNG-containing ISD formulations were designed by employing unique strategies which include the use of poly(lactic acid-co-glycolic acid), poly(lactic acid) with different biodegradable properties, and blends of these polyesters, use solvent mixtures of N-methyl-2-pyrrolidone, triethyl citrate, benzyl benzoate, and vary the polymer/solvent ratios, and various drug loadings. The formulations were evaluated for viscosity, initial burst, in vitro and in vivo long-term release. In vivo investigation in rats showed the sustained-release pharmacokinetic profile of LNG from the ISD formulations for at least five months and continued for more than seven months depending on the composition, and the vaginal cytology studies have demonstrated that formulations have successfully suppressed the rat estrous cycle. After the end of the treatment, a rapid and predictable return of fertility was observed in rats. The optimized lead formulation has shown promising injectability (23 G) and