Date of Award
1-1-2022
Document Type
Dissertation
Degree Name
Ph.D. in Pharmaceutical Sciences
First Advisor
Chalet Tan
Second Advisor
Michael Repka
Third Advisor
Walt Chambliss
School
University of Mississippi
Relational Format
dissertation/thesis
Abstract
Carbon monoxide (CO) is widely known as poisonous gas. Its role as a signaling molecule (gasotransmitter) with various therapeutic effects is less known. Recent years have seen a surge of interest in CO because of its demonstrated therapeutic effect in treating conditions such as inflammation, drug-induced toxicity, ischemia-reperfusion injury, and kidney injury, among others. In developing CO-based therapeutic agents, one key issue is the availability of pharmaceutically acceptable ways of delivering CO. During the past decade, there has been a large number of experiments in cell culture, animal models, and clinical trials using CO gas incubation/inhalation and heavy metal based CO-releasing molecules (CORMs). In collaboration with Dr. Binghe Wang’s lab at Georgia State University, a series of organic CO prodrugs with desirable pharmaceutical properties, including less toxicity, chemical tractability, delivery properties, and fewer unintended reactions, among others, have been developed. The rationale of this dissertation is to conduct a comprehensive preclinical study, including preformulation study, formulation development, in vitro analysis, and in vivo pharmacokinetic study to evaluate the drugability of the organic CO prodrugs with the eventual goal of being able to pack “carbon monoxide in a pill” for the successful clinical application.
In the first chapter, the bioanalytical methods are first discussed. Subsequently, a comprehensive in vitro and in vivo evaluation of the first-generation organic CO prodrugs is discussed. The second-generation sweetener-based CO prodrugs and an activated charcoal-based oral formulation have been developed and discussed in the second chapter. The third chapter discusses the pharmacokinetic studies on the IMCO-104, which is BW-CO-103 with silica immobilized formulation. And then the tissue distribution studies on IMCO-104, BW-CO-306, and BW-AC-306, the in vivo CO analytical methods, and PK considerations are also discussed in this chapter.
In conclusion, this dissertation describes and evaluates the organic CO prodrugs with different chemistry and the associated formulation strategies for in vivo CO delivery. Two generations of CO prodrugs and the respective formulation strategies were evaluated and characterized in vitro and in vivo. We demonstrated the feasibility and prospect of CO oral delivery for clinical application.
Recommended Citation
Wang, Minjia, "Sustained Delivery of Carbon Monoxide (CO) via Organic Co Prodrugs: Pharmacokinetic Studies" (2022). Electronic Theses and Dissertations. 2463.
https://egrove.olemiss.edu/etd/2463
Concentration/Emphasis
Pharmaceutical Science