Author ORCID Identifier

https://orcid.org/0000-0001-9909-7663

Year of Publication

2021

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Pharmacy

Department/School/Program

Pharmaceutical Sciences

First Advisor

Dr. Eric J. Munson

Second Advisor

Dr. Daniel Pack

Abstract

With the looming dominance of poorly water-soluble chemical entities within the pharmaceutical pipeline, the pharmaceutical industry has leaned on the use of supersaturating drug delivery systems (SDDSs) to achieve efficacious concentrations within the gastrointestinal fluids. SDDSs aim to achieve concentrations in solutions greater than the solubility of the lowest energy crystalline form. However, the generation of supersaturated solutions of active pharmaceutical ingredients (APIs) creates a strong crystallization potential, which is undesirable.

In product development, supersaturating products often fail in Phase I and Phase II clinical trials due to poor oral bioavailability and a lack of in vivo efficacy. Pre-clinical testing exists as a filter for product failures; regardless, product failures still occur in the clinical stage of product development leading to delays or cancellations of novel treatments. This disconnect between pre-clinical performance testing and in-vivo outcomes highlights the lack of understanding of the in-vivo oral absorption process of APIs from supersaturated solutions. The pharmaceutical industry would greatly benefit from identifying critical factors associated with the safe and efficacious delivery of pharmaceutical products to patients in need.

Currently, in-vitro dissolution testing remains the most commonly used technique to evaluate product performance. One salient variable to dissolution testing is the dissolution media itself. Maintenance of supersaturation is believed to be part of the complex mechanism by which SDDSs enhance the oral bioavailability of poorly soluble drugs. Studies have shown that the dissolution of SDDS is highly dependent on the media used. The implications of endogenous materials such as bile acids and phospholipids on oral absorption have been studied and accounted for in commercial formulations of simulated gastrointestinal (GI) fluids. However, the impact of mucin, the main glycoprotein in mucus, in solution has been neglected, which results in studying product performance without fully characterizing all the variables.

Mucin is the main component of mucus gels lining the entirety of the gastrointestinal tract, and significant quantities are expected to be found within GI fluids. Several recent studies have shown the impact of mucin on the permeation of lipophilic compounds, indicating the potential for interactions with such molecules. Therefore, it is expected mucin may stabilize supersaturated solutions of poorly water-soluble compounds via similar interactions.

Overall, this dissertation aims to probe the impact of mucin as a solution component capable of stabilizing supersaturation:

  1. The inclusion of mucin into in-vitro media to achieve an improved biorelevance is explored and evaluated as a potential reason as to why the in-vitro dissolution characteristics of ketoconazole do not match that within in-vivo systems. The sensitivity of the in-vitro examination method to seed crystals is also evaluated as a potential confounding factor in in-vitro examinations.
  2. A 17beta-Estradiol (E2) and polysorbate 80 (PS80) micelle system was used to probe the increases in permeability to the diffusion of nano-scale particles through the aqueous boundary layer (ABL). Coupled with diffusion coefficient determination of a model nano-scale species via NMR, a mathematical model was developed to accurately predict the permeability increases due to increases in effective diffusivity due to the nano-scale shuttling of E2 through the ABL.
  3. The ability of mucin to stabilize supersaturated solutions is evaluated in the context of its ability to reduce the thermodynamic activity, or the driving force for crystallization, of several model drugs: 17beta-estradiol, nifedipine, and bicalutamide. The flux of these model drug compounds is evaluated in the absence and presence of mucin using horizontal diffusion cells. A decrease in the flux of API in the systems containing mucin relative to the systems in the absence of mucin indicates a reduction of thermodynamic drug activity.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2021.475

Funding Information

  1. Lyman T. Johnson Fellowship provided by the University of Kentucky Graduate School for the 2017, 2018, and 2019 academic years
  2. Pharmaceutical Sciences Excellence in Graduate Acheivement award provided by the University of Kentucky Department of Pharmaceutical Sciences in January 2021
  3. National Science Foundation Industry-University Cooperative Research Centers: Center for Pharmaceutical Development (IIP-1540011 and industrial contributions). 2016-2021
  4. FDA Grant to National Institute for Pharmaceutical Technology & Education titled "The Critical Path Manufacturing Sector Research Initiative (U01)''; Grant #5U01FD004275

Available for download on Wednesday, June 22, 2022

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