Polymer Reservoirs to Solubilize Hydrophobic Drugs

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Polymer Reservoirs to Solubilize Hydrophobic Drugs

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Research and development of new drug delivery formulations for hydrophobic drugs hold great promise for patients worldwide in the ever-growing pharmaceutical industry. A large portion of the drugs, both in the current market and the development pipeline, suffer from low aqueous solubility, therefore limiting their efficacy for oral administration. One effective way to resolve this problem is the use of an amorphous solid dispersion (ASD), a blend of drug and polymer. An ideal polymer candidate can kinetically stabilize the dispersed drug in its amorphous form in the solid state, while enhancing drug solubility and dissolution in the solution state. Despite recent advances in polymer development for oral drug delivery, the structure-property relationships and the underlying solubility enhancement mechanisms are not fully understood for ASDs. The goals of this dissertation are to develop effective polymers for oral drug delivery, and more importantly, to elucidate the mechanism(s) of drug solubility and dissolution enhancement by using well-defined polymer platforms. Specifically, three model systems were designed and synthesized, including blends of a commercially available polymer and self-assembled micelles in Chapter 3, micelle-forming statistical copolymers and diblock polymers in Chapter 4, and chemically crosslinked polymer nanogels in Chapter 5. It was observed universally in all these three systems that hydrophobic drugs can be sequestered in the slightly hydrophobic polymer reservoirs, and that the drug-polymer partitioning is stronger when the polymer chains are more crowded. The partitioning inhibits drug nucleation and crystal growth in aqueous solution, resulting in enhanced drug solubility. This mechanism is supported by a battery of state-of-the-art characterization experiments, including light scattering, nuclear Overhauser effect and diffusion ordered spectroscopy, cryogenic transmission electron microscopy, small-angle X-ray scattering, and in vitro dissolution tests. Potential applications of the discovered mechanism and the characterization experiments to other drug/polymer systems are discussed as future directions.


University of Minnesota Ph.D. dissertation. August 2018. Major: Chemical Engineering. Advisors: Frank Bates, Timothy Lodge. 1 computer file (PDF); xvii, 204 pages.

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Li, Ziang. (2018). Polymer Reservoirs to Solubilize Hydrophobic Drugs. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/209101.

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