Theory has been used to complement experiment in the development of both drugs and delivery systems. Theoretical methods are capable of identifying the molecular basis of drug formulation inadequacies and systematic theoretical studies may suggest fruitful avenues for material modification. This thesis highlights the utility of computer-based theoretical calculations for guiding the design of drug formulations and enhancing material-drug compatibility and stability. Specifically, the present work explores the applications of semi-empirical methods and atomistic molecular dynamics (MD) simulations to enhance the performance of nano-emulsions and polymer micelle formulations for the delivery of hydrophobic drugs. This work includes three separate studies preceded by an introductory summary of available theoretical techniques.
The first study evaluates the accuracy and reliability of semi-empirical methods and MD simulations as means to select suitable excipients to formulate the anti-cancer drug docetaxel in an emulsion. Here, simulations accurately predict the rank order of drug solubility in various excipients, suggesting that simulation is useful for library enrichment.
In the second study, a drug conjugation approach is used to further improve the stability and solubility of docetaxel in a triglyceride-based nano-emulsion. Here, optimal conjugates are identified with computer-based theoretical calculations and conjugates with formulation-compatible moieties are synthesized. As predicted, the conjugates exhibit enhanced solubility and loading efficiency in a nano-emulsion.
The goal of the third study is to rationally design a stable unimolecular star copolymer that, as a unimer, does not disassemble upon the dilution that accompanies intravenous injection. Here, MD simulation is used to systematically investigate the solution properties of differently composed star copolymers. Overall, star copolymers with a hydrophobic PCL core ≤ 2 kDa and hydrophilic PEG blocks approaching 14.6 kDa per arm are predicted to form unimolecular micelles that remain unimeric at high concentrations.
The studies presented in this thesis demonstrate that theoretical approaches are useful for fast pre-screening of drug formulation materials and for the development of delivery systems and drug derivatives.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:OTU.1807/35730 |
| Date | 24 July 2013 |
| Creators | Huynh, Loan |
| Contributors | Allen, Christine |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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