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Development of a fast and efficient liposomal drug loading technology for poorly water soluble drugs : formulation, characterization, and potential applications

University of British Columbia

More than 70% of drugs exhibit poor water solubility, thereby limiting their clinical applications. Formulating these drugs into liposomes is a feasible approach to increase their solubility and improve the therapeutic efficacy. However, encapsulating hydrophobic drugs into the lipid bilayer of liposomes often results in burst drug release and liposomal instability, due to the weak association between the drugs and the lipid bilayer. Additionally, the capacity of the lipid bilayer is limited, leading to inefficient drug loading. To address this issue, this thesis focused on developing a new loading technology, called Solvent-assisted Active Loading Technology (SALT), to allow stable and efficient loading of poorly water-soluble drugs into the aqueous core of liposomes. This technology involved the addition of a certain amount of a water-miscible organic solvent into the mixture of a poorly soluble drug and preformed liposomes incorporated with a trapping agent inside the aqueous core. The solvent was not only used to help drug dissolution, but also to facilitate drug permeation into the liposomal core to form drug complexes with the trapping agent by increasing the membrane permeability during the drug loading. We have generated multiple examples to demonstrate the robustness and potential utilities of this technology. As a proof-of-principle, the first part of the thesis focused on developing the SALT for stable loading of a model drug, staurosporine (STS, insoluble weakly basic drug), into liposomes and optimizing the fabrication of a liposomal STS formulation for in vivo therapy of tumor. The second part of this dissertation was to explore whether the SALT is a flexible platform for formulating other types of poorly soluble drugs such as gambogic acid (GA, insoluble weakly acidic drug) into liposomes. We also examined whether other miscible solvents (other than DMSO) could be utilized in the system and their roles in promoting drug loading. The third part of this thesis was to demonstrate another utility of the SALT for preparing an oral pediatric formulation of mefloquine with bitterness masking. This thesis work demonstrated that SALT was a robust drug loading technology to develop stable liposomal formulations for poorly soluble drugs with practical utilities.

Text

2018-10-16

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/67586

Pharmaceutical Sciences

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/