The design and development of steric stabilisers for bicontinuous cubic lyotropic liquid crystalline nanostructured particles for drug delivery systems

2017-02-23T02:27:34Z (GMT) by Chong, Josephine Yin Tse
Lyotropic liquid crystalline nanostructured particles, such as cubosomes, have been growing in popularity as drug delivery systems in the last few years. These systems require steric stabilisers to maintain colloidal stability in an aqueous medium. Therefore, it is important to investigate the effectiveness of steric stabilisers stabilising nonlamellar liquid crystalline nanostructured particles in order to understand the structure-property relationships which are important for developing more effective steric stabilisers. In this project, high throughput sample preparation and batch screening techniques were used for investigating steric stabilisers for cubosomes, with a focus on stabilising nonlamellar liquid crystalline dispersions of phytantriol and monoolein. New steric stabilisers were thereupon identified from pre-existing and novel steric stabiliser classes. The motive for screening steric stabilisers was to ultimately develop effective, stable, targeted systems. However, a lack of knowledge on the effectiveness of alternative steric stabiliser compared to the ‘gold-standard’ steric stabiliser, Pluronic®F127, highlighted the need for an efficient, high throughput stability assay. A high throughput technique, an accelerated stability assay (ASA) for assessing the effectiveness of steric stabilisers at maintaining colloidal stability of cubosomes was consequently developed and validated. This technique proved to be useful as it allowed for the performance of different steric stabilisers to be quantitatively compared between each other and especially against frequently used Pluronic®F127. Henceforth, several alternative commercially-available steric stabilisers were identified to have equivalent and/or superior steric stabilising effectiveness as Pluronic®F127. Subsequent to the development of the ASA, two series of custom steric stabilisers were synthesised with varying sizes of their hydrophobic and hydrophilic domains. The first stabiliser series was a PEGylated-lipid copolymer prepared using a high throughput combinatorial one-pot reaction approach. The polymers in the series had a range of structural variables, such as poly(ethylene glycol) (PEG) or lipid (i.e. phytantriol) molar ratio content and PEG length. This enabled the identification of key design parameters to utilise in a more controlled synthetic approach with potential for eventual functionalisation for targeting purposes. Using the controlled RAFT approach, a second stabiliser series containing a PEGylated amphiphilic brush copolymer, with a di-block copolymer structure was prepared. Despite the large differences in structure from known steric stabilisers, some of the stabilisers synthesised from either copolymer series provided effective colloidal stability for cubosomes comparable to that provided by Pluronic®F127. Furthermore the retention of the internal structure of the bulk phase was also conserved in the cubosomes stabilised using the synthesised copolymers. The steric stabilisers and techniques developed in this project are likely to be valuable tools for prospective, custom steric stabiliser designs, as well as in the specific study of steric stabilisation of nonlamellar liquid crystalline nanostructured particles or other colloidal systems.