AbstractOil-in-water nanoemulsions (NE), comprising of an oil dispersed in a water and stabilised by a surfactant, have been increasingly explored as vehicles for the delivery of poorlywater soluble drugs. This interest stems from the ability of NE to increase the apparent aqueous solubility of such drugs. The aims of the current study were several fold and included the determination of the molecular architecture and physico-chemical properties of NE to determine their suitability as vehicles for the parenteral delivery of the hydrophobic drugs, testosterone propionate (TP), curcumin (CUR) and docetaxel (DTX) and establishing the cytotoxicity of NE towards CT26 and HeLa cancer cell lines. Finally a folate derived surfactant was synthesised to explore targeting of the NE.
The study involved the preparation and physico-chemical characterisation of NE stabilised by a range of nonionic surfactants, sometimes in combination with another surfactant and/or cosurfactant. The systems studied included Brij O10 (B), Tween 80 (T), Tween 80 with the cosurfactant, Dermosoft GMCY (TD), and Tween 80 with Dermosoft GMCY and lecithin (TDL). The NE contained as oil, either one of a series of triglyceride oils (namely tripalmitin (hTPN), soybean oil (hSBO), triolein (hGTO), and tristearin (hGTS)) or one of a series of ethyl ester of fatty acid oils (namely ethyl oleate (hEO) and ethyl stearate (hES)). A range of physico-chemical techniques including the phase inversion temperature (PIT), photon correlation spectroscopy (PCS), small angle neutron scattering (SANS), and UV spectroscopy, were used to characterise the NE in terms of their size and shape and ability to solubilise drug.
The Brij O10 NE containing hSBO (B20-hSBO), hTPN (B20-hTPN), hGTO (B20- hGTO) and hEO (B20-hEO) exhibited a larger area of NE formation whereas those containing GTS (B20-hGTS) and ES (B20-hES) produced only a small area of NE existence. The TDL NE incorporated only small amounts of SBO (TDL25-hSBO), while in contrast TD-stabilised NE were found to incorporate high amounts of the oil, EO (TD25-98hEO). The PIT and PCS studies recorded an increase in the PIT and apparent hydrodynamic size upon the addition of oil, suggesting that large molecular volume oils formed a distinct oil core in the NE. A significant enhancement in TP solubilisation in B20 NE was seen with an increase in the amount of oil in the following clear or slightly hazy NE, namely B20-hSBO, B20-85hTPN, B20-99hTPN, B20-99hGTO and B20- 98hEO. However, there was a dramatic decrease in TP solubilisation when the B20-hSBO, B20-85hTPN and B20-99hTPN NE were either cloudy or milky. Interestingly the addition of oil to B20, TD25 and TDL25 micelles did not significantly improve the solubility of CUR and DTX. Solubilisation and PIT studies suggested that both CUR and DTX tended to sit in the surfactant shell. After fitting the SANS data for the all of the NE studied, it was clear that the model which consistently provided the best fit was that of an oblate ellipsoid in which the radius of core of the NE increased with oil content. In addition, the shape of the NE became considerably more elongated as the oil content increased, explaining the decrease in TP solubilisation observed in the cloudy or milky NE.
The cytotoxicity of NE in HeLa and CT26 cell lines suggested that blank B20 NE were toxic while blank TD25 and TDL25 NE were far less toxic. TD25 NE containing 98hEO and TDL25 NE containing hSBO did not show any difference in toxicity in the absence and absence of CUR (a high-dose anticancer agent). As a consequence therefore, DTX (a low-dose anticancer drug) was selected for further study. TDL25 NE containing hSBO in the presence of DTX exhibited a significant different in cytotoxicity when compared to blank TDL25-hSBO NE. In order to selectively deliver DTX to solid tumours expressing folate receptor, folate derived BO10 was successfully synthesised and characterised.
In conclusion, these results suggest that the NE containing a large molar volume oil are the most suitable for the parenteral administration of a poorly water-soluble drug. However, before use the morphology of the NE and the nature of the drug to be solubilised should be carefully examined as both have an effect on the level of solubilisation in the NE.
|Date of Award||2017|
|Supervisor||Margaret Lawrence (Supervisor) & Khuloud Al-Jamal (Supervisor)|