In-Situ Phase Transition from Microemulsion to Liquid Crystal with the Potential for Prolonged Parenteral Drug Delivery

Abstract

Background and Aim: Parenteral microemulsions (MEs) have been employed as delivery vehicles to solubilise both hydrophilic and lipophilic drugs. The spreadability of the delivery vehicle determines the total surface area available for drug release in a biological system. A faster spreading vehicle gives a more rapid drug release profile compared to the slower spreading vehicle. Upon addition of aqueous medium, the occurrence of a possible phase transition from a ME to a liquid crystal (LC) or to a coarse emulsion (CE) leads to differences in their spreadability and drug release. The aim of this study is to investigate and explore the potential of MEs as sustained release parenteral drug delivery systems, through their phase transition behaviour in an aqueous environment. Methods: The MEs were developed by constructing pseudoternary phase diagrams using biocompatible Miglyol 812N and a blend of surfactants (Solutol HS 15 and Span 80) and cosurfactant (ethanol). Following the addition of water, the two selected MEs and their derivatives (e.g. CEs or LCs) were subsequently characterised for their rheology, electroconductivity, volume diameter and microstructure. The in vitro phase transition of the MEs to an LC or a CE was monitored by visual observation of the spreadability in water and the microscopic observation for birefringence at the ME/water interface. The physical stability and release kinetics of the progesterone (a lipophilic model drug) loaded MEs were assessed, at three different temperatures (4 °C, 25 °C and 37 °C) and investigated with the use of Franz diffusion cells. The spreadability and drug release profile of the MEs labelled with 99mTc (a hydrophilic model drug) was confirmed using gamma-scintigraphy. Results and Discussion: LC and CE regions were found adjacent to the ME region in the water-rich areas of the phase diagram. Upon the addition of water, the MEs converted from a Newtonian flow with lower viscosities, low conductivities and small droplets (41.8 nm and 69.8 nm) to a pseudo-plastic flow with higher viscosities and altered conductivities and microstructures, suggesting a phase transition into an LC or a CE. The CE-forming ME dispersed rapidly in water, whereas the LC-forming ME remained in a contracted region with an ‘LC-shell’ forming at the ME/water interface. Owing to the semisolid structure, LC is able to modify the drug diffusion rate through the crystal shell and hence sustain the drug release. Both progesterone-loaded MEs were physically and chemically stable at 4 °C, 25 °C and 37 °C at least for three months. The studies of Franz diffusion cell showed that the LC forming ME resulted in a slower release of progesterone than the CE-forming ME. Gammascintigraphy studies demonstrated the formation of a ‘depot’ with a significantly slower release of 99mTc from the LC-forming ME than that of the CE-forming ME. Moreover, the gamma-scintigraphic images confirmed that the LC-forming ME spread less in the presence of water compared to the CE-forming ME. This evidence strongly demonstrated in-situ phase transformations from MEs to a CE or an LC upon contact with aqueous medium. Conclusion: From the same pseudoternary phase diagram, MEs can be transitioned into a CE or an LC depending on their composition and location in the phase diagram. Owing to its low viscosity, large solubilising capacity for both water-soluble and oil-soluble drugs, and the potential for an in-situ phase transition to an LC in an aqueous environment, the LC-forming ME could be a promising injectable vehicle for prolonged drug release.