Formation of Nano-carrier systems by dense gas processing

Abstract

Nano-carriers such as liposomes, polymersomes and micelles find applications in the delivery of a wide range of compounds including targeted delivery of pharmaceuticals. In pharmaceutical applications, liposomes are employed to increase the bioavailability, reduce toxicity and avoid undesirable interactions of active pharmaceutical ingredients. A number of conventional methods are used to produce nano-carriers. However, most of the conventional techniques require large amounts of organic solvents during the production and, hence, further purification steps are required. Additional purification is costly and may impose harsh working conditions on the nano-carriers that could damage the nano-carriers. Therefore, dense gas techniques have recently received attention for the production of nano-carriers. Dense gas techniques reduce, or even eliminate, the amount of organic solvents required by conventional methods, which make them ideal manufacturing techniques for nano-carriers for pharmaceutical application. In this work, a novel dense gas technique Depressurization of an Expanded Solution into Aqueous Media (DESAM) was used to produce liposomes, polymersomes, and micelles. The DESAM process is a fast single-step production method that is conducted at moderate pressures and temperatures. The liposomes, polymersomes and micelles generated by DESAM had average hydrodynamic diameters of 250 nm, 415 nm, and 100 nm respectively. The polymersomes and micelles produced had undetectable residual solvent by Gas Chromatography (GC). However, there was 2.2% v/v of ethanol detected in liposomes produced by the DESAM process. Although DESAM was used successfully to produce nano-carriers with minimal residual solvent, it is a batch process with limited scope for process optimisation. Hence, a novel semi-continuous dense gas technique was introduced to overcome the limitations of DESAM. In the semi-continuous process, removal of organic solvent is viable within the nano-carrier formation step. The nano-carriers produced using the semi-continuous process had undetectable residual solvent by GC. In addition, the new process provides more control over the experimental parameters than DESAM. Drug encapsulation for both liposomes and polymersomes was also studied by using the model drug isoniazid (anti-tuberculosis drug) in both DESAM and the semi-continuous processes. Both the processes capability to produce a range of drug-loaded nano-carriers has been demonstrated.