Abstract
A major challenge faced with the manufacture of liposomes is the high volumes of organic solvents used during manufacturing. Therefore, we have implemented an organic solvent-free production method for drug-loaded liposomes and demonstrated its applicability with both aqueous core-loaded and bilayer-loaded drugs. Liposomes were produced by high shear mixing dry powder lipids with an aqueous buffer, followed by down-sizing using a Microfluidizer processor. Liposomes were purified via tangential flow filtration and characterised in terms of size, polydispersity index, zeta potential and drug loading. Doxorubicin-loaded PEGylated liposomes can be manufactured using this solvent-free method with particle sizes of 100-110nm, low polydispersity index (PDI) (<0.2) and high drug loading (97-98%). If required, liposomes can be further down-sized via microfluidic processing without impacting drug loading. Similar results were achieved with non-PEGylated liposomes. With bilayer-loaded amphotericin B liposomes, again liposomes can be prepared within a clinically appropriate size range (100-110nm in size, low PDI) with high drug loading (98-100%). We apply a simple and scalable solvent-free method for the production of both aqueous core or bilayer drug-loaded liposomes.
Highlights
Liposomes have been extensively investigated for the delivery of both hydrophobic and hydrophilic drugs due to their ability to improve drug efficacy through targeting.[1]
Size-controlled high drug-loaded liposomes can be produced by the solvent-free method
Higher pressures were adopted (Figure 2); at 18 000 psi, liposomes significantly decreased in size (P < 0.05) to 120 nm after 1 pass, down to 95 nm (z-average diameter) by pass 3 (0.19 polydispersity index (PDI))
Summary
Liposomes have been extensively investigated for the delivery of both hydrophobic and hydrophilic drugs due to their ability to improve drug efficacy through targeting.[1]. At the bench-scale, the thin film hydration method remains the most widely adopted method to manufacture liposomes and it is based on the dissolution of the lipid components with or without a drug in an organic solvent. Other methods to produce liposomes include reverse-phase evaporation and ethanol injection.[5] When considering the choice of solvent, safe handling, removal and disposal is a key consideration as organic solvents can be associated with chronic health effects, especially halogenated solvents[6] and maximum allowable concentration limits for solvents within formulations are defined by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines.[7] Solvents are grouped into four classes as per the ICH Q3C guidelines. Class 2 solvents (chloroform and methanol) should be limited as they are possible causative agents of irreversible toxicity.
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