Development and Characterization of the Solvent-Assisted Active Loading Technology (SALT) for Liposomal Loading of Poorly Water-Soluble Compounds

Abstract

A large proportion of pharmaceutical compounds exhibit poor water solubility, impacting their delivery. These compounds can be passively encapsulated in the lipid bilayer of liposomes to improve their water solubility, but the loading capacity and stability are poor, leading to burst drug leakage. The solvent-assisted active loading technology (SALT) was developed to promote active loading of poorly soluble drugs in the liposomal core to improve the encapsulation efficiency and formulation stability. By adding a small volume (~5 vol%) of a water miscible solvent to the liposomal loading mixture, we achieved complete, rapid loading of a range of poorly soluble compounds and attained a high drug-to-lipid ratio with stable drug retention. This led to improvements in the circulation half-life, tolerability, and efficacy profiles. In this mini-review, we summarize our results from three studies demonstrating that SALT is a robust and versatile platform to improve active loading of poorly water-soluble compounds. We have validated SALT as a tool for improving drug solubility, liposomal loading efficiency and retention, stability, palatability, and pharmacokinetics (PK), while retaining the ability of the compounds to exert pharmacological effects.

Keywords: cancer; child friendly formulation; gambogic acid; liposome; loading gradients; mefloquine; remote loading; staurosporine; water miscible solvents.

Figure 1

The two major methods for liposomal drug loading. (A) Passive loading involves co-current loading and liposomal formation. (B) In active loading, liposomes are formed containing a gradient used to load drugs.

Figure 2

Solvent-assisted active loading technology (SALT) mechanism overview for liposomal loading of a poorly water-soluble drug.

Figure 3

Cryo-TEM images of the drug free liposomes (a) and the staurosporine (STS)-Lipo loaded using 5% dimethyl sulfoxide (DMSO) (b) 60% DMSO (c). Scale bar represents 100 nm. Reprinted with permission from Tang et al., Pharmaceutical Research, published by Springer Nature, 2016 [24].

Figure 4

The solvent effect on drug loading in the SALT system. The figure is reprinted with permission from Tang et al., Biomaterials; published by Elsevier, 2018 [13].

Figure 5

Cryo-TEM images of empty liposomes (DOPC/Chol/DSPE-PEG2K, 85/10/5 by mol%) (A) and Lipo-GA (B). The figure is reprinted with permission from Tang et al., Biomaterials; published by Elsevier, 2018 [13].

Figure 6

Quantification of bitterness of various drug formulations using the e-tongue. Data = mean ± Standard Deviation (SD) (n = 3). The figure is adapted with permission from Tang et al., Molecular Pharmaceutics; published by American Chemical Society, 2017 [23].