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.
Highlights
When working with poorly water-soluble drugs, soluble drugs, the drugs are first dissolved with lipids in an organic solvent, followed by solvent the drugs are first dissolved with lipids in thin an organic solvent, followed by solvent to evaporation to prepare a drug containing film, which is later hydrated with an evaporation aqueous phase prepare a drug containing thin film, which is later hydrated with an aqueous phase to prepare liposomes
We hypothesized that including a small volume of water-miscible solvent in the loading mixture of liposomes and a hydrophobic drug could help solubilize the drug in the aqueous phase, increase the drug penetration through the liposomal bilayer and boost active loading encapsulation efficiency. pH adjustment is among the most commonly-used methods to increase drug solubility
Adjustment, the Solvent-assisted active loading technology (SALT)/liposome technique enhanced the solubility of our model drugs Staurosporine, Gambogic Acid and Mefloquine from 120 μg/mL to 1 mg/mL, 5 μg/mL to 1 mg/mL, and 0.6 mg/mL to
Summary
Clinical translation of pharmaceutical compounds is often hindered by poor solubility. Of new chemical entities are not appreciably soluble in water, often resulting in limited therapeutic use, or abandonment as drug candidates [1,2]. Methods for improving apparent solubility include salt formulations, excipients, amorphous solid dispersions, pH adjustment, co-solvents, and nanocarriers [1,2]. There has been interest in the development of systematic approaches to overcoming low soluble compounds, as outlined in the developability classification system which describes a categorization of compounds based on permeability and solubility [3]. There has been growing interest in the use of nanocarriers as a vehicle to overcome issues of solubility, as they serve as a platform technology and provide cell targeting [4]. Lipid-based nanocarriers (LNCs) represent a class of lipid particles, including solid lipid nanoparticles, micro- or nano-emulsions, polymer-lipid hybrid nanoparticles, and liposomes.
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