Liposome drugs' loading efficiency: A working model based on loading conditions and drug's physicochemical properties

The un-ionized forms of gradient-forming salts (e.g., acetic acid) permeate the liposome lipid bilayer faster than their ionized forms.

“The degree of ionization of these compounds is pH dependent, and their ionized species (i.e., ammonium and acetate) have a very low permeability coefficient and octanol-to-buffer partition coefficient; therefore they either do not, or only very slowly, permeate the liposome lipid bilayer, while their un-ionized species have high permeability, as well as octanol-to-buffer partition coefficient (exe”

The magnitude of the intraliposome-high/extraliposome-low transmembrane ion gradient is the driving force for remote loading.

“The magnitude of the intraliposome high/external medium low transmembrane gradient of such ions is the driving force for remote loading, as they can be exchanged with amphipathic drugs that are weak acids or bases.”

A transmembrane calcium acetate gradient is most suitable for loading amphipathic weak acids.

“Overall, from our own experience, we concluded that a transmembrane ammonium sulfate gradient is most suitable for stable encapsulation of amphipathic weak bases [16]–[19], [25], [26], while a transmembrane calcium acetate gradient is most suitable for loading amphipathic weak acids [16], [27], [28].”