Preserving the supersaturation generation capability of amorphous drug-polysaccharide nanoparticle complex after...

While the supersaturation generation capability of amorphous nanopharmaceuticals (NPs) in their aqueous suspension form has been well established, their supersaturation generation is adversely affected after drying. Herein we investigated the effects of freeze drying on the supersaturation generation capability of a new class of amorphous NPs referred to as drug nanoplex prepared and stabilized by electrostatic complexation of drug molecules with polysaccharides (dextran sulfate). Using ciprofloxacin as the model drug, two types of freeze-drying adjuvants were investigated, i.e., (1) highly water-soluble excipient (trehalose, mannitol), whose role was to prevent irreversible NPs aggregations upon drying, and (2) crystallization inhibitor (hydroxypropylmethylcellulose (HPMC)), whose role was to suppress crystallization of the dissolved drug and the remaining solid phase. The results showed that dual-adjuvant formulations (i.e. trehalose-HPMC and mannitol-HPMC) were required to preserve the supersaturation generation capability of the drug nanoplex suspension after drying. Freeze drying with only one adjuvant type, or incorporating HPMC as physical mixtures with the freeze-dried nanoplex, were ineffective in preserving the supersaturation. The dual-adjuvant formulations produced prolonged supersaturation levels over 240min at ≈6-8× of the saturation solubility with comparable area under the curve (AUC) in the concentration versus time plot as that exhibited by the suspension form.