A novice cocrystal nanomicelle formulation of 5-fluorouracil with proline: The design, self-assembly and in vitro/vivo biopharmaceutical characteristics

Abstract

To fully play the advantages of cocrystallization and nano-preparation techniques in regulating in vitro/vivo biopharmaceutical properties of anticancer drug 5-fluorouracil (FU), and further exploit new avenues in its formulation development, a recombination strategy of cocrystallization and nano-micellar self-assembly techniques is proposed. Thereinto, the cocrystallization technique is aiming at augmenting antitumor ability by ameliorating physicochemical performances of FU, while the nano-micellar self-assembly technique is mainly employed to achieve slowed release and long-term efficacy. Guided by this strategy, a new zwitterionic cocrystal of FU with L-proline (PL), FU-PL, is successfully synthesized, and then incorporated into carriers PEG-PCL to gain cocrystal micelles. The structure of FU-PL cocrystal and morphology of the cocrystal micelles are respectively characterized via various analytical means. The comparative studies of in vivo/vitro properties are systematacially conducted by theoretical and experimental methods. The results showcase that the cocrystal's solubility and permeability are 4.60 and 3.89 folds higher than those of pristine drug FU at pH 6.8, separately; and the drug loading and entrapment efficiency of the obtained cocrystal micelles with spherical particles of 146 nm are 2.39 and 1.74 times than those of FU micelles itself, respectively. Particularly, both the cocrystal and its micelles eventually bring about the excellent antitumor activity, but the cocrystal micelles improve even more significantly in comparison with the cocrystal. These in vitro advantages have promoted the in vivo absorption with increased relative bioavailability (FREL) of 2.72 relative to FU-PL cocrystal. More particularly, the cocrystal micelles have preferable sustained-release action relative to FU micelles, thus more efficaciously prolonging the half-life and therapy duration. All these findings not only supply a novice slow-release dosage form for FU with greater efficiency, but also fill the blank of the micelle researches for antitumor pharmaceutical cocrystals.