Further enhanced dissolution and oral bioavailability of docetaxel by coamorphization with a natural P-gp inhibitor myricetin

Abstract The current study aims to improve the dissolution and oral bioavailability of a BCS IV drug docetaxel (DOC) by coamorphization with a natural P-gp inhibitor myricetin (MYR). A single-phase coamorphous form of DOC with MYR in a 1:1 molar ratio was prepared by solvent-evaporation method and characterized by differential scanning calorimetry, thermogravimetric analysis and powder X-ray diffraction. In comparison to crystalline DOC, amorphous DOC showed similar equilibrium aqueous solubility, temporary improvement in the intrinsic dissolution rate (IDR) and supersaturated dissolution; while coamorphous DOC-MYR exhibited a persistent enhanced IDR and prolonged highly supersaturated dissolution. In addition, coamorphous DOC-MYR demonstrated significantly superior physical stability compared to amorphous DOC under the long-term storage condition and accelerated condition. Compared with oral administration of crystalline DOC to rats, amorphous DOC showed a significant increase in C max (2.6-fold) and a marginal increase in AUC (1.3-fold) of DOC; but coamorphous DOC-MYR performed a 3.9-fold higher C max and 3.1-fold higher AUC. In conclusion, coamorphization of DOC with MYR was a promising approach to enhance both dissolution and oral absorption of poorly soluble and permeable DOC.