Efflux Inhibitor Bicalutamide Increases Oral Bioavailability of the Poorly Soluble Efflux Substrate Docetaxel in Co-Amorphous Anti-Cancer Combination Therapy

Molecules

Holger Grohganz¹  Adam Bohr¹  Korbinian Löbmann¹  Yingya Wang¹  Necati Harmankaya¹  ThaisLeite Nascimento¹  JohanJuhl Weisser¹  Thomas Rades¹ 

[1] Department of Pharmacy, University of Copenhagen, 2100 Copenhagen, Denmark;

关键词: Anti-cancer;    docetaxel;    bicalutamide;    co-amorphous;    oral delivery;    efflux inhibitor;    in vivo;   

DOI  :  10.3390/molecules24020266

来源: DOAJ

【 摘 要 】

Many anti-cancer drugs are difficult to formulate into an oral dosage form because they are both poorly water-soluble and show poor permeability, the latter often as a result of being an intestinal efflux pump substrate. To obtain a more water-soluble formulation, one can take advantage of the higher solubility of the amorphous form of a given drug, whereas to increase permeability, one can make use of an efflux pump inhibitor. In this study, a combination of these two strategies was investigated using the co-amorphous approach, forming an amorphous mixture of two anti-cancer drugs, docetaxel (DTX) and bicalutamide (BIC). The efflux substrate, DTX, was combined with the efflux inhibitor, BIC, and prepared as a single phase co-amorphous mixture at a 1:1 molar ratio using vibrational ball milling. The co-amorphous formulation was tested in vitro and in vivo for its dissolution kinetics, supersaturation properties and pharmacokinetics in rats. The co-amorphous formulation showed a faster in vitro dissolution of both drugs compared to the control groups, but only DTX showed supersaturation (1.9 fold) compared to its equilibrium solubility. The findings for the co-amorphous formulation were in agreement with the pharmacokinetics data, showing a quicker onset in plasma concentration as well as a higher bioavailability for both DTX (15-fold) and BIC (3-fold) compared to the crystalline drugs alone. Furthermore, the co-amorphous formulation remained physically stable over 1.5 years at 4 °C under dry conditions.

【 授权许可】

Unknown