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Molecules 2019, 24(2), 266; https://doi.org/10.3390/molecules24020266

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

1
Department of Pharmacy, University of Copenhagen, 2100 Copenhagen, Denmark
2
Laboratory of Pharmaceutical Nanotechnology and Drug Delivery Systems, School of Pharmacy, Federal University of Goiás, Goiânia 74605-170, Brazil
*
Author to whom correspondence should be addressed.
Received: 26 November 2018 / Revised: 7 January 2019 / Accepted: 8 January 2019 / Published: 11 January 2019
(This article belongs to the Collection Poorly Soluble Drugs)
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Abstract

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. View Full-Text
Keywords: Anti-cancer; docetaxel; bicalutamide; co-amorphous; oral delivery; efflux inhibitor; in vivo Anti-cancer; docetaxel; bicalutamide; co-amorphous; oral delivery; efflux inhibitor; in vivo
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Bohr, A.; Nascimento, T.L.; Harmankaya, N.; Weisser, J.J.; Wang, Y.; Grohganz, H.; Rades, T.; Löbmann, K. Efflux Inhibitor Bicalutamide Increases Oral Bioavailability of the Poorly Soluble Efflux Substrate Docetaxel in Co-Amorphous Anti-Cancer Combination Therapy. Molecules 2019, 24, 266.

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