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.
Highlights
Oral administration of anti-cancer drugs is preferred over intravenous delivery as it provides a more convenient therapy for patients, who can administer the drug by themselves at home, avoiding hospitalization and reducing healthcare costs
It can be seen that upon ball milling the characteristic diffraction peaks of the crystalline starting materials disappeared and an amorphous halo was observed for each ball milled sample, i.e. the pure drugs as well as their mixture became amorphous during the ball milling process
In our study we found that the co-amorphous formulation of DTX and BIC resulted in a 15-fold increase in bioavailability compared with the crystalline control and a Cmax of 132 ng/mL compared with 15 ng/mL for the crystalline control
Summary
Oral administration of anti-cancer drugs is preferred over intravenous delivery as it provides a more convenient therapy for patients, who can administer the drug by themselves at home, avoiding hospitalization and reducing healthcare costs. Molecules 2019, 24, 266 poorly water-soluble and show poor permeability, the latter often because the drug is substrate to intestinal efflux pumps [5]. They are mainly administered parenterally via intravenous infusion at the clinical setting, despite the disadvantages associated with their administration. Many of these drugs need to be dissolved in a mixture of water, ethanol and solubilizers, such as polysorbate and chremophor, the latter causing severe side effects and allergic reactions [6]
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