Complexes of abiraterone acetate, process for the preparation thereof and pharmaceutical compositions containing them
The present disclosure relates to pharmaceutically acceptable complex formulae comprising complexes of Abiraterone acetate and pharmaceutically acceptable excipients, process for the preparation thereof and pharmaceutical compositions containing them. The complex formulae of the present disclosure have improved physicochemical properties which results in reduced food effect which allows significant dose reduction and the abandoning of the requirement of taking the drug on an empty stomach.
1. A stable solid complex with improved physicochemical characteristics and enhanced biological performance comprising a) Abiraterone acetate; b) at least one complexing agent which is a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; and c) a pharmaceutically acceptable excipient which is sodium deoxycholate;
wherein said complex is not obtained via a milling process, by high pressure homogenization process, encapsulation process or solid dispersion process; said complex has a particle size less than 600 nm, and possesses one or more among the following features:
a) it is instantaneously redispersible in physiological relevant media;
b) it has increased dissolution rate compared to Zytiga (containing 250 mg of abiraterone acetate per tablet);
c) it is stable in solid form and in colloid solution and/or dispersion;
d) its apparent solubility in water is of at least 0.6 mg/mL;
e) it has a permeability of 0.5×10 −6 cm/s in a parallel artificial membrane permeability assay (PAMPA) when dispersed in distilled water, which does not decrease in time at least for 3 months;
f) exhibits no positive food effect (fed/fasted ration is under 1.25) which allows significant dose reduction and the abandoning of the requirement of taking the drug on an empty stomach; and
g) the variability of exposure is significantly reduced when compared to Zytiga,
said process comprising the step of mixing a solution of the active agent and at least one complexing agent and optionally one or more pharmaceutically acceptable excipient in a pharmaceutically acceptable solvent with an aqueous solution containing optionally least one pharmaceutically acceptable excipient.
2. The process as recited in claim 1 , wherein said process is performed in a continuous flow instrument.
3. The process as recited in claim 2 , wherein said continuous flow instrument is a microfluidic flow instrument.
4. The process as recited in claim 1 , wherein said pharmaceutically acceptable solvent is chosen from water, methanol, ethanol, isopropanol, n-propanol, acetone, acetonitrile, dimethyl-sulfoxide, tetrahydrofuran, or combinations thereof.
5. The process as recited in claim 4 , wherein said pharmaceutically acceptable solvent is a combination of water and tetrahydrofuran.
6. The process as recited in claim 1 , wherein said solvents are miscible with each other and the aqueous solvent comprises 0.1 to 99.9% weight of the final solution.