STABLE PHARMACEUTICAL COMPOSITIONS OF APIXABAN
Liquid pharmaceutical compositions of apixaban or pharmaceutically acceptable salts thereof are described. More specifically, stable oral liquid pharmaceutical compositions of apixaban for oral administration are provided, wherein the composition is stable for extended periods of time. More specifically, stable liquid pharmaceutical compositions of apixaban at concentrations of 0.4 mg/mL or more are provided. Stable oral liquid compositions of apixaban, methods for their administration, processes for their production, and use of these compositions for treatment of diseases treatable by apixaban are disclosed.
1 . A stable oral solution comprising:
(i) apixaban at a concentration of about 0.4 mg/ml;
(ii) water at a concentration of about 38% w/w;
(iii) polysorbate,
(iv) propylene glycol at a concentration of about 33% w/w;
(v) sodium lauryl sulphate;
(vi) glycerin,
(viii) polyvinyl pyrrolidone,
(ix) a preservative,
(x) a buffering agent,
(xi) a pH adjusting agent,
wherein the stable oral solution is free of polyethylene glycol;
wherein the oral solution is physically stable for at least 6 months at 40° C./75% RH and at 25° C./60% RH, and
wherein the oral solution is chemically stable with no more than 10% loss of apixaban for at least 6 months at 40° C./75% RH and at 25° C./60% RH.
2 . The stable oral solution according to claim 1 , wherein the solution comprises
(i) polysorbate at a concentration of 0.1% w/w to about 0.7% w/w,
(ii) sodium lauryl sulphate at a concentration of about 0.5% w/w to 2% w/w;
(iii) glycerin at a concentration of about 15% w/w to 25% w/w,
(iv) polyvinyl pyrrolidone at a concentration of about 1% w/w to 10% w/w,
(v) a preservative at a concentration of 0% w/w to about 5% w/w/,
(vi) a buffering agent at a concentration of 0% w/w to 5% w/w, and
(vii) a pH adjusting agent at a concentration of 0% w/w to about 5% w/w,
3 . The stable oral solution according to claim 1 , wherein a level of the 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid impurity is less than about 0.5% w/w as determined by HPLC at a wavelength of 270 nm.
4 . The stable oral solution according to claim 1 , wherein a level of the 5-((4-(3-carbamoyl-1-(4-methoxy phenyl)-7-oxo-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)phenyl)amino)pentanoic acid impurity is less than about 0.5% w/w as determined by HPLC at a wavelength of 270 nm.
5 . The stable oral solution according to claim 1 , wherein a level of the 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide impurity is less than about 0.5% w/w as determined by HPLC at a wavelength of 270 nm.
6 . The stable oral solution according to claim 1 , wherein the pH of the stable oral solution is about 3 to about 8.
7 . A method of treatment to reduce a risk of stroke and systemic embolism in a patient with nonvalvular atrial fibrillation, comprising administering a therapeutically effective amount of the stable oral solution according to claim 1 to a patient in need thereof.
8 . A method for prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE), comprising administering a therapeutically effective amount of the stable oral solution according to claim 1 to a patient in need thereof.
9 . The method according to claim 1 , wherein the patient is a pediatric or geriatric patient.