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 of:
(i) apixaban at a concentration of about 0.4 mg/mL;
(ii) water at a concentration of about 38% w/w;
(iii) polysorbate at a concentration of about 0.7% w/w,
(iv) propylene glycol at a concentration of about 33% w/w;
(v) sodium lauryl sulphate at a concentration of about 1% w/w;
(vi) glycerin at a concentration of about 21% w/w,
(viii) polyvinyl pyrrolidone at a concentration of about 4% w/w,
(ix) a preservative at a concentration of about 0.1% w/w,
(x) a buffering agent at a concentration about 0.04% w/w,
(xi) a pH adjusting agent at a concentration of 0% w/w to about 5% w/w,
(xii) a sweetener at a concentration of about 0.2% w/w, and
(xiii) a flavoring agent at a concentration of about 0.3% w/w;
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,
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,
wherein the buffering agent is citric acid and sodium citrate dihydrate; and
wherein the pH adjusting agent is HCl, NaOH or a combination thereof.
2. 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.
3. The stable oral solution according to claim 1 , wherein a level of the 5- ((4-(3-carbamoyl-1-(4-methoxy phenyl)-7oxo-1,4,5,7-tetrahydro-6H-pyrazolo[3,4c]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.
4. 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.
5. 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 at a concentration of about 0.7% w/w,
(iv) propylene glycol at a concentration of about 33% w/w;
(v) sodium lauryl sulphate at a concentration of about 1% w/w;
(vi) glycerin at a concentration of about 21% w/w,
(viii) polyvinyl pyrrolidone at a concentration of about 4% w/w,
(ix) a preservative at a concentration of about 0.1% w/w,
(x) a buffering agent at a concentration about 0.04% w/w,
(xi) a pH adjusting agent at a concentration of 0% w/w to about 5% w/w,
(xii) a sweetener at a concentration of about 0.2% w/w, and
(xiii) a flavoring agent at a concentration of about 0.3% w/w;
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,
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,
wherein the buffering agent is citric acid and sodium citrate dihydrate; and
wherein the pH adjusting agent is HCl, NaOH or a combination thereof.
6. The stable oral solution comprising:
(i) apixaban at a concentration of about 0.4 mg/mL;
(ii) water at a concentration of about 260 to about 270 mg/mL;
(iii) polysorbate at a concentration of about 5-10 mg/mL;
(iv) propylene glycol at a concentration of about 350-440 mg/mL;
(v) sodium lauryl sulphate at a concentration of about 10-15 mg/mL;
(vi) glycerin at a concentration of about 230-240 mg/mL;
(viii) polyvinyl pyrrolidone at a concentration of about 12-60 mg/mL or hydroxypropyl methyl cellulose at a concentration of about 10 mg/mL;
(ix) a preservative at a concentration of about 1-3 mg/mL;
(x) a buffering agent at a concentration about 0.2-1.0 mg/mL;
(xi) a pH adjusting agent at a concentration of 0% w/w to about 5% w/w,
(xii) a sweetener at a concentration of about 2-240 mg/mL; and
(xiii) a flavoring agent at a concentration of about 0-5 mg/mL;
wherein the stable oral solution is free of polyethylene glycol;
wherein the pH of the stable oral solution is about 3 to about 8;
wherein the oral solution is physically stable for at least 6 months at 40° C./75% RH and at 25° C./60% RH,
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,
wherein the buffering agent is citric acid and sodium citrate dihydrate; and
wherein the pH adjusting agent is HCl, NaOH or a combination thereof.
7. The stable oral solution according to claim 6 , wherein the stable oral solution consists of components (i)-(xiii).
8. The stable oral solution according to claim 6 , wherein the pH of the stable oral solution is about 4 to about 6.
9. The stable oral solution according to claim 6 , wherein the pH of the stable oral solution is about 4.5 to about 5.5.
10. The stable oral solution according to claim 6 , wherein at least one of the following conditions are met;
(a) the preservative is methyl paraben, propyl paraben, or a combination thereof;
(b) the sweetener is fructose corn syrup, sucralose, or a combination thereof; or
(c) the flavoring agent is orange flavor.
11. The stable oral solution according to claim 6 , wherein the stable oral solution comprises:
(ii) water at a concentration of about 260-265 mg/mL;
(iii) polysorbate at a concentration of about 5-10 mg/mL;
(iv) propylene glycol at a concentration of about 360-370 mg/mL;
(v) sodium lauryl sulphate at a concentration of about 10-15 mg/mL;
(vi) glycerin at a concentration of about 230-235 mg/mL;
(viii) polyvinyl pyrrolidone at a concentration of about 45-50 mg/mL;
(ix) a preservative at a concentration of about 1 mg/mL;
(x) a buffering agent at a concentration about 0.2-0.5 mg/mL;
(xii) a sweetener at a concentration of about 235-240 mg/mL; and
(xiii) a flavoring agent at a concentration of about 2-3 mg/mL.
12. The stable oral solution according to claim 6 , wherein the stable oral solution comprises:
(ii) water at a concentration of about 460-465 mg/mL;
(iii) polysorbate at a concentration of about 5-10 mg/mL;
(iv) propylene glycol at a concentration of about 430-440 mg/mL;
(v) sodium lauryl sulphate at a concentration of about 10-15 mg/mL;
(vi) glycerin at a concentration of about 235 mg/mL;
(viii) hydroxypropyl methyl cellulose at a concentration of about 10 mg/mL;
(ix) a preservative at a concentration of about 2-3 mg/mL;
(x) a buffering agent at a concentration about 0.2-0.5 mg/mL; and
(xii) a sweetener at a concentration of about 4-5 mg/mL.
13. The stable oral solution according to claim 6 , wherein the stable oral solution comprises:
(ii) water at a concentration of about 260-265 mg/mL;
(iii) polysorbate at a concentration of about 5-10 mg/mL;
(iv) propylene glycol at a concentration of about 360-370 mg/mL;
(v) sodium lauryl sulphate at a concentration of about 10-15 mg/mL;
(vi) glycerin at a concentration of about 230-235 mg/mL;
(viii) polyvinyl pyrrolidone at a concentration of about 45-50 mg/mL;
(ix) a preservative at a concentration of about 2-3 mg/mL;
(x) a buffering agent at a concentration about 0.2-0.5 mg/mL; and
(xii) a sweetener at a concentration of about 235-240 mg/mL.
14. The stable oral solution according to claim 6 , wherein the stable oral solution comprises:
(ii) water at a concentration of about 260-265 mg/mL;
(iii) polysorbate at a concentration of about 5-10 mg/mL;
(iv) propylene glycol at a concentration of about 380-385 mg/mL;
(v) sodium lauryl sulphate at a concentration of about 10-15 mg/mL;
(vi) glycerin at a concentration of about 230-235 mg/mL;
(viii) polyvinyl pyrrolidone at a concentration of about 30 mg/mL;
(ix) a preservative at a concentration of about 1-2 mg/mL;
(x) a buffering agent at a concentration about 0.2-0.5 mg/mL; and
(xii) a sweetener at a concentration of about 235-240 mg/mL.
15. The stable oral solution according to claim 6 , wherein the stable oral solution comprises:
(ii) water at a concentration of about 260-265 mg/mL;
(iii) polysorbate at a concentration of about 5-10 mg/mL;
(iv) propylene glycol at a concentration of about 350-360 mg/mL;
(v) sodium lauryl sulphate at a concentration of about 10-15 mg/mL;
(vi) glycerin at a concentration of about 230-235 mg/mL;
(viii) polyvinyl pyrrolidone at a concentration of about 60 mg/mL;
(ix) a preservative at a concentration of about 1-2 mg/mL;
(x) a buffering agent at a concentration about 0.2-0.5 mg/mL; and
(xii) a sweetener at a concentration of about 235-240 mg/mL.
16. The stable oral solution according to claim 6 , wherein the stable oral solution comprises:
(ii) water at a concentration of about 260-265 mg/mL;
(iii) polysorbate at a concentration of about 5-10 mg/mL;
(iv) propylene glycol at a concentration of about 400-405 mg/mL;
(v) sodium lauryl sulphate at a concentration of about 10-15 mg/mL;
(vi) glycerin at a concentration of about 230-235 mg/mL;
(viii) polyvinyl pyrrolidone at a concentration of about 10-15 mg/mL;
(ix) a preservative at a concentration of about 1-2 mg/mL;
(x) a buffering agent at a concentration about 0.2 mg/mL;
(xii) a sweetener at a concentration of about 235-240 mg/mL; and
(xiii) a flavoring agent at a concentration of about 2-4 mg/mL.