Methods of preparing pre-mixed, ready-to-use pharmaceutical compositions
Provided herein are ready-to-use premixed pharmaceutical compositions of nicardipine or a pharmaceutically acceptable salt and methods for use in treating cardiovascular and cerebrovascular conditions.
1. A method for making a pharmaceutical composition for intravenous administration comprising:
preparing a pre-mixed aqueous solution with a pH from about 3.6 to about 4.4 comprising:
a tonicity agent,
a buffer, and
from about 0.1 mg/mL to about 0.4 mg/mL nicardipine hydrochloride;
and filling a pharmaceutically acceptable container with the aqueous solution such that the aqueous solution is in contact with non-polar polymers, the aqueous solution when stored in the container for at least three months at room temperature exhibiting (i) less than a 10% decrease in the concentration of nicardipine or pharmaceutically acceptable salt thereof and (ii) a total impurity formation of less than about 3%.
2. The method according to claim 1 , in which the tonicity agent is selected from the group consisting of dextrose and sodium chloride.
3. The method according to claim 1 , wherein the aqueous solution further comprises a cosolvent.
4. The method according to claim 3 , in which the cosolvent is sorbitol.
5. A method for making a pharmaceutical composition for intravenous administration comprising:
packaging in a pharmaceutically acceptable container a pre-mixed aqueous solution with a pH from about 3.6 to about 4.4 comprising:
from about 0.1 mg/mL to about 0.4 mg/mL nicardipine hydrochloride;
a tonicity agent selected from (i) about 4.5% to about 5% dextrose or (ii) about 0.8% to about 0.9% sodium chloride; and
a buffer;
such that the aqueous solution contained in the pharmaceutically acceptable container is in contact with non-polar polymers, the aqueous solution when stored in the container for at least three months at room temperature exhibiting (i) less than a 10% decrease in the concentration of the nicardipine hydrochloride and (ii) a total impurity formation of less than about 3%.
6. The method of claim 5 , wherein the aqueous solution further comprises at least one pH adjuster selected from the group consisting of hydrochloric acid, sodium hydroxide and a mixture thereof.
7. The method of claim 5 , wherein the aqueous solution further comprises from about 1 mg/ml to about 4 mg/ml sorbitol.
8. The method of claim 5 , wherein the non-polar polymers comprise copolyester, polyethylene or polyolefin.
9. A method for making a pharmaceutical composition for intravenous administration comprising:
packaging in a pharmaceutically acceptable container a pre-mixed aqueous solution with a pH from about 3.6 to about 4.4 comprising:
from about 0.1 mg/mL to about 0.2 mg/mL nicardipine hydrochloride;
a tonicity agent selected from (i) about 46 mg/mL to about 50 mg/mL dextrose or (ii) about 8.3 mg/mL to about 9 mg/mL sodium chloride; and
a buffer;
such that the aqueous solution contained in the pharmaceutically acceptable container is in contact with non-polar polymers, the aqueous solution when stored in the container for at least three months at room temperature exhibiting (i) less than a 10% decrease in the concentration of the nicardipine hydrochloride and (ii) a total impurity formation of less than about 3%.
10. The method of claim 1 , wherein the non-polar polymers comprise copolyester, polyethylene or polyolefin.
11. The method of claim 9 , wherein the non-polar polymers comprise copolyester, polyethylene or polyolefin.
12. The method of claim 1 , wherein the non-polar polymers comprise polyethylene.
13. The method of claim 5 , wherein the non-polar polymers comprise polyethylene.
14. The method of claim 9 , wherein the non-polar polymers comprise polyethylene.
15. The method of claim 1 , wherein the aqueous solution when stored in the container for at least one year at room temperature exhibits (i) less than a 10% decrease in the concentration of the nicardipine hydrochloride and (ii) a total impurity formation of less than about 3%.
16. The method of claim 5 , wherein the aqueous solution when stored in the container for at least one year at room temperature exhibits (i) less than a 10% decrease in the concentration of the nicardipine hydrochloride and (ii) a total impurity formation of less than about 3%.
17. The method of claim 9 , wherein the aqueous solution when stored in the container for at least one year at room temperature exhibits (i) less than a 10% decrease in the concentration of the nicardipine hydrochloride and (ii) a total impurity formation of less than about 3%.
18. The method of claim 1 , wherein the aqueous solution further comprises from 0 mg/mL to about 4 mg/mL sorbitol.
19. The method of claim 5 , wherein the aqueous solution further comprises from 0 mg/mL to about 4 mg/mL sorbitol.
20. The method of claim 9 , wherein the aqueous solution further comprises from 0 mg/mL to about 4 mg/mL sorbitol.
21. The method of claim 1 , wherein the pre-mixed aqueous solution comprises from about 0.1 mg/mL to about 0.2 mg/mL nicardipine hydrochloride.
22. The method of claim 5 , wherein the pre-mixed aqueous solution comprises from about 0.1 mg/mL to about 0.2 mg/mL nicardipine hydrochloride.