Norepinephrine compositions and methods therefor
The inventive subject matter is directed to compositions and methods for ready-to-inject norepinephrine compositions with improved stability. Most preferably, compositions presented herein are substantially antioxidant free and exhibit less than 10% isomerization of R-norepinephrine and exhibit less than 5% degradation of total norepinephrine.
1. A sterile storage stable ready-to-inject norepinephrine composition, comprising:
an aqueous pharmaceutically acceptable solution containing norepinephrine, a tonicity agent, and a metal ion chelator;
wherein the composition contains the norepinephrine in an amount of equal or less than 100 μg/ml;
wherein the norepinephrine is present as an R-isomer in an amount of at least at least 90% of total norepinephrine;
wherein the aqueous solution comprises the metal ion chelator in an amount of between 1 μg/ml and 100 μg/ml, and wherein the metal ion chelator is a bicarboxylic acid;
wherein the tonicity agent is selected from the group consisting of a pharmaceutically acceptable salt, glycerol, a sugar alcohol, and a sugar; and
wherein the pH of the aqueous solution is in a range of between 3.7-5.0, and wherein the composition is substantially antioxidant-free.
2. The norepinephrine composition of claim 1 , wherein the composition has, after three months of storage in a container, less than 10% of the R-isomer and equal or less than 5% degradation of total norepinephrine.
3. The norepinephrine composition of claim 1 , wherein the norepinephrine is present at a concentration of about 16 μg/ml.
4. The norepinephrine composition of claim 1 , wherein the norepinephrine is present at a concentration of about 32 μg/ml.
5. The norepinephrine composition of claim 1 , wherein the norepinephrine is present at a concentration of about 64 μg/ml.
6. The norepinephrine composition of claim 1 , wherein the chelating agent is present in an amount of between 1 μg/ml and 10 μg/ml.
7. The norepinephrine composition of claim 1 wherein the chelating agent is present in an amount of between 10 μg/ml and 100 μg/ml.
8. The norepinephrine composition of claim 1 , wherein the pH of the aqueous solution is between 3.7 and 4.0.
9. The norepinephrine composition of claim 1 , wherein the aqueous solution comprises deoxygenated water having dissolved oxygen at a concentration of equal or less than 1 ppm.
10. The norepinephrine composition of claim 1 , wherein the container is disposed in a second container that includes a metal-free oxygen scavenger, and optionally wherein the container and/or the second container is configured to reduce light-mediated oxidation of the norepinephrine.
11. A storage stable, substantially antioxidant-free, ready-to-inject norepinephrine composition that exhibits, after three months of storage in a container, less than 10% of isomerization of an R-isomer of norepinephrine to an S-isomer and equal or less than 5% degradation of total norepinephrine, comprising:
an R-isomer of norepinephrine in an aqueous solution that contains the R-isomer of norepinephrine in an amount of between 10-100 μg/ml;
wherein the aqueous solution comprises a bicarboxylic acid metal ion chelator in an amount of between 1 μg/ml and 100 μg/ml;
wherein the aqueous solution comprises a tonicity agent selected from the group consisting of a pharmaceutically acceptable salt, glycerol, a sugar alcohol, and a sugar; and
wherein the pH of the aqueous solution is in a range of between 3.7-5.0, and wherein the composition is substantially antioxidant-free.
12. A method of preparing a storage stable, substantially antioxidant-free, ready-to-inject norepinephrine composition that exhibits, after three months of storage in a container, less than 10% of isomerization of an R-isomer of norepinephrine to an S-isomer and equal or less than 5% degradation of total norepinephrine, the method comprising:
admixing norepinephrine, metal ion chelator, and a tonicity agent to a solution to produce an aqueous solution that contains the norepinephrine in an amount of equal or less than 100 μg/ml;
wherein the norepinephrine is present as an R-isomer in an amount of at least at least 90% of total norepinephrine;
wherein the metal ion chelator is present in the aqueous solution in an amount of between 1 μg/ml and 100 μg/ml, and wherein the metal ion chelator is a bicarboxylic acid;
wherein the tonicity agent is selected from the group consisting of a pharmaceutically acceptable salt, glycerol, a sugar alcohol, and a sugar; and
adjusting pH of the aqueous solution to a range of between 3.7-5.0, and wherein the composition is substantially antioxidant-free.
13. The method of claim 12 wherein the norepinephrine is present at a concentration of about 16 μg/ml.
14. The method of claim 12 wherein the norepinephrine is present at a concentration of about 32 μg/ml.
15. The method of claim 12 wherein the norepinephrine is present at a concentration of about 64 μg/ml.
16. The method of claim 12 wherein the pH of the aqueous solution is adjusted to a range of between 3.7 and 4.0.
17. The method of claim 12 wherein the aqueous solution comprises deoxygenated water having dissolved oxygen at a concentration of equal or less than 1 ppm.
18. The method of claim 12 further comprising a step of heat sterilizing the aqueous solution.
19. The method of claim 12 further comprising a step of packaging the aqueous solution in the container, and placing the container in a second container that includes a metal-free oxygen scavenger, and optionally wherein the container and/or the second container is configured to reduce light-mediated oxidation of the norepinephrine.