Claims for Patent: 11,413,259

Summary for Patent: 11,413,259

Title:	Norepinephrine compositions and methods therefor
Abstract:	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.
Inventor(s):	Tushar Hingorani, Kumaresh Soppimath
Assignee:	Nevakar Injectables Inc
Application Number:	US16/839,450
Patent Claims:	1. A method of preparing a storage stable, substantially antioxidant-free ready-to-administer 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 an R-isomer of norepinephrine bitartrate to a solution to produce an aqueous solution that contains the R-isomer of norepinephrine in an amount of equal or less than 100 μg/ml; wherein aqueous solution comprises a chelating agent in an amount of between 1 μg/ml and 100 μg/ml, and a pharmaceutically acceptable salt in an amount of between 0.6 wt % and 1.2 wt %; and adjusting pH of the aqueous solution to a range of between 3.7-5.0. 2. The method of claim 1 wherein the norepinephrine is present at a concentration of about 16 μg/ml. 3. The method of claim 1 wherein the norepinephrine is present at a concentration of about 32 μg/ml. 4. The method of claim 1 wherein the norepinephrine is present at a concentration of about 64 μg/ml. 5. The method of claim 1 wherein the chelating agent is present in an amount of between 1 μg/ml and 10 μg/ml. 6. The method of claim 1 wherein the chelating agent is selected from the group consisting of a bicarboxylic acid, a tricarboxylic acid, and an aminopolycarboxylic acid. 7. The method of claim 1 wherein the pH of the aqueous solution is adjusted to a range of between 3.7 and 4.0. 8. The method of claim 1 wherein the aqueous solution comprises deoxygenated water having dissolved oxygen at a concentration of equal or less than 1 ppm. 9. The method of claim 1 further comprising a step of heat sterilizing the aqueous solution. 10. The method of claim 1 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. 11. A storage stable, substantially antioxidant-free ready-to-administer 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 bitartrate in an aqueous solution that contains the R-isomer of norepinephrine in an amount of equal or less than 100 μg/ml; wherein aqueous solution comprises a chelating agent in an amount of between 1 μg/ml and 100 μg/ml, and a pharmaceutically acceptable salt in an amount of between 0.6 wt % and 1.2 wt %; and wherein the pH of the aqueous solution is in a range of between 3.7-5.0. 12. The norepinephrine composition of claim 11 wherein the norepinephrine is present at a concentration of about 16 μg/ml. 13. The norepinephrine composition of claim 11 wherein the norepinephrine is present at a concentration of about 32 μg/ml. 14. The norepinephrine composition of claim 11 wherein the norepinephrine is present at a concentration of about 64 μg/ml. 15. The norepinephrine composition of claim 11 wherein the chelating agent is present in an amount of between 1 μg/ml and 10 μg/ml. 16. The norepinephrine composition of claim 11 wherein the chelating agent is selected from the group consisting of a bicarboxylic acid, a tricarboxylic acid, and an aminopolycarboxylic acid. 17. The norepinephrine composition of claim 11 wherein the pH of the aqueous solution is between 3.7 and 4.0. 18. The norepinephrine composition of claim 11 wherein the aqueous solution comprises deoxygenated water having dissolved oxygen at a concentration of equal or less than 1 ppm. 19. The norepinephrine composition of claim 11 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. 20. A storage stable, substantially antioxidant-free ready-to-administer 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 bitartrate in an aqueous solution that contains the R-isomer of norepinephrine in an amount of at least 64 μg/ml; wherein aqueous solution comprises a chelating agent in an amount of between 1 μg/ml and 100 μg/ml, and a pharmaceutically acceptable salt in an amount of between 0.6 wt % and 1.2 wt %; wherein the chelating agent is selected from the group consisting of a bicarboxylic acid, a tricarboxylic acid, and an aminopolycarboxylic acid; and wherein the pH of the aqueous solution is in a range of between 3.7-5.0.