Norepinephrine compositions and methods therefor
View Patent ↗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 method of controlling S-isomer content in a ready-to-administer norepinephrine composition comprising:
admixing an R-isomer of norepinephrine or salt thereof, a chelating agent and a tonicity agent into an aqueous acidic solution having a pH between 3.7 and 4.3;
wherein the chelating agent is present in an amount of between 1 μg/ml and 100 μg/ml, and wherein the tonicity agent is present in an amount of between 0.6 wt % and 1.2 wt %; and
wherein the concentration of norepinephrine or salt thereof is between 10 μg/ml and 100 μg/ml, and wherein the composition is substantially free of anti-oxidants.
2. The method of claim 1 wherein, the norepinephrine or a salt thereof in the composition comprises at least about 95% R-isomer of norepinephrine after storage at 25±2° C. and 60±5% relative humidity, over at least three months as determined by HPLC.
3. The method of claim 1 wherein, the norepinephrine or a salt thereof in the composition comprises at least about 90% R-isomer of norepinephrine after storage at 25±2° C. and 60±5% relative humidity, over at least three months as determined by HPLC.
4. The method of claim 1 wherein, the norepinephrine or a salt thereof in the composition comprises equal or less than about 10% S-isomer of norepinephrine or a salt thereof after storage at 25±2° C. and 60±5% relative humidity, over at least three months as determined by HPLC.
5. The method of claim 1 , wherein the norepinephrine or a salt thereof in the composition comprises equal or less than about 5% S-isomer of norepinephrine or a salt thereof after storage at 25±2° C. and 60±5% relative humidity, over at least three months as determined by HPLC.
6. The method of claim 2 wherein the composition comprises equal or less than about 5% of total degradation of norepinephrine or salt thereof excluding s-isomer after storage at 25±2° C. and 60±5% relative humidity, over at least three months as determined by HPLC.
7. The method of claim 3 wherein the composition comprises equal or less than about 3% of total degradation of norepinephrine or salt thereof excluding s-norepinephrine after storage at 25±2° C. and 60±5% relative humidity, over at least three months as determined by HPLC.
8. The method of claim 4 wherein the composition comprises equal or less than about 1% of total degradation of norepinephrine or salt thereof excluding S-norepinephrine after storage at 25±2° C. and 60±5% relative humidity, over at least three months as determined by HPLC.
9. The method of claim 1 , wherein the norepinephrine salt is a bitartrate salt of norepinephrine.
10. The method of claim 1 , wherein the R-isomer of norepinephrine or salt thereof is present in the aqueous acidic solution at a concentration of about 16 μg/ml, about 32 μg/ml, or about 64 μg/ml.
11. 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.
12. The method of claim 11 , wherein the chelating agent is an aminopolycarboxylic acid.
13. The method of claim 12 , wherein the aminopolycarboxylic acid is present in aqueous acidic solution at a concentration of about 10 μg/mL.
14. The method of claim 1 , wherein the chelating agent is present in the aqueous acidic solution at a concentration of between 1 μg/ml and 10 μg/ml.
15. The method of claim 1 , wherein the chelating agent is present in the aqueous acidic solution at a concentration of between 10 μg/ml and 100 μg/ml.
16. The method of claim 1 , wherein the aqueous acidic solution is prepared from deoxygenated water having dissolved oxygen at a concentration of equal or less than 1 ppm.
17. The method of claim 1 , further comprising a step of packaging the composition in a primary container, and placing the primary container in a secondary container that includes a metal-free oxygen scavenger.
18. The method of claim 17 wherein the primary container and/or the secondary container is configured to reduce light-mediated oxidation of the norepinephrine.