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-nor epinephrine and exhibit less than 5% degradation of total norepinephrine.
1. A ready-to-administer norepinephrine composition, comprising:
an aqueous solution comprising a chelating agent and a pharmaceutically acceptable salt;
wherein the chelating agent is an aminopolycarboxylic acid present in an amount of equal or less than 100 μg/ml, and wherein the pharmaceutically acceptable salt is present in an amount of at least 0.7 wt %;
norepinephrine bitartrate dissolved at a concentration of between 16 and 64 μg/ml, and wherein the norepinephrine is an R-isomer;
wherein the ready-to-administer norepinephrine composition is substantially free of antioxidants; and
wherein the ready-to-administer norepinephrine composition is formulated to have a pH range of between 3.8 and 4.2 and has a composition such that after storage over at least three months equal or less than 10% of the R-isomer form will isomerize to the S-isomer and such that equal or less than 5% of the total norepinephrine will degrade to degradation products.
2. The composition of claim 1 wherein the ready-to-administer norepinephrine composition has a pH between 3.8 and 4.1.
3. The composition of claim 1 wherein the ready-to-administer norepinephrine composition has a pH between 3.9 and 4.2.
4. The composition of claim 1 wherein the ready-to-administer norepinephrine composition has a pH of 4.0.
5. The composition of claim 1 wherein the aqueous solution is water.
6. The composition of claim 1 wherein the chelating agent is ethylenediaminetetraacetic acid (EDTA).
7. The composition of claim 1 wherein the chelating agent is present at a concentration of between 10 μg/ml and 100 μg/ml.
8. The composition of claim 1 wherein the chelating agent is 10 μg/ml.
9. The composition of claim 1 wherein the aqueous solution is water, wherein the chelating agent is ethylenediaminetetraacetic acid (EDTA) at a concentration of between 10 μg/ml and 100 μg/ml.
10. The composition of claim 1 wherein the pharmaceutically acceptable salt is present in an amount of 0.9 wt %.
11. The composition of claim 9 wherein the pharmaceutically acceptable salt is present in an amount of 0.9 wt %.
12. The composition of claim 1 wherein the norepinephrine is present at a concentration of about 16 μg/ml, about 32 μg/ml, or about 64 μg/ml.
13. The composition of claim 9 wherein the norepinephrine is present at a concentration of about 16 μg/ml, about 32 μg/ml, or about 64 μg/ml.
14. The composition of claim 11 wherein the norepinephrine is present at a concentration of about 16 μg/ml, about 32 μg/ml, or about 64 μg/ml.
15. The composition of claim 1 wherein the storage over at least three months is at 40° C. and 75% (+/−5%) relative humidity.
16. The composition of claim 1 wherein equal or less than 6% of the R-isomer form will isomerize to the S-isomer.
17. The composition of claim 9 wherein equal or less than 6% of the R-isomer form will isomerize to the S-isomer.
18. The composition of claim 1 wherein equal or less than 3.5% of the total norepinephrine will degrade to degradation products.
19. The composition of claim 1 wherein the composition has a dissolved oxygen concentration of equal or less than 1 ppm.