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 sterile, ready-to-administer, packaged norepinephrine composition, comprising:
a container filled with a sterile, ready-to-administer norepinephrine composition and packaged in a secondary container;
wherein the sterile, ready-to-administer norepinephrine composition comprises norepinephrine or a salt thereof in an amount of between 10 μg/ml and 100 μg/ml, a chelating agent in an amount of between 1 μg/ml and 100 μg/ml, a tonicity adjusting agent in an amount of between 0.6 wt % and 1.2 wt %, and an aqueous acidic solution, wherein the norepinephrine comprises at least 95% of R-isomer of norepinephrine;
wherein the sterile, ready-to-administer norepinephrine composition is substantially free of antioxidants;
wherein the sterile, ready-to-administer norepinephrine composition has a pH of between 3.7 and 4.3; and
wherein the sterile, ready-to-administer, packaged norepinephrine 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.
2. The sterile, ready-to-administer, packaged norepinephrine composition of claim 1 , wherein the container is a large volume, polymeric, semi-permeable infusion container.
3. The sterile, ready-to-administer, packaged norepinephrine composition of claim 1 , wherein the container is a polymer bag.
4. The sterile, ready-to-administer, packaged norepinephrine composition of claim 3 , wherein the polymer is polypropylene, polyethylene, or low-density polyethylene.
5. The sterile, ready-to-administer, packaged norepinephrine composition of claim 1 , wherein the secondary container is impervious to light.
6. The sterile, ready-to-administer, packaged norepinephrine composition of claim 1 , wherein the secondary container is impervious to light of a wavelength that promotes photo-initiated degradation of the norepinephrine or salt thereof in the sterile, ready-to-administer norepinephrine composition.
7. The sterile, ready-to-administer, packaged norepinephrine composition of claim 1 , wherein the container and/or the secondary container includes an oxygen scavenger.
8. The sterile, ready-to-administer, packaged norepinephrine composition of claim 7 , wherein the oxygen scavenger is a metal-free oxygen scavenger.
9. The sterile, ready-to-administer, packaged norepinephrine composition of claim 1 , wherein the secondary container comprises an aluminum overwrap.
10. The sterile, ready-to-administer, packaged norepinephrine composition of claim 1 , wherein the container is a polymer bag and the secondary container comprises an aluminum overwrap.
11. The sterile, ready-to-administer, packaged norepinephrine composition of claim 1 , wherein the sterile, ready-to-administer norepinephrine composition has a pH between 3.7 and 4.0.
12. The sterile, ready-to-administer, packaged norepinephrine composition of claim 1 , wherein the norepinephrine is norepinephrine bitartrate.
13. The sterile, ready-to-administer, packaged norepinephrine composition of claim 1 , wherein the norepinephrine is present in the sterile, ready-to-administer norepinephrine composition in an amount of about 16 μg/ml, about 32 μg/ml, or about 64 μg/ml.
14. The sterile, ready-to-administer, packaged norepinephrine composition of claim 1 , wherein the chelating agent is selected from a group consisting of a bicarboxylic acid, a tricarboxylic acid, and an aminopolycarboxylic acid.
15. The sterile, ready-to-administer, packaged norepinephrine composition of claim 1 , wherein the chelating agent is ethylenediaminetetraacetic acid (EDTA).
16. The sterile, ready-to-administer, packaged norepinephrine composition of claim 1 , where the tonicity adjusting agent is sodium chloride.
17. The sterile, ready-to-administer, packaged norepinephrine composition of claim 1 , wherein the aqueous acidic solution has dissolved oxygen at a concentration of equal or less than 1 ppm.
18. The sterile, ready-to-administer, packaged norepinephrine composition of claim 1 , wherein the norepinephrine or a salt thereof in the sterile, ready-to-administer, packaged norepinephrine composition comprises equal or less than about 10% S-isomer of norepinephrine or salt thereof after storage at 25±2° C. and 60±5% relative humidity, over at least three months as determined by HPLC.
19. The sterile, ready-to-administer, packaged norepinephrine composition of claim 1 , wherein the sterile, ready-to-administer norepinephrine composition comprises equal or less than about 5% of total degradation of norepinephrine or salt thereof excluding S-isomer of norepinephrine after storage at 25±2° C. and 60±5% relative humidity, over at least three months as determined by HPLC.