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 method of preparing a sterile, ready-to-administer norepinephrine composition, comprising the steps of:
(a) combining norepinephrine or a salt thereof, a chelating agent, a tonicity adjusting agent, and an aqueous acidic solution to form a liquid parenteral composition, wherein the norepinephrine comprises at least 95% of R-isomer of norepinephrine, wherein the norepinephrine or salt thereof is present in the liquid parenteral composition in an amount of between 10 μg/ml and 100 μm/ml, wherein the chelating agent is present in the liquid parenteral composition in an amount of between 1 μg/ml and 100 μm/ml, and wherein the tonicity adjusting agent is present in the liquid parenteral composition in an amount of between 0.6 wt % and 1.2 wt %;
(b) adjusting the pH of the liquid parenteral composition to a pH range of between 3.7 and 4.3;
(c) filling the liquid parenteral composition into a container; and
(d) heat sterilizing the liquid parenteral composition in the container to sterility to form the sterile, ready-to-administer norepinephrine composition;
wherein the sterile, ready-to-administer norepinephrine composition is substantially free of antioxidants; and
wherein the sterile ready-to-administer 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 method of claim 1 , further comprising a step of placing the container into a secondary container.
3. The method of claim 2 , wherein the container and/or the secondary container include a metal-free oxygen scavenger.
4. The method of claim 2 , wherein the container is a polypropylene bag and the secondary container comprises an aluminum overwrap.
5. The method of claim 4 , wherein the aluminum overwrap comprises an oxygen scavenger.
6. The method of claim 1 , wherein the heat sterilizing step is performed using a steam sterilizer with an air over-pressure sterilization cycle.
7. The method of claim 1 , wherein the heat sterilizing is performed at 121° C.
8. The method of claim 7 , wherein the heat sterilizing is performed for at least 5 minutes.
9. The method of claim 7 , wherein the heat sterilizing is performed for at least 10 minutes.
10. The method of claim 7 , wherein the heat sterilizing is performed for at least 15 minutes.
11. The method of claim 1 , further comprising a step of (e) cooling the sterile, ready-to-administer norepinephrine composition.
12. The method of claim 11 , wherein the sterile, ready-to-administer norepinephrine composition is cooled to 70° C.-95° C.
13. The method of claim 11 , wherein the cooling step comprises spontaneous cooling to about 95° C. followed by forced cooling to about 70° C.
14. The method of claim 1 , wherein the liquid parenteral composition has a pH between 3.7 and 4.0.
15. The method of claim 1 , wherein norepinephrine in the sterile ready-to-administer norepinephrine composition is norepinephrine bitartrate.
16. The method of claim 1 , wherein the norepinephrine is present in the liquid parenteral composition at a concentration of about 16 μg/ml, about 32 μg/ml, or about 64 μg/ml.
17. 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.
18. The method of claim 1 , wherein the chelating agent is ethylenediaminetetraacetic acid (EDTA).
19. The method of claim 1 , where the tonicity adjusting agent is sodium chloride.
20. The method of claim 1 , wherein the aqueous acidic solution has dissolved oxygen at a concentration of equal or less than 1 ppm.
21. The method of claim 1 , wherein the sterile ready-to-administer norepinephrine composition comprises equal or less than about 10% of S-isomer of norepinephrine or a salt thereof after the heat sterilizing step.
22. The method of claim 1 , wherein the norepinephrine or a salt thereof in the sterile ready-to-administer 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.
23. The method 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.