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 ready-to-administer norepinephrine composition, comprising:
an aqueous acidic solution having a pH range of between 3.7 and 4.3, wherein the aqueous acidic solution further comprises a chelating agent and a pharmaceutically acceptable salt;
wherein the chelating agent is present in an amount of between 1 μg/ml and 100 μg/ml, and wherein the pharmaceutically acceptable salt is present in an amount of between 0.6 wt % and 1.2 wt %;
norepinephrine dissolved at a concentration suitable for administration to a patient in need thereof, 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 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 aqueous acidic solution has a pH between 3.7 and 4.0.
3. The composition of claim 1 wherein the chelating agent is selected from the group consisting of a bicarboxylic acid, a tricarboxylic acid, and an aminopolycarboxylic acid.
4. The composition of claim 1 wherein the chelating agent is present at a concentration of between 10 μg/ml and 100 μg/ml.
5. The composition of claim 1 wherein the pharmaceutically acceptable salt is sodium chloride.
6. The composition of claim 1 wherein the composition is heat sterilized.
7. The composition of claim 1 wherein the norepinephrine is present at a concentration of between 10 μg/ml and 100 μg/ml.
8. The composition of claim 1 wherein the norepinephrine is present at a concentration of 16 μg/ml (+/−10%), 32 μg/ml (+/−10%), or 64 μg/ml (+/−10%).
9. The composition of claim 1 wherein the storage over at least three months is at 40° C. and 75% (+/−5) relative humidity.
10. The composition of claim 1 wherein equal or less than 6% of the R-isomer form will isomerize to the S-isomer.
11. The composition of claim 1 wherein equal or less than 3.5% of the total norepinephrine will degrade to degradation products.
12. The composition of claim 1 wherein the composition has a dissolved oxygen concentration of equal or less than 1 ppm.
13. A method of preparing a ready-to-administer norepinephrine composition according to claim 1 , comprising:
formulating a liquid parenteral composition that contains in an aqueous acidic solution norepinephrine as an R-isomer such that:
(a) the formulation exhibits less than 10% of isomerization of the R-isomer to an S-isomer after three months of storage of the liquid composition, and
(b) the formulation exhibits equal or less than 5% degradation of total norepinephrine after three months of storage of the liquid composition;
wherein the aqueous acidic solution has a pH range of between 3.7 and 4.3, and wherein the aqueous acidic solution further comprises a chelating agent and a pharmaceutically acceptable salt;
wherein the total norepinephrine is present in the liquid parenteral composition at a concentration of between 10 μg/ml and 100 μg/ml; and
wherein the ready-to-administer norepinephrine composition is substantially free of antioxidants,
thereby obtaining a ready-to-administer norepinephrine composition according to claim 1 .
14. The method of claim 13 wherein the aqueous acidic solution has a pH between 3.7 and 4.0.
15. The method of claim 13 wherein the norepinephrine is present at a concentration of 16 μg/ml (+/−10%), 32 μg/ml (+/−10%), or 64 μg/ml (+/−10%).
16. The method of claim 13 wherein the step of formulating the liquid parenteral composition uses deoxygenated water having dissolved oxygen at a concentration of equal or less than 1 ppm.
17. The method of claim 13 further comprising a step of heat sterilizing the liquid parenteral composition.
18. The method of claim 17 further comprising a step of packaging the liquid parenteral composition in a 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.
19. A method of treating hypotension, comprising:
administering the ready-to-administer norepinephrine composition according to claim 1 at an initial dose per minute; and
administering the ready-to-administer norepinephrine composition according to claim 1 at a second dose per minute, wherein the initial dose per minute is greater than the second dose per minute.
20. The method of claim 19 , wherein the initial dose per minute is a dose of between 8 and 12 μg/min, and wherein the second dose per minute is a dose of between 2 and 4 μg/min.