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 sterile and ready to ready-to-administer norepinephrine composition, comprising:
an aqueous acidic solution having a pH range of between 3.7 and 4.3, wherein the aqueous solution further comprises a chelating agent, and a pharmaceutically acceptable salt or tonicity agent;
wherein the ready-to-administer norepinephrine composition is substantially free of antioxidants;
norepinephrine dissolved in the composition at a concentration of between about 16 μg/ml (+/−10%) and 128 μg/ml (+/−10%), wherein the norepinephrine is an R-isomer of norepinephrine; and
wherein the ready-to-administer norepinephrine composition is formulated such that after terminal sterilization and storage over at least three months at 25° C. and 60% relative humidity 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, or wherein the tonicity agent is glycerol, thioglycerol, mannitol, lactose, and dextrose.
6 . The composition of claim 1 wherein the composition is heat sterilized at 121° C. for at least 15 minutes.
7 . The composition of claim 1 wherein the norepinephrine is present at a concentration of at least 100 μg/ml.
8 . The composition of claim 1 wherein the norepinephrine is present at a concentration of 16 μg/ml (+/−10%), 64 μg/ml (+/−10%), or 128 μg/ml (+/−10%).
9 . The composition of claim 1 wherein the storage is over at least 6 months.
10 . The composition of claim 1 wherein equal or less than 5% of the R-isomer form will isomerize to the S-isomer.
11 . The composition of claim 1 wherein equal or less than 0.1% of the total impurities are present after terminal sterilization and storage.
12 . The composition of claim 1 wherein the composition has a dissolved oxygen concentration of equal or less than 1 ppm.
13 . A kit, 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 in an aqueous acidic solution having a pH range of between 3.7 and 4.3 a chelating agent, a pharmaceutically acceptable salt or tonicity agent, and dissolved norepinephrine at a concentration of between about 16 μg/ml (+/−10%) and 128 μg/ml (+/−10%), wherein the norepinephrine is an R-isomer of norepinephrine;
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 terminal sterilization and storage over at least three months at 25° C. and 60% relative humidity 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.
14 . The kit of claim 13 , wherein the container is a large volume, polymeric, semi-permeable infusion container.
15 . The kit of claim 13 , wherein the container is a polymer bag.
16 . The kit of claim 15 , wherein the polymer is polypropylene, polyethylene, or low-density polyethylene.
17 . The kit of claim 13 , wherein the secondary container is impervious to light.
18 . The kit of claim 13 , wherein the container and/or the secondary container includes an oxygen scavenger.
19 . A method of treating hypotension, comprising:
administering a ready-to-inject norepinephrine composition according to claim 1 at an initial dose per minute; and
administering the ready-to-inject norepinephrine composition 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.