Epinephrine compositions and containers
The inventive subject matter provides ready-to-administer, preferably anti-oxidant free, epinephrine compositions with improved stability, and methods for preparing the same. Contemplated compositions can be packaged using blow-fill-seal technology or packaged into flexible IV bags and maintain degradation of the epinephrine at a level of less than 5 wt % when stored over at least one months at between 2-40° C.
1. A sterile storage stable ready-to-inject epinephrine composition, comprising:
an aqueous pharmaceutically acceptable carrier containing epinephrine, a tonicity agent, and a metal ion chelator;
wherein the epinephrine is present at a concentration of equal or less than 0.07 mg/ml, and wherein at least about 90 mol % of the epinephrine is an R-isomer;
wherein the composition has a pH of between 3.0-4.7;
wherein the metal ion chelator is a bicarboxylic acid, a tricarboxylic acid, or an aminopolycarboxylic acid;
wherein the metal ion chelator is present in the composition at a concentration of between about 1 and 50 μg/ml; and
wherein the composition has a total impurities concentration of equal to or less than 0.3% after storage of at least one month at 25° C.
2. The composition of claim 1 , wherein the epinephrine is present at a concentration of equal or less than 0.04 mg/ml.
3. The composition of claim 1 , wherein the epinephrine is present at a concentration of equal or less than 0.02 mg/ml.
4. The composition of claim 1 , wherein the epinephrine is present as epinephrine base, and wherein bitartrate is present as a buffer.
5. The composition of claim 1 , wherein the composition comprises dissolved oxygen in an amount of equal or less than 3.0 ppm O 2 .
6. The composition of claim 1 , wherein the composition comprises a buffer at a concentration of between 1-50 mM.
7. The composition of claim 1 , wherein the tonicity agent is selected from the group consisting of glycerol, mannitol, lactose, and dextrose.
8. The composition of claim 1 , wherein the composition is an autoclaved sterile composition, and wherein an S-isomer content after autoclaving and after storage of at least one month at 25 ° C. is equal or less than 0.7% .
9. The composition of claim 1 , wherein the composition, after storage of at least one month at 25 ° C., changes pH no more than 0.5 pH units.
10. A method of producing a sterile and storage stabile ready-to-inject epinephrine composition, comprising:
combining an aqueous pharmaceutically acceptable carrier with epinephrine, a tonicity agent, and metal ion chelator such that the epinephrine has a concentration of equal or less than 0.07 mg/ml;
wherein at least about 90 mol % of the epinephrine is an R-isomer;
wherein the metal ion chelator is a bicarboxylic acid, a tricarboxylic acid, or an aminopolycarboxylic acid; and
wherein the metal ion chelator is present in the composition at a concentration of between about 1 and 50 μg/ml;
adjusting a pH of the ready-to-inject epinephrine composition to between 3.0-4.7;
packaging the ready-to-inject epinephrine composition into a container under an inert gas; and
autoclaving the ready-to-inject epinephrine composition to sterility, wherein the composition has a total impurities concentration of equal to or less than 0.3% after storage of at least one month at 25° C.
11. The method of claim 10 , wherein the epinephrine is present at a concentration of equal or less than 0.04 mg/ml.
12. The method of claim 10 , wherein the epinephrine is present at a concentration of equal or less than 0.02 mg/ml.
13. The method of claim 10 , wherein the epinephrine is present as epinephrine base, and wherein as bitartrate is present as a buffer.
14. The method of claim 10 , wherein the composition comprises dissolved oxygen in an amount of equal or less than 3 ppm O 2 .
15. The method of claim 10 , wherein the composition after autoclaving and after storage of at least one month at 25 ° C. has an S-isomer content of equal or less than 0.7% .
16. The method of claim 10 , further comprising a step of placing the container into a secondary light impervious container.
17. The method of claim 16 , further comprising a step of placing an oxygen scavenger into a space between the container and the secondary container.