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 method of producing a storage stable ready-to-inject epinephrine composition, comprising:
combining an aqueous pharmaceutically acceptable carrier with epinephrine in an amount such that the epinephrine is present in the ready-to-inject epinephrine composition at a concentration of equal or less than 0.07 mg/mL;
wherein substantially all of the epinephrine is an R-isomer;
wherein the aqueous pharmaceutically acceptable carrier has dissolved oxygen in an amount of equal or less than 2 ppm;
adjusting the pH of the ready-to-inject epinephrine composition to a pH of between 3.0-4.7;
including into the ready-to-inject epinephrine composition a metal ion chelator selected from the group consisting of EDTA, EGTA, and diethylenetriaminepentaacetic acid, and wherein the metal ion chelator is present in the composition at a concentration of between about 1 and 50 mcg/mL;
packaging the ready-to-inject epinephrine composition into a container under an inert gas;
sterilizing the ready-to-inject epinephrine composition; and
wherein the ready-to-inject epinephrine composition is substantially antioxidant-free and has, after storage of at least one month, total impurities of equal or less than 0.7% and equal or less than 4% S-isomer content.
2. The method of claim 1 , wherein the step of sterilizing comprises autoclaving.
3. The method of claim 2 , wherein the step autoclaving uses saturated steam at 121° C. for at least 10 minutes.
4. The method of claim 2 , wherein the step autoclaving is performed when the ready-to-inject epinephrine composition is in a polymeric container.
5. The method of claim 1 , wherein the container is a polymeric container that is further packaged into a metallized over-container.
6. The method of claim 1 , wherein the epinephrine is present in the composition at a concentration of between about 0.005 mg/ml and 0.050 mg/ml.
7. The method of claim 1 , wherein the epinephrine is present in the ready-to-inject composition at a concentration of between about 0.006-0.010 mg/ml.
8. The method of claim 1 , wherein the epinephrine is present in the ready-to-inject composition at a concentration of between about 0.010-0.025 mg/ml.
9. The method of claim 1 , wherein the epinephrine is present in the ready-to-inject composition at a concentration of between about 0.025-0.045 mg/ml.
10. The method of claim 1 , wherein the epinephrine is present in the ready-to-inject composition as a pharmaceutically acceptable salt.
11. The method of claim 1 , wherein the ready-to-inject epinephrine composition has, after storage of at least one month, a pH of between about 3.5-4.5.
12. The method of claim 1 , wherein the ready-to-inject epinephrine composition has, after storage of at least one month, a pH of between about 3.8-4.2.
13. The method of claim 1 , wherein the aqueous pharmaceutically acceptable carrier further comprises a buffer at a concentration of between 1 mM and 25 mM.
14. The method of claim 13 , wherein the buffer is selected from the group consisting of an acetate buffer, a citrate buffer, a phosphate buffer, a tartrate buffer, and a borate buffer, and wherein the composition further optionally comprises a tonicity agent selected from the group consisting of sodium chloride, glycerol, thioglycerol, mannitol, lactose, and dextrose.
15. The method of claim 1 , wherein the ready-to-inject epinephrine composition has, after storage of at least one month, total impurities of equal or less than 0.5% and equal or less than 1% S-isomer content.
16. The method of claim 1 , wherein the ready-to-inject epinephrine composition has, after storage of at least one month, total impurities of equal or less than 0.2% and equal or less than 1.5% S-isomer content.
17. The method of claim 1 , wherein the ready-to-inject epinephrine composition has, after storage of at least one month, total impurities of equal or less than 0.3% and equal or less than 0.7% S-isomer content.
18. The method of claim 1 , wherein the ready-to-inject epinephrine composition has, after sterilization, total impurities of equal or less than 0.5% and equal or less than 2.0% S-isomer content, wherein the mode of sterilization is autoclaving.
19. The method of claim 1 , wherein the ready-to-inject epinephrine composition has, after sterilization, total impurities of equal or less than 0.2% and equal or less than 1.5% S-isomer content, wherein the mode of sterilization is autoclaving.