Stabilization of epinephrine formulations
The disclosure herein relates to the innovative epinephrine formulations in aqueous solution of medicinal products that enhance the physicochemical stabilities of epinephrine and extend the product shelf life. In some instances, the formulations comprise epinephrine or a salt thereof, a complexing agent, and a “non-sulfite” antioxidant. The epinephrine formulations substantially demonstrated the superior physicochemical stabilities to conventional sulfite formulation of commercial medications currently available. In some instances, sulfite-free formulations further provide further benefit (e.g., safety benefits) to sulfite-sensitive patients. The compositions, methods for preparing the formulations, and methods of using the same (e.g., in the treatment of anaphylaxis) are also provided.
1. A pharmaceutical composition comprising:
epinephrine;
cysteine being present in the composition in an amount of about 0.05 wt. % to about 0.005 wt. % on a free base basis; and
an aqueous medium;
wherein the pharmaceutical composition has a pH of at least 3.5.
2. The pharmaceutical composition of claim 1 , wherein cysteine is present in a concentration of about 0.005 wt. % to about 0.035 wt. %.
3. The pharmaceutical composition of claim 2 , wherein cysteine present in a concentration of about 0.005 wt. % to about 0.03 wt. %.
4. The pharmaceutical composition of claim 1 , wherein cysteine is present in a concentration of about 0.01 wt. % to about 0.05 wt. %.
5. The pharmaceutical composition of claim 4 , wherein cysteine is present in a concentration of about 0.01 wt. % to about 0.035 wt. %.
6. The pharmaceutical composition of claim 5 , wherein cysteine is present in a concentration of about 0.01 wt. % to about 0.03 wt. %.
7. The pharmaceutical composition of any one of the preceding claims, wherein after 12 months of storage at 25±2° C. and 60±5% relative humidity (RH), (i) the composition comprises at least 90 wt. % of the epinephrine in the composition prior to storage;
and (ii) the composition is substantially colorless.
8. The pharmaceutical composition of any one of the preceding claims, wherein after at least 1 year of storage at 25° C./60%RH, less than 10% of the epinephrine is d-epinephrine.
9. The pharmaceutical composition of any one of the preceding claims, wherein after at least 1.5 years of storage at 25° C./60%RH, less than 10% of the epinephrine is d-epinephrine.
10. The pharmaceutical composition of any one of the preceding claims, wherein after at least 2 years of storage at 25° C./60%RH, less than 10% of the epinephrine is d-epinephrine.
11. The pharmaceutical composition of any one of the preceding claims, wherein the epinephrine is present in the composition in an amount of about 0.0005 wt. % to about 1 wt. % on a free base basis.
12. The pharmaceutical composition of any one of the preceding claims, wherein cysteine is present in the composition in a weight ratio of cysteine to epinephrine of about 7:10 down to a ratio of about 1:20.
13. The pharmaceutical composition of any one of the preceding claims, wherein a weight ratio of cysteine-to-epinephrine is 1:10 to about 7:10.
14. The pharmaceutical composition of any one of the preceding claims, wherein a weight ratio of cysteine-to-epinephrine is about 2:10 to about 4:10.
15. The pharmaceutical composition of any one of the preceding claims, wherein the cysteine is present in the composition in an amount of greater than 0.001 wt. % or more.
16. The pharmaceutical composition of any one of the preceding claims, further comprising as a pH buffering agent citric acid and/or citrate.
17. The pharmaceutical composition of any one of the preceding claims, wherein the combined weight of pH buffering agent(s) citric acid and citrate constitute about 0.01 wt. % or less of the composition.
18. The pharmaceutical composition of any one of the preceding claims, further comprising a chelating agent edetate.
19. The pharmaceutical composition of any one of the preceding claims, wherein a chelating agent (edetate) is present in the composition in an amount of about 0.01 wt. % or less.
20. The pharmaceutical composition of any one of the preceding claims, wherein a tonicity modifier is present in the composition in an amount suitable to provide a solution osmolality in the range of about 200 mOsm/kg to about 400 mOsm/kg.
21. The pharmaceutical composition of any one of the preceding claims, wherein the composition is an aqueous solution having a pH of about 3.5 to about 6.5.
22. The pharmaceutical composition of any one of the preceding claims, wherein the aqueous medium is water suitable for injection.
23. The pharmaceutical composition of any one of the preceding claims, wherein the composition is loaded into an administrative device, the administrative device being a syringe or a cartridge suitable for use in a manual and/or auto injector.