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:
l-epinephrine;
free of an epinephrine degradation product, the epinephrine degradation product being epinephrine sulfonic acid (ESA);
one or more antioxidant, the antioxidant being present in the composition in an amount of about 0.005 wt. % to about 0.03 wt. %, wherein the one or more antioxidant comprises cysteine, thioglycerol, or any combination thereof; and
an aqueous medium;
wherein the pharmaceutical composition has a pH of about 2.5 to about 3.5 and a weight ratio of the antioxidant to l-epinephrine is about 1:10 to about 7:10.
2. The pharmaceutical composition of claim 1 , wherein the one or more antioxidant is cysteine.
3. The pharmaceutical composition of claim 1 , wherein (i) after six months of storage at 40±2° C. and 75±5% relative humidity (RH), the composition comprises at least 90 wt. % of the l-epinephrine in the composition prior to storage; (ii) after 12 months of storage at 25±2° C. and 60±5% relative humidity (RH) the composition comprises at least 90 wt. % of the l-epinephrine in the composition prior to storage; and (iii) after 12 months of storage at 25±2° C. and 60±5% relative humidity (RH) the composition is substantially colorless.
4. The pharmaceutical composition of claim 1 , wherein after at least 1 year of storage at 25° C./60% RH, less than 10% of the l-epinephrine is d-epinephrine.
5. The pharmaceutical composition of claim 1 , wherein the l-epinephrine is present in the composition in an amount of about 0.01 wt. % to about 1 wt. % on a free base basis.
6. The pharmaceutical composition of claim 1 , wherein the l-epinephrine is present in the composition in an amount of about 0.05 wt. % to about 0.15 wt. % on a free base basis.
7. The pharmaceutical composition of claim 1 , further comprising a complexing agent, wherein the complexing agent is one or more cyclodextrin.
8. The pharmaceutical composition of claim 7 , wherein the cyclodextrin is present in the composition in a molar ratio of cyclodextrin-to-l-epinephrine of about 1:10 to about 10:1.
9. The pharmaceutical composition of claim 8 , wherein the cyclodextrin is present in the composition in a molar ratio of cyclodextrin-to-l-epinephrine of about 1:3 to about 2:1.
10. The pharmaceutical composition of claim 1 , further comprising one or more pH buffering agent, the combined weight of pH buffering agent(s) constituting about 0.01 wt. % or less of the composition.
11. The pharmaceutical composition of claim 1 , further comprising an edetate, the edetate being present in the composition in an amount of about 0.01 wt. % or less.
12. The pharmaceutical composition of claim 1 , 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.