Epinephrine liquid formulations
The invention provides a stable, pharmaceutical formulation comprising epinephrine or a pharmaceutically acceptable salt thereof. The formulation includes an organic acid, a tonicity agent, and water, has a pH of about 3.0 to about 3.6, and is substantially free of a conjugate base of the organic acid.
1 . A pharmaceutical formulation comprising:
epinephrine or a pharmaceutically acceptable salt thereof,
citric acid;
a tonicity agent;
a sulfite antioxidant; and
water;
wherein the formulation has a pH of from 3.0 to 3.6 and is substantially free of a conjugate base of citric acid and an aminopolycarboxylic acid.
2 . The formulation of claim 1 , wherein the epinephrine or pharmaceutically acceptable salt thereof is present at a concentration of from 0.1 mg/mL to 10 mg/mL.
3 . The formulation of claim 1 , wherein the citric acid is present at a concentration of from 0.1 mg/mL to 25 mg/mL.
4 . The formulation of claim 1 , wherein a weight ratio of the epinephrine or pharmaceutically acceptable salt thereof to the citric acid is from 1:5 to 10:1.
5 . The formulation of claim 1 , wherein the sulfite antioxidant is sodium metabisulfite.
6 . The formulation of claim 1 , further comprising a preservative.
7 . A pharmaceutical product comprising a container and the formulation of claim 1 contained therein.
8 . The pharmaceutical product of claim 7 , wherein the formulation has a pH drift of less than 0.3 pH units following storage of the product for at least 12 months at room temperature.
9 . The pharmaceutical product of claim 7 , wherein the formulation contains not more than 5% of total impurities and not more than 3% of S-epinephrine relative to the amount of epinephrine as determined by a peak area percent method by high-performance liquid chromatography after storage of the product for at least 12 months at room temperature.
10 . A pharmaceutical formulation comprising:
0.5-2.0 mg/mL of epinephrine or a pharmaceutically acceptable salt thereof;
0.25-1.0 mg/mL of citric acid;
a tonicity agent;
a sulfite antioxidant; and
water;
wherein the formulation has a pH of from 3.0 to 3.6 and is substantially free of a conjugate base of citric acid and an aminopolycarboxylic acid.
11 . The formulation of claim 10 , wherein a weight ratio of the epinephrine or pharmaceutically acceptable salt thereof to the citric acid is from 1:1 to 4:1.
12 . The formulation of claim 11 , wherein the formulation has an osmolality of 260-320 mOsm/kg.
13 . The formulation of claim 10 , wherein the tonicity agent is sodium chloride.
14 . The formulation of claim 10 , wherein the sulfite antioxidant is sodium metabisulfite.
15 . The formulation of claim 10 , further comprising a paraben.
16 . A pharmaceutical product comprising a container and the formulation of claim 10 contained therein.
17 . The pharmaceutical product of claim 16 , wherein the formulation has a pH drift of less than 0.3 pH units following storage of the product for at least 12 months at room temperature.
18 . The pharmaceutical product of claim 16 , wherein the formulation contains not more than 5% of total impurities and not more than 3% of S-epinephrine relative to the amount of epinephrine as determined by a peak area percent method by high-performance liquid chromatography after storage of the product for at least 12 months at room temperature.
19 . A pharmaceutical formulation comprising:
1.0 mg/mL of epinephrine or a pharmaceutically acceptable salt thereof,
0.5 mg/mL of citric acid;
8.6 mg/mL of sodium chloride;
0.25 mg/mL of sodium metabisulfite; and
water;
wherein the formulation has a pH of from 3.0 to 3.6 and is substantially free of a conjugate base of citric acid and an aminopolycarboxylic acid.
20 . The formulation of claim 19 , further comprising 1 mg/mL of methylparaben.
21 . A pharmaceutical product comprising a container and the formulation of claim 19 contained therein.
22 . The pharmaceutical product of claim 21 , wherein the formulation has a pH drift of less than 0.3 pH units following storage of the product for at least 12 months at room temperature.
23 . The pharmaceutical product of claim 21 , wherein the formulation contains not more than 5% of total impurities and not more than 3% of S-epinephrine relative to the amount of epinephrine as determined by a peak area percent method by high-performance liquid chromatography after storage of the product for at least 12 months at room temperature.