STABLE INJECTABLE EPINEPHRINE FORMULATIONS INCLUDING A METAL-CHELATING AGENT
Disclosed herein are pharmaceutical formulations including epinephrine that have increased epinephrine retention over long-term storage, e.g., 30-months. In one aspect, a formulation includes: one or more of 0.1 mg/mL of epinephrine or a pharmaceutically acceptable salt thereof provided without any overage, a tonicity regulating agent including 8.2 mg/mL of sodium chloride, a pH adjusting agent including a mixture of 1.5 mg/mL sodium citrate dihydrate, 3.3 mg/mL of citric acid monohydrate, and, optionally, an as-needed amount of sodium hydroxide to maintain the pH level of the formulation within a range of 3.6 to 4.0, 0.075 mg/mL of sodium metabisulfite, and 4 μg/mL of ethylene diamine tetra-acetate disodium. The formulation has an API recovery of 94.5% or more after at least 30 months of storage at long-term storage conditions defined as 25° C.±2° C. at 1 atmosphere. In addition, in another aspect, a formulation includes 1 mg/mL of epinephrine and other ingredients.
1 . A pharmaceutical formulation comprising:
0.1 mg/mL of one or more of epinephrine or a pharmaceutically-acceptable salt thereof;
a tonicity regulating agent including 8.2 mg/mL of sodium chloride;
a pH adjusting agent including a mixture of 1.5 mg/mL sodium citrate dihydrate, 3.3 mg/mL of citric acid monohydrate, and, optionally, an as-needed amount of sodium hydroxide to maintain a pH level of the pharmaceutical formulation within a range from 3.6 to 4.0;
0.075 mg/mL of sodium metabisulfite; and
4 μg/mL of ethylene diamine tetra-acetate disodium (EDTA);
wherein the pharmaceutical formulation is configured to have an API recovery of 94.5% or more responsive to at 30 months of storage at long-term storage conditions defined as 25° C.±2° C. at 1 atmosphere (atm).
2 . The pharmaceutical formulation of claim 1 , wherein the pharmaceutical formulation is configured to be injected intravenously, subcutaneously, or intramuscularly.
3 . The pharmaceutical formulation of claim 1 , wherein the pharmaceutical formulation comprises no more than 4.9% (w/w) of Impurity F after storage at a temperature of 40° C. for a duration of at least 3 consecutive months, wherein w/w denotes a weight percentage based on a total weight of the API initially included in the pharmaceutical formulation.
4 . The pharmaceutical formulation of claim 1 , wherein the pharmaceutical formulation comprises no more than 8.6% (w/w) of Impurity F after storage at a temperature of 40° C. for a duration of at least 6 consecutive months, wherein w/w denotes a weight percentage based on a total weight of the API initially included in the pharmaceutical formulation.
5 . The pharmaceutical formulation of claim 1 , wherein the pharmaceutical formulation comprises no more than 5.7% (w/w) of total related impurities excluding dextrorotatory-epinephrine (D-epinephrine) after storage at a temperature of 40° C. for a duration of at least 3 consecutive months, wherein w/w denotes a weight percentage based on a total weight of the API initially included in the pharmaceutical formulation.
6 . The pharmaceutical formulation of claim 1 , wherein the pharmaceutical formulation comprises no more than 10.4% (w/w) of total related impurities excluding dextrorotatory-epinephrine (D-epinephrine) after storage at a temperature of 40° C. for a duration of at least 6 consecutive months, wherein w/w denotes a weight percentage based on a total weight of the API initially included in the pharmaceutical formulation.
7 . The pharmaceutical formulation of claim 1 , wherein the pharmaceutical formulation comprises no more than 3.1% (w/w) of Impurity F after storage at a temperature of 25° C.±2° C. for a duration of at least 12 consecutive months, wherein w/w denotes a weight percentage based on a total weight of the API initially included in the pharmaceutical formulation.
8 . The pharmaceutical formulation of claim 1 , wherein the pharmaceutical formulation comprises no more than 3.6% (w/w) of total related impurities excluding D-epinephrine after storage at a temperature of 25° C.±2° C. for a duration of at least 12 consecutive months, wherein w/w denotes a weight percentage based on a total weight of the API initially included in the pharmaceutical formulation.
9 . The pharmaceutical formulation of claim 1 , wherein the pharmaceutical formulation comprises no more than 4.6% (w/w) of Impurity F after storage at a temperature of 25° C.±2° C. for a duration of at least 18 consecutive months, wherein w/w denotes a weight percentage based on a total weight of the API initially included in the pharmaceutical formulation.
10 . The pharmaceutical formulation of claim 1 , wherein the pharmaceutical formulation comprises no more than 2.2% (w/w) of D-epinephrine after storage at a temperature of 25° C.±2° C. for a duration of at least 18 consecutive months, wherein w/w denotes a weight percentage based on a total weight of the API initially included in the pharmaceutical formulation.
11 . The pharmaceutical formulation of claim 1 , wherein the pharmaceutical formulation comprises no more than 5.4% (w/w) of total related impurities excluding D-epinephrine after storage at a temperature of 25° C.±2° C. for a duration of at least 18 consecutive months, wherein w/w denotes a weight percentage based on a total weight of the API initially included in the pharmaceutical formulation.
12 . The pharmaceutical formulation of claim 1 , wherein the epinephrine is provided without an overage.
13 . The pharmaceutical formulation of claim 1 , wherein the pharmaceutical formulation is substantially free of tartrate and acids, bases, and/or salts thereof.
14 . A pre-filled syringe containing a pharmaceutical formulation, the pharmaceutical formulation comprising:
one or more of epinephrine or a pharmaceutically-acceptable salt thereof at a concentration of 0.1 mg/mL;
a tonicity regulating agent comprising sodium chloride at a concentration of 8.2 mg/mL;
a pH adjusting agent comprising 1.5 mg/mL sodium citrate dihydrate, 3.3 mg/mL of citric acid monohydrate and, optionally, sodium hydroxide, the pH adjusting agent configured to maintain a pH level of the pharmaceutical formulation from about 3.6 to 4.0;
an antioxidant comprising sodium metabisulfite at a concentration of 0.075 mg/mL; and
a transition metal complexing agent comprising 4 μg/mL of ethylene diamine tetra-acetate disodium (EDTA);
wherein the pharmaceutical formulation is configured to have an API recovery of 94.5% (w/w) or more responsive to a storage period of at least 30 months at long-term storage conditions defined as 25° C.±2° C. at 1 atmosphere (atm).
15 . The pre-filled syringe of claim 14 , wherein the pharmaceutical formulation is configured to be injected intravenously, subcutaneously, or intramuscularly.
16 . The pre-filled syringe of claim 14 , wherein the pharmaceutical formulation comprises no more than 4.9% (w/w) of Impurity F after storage at a temperature of 40° C. for a duration of at least 3 consecutive months, wherein w/w denotes a weight percentage based on a total weight of the API initially included in the pharmaceutical formulation.
17 . The pre-filled syringe of claim 14 , wherein the pharmaceutical formulation comprises no more than 8.6% (w/w) of Impurity F after storage at a temperature of 40° C. for a duration of at least 6 consecutive months, wherein w/w denotes a weight percentage based on a total weight of the API initially included in the pharmaceutical formulation.
18 . The pre-filled syringe of claim 14 , wherein the pharmaceutical formulation comprises no more than 5.7% (w/w) of total related impurities excluding dextrorotatory-epinephrine (D-epinephrine) after storage at a temperature of 40° C. for a duration of at least 3 consecutive months, wherein w/w denotes a weight percentage based on a total weight of the API initially included in the pharmaceutical formulation.
19 . The pre-filled syringe of claim 14 , wherein the pharmaceutical formulation comprises no more than 3.1% (w/w) of Impurity F after storage at a temperature of 25° C.±2° C. for a duration of at least 12 consecutive months, wherein w/w denotes a weight percentage based on a total weight of the API initially included in the pharmaceutical formulation.
20 . The pre-filled syringe of claim 14 , wherein the pharmaceutical formulation comprises no more than 3.6% (w/w) of total related impurities excluding D-epinephrine after storage at a temperature of 25° C.±2° C. for a duration of at least 12 consecutive months, wherein w/w denotes a weight percentage based on a total weight of the API initially included in the pharmaceutical formulation.
21 . The pre-filled syringe of claim 14 , wherein the pharmaceutical formulation comprises no more than 4.6% (w/w) of Impurity F after storage at a temperature of 25° C.±2° C. for a duration of at least 18 consecutive months, wherein w/w denotes a weight percentage based on a total weight of the API initially included in the pharmaceutical formulation.
22 . The pre-filled syringe of claim 14 , wherein the pharmaceutical formulation comprises no more than 2.2% (w/w) of D-epinephrine after storage at a temperature of 25° C.±2° C. for a duration of at least 18 consecutive months, wherein w/w denotes a weight percentage based on a total weight of the API initially included in the pharmaceutical formulation.
23 . The pre-filled syringe of claim 14 , wherein the pharmaceutical formulation comprises no more than 5.4% (w/w) of total related impurities excluding D-epinephrine after storage at a temperature of 25° C.±2° C. for a duration of at least 18 consecutive months, wherein w/w denotes a weight percentage based on a total weight of the API initially included in the pharmaceutical formulation.
24 . The pre-filled syringe of claim 14 , wherein epinephrine is provided without an overage.
25 . The pre-filled syringe of claim 14 , wherein the pharmaceutical formulation is substantially free of tartrate and acids, bases, and/or salts thereof.
26 . A pharmaceutical formulation configured to be administered as a single dose from a pre-filled 10 milliliter (mL) syringe, each single dose comprising:
0.1 mg/mL of an active pharmaceutical ingredient (API) comprising one or more of epinephrine or a pharmaceutically acceptable salt thereof;
0.1 mg/mL or less of an antioxidant comprising one or more of sodium metabisulfite or sodium bisulfate;
between 1 μg/mL and 8 μg/mL of a metal-chelating agent comprising ethylene diamine tetra-acetate disodium (EDTA);
a pH-stabilizing buffer system comprising 3.3 mg/mL of citric acid and 1.5 mg/mL of sodium citrate; and
between 5 mg/mL and 9 mg/mL of a tonicity regulating agent comprising sodium chloride, the tonicity regulating agent configured to regulate an osmolality of the pharmaceutical formulation between 210 milliosmoles per kilogram (mOsmol/kg) and 300 mOsmol/kg;
wherein the pharmaceutical formulation is configured to have an API recovery of 94.5% or more responsive to 30 months of storage at long-term storage conditions defined as 25° C.±2° C. at 1 atmosphere (atm).