EPINEPHRINE FORMULATIONS
A method of making a pharmaceutical composition in a pre-filled syringe including preparing a batch solution by providing a solvent having an initial dissolved oxygen content, sparging the solvent with a first inert gas until the solvent has a reduced dissolved oxygen content that is lower than the initial dissolved oxygen content, and combining the solvent with an active agent and an antioxidant. The solvent is continuously sparged with the first inert gas during combination with the active agent and the antioxidant. The method also includes introducing at least a portion of the batch solution into a syringe while sparging the batch solution with a second inert gas that is the same as or different from the first inert gas. The pharmaceutical composition in the pre-filled syringe has a concentration of total impurities of the active agent of no more than about 5.5% (w/v) after three months of storage in accelerated storage conditions. Also described are pharmaceutical compositions in a pre-filled syringe.
1 . A method of making a pharmaceutical composition in a pre-filled syringe comprising:
(a) preparing a batch solution, wherein preparing the batch solution comprises:
providing a solvent having an initial dissolved oxygen content,
sparging the solvent with a first inert gas until the solvent has a reduced dissolved oxygen content that is lower than the initial dissolved oxygen content, wherein the reduced dissolved oxygen content is less than about 0.5 ppm, and
combining the solvent with an active agent and an antioxidant, wherein the solvent is continuously sparged with the first inert gas during combination with the active agent and the antioxidant, and
(b) introducing at least a portion of the batch solution of (a) into a syringe to provide the pharmaceutical composition in the pre-filled syringe,
wherein the batch solution of (a) is sparged with a second inert gas when provided in the pre-filled syringe, and
wherein the second inert gas is the same as or different from the first inert gas,
wherein the pharmaceutical composition in the pre-filled syringe has a concentration of total impurities of the active agent of no more than about 5.5% (w/v) after three months of storage in accelerated storage conditions.
2 . The method of claim 1 , wherein the active agent comprises epinephrine.
3 . The method of claim 2 , wherein the antioxidant comprises sodium metabisulfite and the pharmaceutical composition in the prefilled syringe has a concentration of sodium metabisulfite of from about 0.001 to about 0.2 mg/mL.
4 . The method of claim 2 , wherein the pharmaceutical composition in the prefilled syringe has a concentration of epinephrine of from about 0.01 to about 2 mg/mL.
5 . The method of claim 1 , wherein the first inert gas comprises nitrogen.
6 . The method of claim 1 , wherein the solution of (a) is passed through a filter prior to being provided in the pre-filled syringe such that the pharmaceutical composition in the pre-filled syringe is sterile.
7 . The method of claim 6 , wherein the filter comprise pores with an average pore size of about 0.22 μm.
8 . The method of claim 1 , wherein preparing the solution of (a) further comprises combining the solvent with one or more of a tonicity adjusting agent, a buffer system, a chelating agent, and a pH adjusting agent.
9 . The method of claim 8 , wherein the tonicity adjusting agent comprises sodium chloride, the buffer system comprises tartaric acid and sodium hydroxide, the chelating agent comprises EDTA, and the pH adjusting agent comprises hydrochloric acid.
10 . The method of claim 1 , wherein the solvent comprises water for injection (WFI).
11 . The method of claim 1 , wherein preparing the solution of (a) further comprises combining the solvent with additional solvent after combination with the active agent and/or the antioxidant, and wherein the solution of (a) has a final dissolved oxygen content of no more than about 0.9 ppm.
12 . The method of claim 2 , wherein the pharmaceutical composition in the pre-filled syringe has a concentration of D-epinephrine of no more than about 5% (w/v) after three months of storage in accelerated storage conditions.
13 . The method of claim 12 , wherein the concentration of D-epinephrine after three months of storage in accelerated storage conditions is no more than about 1.4% (w/v).
14 . The method of claim 2 , wherein the pharmaceutical composition in the pre-filled syringe has a concentration of D-epinephrine of no more than about 5% (w/v) after six months of storage in accelerated storage conditions.
15 . The method of claim 14 , wherein the concentration of D-epinephrine after six months of storage in accelerated storage conditions is no more than about 2.2% (w/v).
16 . A pharmaceutical composition provided in a pre-filled syringe prepared by a method comprising:
(a) preparing a batch solution, wherein preparing the batch solution comprises:
providing a solvent having an initial dissolved oxygen content,
sparging the solvent with a first inert gas until the solvent has a reduced dissolved oxygen content that is lower than the initial dissolved oxygen content, wherein the reduced dissolved oxygen content is less than about 0.5 ppm, and
combining the solvent with an active agent and an antioxidant, wherein the solvent is continuously sparged with the first inert gas during combination with the active agent and the antioxidant, and
(b) introducing at least a portion of the batch solution of (a) into a syringe to provide the pharmaceutical composition in the pre-filled syringe,
wherein the batch solution of (a) is sparged with a second inert gas when provided in the pre-filled syringe, and
wherein the second inert gas is the same as or different from the first inert gas,
wherein the pharmaceutical composition in the pre-filled syringe has a concentration of total impurities of the active agent of no more than about 5.5% (w/v) after three months of storage in accelerated storage conditions.
17 . The pharmaceutical composition of claim 16 , wherein the active agent comprises epinephrine, and wherein the pharmaceutical composition in the pre-filled syringe has a concentration of D-epinephrine of no more than about 5% (w/v) after three months of storage in accelerated storage conditions.
18 . The pharmaceutical composition of claim 17 , wherein the concentration of D-epinephrine after three months of storage in accelerated storage conditions is no more than about 1.4% (w/v).
19 . The pharmaceutical composition of claim 16 , wherein the active agent comprises epinephrine, and wherein the pharmaceutical composition in the pre-filled syringe has a concentration of D-epinephrine of no more than about 5% (w/v) after six months of storage in accelerated storage conditions.
20 . The pharmaceutical composition of claim 19 , wherein the concentration of D-epinephrine after six months of storage in accelerated storage conditions is no more than about 2.2% (w/v).