LEVOTHYROXINE LIQUID FORMULATIONS
A stable liquid formulation for parenteral administration that includes levothyroxine or a pharmaceutically acceptable salt thereof. The formulation includes a low concentration of an antioxidant, an amino acid as a pH adjuster and a stabilization agent in an aqueous solution that has a pH of about 9 to about 11.5. The parenteral liquid formulation is a stable formulation that is supplied as a ready-to-use or ready-to-administer product in a container or vial.
1 . A parenteral liquid formulation comprising:
a. levothyroxine or a pharmaceutically acceptable salt thereof;
b. an antioxidant selected from the group consisting of about 0.005 to about 0.06 weight percent by volume of glutamic acid, about 0.001 to about 0.03 weight percent by volume of monothioglycerol, and a combination thereof,
wherein the parenteral liquid formulation has a pH of about 9.0 to about 11.5 and the parenteral liquid formulation is stable for at least 3 months at 40° C.
2 . The parenteral liquid formulation of claim 1 , wherein levothyroxine or a pharmaceutically acceptable salt thereof is levothyroxine sodium.
3 . The parenteral liquid formulation of claim 2 , wherein the levothyroxine sodium is present at a concentration of from about 20 mcg/mL to about 125 mcg/mL.
4 . The parenteral liquid formulation of claim 2 , wherein the levothyroxine sodium is present at a concentration of from about 400 mcg/mL to about 800 mcg/mL.
5 . The parenteral liquid formulation of claim 1 , wherein the monothioglycerol is present at a concentration of from about 0.005 to about 0.03 weight percent by volume.
6 . The parenteral liquid formulation of claim 1 , wherein the monothioglycerol is the sole antioxidant in the parenteral liquid formulation.
7 . The parenteral liquid formulation of claim 1 , further comprising an amino acid pH adjuster.
8 . The parenteral liquid formulation of claim 7 , wherein the amino acid is arginine.
9 . The parenteral liquid formulation of claim 8 , wherein the arginine is present at about 1 mg/mL to about 15 mg/mL.
10 . The parenteral liquid formulation of claim 1 , further comprising propylene glycol at about 10 to about 60 weight percent by volume.
11 . The parenteral liquid formulation of claim 1 , wherein the pH is about 9.0 to about 11.0.
12 . The parenteral liquid formulation of claim 1 , wherein the liquid parenteral formulation comprises not more than about 1.0% of an individual impurity after storage for 3 months at 40° C.
13 . The parenteral liquid formulation of claim 1 , wherein the liquid parenteral formulation comprises not more than about 1.0% of an individual impurity after storage for 3 months at 5° C.
14 . The parenteral liquid formulation of claim 1 , wherein the parenteral liquid formulation is a ready-to-use or ready-to-administer formulation.
15 . The parenteral liquid formulation of claim 14 , wherein the formulation is supplied in a glass vial comprising a gas head space, the gas in the head space comprising not more than 5% by volume of oxygen.
16 . The parenteral liquid formulation of claim 15 , wherein the glass vial is amber or flint color.
17 . The parenteral liquid formulation of claim 1 , wherein the formulation retains about 95% or more of the initial concentration of levothyroxine or a pharmaceutically acceptable salt thereof after storage for 3 months at 40° C.
18 . The parenteral liquid formulation of claim 1 , wherein the formulation retains about 98% or more of the initial concentration of levothyroxine or a pharmaceutically acceptable salt thereof after storage for 3 months at 40° C.
19 . The parenteral liquid formulation of claim 1 , wherein the formulation retains about 98% or more of the initial concentration of levothyroxine or a pharmaceutically acceptable salt thereof after storage for 3 months at 5° C.
20 . A parenteral liquid formulation comprising:
a. about 20 mcg/mL to about 125 mcg/mL of levothyroxine sodium;
b. about 1.0 mg/mL to about 15.0 mg/mL of arginine;
c. about 25 to about 60 weight percent by volume of propylene glycol;
d. about 0.0025 to about 0.03 weight percent by volume of monothioglycerol; and
wherein the parenteral liquid formulation has a pH of about 9.0 to about 11.5 and the parenteral liquid formulation is stable for at least 3 months at 40° C.
21 . The parenteral liquid formulation of claim 20 , wherein the monothioglycerol is present at a concentration of from about 0.005 to about 0.02 weight percent by volume.
22 . The parenteral liquid formulation of claim 20 , wherein the liquid parenteral formulation comprises not more than about 1.0% of an individual impurity after storage for 3 months at 40° C.
23 . The parenteral liquid formulation of claim 20 , wherein the liquid parenteral formulation comprises not more than about 1.0% of an individual impurity after storage for 3 months at 5° C.
24 . The parenteral liquid formulation of claim 20 , wherein the liquid parenteral formulation retains about 95% or more of the initial concentration of levothyroxine or a pharmaceutically acceptable salt thereof after storage for 3 months at 40° C.
25 . The parenteral liquid formulation of claim 20 , wherein the liquid parenteral formulation retains about 95% or more of the initial concentration of levothyroxine or a pharmaceutically acceptable salt thereof after storage for 3 months at 5° C.
26 . The parenteral liquid formulation of claim 20 , wherein the parenteral liquid formulation is a ready-to-use or ready-to-administer formulation supplied in a glass vial.