Levothyroxine liquid formulations
The present invention is directed to a pharmaceutical product which includes a liquid formulation comprising levothyroxine or a pharmaceutically acceptable salt thereof. The formulation of the present invention includes a cyclodextrin, water, and an amine, and has a pH above the buffering range of the amine. The liquid formulation of the invention is stable and ready-to-use.
1 . A pharmaceutical product comprising a liquid formulation comprising about 5 mcg/mL to about 100 mcg/mL of levothyroxine sodium, a stabilizing agent comprising an alkanolamine and a salt of iodine, and water, wherein the formulation has a pH of from about 9.0 to about 11.5 and retains about least about 95% of the initial concentration of levothyroxine or pharmaceutically acceptable salt thereof after storage for two months at 40° C. and is stable for at least 12 months at room temperature.
2 . The pharmaceutical product of claim 1 , wherein the formulation is provided in a clear glass container selected from the group consisting of a flint colored molded vial, a flint colored tubing vial, an ampoule, a cartridge, and a syringe.
3 . The pharmaceutical product of claim 1 , wherein the clear glass container is not treated with ammonium sulfate.
4 . The pharmaceutical product of claim 1 , wherein the alkanolamine is selected from one or more of tromethamine, bis(2-hydroxyethyl)-imino-tris (hydroxymethyl) methane, monoethanolamine, diethanolamine, triethanolamine, 2-amino-2-methyl-1,3-propanediol, 2-dimethylamino-2-methyl-1-propanediol, 2-amino-2-ethylpropanol, 2-amino-1-butanol, and 2-amino-2-methyl-1-propanol.
5 . The pharmaceutical product of claim 4 , wherein the alkanolamine is tromethamine which is present at a concentration of about 1 mg/mL to about 50 mg/mL.
6 . The pharmaceutical product of claim 1 , wherein the salt of iodine is sodium iodide or potassium iodide.
7 . The pharmaceutical product of claim 6 , wherein the salt of iodine is sodium iodide which is present at a concentration of about 10 mcg/mL to about 500 mcg/mL.
8 . The pharmaceutical product of claim 1 , wherein the formulation has a pH of from about 9.8 to about 10.8.
9 . The pharmaceutical product of claim 1 , wherein the formulation contains not more than 2.0% liothyronine (T3).
10 . The pharmaceutical product of claim 1 , wherein the formulation contains not more than 5.0% total impurities.
11 . The pharmaceutical product of claim 1 , wherein the formulation is stable for at least 18 months at room temperature.
12 . The pharmaceutical product of claim 1 , wherein the formulation retains at least about 90% of the initial concentration of levothyroxine or pharmaceutically acceptable salt thereof after storage for at least 12 months at room temperature.
13 . The pharmaceutical product of claim 1 , wherein the formulation retains at least about 90% of the initial concentration of levothyroxine or pharmaceutically acceptable salt thereof after storage for at least 18 months at room temperature.
14 . The pharmaceutical product of claim 1 , wherein the formulation does not contain a buffer.
15 . A method of preparing a pharmaceutical product comprising:
(a) filling purified water into a container,
(b) dissolving a stabilizing agent comprising an alkanolamine and a salt of iodine in the water to form a solution,
(c) adjusting the pH of the solution to 9.0 to 11.5 with sodium hydroxide and/or hydrochloric acid to form a pH adjusted solution,
(d) adding levothyroxine sodium to the pH adjusted solution to form an initial drug solution,
(e) adding purified water to the drug solution to form a final drug solution,
(f) filtering the final drug solution through a 0.22 mm filter to form a filtered final drug solution, and
(g) filling the filtered final drug solution into one or more clear glass containers and sealing the containers, thereby preparing the pharmaceutical product.
16 . The method of claim 15 , wherein nitrogen is bubbled through the solutions of steps (b)-(e).
17 . The method of claim 15 , wherein the containers are filled and sealed under nitrogen.
18 . The method of claim 15 , wherein the pH is adjusted to about 10.3.
19 . A pharmaceutical product comprising a liquid formulation comprising about 5 mcg/mL to about 100 mcg/mL of levothyroxine sodium, glycerol, and water, wherein the formulation has a pH of from about 7.0 to about 9.0.
20 . The pharmaceutical product of claim 19 , wherein the glycerol is present in a concentration of about 100 mg/mL.
21 . The pharmaceutical product of claim 5 , wherein the salt of iodine is sodium iodide or potassium iodide.
22 . The pharmaceutical product of claim 21 , wherein the salt of iodine is sodium iodide which is present at a concentration of about 10 mcg/mL to about 500 mcg/mL.
23 . The pharmaceutical product of claim 22 , wherein the formulation has a pH of from about 9.8 to about 10.8.
24 . The pharmaceutical product of claim 23 , wherein the formulation contains not more than 2.0% liothyronine (T3) and not more than 5.0% total impurities.
25 . The pharmaceutical product of claim 23 , wherein the formulation retains at least about 90% of the initial concentration of levothyroxine or pharmaceutically acceptable salt thereof after storage for at least 18 months at room temperature.
26 . The pharmaceutical product of claim 5 , wherein the tromethamine is present at a concentration of about 10 mg/mL.
27 . The pharmaceutical product of claim 26 , wherein the salt of iodine is sodium iodide or potassium iodide.
28 . The pharmaceutical product of claim 27 , wherein the salt of iodine is sodium iodide which is present at a concentration of about 140 mcg/mL.
29 . The pharmaceutical product of claim 28 , wherein the formulation has a pH of from about 9.8 to about 10.8.
30 . The pharmaceutical product of claim 29 , wherein the formulation contains not more than 2.0% liothyronine (T3) and not more than 5.0% total impurities.
31 . The pharmaceutical product of claim 29 , wherein the formulation retains at least about 90% of the initial concentration of levothyroxine or pharmaceutically acceptable salt thereof after storage for at least 18 months at room temperature.
32 . The pharmaceutical product of claim 30 , wherein the formulation retains at least about 90% of the initial concentration of levothyroxine or pharmaceutically acceptable salt thereof after storage for at least 18 months at room temperature.