Stable growth hormone liquid formulation
The present invention is directed to stable liquid growth hormone formulations that remain stable after physical agitation, and after exposure to one or more freeze-thaw events. Formulations of the present invention can be stored long term at a variety of temperatures, even frozen. In the present invention, a combination of buffer and stabilizing agents, including a non-ionic surfactant (e.g., polysorbate 20), a polymer stabilizer (e.g., polyethylene glycol), and other optional stabilizers combine to provide unexpected stability to aqueous formulations of a growth hormone (e.g., human growth hormone).
1. A formulation consisting of a therapeutically effective amount of a human growth hormone in an aqueous solution, a buffer that maintains the pH of the formulation at a pH of 5 to 7, a non-ionic polysorbate surfactant, a polymer stabilizer wherein said polymer stabilizer is a polyethylene glycol which has a molecular weight in the range of about 3000 to about 20,000, methionine, and one or more optional excipients selected from the group consisting of a divalent cation present in a magnesium salt selected from the group consisting of magnesium hydroxide, magnesium chloride, magnesium sulfate, magnesium citrate, and magnesium edentate; a tonicity agent; and a preservative, wherein the formulation remains stable after at least one freezing and subsequent thawing event.
2. The formulation of claim 1 , wherein the human growth hormone is a recombinant form of human growth hormone.
3. The formulation of claim 2 , wherein the recombinant form of human growth hormone is present in the formulation at a concentration of 0.1 mg/ml to 20 mg/ml.
4. The formulation of claim 1 , wherein the buffer is selected from the group consisting of sodium citrate, sodium edentate, sodium succinate, and histidine hydrochloride.
5. The formulation of claim 1 , wherein the non-ionic polysorbate surfactant is present at a concentration of about 0.02% to about 10%.
6. The formulation of claim 1 , wherein the non-ionic polysorbate surfactant is selected from the group consisting of polysorbate 20 and polysorbate 80.
7. The formulation of claim 1 , wherein the polyethylene glycol is present at a concentration of about 0.25% or about 1%.
8. The formulation of claim 1 , wherein the tonicity agent is sorbitol.
9. The formulation of claim 1 , wherein the preservative is selected from the group consisting of phenol and benzyl alcohol.
10. A formulation consisting of about 0.1 mg/ml to about 20 mg/ml of a recombinant form of human growth hormone in an aqueous solution, a citrate or edentate buffer that maintains the formulation at a pH of about 5 to about 7, about 0.04% to about 5% (w/w) of a polysorbate surfactant, about 0.25% or about 1% (w/v) of polyethylene glycol, methionine, and one or more optional excipients selected from the group consisting of a sufficient concentration of sorbitol for the formulation to be approximately isotonic, magnesium chloride or magnesium hydroxide, and a preservative, wherein the formulation remains stable after at least one freeze thaw event.
11. The formulation of claim 10 , wherein the preservative is phenol or benzyl alcohol.
12. The formulation of claim 10 , wherein at least about 90% of the recombinant form of human growth hormone remains in solution after exposure of the formulation to three or more freeze-thaw events.
13. The formulation of claim 10 where the formulation is stable at about 2° C. to about 8° C. for at least 52 weeks.
14. The formulation of claim 13 wherein after 52 weeks at about 2° C. to about 8° C. at least one of
(i) total aggregate as measured by size exclusion HPLC is less than about 0.5%,
(ii) total deamidation as measured by anion exchange HPLC is less than about 7%, or
(iii) the recombinant form of human growth hormone recovery as measured by reverse phase HPLC is greater than or equal to 85%.