LIQUID FORMULATION OF LONG-ACTING HUMAN GROWTH HORMONE CONJUGATE

• US 20130115231A1
• Filed: 07/14/2011
• Published: 05/09/2013
• Est. Priority Date: 07/14/2010
• Status: Active Grant

• Current Assignee: Hanmi Science Co., Ltd
• Original Assignee: Hanmi Science Co., Ltd
• Inventors: Hong, Sung Hee, Lee, Byung Sun, Im, Dae Seong, Lee, Jae Min, Bae, Sung Min, Kwon, Se Chang
• Granted Patent: US 9,061,072 B2
• Time in Patent Office: Days
• US Class Current: 424/179.1
• CPC Class Codes: A61K 38/27 Growth hormone [GH], i.e. somatotropin
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 47/68 the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/08 Solutions composition of solutions A61K47/00
• CPC Class Codes: A61P 5/06 of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
• CPC Class Codes: C07K 2319/30 Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto

Abstract

Disclosed is a liquid formulation of long-acting human growth hormone (hGH) conjugate, free of albumin, which can guarantee the stability of the long-acting hGH conjugate when stored over a long period of time, wherein the long-acting human growth hormone conjugate includes a human growth hormone linked to an immunoglobulin Fc region, and has a prolonged in vivo stability compared to the native form. The liquid formulation of hGH conjugate including a pH 5.0˜6.0 buffer, a sugar alcohol, a salt and a non-ionic surfactant is free of human serum albumin and other hazardous factors which are potentially contaminated with viruses, and can provide excellent storage stability customized for a long-acting hGH conjugate composed of an hGH polypeptide and an immunoglobulin Fc region which has higher molecular weight and in vivo durability, compared to the native.

Claims

1. A liquid formulation of long-acting human growth hormone conjugate, comprising a pharmaceutically effective amount of the long-acting human growth hormone conjugate in which human growth hormone is linked to an immunoglobulin Fc region, and an albumin-free stabilizer, said stabilizer comprising a buffer of pH 5.0-6.0, a sugar alcohol, a non-ionic surfactant and a salt.

2. The liquid formulation of long-acting human growth hormone conjugate of claim 1, wherein the sugar alcohol is selected from the group consisting of mannitol, sorbitol and a combination thereof.

3. The liquid formulation of long-acting human growth hormone conjugate of claim 1, wherein the sugar alcohol is used in an amount of from 1 to 10% (w/v) based the total volume of the formulation.

4. The liquid formulation of long-acting human growth hormone conjugate of claim 1, wherein the buffer is a citrate or phosphate buffer.

5. The liquid formulation of long-acting human growth hormone conjugate of claim 1, wherein the buffer ranges in pH from 5.2 to 6.0.

6. The liquid formulation of long-acting human growth hormone conjugate of claim 1, wherein the buffer ranges in pH from 5.2 to 5.5.

7. The liquid formulation of long-acting human growth hormone conjugate of claim 1, wherein the salt is sodium chloride.

8. The liquid formulation of long-acting human growth hormone conjugate of claim 1, wherein the salt is used in a concentration of from 5 to 200 mM.

9. The liquid formulation of long-acting human growth hormone conjugate of claim 1, wherein the non-ionic surfactant is polysorbate 80.

10. The liquid formulation of long-acting human growth hormone conjugate of claim 1, wherein the non-ionic surfactant is used in an amount of from 0.001 to 0.05% (w/v) based on the total volume of the formulation.

11. The liquid formulation of long-acting human growth hormone conjugate of claim 1, wherein the stabilizer further comprises one or more ingredient selected from the group consisting of a sugar, a polyalcohol and an amino acid.

12. The liquid formulation of long-acting human growth hormone conjugate of claim 1, wherein the long-acting human growth hormone conjugate comprises human growth hormone and an immunoglobulin Fc region with a linkage via a polyethylene glycol, and the stabilizer comprises a citrate buffer with a pH of 5.2 to 6.0, 1-10% (w/v) mannitol, 0.001-0.05% polysorbate 80, and 5-200 mM NaCl.

13. The liquid formulation of long-acting human growth hormone conjugate of claim 1, wherein the human growth hormone has an amino acid sequence identical to that of a native human growth hormone.

14. The liquid formulation of long-acting human growth hormone conjugate of claim 1, wherein the immunoglobulin Fc region is derived from IgG, IgA, IgD, IgE or IgM.

15. The liquid formulation of long-acting human growth hormone conjugate of claim 14, wherein the immunoglobulin Fc region is a hybrid Fc region of different domains of immunoglobulins selected from the group consisting of IgG, IgA, IgD, IgE, and IgM.

16. The liquid formulation of long-acting human growth hormone conjugate of claim 14, wherein the immunoglobulin Fc region is a dimer or multimer of a single stranded immunoglobulin having domains of the same origin.

17. The liquid formulation of long-acting human growth hormone conjugate of claim 14, wherein the immunoglobulin Fc region is an IgG4 Fc region.

18. The liquid formulation of long-acting human growth hormone conjugate of claim 17, wherein the immunoglobulin Fc region is an aglycosylated human IgG4 Fc region.

19. The liquid formulation of long-acting human growth hormone conjugate of claim 1, wherein the long-acting human growth hormone conjugate comprises a human growth hormone and an immunoglobulin Fc region with a linkage via a non-peptidyl polymer.

20. The liquid formulation of long-acting human growth hormone conjugate of claim 19, wherein the non-peptidyl polymer is selected from the group consisting of polyethylene glycol, polypropylene glycol, copolymers of ethylene glycol and propylene glycol, polyoxyethylated polyols, polyvinyl alcohol, polysaccharides, dextran, polyvinyl ethyl ether, polylactic acid (PLA), PLGA (polylactic-glycolic acid), lipid polymers, chitins, hyaluronic acid, and a combination thereof.

21. A method for producing the liquid formulation of long-acting human growth hormone conjugate as in claim 1, comprising:

a) preparing a long-acting human growth hormone conjugate; and

b) combining the long-acting human growth hormone conjugate with a stabilizer, said stabilizer comprising a buffer with a pH of 5.0-6.0, a sugar alcohol, a non-ionic surfactant and a salt.