Liquid formulation of highly concentrated long-acting human growth hormone conjugate

Abstract

A liquid formulation of highly concentrated long-acting human growth hormone conjugate contains a pharmaceutically effective amount of the long-acting human growth hormone conjugate in which human growth hormone (hGH) is linked to an immunoglobulin Fc region, and an albumin-free stabilizer, said stabilizer comprising a buffer, a non-ionic surfactant, a sugar alcohol, and sodium chloride as an isotonic agent. A method for preparing the same is provided.

1 . A liquid formulation of highly concentrated long-acting human growth hormone (hGH) conjugate, comprising a pharmaceutically effective amount of the long-acting human growth hormone conjugate in which human growth hormone (hGH) is linked to an immunoglobulin Fc region, and an albumin-free stabilizer, said stabilizer comprising a buffer, a non-ionic surfactant, a sugar alcohol and sodium chloride as an isotonic agent. 
     
     
         2 . The liquid formulation according to  claim 1 , wherein the buffer is an acetate buffer. 
     
     
         3 . The liquid formulation according to  claim 1 , wherein a concentration of the long-acting human growth hormone conjugate ranges from 20 to 100 mg/mL. 
     
     
         4 . The liquid formulation according to  claim 1 , wherein the sugar alcohol is selected from the group consisting of mannitol, sorbitol and a combination thereof. 
     
     
         5 . The liquid formulation according to  claim 4 , wherein the sugar alcohol is used at a concentration ranging from 1 to 10% (w/v) of the total volume of the formulation. 
     
     
         6 . The liquid formulation according to  claim 1 , wherein pH of the buffer ranges from 5.0 to 6.0. 
     
     
         7 . The liquid formulation according to  claim 1 , wherein the sodium chloride is used at a concentration ranging from 5 to 200 mM. 
     
     
         8 . The liquid formulation according to  claim 1 , wherein the non-ionic surfactant is polysorbate 80. 
     
     
         9 . The liquid formulation according to  claim 8 , wherein the non-ionic surfactant is used at a concentration ranging from 0.001 to 0.05% (w/v) of the total volume of the formulation. 
     
     
         10 . The liquid formulation according to  claim 1 , wherein the stabilizer further comprises one or more ingredients selected from the group consisting of a sugar, a polyhydric alcohol and an amino acid. 
     
     
         11 . The liquid formulation according to  claim 1 , comprising a preservative. 
     
     
         12 . The liquid formulation according to  claim 11 , wherein the preservative is a benzyl alcohol or m-cresol. 
     
     
         13 . The liquid formulation according to  claim 12 , wherein the preservative is used at a concentration ranging from 1 to 10 mg/mL. 
     
     
         14 . The liquid formulation according to  claim 1 , wherein the human growth hormone (hGH) has the same amino acid sequence as a wild-type human growth hormone. 
     
     
         15 . The liquid formulation according to  claim 1 , wherein the immunoglobulin Fc region is derived from IgG, IgA, IgD, IgE or IgM. 
     
     
         16 . The liquid formulation according to  claim 15 , wherein each domain of the immunoglobulin Fc region is a hybrid of domains with different origin which are derived from immunoglobulin selected from the group consisting of IgG, IgA, IgD, IgE, and IgM. 
     
     
         17 . The liquid formulation according to  claim 15 , wherein the immunoglobulin Fc region is a dimer or multimer composed of a single-chain immunoglobulin consisting of domains with the same origin. 
     
     
         18 . The liquid formulation according to  claim 15 , wherein the immunoglobulin Fc region is an IgG4 Fc region. 
     
     
         19 . The liquid formulation according to  claim 18 , wherein the immunoglobulin Fc region is an aglycosylated human IgG4 Fc region. 
     
     
         20 . The liquid formulation according to  claim 1 , wherein the long-acting human growth hormone conjugate is a conjugate in which the human growth hormone is linked with the immunoglobulin Fc region via a non-peptidyl polymer, or by using a genetic recombination technique. 
     
     
         21 . The liquid formulation according to  claim 20 , wherein the non-peptidyl polymer is selected from the group consisting of biodegradable polymers such as polyethylene glycol, polypropylene glycol, copolymers of ethylene glycol and propylene glycol, polyoxyethylated polyols, polyvinyl alcohol, polysaccharides, dextran, polyvinyl ethyl ether, polylactic acid (PLA), and polylactic-glycolic acid (PLGA), lipid polymers, chitins, hyaluronic acid, and a combination thereof. 
     
     
         22 . The liquid formulation according to  claim 21 , wherein the non-peptidyl polymer is a polyethylene glycol. 
     
     
         23 . A liquid formulation of highly concentrated long-acting human growth hormone conjugate, comprising a long-acting human growth hormone conjugate in which human growth hormone (hGH) is linked to an immunoglobulin fragment via polyethylene glycol, and an albumin-free stabilizer, said stabilizer comprising an acetate buffer, a mannitol, a polysorbate 80, and sodium chloride. 
     
     
         24 . The liquid formulation according to  claim 23 , further comprising a preservative. 
     
     
         25 . A method for preparing the liquid formulation of  claim 1 , comprising mixing a long-acting human growth hormone conjugate with a stabilizer, said stabilizer comprising a buffer, a sugar alcohol, a non-ionic surfactant and a sodium chloride as an isotonic agent. 
     
     
         26 . The method according to  claim 25 , wherein the method further comprises mixing a preservative with the long-acting human growth hormone conjugate and the stabilizer.