Composition for treating diabetes comprising long-acting insulin conjugate and long-acting insulinotropic peptide conjugate

Abstract

The present invention relates to a composition for the prevention or treatment of diabetes comprising a long-acting insulin conjugate and a long-acting insulinotropic peptide conjugate, and a therapeutic method for the treatment of diabetes, and more particularly, concurrent administration of the long-acting insulin conjugate and the long-acting insulinotropic peptide conjugate inhibits weight gain caused by insulin treatment, and vomiting and nausea caused by insulinotropic peptide treatment, and reduces the required dose of insulin, thereby remarkably improving drug compliance. Moreover, each of the long-acting insulin conjugate and the long-acting insulinotropic peptide conjugate of the present invention is prepared by linking insulin or insulinotropic peptide with an immunoglobulin Fc region via a non-peptidyl linker, thereby showing improved in-vivo duration of efficacy and stability.

1 . A pharmaceutical composition for the prevention or treatment of diabetes comprising a long-acting insulin conjugate and a long-acting insulinotropic peptide conjugate, wherein each of the long-acting insulin conjugate and the long-acting insulinotropic peptide conjugate is prepared by liking insulin or insulinotropic peptide with an immunoglobulin Fc region via a non-peptidyl linker selected from the group consisting of polyethylene glycol, polypropylene glycol, ethylene glycol-propylene glycol copolymer, polyoxyethylated polyol, polyvinyl alcohol, polysaccharide, dextran, polyvinyl ethyl ether, a biodegradable polymer, a lipid polymer, chitin, hyaluronic acid, and a combination thereof. 
     
     
         2 . The composition according to  claim 1 , wherein the insulin is a native insulin, a basal insulin, an insulin variant prepared by any one of substitution, addition, deletion, modification or a combination thereof of the amino acid sequences of the native insulin, an insulin derivative, or a fragment thereof. 
     
     
         3 . The composition according to  claim 1 , wherein the insulin is modified with a non-peptidyl polymer. 
     
     
         4 . The composition according to  claim 3 , wherein the non-peptidyl polymer is selected from the group consisting of polyethylene glycol, polypropylene glycol, ethylene glycol-propylene glycol copolymer, polyoxyethylated polyol, polyvinyl alcohol, polysaccharide, dextran, polyvinyl ethyl ether, a biodegradable polymer, a lipid polymer, chitin, hyaluronic acid, and a combination thereof. 
     
     
         5 . The composition according to  claim 1 , wherein the insulinotropic peptide is selected from the group consisting of GLP-1, exendin-3, exendin-4, agonists thereof, derivatives thereof, fragments thereof, variants thereof, and combinations thereof. 
     
     
         6 . The composition according to  claim 1 , wherein the insulinotropic peptide is prepared by substituting the N-terminal histidine residue of insulinotropic peptide with a substance selected from the group consisting of des-amino-histidyl, dimethyl-histidyl, beta-hydroxy imidazopropionyl, 4-imidazoacetyl, and beta-carboxy imidazopropionyl. 
     
     
         7 . The composition according to  claim 1 , wherein the insulinotropic peptide is selected from the group consisting of a native exendin-4, an exendin-4 derivative prepared by deleting N-terminal amine group, an exendin-4 derivative prepared by substituting N-terminal amine group with hydroxyl group, an exendin-4 derivative prepared by modifying N-terminal amine group with dimethyl group, an exendin-4 derivative prepared by deleting α-carbon of the first amino acid of exendin-4 (histidine), an exendin-4 variant prepared by substituting 12th amino acid (lysine) of exendin-4 with serine, and an exendin-4 variant prepared by substituting 12th amino acid (lysine) of exendin-4 with arginine. 
     
     
         8 . The composition according to  claim 1 , wherein the immunoglobulin Fc region is aglycosylated. 
     
     
         9 . The composition according to  claim 1 , wherein the immunoglobulin Fc region is composed of one to four domains selected from the group consisting of CH1, CH2, CH3 and CH4 domains. 
     
     
         10 . The composition according to  claim 1 , wherein the immunoglobulin Fc region further includes a hinge region. 
     
     
         11 . The composition according to  claim 1 , wherein the immunoglobulin Fc region is an Fc region derived from IgG, IgA, IgD, IgE, or IgM. 
     
     
         12 . The composition according to  claim 1 , wherein each domain of the immunoglobulin Fc region is a hybrid domain of a different origin selected from the group consisting of IgG, IgA, IgD, IgE, and IgM. 
     
     
         13 . The composition according to  claim 1 , wherein the immunoglobulin Fc region is a dimer or a multimer composed of single-chain immunoglobulins of the same origin. 
     
     
         14 . The composition according to  claim 1 , further comprising a pharmaceutically acceptable carrier. 
     
     
         15 . The composition according to  claim 1 , wherein the long-acting insulin conjugate and the long-acting insulinotropic peptide conjugate are administered simultaneously, sequentially, or reversely. 
     
     
         16 . A method for preventing or treating diabetes, comprising the step of administering the composition of  claim 1  to a subject having diabetes or at risk of having diabetes. 
     
     
         17 . The method according to  claim 16 , wherein the administration step is performed by concurrent administration of the long-acting insulin conjugate and the long-acting insulinotropic peptide conjugate. 
     
     
         18 . The method according to  claim 17 , wherein the concurrent administration is performed by administrating the long-acting insulin conjugate and the long-acting insulinotropic peptide conjugate simultaneously, sequentially, or reversely. 
     
     
         19 . A pharmaceutical composition for the prevention or treatment of diabetes comprising a long-acting insulin conjugate and an insulinotropic peptide. 
     
     
         20 . A pharmaceutical composition for the prevention or treatment of diabetes comprising insulin and a long-acting insulinotropic peptide conjugate.