New stabilizing agent for pharmaceutical proteins

Abstract

A method for stabilising a human blood protein or human blood plasma protein with a molecular weight of >10 KDa by adding melezitose to a solution comprising the human blood protein or human blood plasma protein with a molecular weight of >10 KDa.

1 . A method for stabilizing a human blood protein or human blood plasma protein with a molecular weight of >10 KDa comprising adding melezitose to a solution comprising the human blood protein or human blood plasma protein with a molecular weight of >10 KDa. 
     
     
         2 . The method of  claim 1  wherein the solution is optionally transferred into the solid state by lyophilization. 
     
     
         3 . The method of  claim 1  wherein melezitose is present in an amount of up to 1,000 mM. 
     
     
         4 . The method of  claim 1  wherein the human blood protein or human blood plasma protein with a molecular weight of >10 KDa is a pharmaceutically or biologically relevant human blood protein or human blood plasma protein. 
     
     
         5 . The method of  claim 4  wherein the pharmaceutically or biologically relevant protein is a recombinantly produced human blood protein or human blood plasma protein with a molecular weight of >10 KDa. 
     
     
         6 . The method of  claim 4  wherein the pharmaceutically or biologically relevant protein is from a human, plant, insect, or other source, or is a mutated, artificial, synthetic, fusion or chimeric protein or a derivative coupled with one or more chemical compounds, or combinations thereof. 
     
     
         7 . The method of  claim 6  wherein the human blood protein or human blood plasma protein with a molecular weight of >10 KDa is a blood clotting factor. 
     
     
         8 . The method of  claim 6  wherein the human blood protein or human blood plasma protein with a molecular weight of >10 KDa is a transport protein, a protease inhibitor an immunoglobulin, a cell related plasma protein, an apolipoprotein, a complement factor a growth factor, an antiangionetic protein, a highly glycosylated protein or another human blood protein or human blood plasma with a molecular weight of >10 KDa or a derivative or mutein thereof. 
     
     
         9 . The method of  claim 1  wherein at least one surface active agent selected from the group consisting of recombinant albumin, Polysorbate 80, Polysorbate 20 and a Poloxamer, is present. 
     
     
         10 . The method of  claim 1  wherein at least one buffering agent selected from the group consisting of histidine, sodium citrate, HEPES, Tris, MOPS and PIPES is present. 
     
     
         11 . The method of  claim 1  wherein at least one further stabilizer selected from the group consisting of sugars, amino acids, polyols, co-factors and combinations thereof is present and/or wherein at least one tonicity modifier selected from the group consisting of sodium chloride, arginine, glycine, potassium chloride, sugars and sugar alcohols is present and/or wherein at least one bulking agent selected from the group consisting of glycine, mannitol, sodium chloride, arginine and sucrose is present. 
     
     
         12 . A composition comprising a human blood protein or human blood plasma protein with a molecular weight of >10 KDa and melezitose. 
     
     
         13 . The composition of  claim 12  in liquid or solid state. 
     
     
         14 . The composition of  claim 12  further comprising a bulking agent, a surfactant, a buffering agent, a further stabilizer and/or tonicity modifier. 
     
     
         15 . The method of  claim 1 , which is performed in an in-process stabilization, in a lyophilization process, in solution, during purification, or during production; or which is for long term stabilization to improve shelf-life, wherein the long-term is at least 6 months. 
     
     
         16 . The composition of  claim 12 , wherein the protein is factor VIII. 
     
     
         17 . The composition of  claim 12 , wherein the protein is factor IX. 
     
     
         18 . The composition of  claim 12 , wherein the protein is HES-G-CSF. 
     
     
         19 . The method of  claim 3 , wherein the wherein melezitose is present in an amount from about 10 mM to about 200 mM. 
     
     
         20 . The method of  claim 3 , wherein the wherein melezitose is present in an amount from about 10 mM to about 100 mM. 
     
     
         21 . The method of  claim 7 , wherein the blood clotting factor is fibrinogen, fibrin monomer, prothrombin, thrombin, FV, FVa, FX, FXa, FIX, FIXa, FVII, FVIIa, FVIII, FXI, FXIa, FXII, FXIIa, FXIII, FXIIIa, von Willebrand factor, or ADAMTS13, or a derivative or mutein thereof. 
     
     
         22 . The method of  claim 8 , wherein the transport protein is albumin, transferrin, ceruloplasmin, haptoglobin, hemoglobin, or hemopexin; the protease inhibitor is β-antithrombin, α-antithrombin, α2-macroglobulin, Cl-inhibitor, tissue factor pathway inhibitor (TFPI), heparin cofactor II, protein C inhibitor (PAI-3), Protein C, Protein S, or Protein Z; the immunonoglobulin is a polyclonal antibody (IgG), monoclonal antibody, IgG1, IgG2, IgG3, IgG4, IgA, IgA1, IgA2, IgM, IgE, IgD, or Bence Jones protein; the cell related plasma protein is fibronectin, thromboglobulin, or platelet factor4; the apolipoprotein is apo A-I, apo A-II, or apo E; the complement factor is Factor B, Factor D, Factor H, Factor I, C3b-Inactivator, properdin, or C4-binding protein; the growth factor is Platelet derived growth factor (PDGF), Epidermal growth factor (EGF), Transforming growth factor alfa (TGF-α), Transforming growth factor beta (TGF-β), Fibroblast growth factor (FGF) or Hepatocyte growth factor; the antiangionetic protein is latent-antithrombin or prelatent-antithrombin; the highly glycosylated protein is alfa-1-acid glycoprotein, antichymotrypsin, inter-α-trypsin inhibitor, α-2-HS glycoprotein, or C-reactive protein; and the other human blood protein or human blood plasma protein with a molecular weight of >10 Kda is histidine-rich glycoprotein, mannan binding lectin, GC-globulin, plasminogen, α-1 microglobulin, C-reactive protein or a blood factor. 
     
     
         23 . The method of  claim 9 , wherein the Poloxamer is Poloxamer 188. 
     
     
         24 . The method of  claim 15 , wherein the production is in cell culture. 
     
     
         25 . The method of  claim 15 , wherein the long-term is at least 36 months. 
     
     
         26 . The method of  claim 22 , wherein the blood factor is erythropoeitin, interferon, tumor factors, tPA, or G-CSF, or a derivative or mutein thereof.