Aqeous composition comprising at least one protein and one solubilizing agent, preparation thereof and uses thereof

Abstract

A liquid composition which has, in an aqueous medium, one or more protein(s) and one or more solubilizing agent(s) chosen from anionic compounds of non-saccharide structure, the structure of which contains at least one aromatic nucleus having at least 6 ring members and at least one carboxylic acid group in salified form, and which has, in its acid form, a molar mass between 130 and 500 g/mol. A process for solubilizing one or more protein(s), wherein at least one solubilizing agent chosen from anionic compounds of non-saccharide structure, the structure of which contains at least one aromatic nucleus having at least 6 ring members and at least one carboxylic acid group in salified form, and which has, in its acid form, a molar mass between 130 and 500 g/mol, is added to an aqueous protein preparation in order to solubilize the protein is also provided.

1 . A process for solubilizing one or more protein(s) in water, wherein at least one solubilizing agent chosen from the group consisting of anionic compounds of non-saccharide structure, said structure of which contains at least one aromatic nucleus comprising at least 6 ring members (6 atoms) and at least one carboxylic acid group in salified form and which, in its acid form, has a molar mass of between 130 and 500 g/mol, is added to an aqueous protein composition. 
     
     
         2 . The solubilization of proteins within an aqueous composition, of at least one solubilizing agent chosen from the group consisting of anionic compounds of non-saccharide structure, said structure of which contains at least one aromatic nucleus comprising at least 6 ring members (6 atoms) and at least one carboxylic acid group in salified form, and which has, in its acid form, a molar mass of between 130 and 500 g/mol. 
     
     
         3 . The process for solubilizing agent(s) correspond(s) to general formula (I) below: 
       
         
           
           
               
               
           
         
       
       with:
 Ar denoting an aromatic nucleus comprising at least 6 ring members; 
 X denoting a saturated or unsaturated, linear or branched divalent radical, the main chain of which consists of 1 to 4 carbon atoms and optionally 1 or 2 heteroatoms chosen from nitrogen and oxygen atoms, it being possible for said main chain to optionally bear one or more substituents; 
 Y 1  and Y 2  denoting, independently of one another: a hydrogen atom; an —OH group; an —OR 1  group with R 1  denoting an alkyl radical containing from 1 to 6 carbon atoms or a hydroxyalkyl radical containing from 1 to 6 carbon atoms; and preferably Y 1  and Y 2  denote, independently of one another, a hydrogen atom or an —OH group; and 
 M denoting a cation. 
 
     
     
         4 . The process as claimed in  claim 3 , wherein, in formula (I), Ar denotes a benzene nucleus or an indole nucleus. 
     
     
         5 . The process as claimed in  claim 3 , wherein the solubilizing agent(s) correspond(s) to formula (Ia) below: 
       
         
           
           
               
               
           
         
         with X, Y 1 , Y 2  and M as defined in  claim 3 . 
       
     
     
         6 . The process as claimed in  claim 3 , wherein the solubilizing agent(s) correspond(s) to formula (Ib) below: 
       
         
           
           
               
               
           
         
         with X, Y 1 , Y 2  and M as defined in  claim 3 . 
       
     
     
         7 . The process as claimed in  claim 3 , wherein, in formula (I), (Ia) or (Ib), the divalent radical X bears, on its main chain, one or more substituents corresponding to the general formula:
   -L-Z   with:   L denotes a single bond or a group chosen from an amide group —NHCO—, a carbamate group —NHCOO— or a urea group —NHCONH—; and   Z denotes a hydroxyl group (—OH); a saturated or unsaturated, linear or branched radical comprising from 1 to 4 carbon atoms, said carbon atoms bearing at least one hydroxyl group —[CH 2 ] X —[OH] Y ; a salified carboxylic acid group (—COOM′ with M′=Na +  or K + ); or a saturated or unsaturated, linear or branched radical comprising from 1 to 12 carbon atoms and optionally one or more heteroatoms.   
     
     
         8 . The process as claimed in  claim 7 , wherein L denotes a single bond or an amide group. 
     
     
         9 . The process as claimed in  claim 1 , wherein the solubilizing agent is resulting from a natural or synthetic amino acid bearing an aromatic ring, chosen from phenylalanine, tyrosine and tryptophan, and phenylalanine. 
     
     
         10 . The process as claimed in  claim 1 , wherein the solubilizing agent is chosen from the group consisting of N-hydroxyacetylphenylalanine and N-hydroxyacetyltryptophan, corresponding to the formulae below: 
       
         
           
           
               
               
           
         
         used in the form of a sodium salt or of a potassium salt. 
       
     
     
         11 . The process as claimed in  claim 1 , wherein the solubilizing agent is resulting from a phenol. 
     
     
         12 . The process as claimed in  claim 1 , wherein the solubilizing agent is chosen from the following compounds, used in the form of sodium salts or of potassium salts: 
       
         
           
                 
                 
                 
               
                     
                     
                 
                     
                   Name 
                   Structure 
                 
                     
                     
                 
                     
                   Phenylacetic acid 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                     
                 
                     
                   Mandelic acid 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                     
                 
                     
                   Hydrocinnamic acid 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                     
                 
                     
                   Trans-cinnamic acid 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                     
                 
                     
                   2-Phenoxypropionic acid 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                     
                 
                     
                   3-Phenyllactic acid 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                     
                 
                     
                   Phenylsuccinic acid 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                     
                 
                     
                   Alpha-hydroxyhippuric acid 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                     
                 
             
                
                
                
               
               
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         13 . The process as claim in  claim 1 , wherein said aqueous composition comprises the solubilizing agent(s) in a total concentration of between 1 g/1 and 100 g/l. 
     
     
         14 . The process as claim in  claim 1 , wherein said aqueous composition contains a total concentration of protein(s) of between 0.5 and 400 mg/ml. 
     
     
         15 . The process as claim in  claim 1 , wherein the molar ratio between the total amount of solubilizing agent(s) and the total amount of protein(s) in the composition is greater than or equal to 20. 
     
     
         16 . The process as claim in  claim 1 , wherein said aqueous composition is intended to be administered by intravenous injection, by subcutaneous injection or by intramuscular injection. 
     
     
         17 . A liquid composition comprising, in an aqueous medium, one or more protein(s) chosen from proteins containing at least one antibody fragment from monoclonal antibodies (mAbs), polyclonal antibodies, fusion proteins, nanobodies, bispecific antibodies and antibodies coupled to cytotoxic active ingredients (ADCs—antibody-drug conjugates) and one or more solubilizing agent(s), wherein the solubilizing agent(s) correspond(s) to general formula (I) below: 
       
         
           
           
               
               
           
         
       
       with:
 Ar denoting an aromatic nucleus comprising at least 6 ring members; 
 X denoting a saturated or unsaturated, linear or branched divalent radical, the main chain of which consists of 1 to 4 carbon atoms and optionally 1 or 2 heteroatoms chosen from nitrogen and oxygen atoms, it being possible for said main chain to optionally bear one or more substituents; 
 Y 1  and Y 2  denoting, independently of one another: a hydrogen atom; an OH group; an —OR 1  group with R 1  denoting an alkyl radical containing from 1 to 6 carbon atoms or a hydroxyalkyl radical containing from 1 to 6 carbon atoms; and preferably Y 1  and Y 2  denote, independently of one another, a hydrogen atom or an OH group; and 
 M denoting a cation. 
 
     
     
         18 . The composition as claimed in  claim 17 , wherein, in formula (I), Ar denotes a benzene nucleus or an indole nucleus. 
     
     
         19 . The composition as claimed in  claim 1 , wherein the solubilizing agent(s) correspond(s) to formula (Ia) below: 
       
         
           
           
               
               
           
         
         with X, Y 1 , Y 2  and M as: 
         X denoting a saturated or unsaturated, linear or branched divalent radical, the main chain of which consists of 1 to 4 carbon atoms and optionally 1 or 2 heteroatoms chosen from nitrogen and oxygen atoms, it being possible for said main chain to optionally bear one or more substituents; 
         Y 1  and Y 2  denoting, independently of one another: a hydrogen atom; an —OH group; an —OR 1  group with R 1  denoting an alkyl radical containing from 1 to 6 carbon atoms or hydroxyalkyl radical containing from 1 to 6 carbon atoms; and preferably Y 1  and Y 2  denote, independently of one another, a hydrogen atom or an —OH group; and 
         M denoting a cation. 
       
     
     
         20 . The composition as claimed in  claim 1 , wherein the solubilizing agent(s) correspond(s) to formula (Ib) below: 
       
         
           
           
               
               
           
         
         with X, Y 1 , Y 2  and M as; 
         X denoting a saturated or unsaturated, linear or branched divalent radical, the main chain of which consists of 1 to 4 carbon atoms and optionally 1 or 2 heteroatoms chosen from nitrogen and oxygen atoms, it being possible for said main chain to optionally bear one or more substituents; 
         Y 1  and Y 2  denoting, independently of one another: a hydrogen atom; an —OH group; an —OR 1  group with R 1  denoting an alkyl radical containing from 1 to 6 carbon atoms or hydroxyalkyl radical containing from 1 to 6 carbon atoms; and preferably Y 1  and Y 2  denote, independently of one another, a hydrogen atom or an —OH group; and 
         M denoting a cation. 
       
     
     
         21 . The composition as claimed in  claim 1 , wherein, in formula (I), (Ia) or (Ib), the divalent radical X bears on its main chain one or more substituents corresponding to the general formula:
   -L-Z   with:   L denotes a single bond or a group chosen from an amide group —NHCO—, a carbamate group —NHCOO— or a urea group —NHCONH—; and   Z denotes a hydroxyl group (—OH); a saturated or unsaturated, linear or branched radical comprising from 1 to 4 carbon atoms, said carbon atoms bearing at least one hydroxyl group —[CH 2 ] X —[OH] Y ; a salified carboxylic acid group (—COOM′ with M′=Na +  or K + ); or a saturated or unsaturated, linear or branched radical comprising from 1 to 12 carbon atoms and optionally one or more heteroatoms.   
     
     
         22 . The composition as claimed in  claim 1 , wherein L denotes a single bond or an amide group. 
     
     
         23 . The composition as claimed in  claim 1 , wherein the solubilizing agent is resulting from a natural or synthetic amino acid bearing an aromatic ring chosen from phenylalanine, tyrosine and tryptophan, and phenylalanine. 
     
     
         24 . The composition as claimed in  claim 1 , wherein the solubilizing agent is chosen from the group consisting of N-hydroxyacetylphenylalanine and N-hydroxyacetyltryptophan, corresponding to the formulae below: 
       
         
           
           
               
               
           
         
         used in the form of a sodium salt or of a potassium salt. 
       
     
     
         25 . The composition as claimed in  claim 1 , wherein the solubilizing agent is resulting from a phenol. 
     
     
         26 . The composition as claimed in  claim 1 , wherein the solubilizing agent is chosen from the following compounds, used in the form of sodium salts or of potassium salts: 
       
         
           
                 
                 
                 
               
                     
                     
                 
                     
                   Name 
                   Structure 
                 
                     
                     
                 
                     
                   Phenylacetic acid 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                     
                 
                     
                   Mandelic acid 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                     
                 
                     
                   Hydrocinnamic acid 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                     
                 
                     
                   Trans-cinnamic acid 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                     
                 
                     
                   2-Phenoxypropionic acid 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                     
                 
                     
                   3-Phenyllactic acid 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                     
                 
                     
                   Phenylsuccinic acid 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                     
                 
                     
                   Alpha-hydroxyhippuric acid 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                     
                 
             
                
                
                
               
               
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         27 . The composition as claimed in  claim 1 , which comprises the solubilizing agent(s) in a total concentration of between 1 g/1 and 100 g/l. 
     
     
         28 . The composition as claimed in  claim 1 , which contains a total concentration of protein(s) of between 0.5 and 400 mg/ml. 
     
     
         29 . The composition as claimed in  claim 1 , wherein the molar ratio between the total amount of solubilizing agent(s) and the total amount of protein(s) in the composition is greater than or equal to 20. 
     
     
         30 . The composition as claimed in  claim 1 , which is intended to be administered by intravenous injection, by subcutaneous injection or by intramuscular injection.