Rapid acting insulin formulation comprising an oligosaccharide

Abstract

A composition in aqueous solution, including an insulin and at least one oligosaccharide whose average degree of polymerization is between 3 and 13 and whose polydispersity index PDI is above 1.0, the oligosaccharide having partially substituted carboxyl functional groups, the unsubstituted carboxyl functional groups being salifiable.

1 . A composition in aqueous solution, comprising insulin and at least one oligosaccharide whose average degree of polymerization is between 3 and 13 and whose polydispersity index PDI is above 1.0, said oligosaccharide having partially substituted carboxyl functional groups, the unsubstituted carboxyl functional groups being salifiable. 
     
     
         2 . The composition as claimed in  claim 1 , wherein it further comprises at least one polyanionic compound. 
     
     
         3 . The composition as claimed in  claim 1 , wherein the insulin is a human insulin. 
     
     
         4 . The composition as claimed in  claim 1 , wherein the insulin is an insulin analog. 
     
     
         5 . The composition as claimed in  claim 4 , wherein the insulin analog is selected from the group comprising consisting of insulin lispro (Humalog®), insulin aspart (Novolog®, Novorapid®) and insulin glulisine (Apidra®). 
     
     
         6 . The composition as claimed in  claim 4 , wherein the insulin analog is insulin lispro (Humalog®). 
     
     
         7 . The composition as claimed in  claim 1 , wherein the oligosaccharide/insulin weight ratio is between 0.4 and 10. 
     
     
         8 . The composition as claimed in  claim 1 , wherein the concentration of polyanionic compound is between 1.4 and 35 mg/mL 
     
     
         9 . The composition as claimed in  claim 1 , wherein oligosaccharide is selected from the oligosaccharides of the following general formula I: 
       
         
           
           
               
               
           
         
         In which:
 the oligosaccharide is a dextran, 
 F results from the coupling between linker arm R and an —OH function of the oligosaccharide and being either an ester, carbamate or ether function, 
 R is a chain comprising between 1 and 15 carbons, optionally branched and/or unsaturated, comprising one or more heteroatoms, such as O, N and/or S, and having at least one carboxyl function, 
 Phe is a residue of a phenylalanine derivative, of absolute configuration L or D, produced from coupling between the amine of the phenylalanine derivative and at least one acid carried by group R prior to attachment to Phe, 
 n represents the mole fraction of R substituted with Phe and is between 0.3 and 0.9, 
 i represents the average mole fraction of groups F-R-[Phe]n borne per saccharide unit and is between 0.5 and 2.5; 
 when R is not substituted with Phe, the acid or acids of group R are carboxylates with an alkaline cation. 
 
       
     
     
         10 . The composition as claimed in  claim 2 , wherein the anionic compound is selected from the group consisting of anionic molecules, anionic polymers and of compounds consisting of a skeleton formed from a discrete number p between 1 and 8 (1≦p≦8) of identical or different saccharide units, bound by identical or different glycosidic bonds that are naturally carriers of carboxyl groups or are substituted with carboxyl groups. 
     
     
         11 . A pharmaceutical formulation comprising a composition as claimed in  claim 1 . 
     
     
         12 . The pharmaceutical formulation as claimed in  claim 11 , wherein the concentration of insulin is between 240 and 3000 μM (40 to 500 IU/mL). 
     
     
         13 . The pharmaceutical formulation as claimed in  claim 11 , wherein the concentration of insulin is between 600 and 1200 μM (100 and 200 IU/mL). 
     
     
         14 . A method for preparing a pharmaceutical formulation of insulin, comprising at least one oligosaccharide whose average degree of polymerization is between 3 and 13 and whose polydispersity index PIN is above 1.0, alone nixed with a polyanionic compound, that makes it possible, after administration, to accelerate the passage of insulin into the blood and reduce glycemia more rapidly relative to an oligosaccharide-free formulation alone or mixed with a polyanionic compound. 
     
     
         15 . The method as claimed in  claim 14 , wherein the oligosaccharide is selected from the oligosaccharides of the following general formula I: 
       
         
           
           
               
               
           
         
         In which:
 the oligosaccharide is a dextran, 
 F results from the coupling between linkage R and an —OH function of the oligosaccharide and being either an ester function, carbamate or ether function, 
 R is a chain comprising between 1 and 15 carbons, optionally branched and/or unsaturated, comprising one or more heteroatoms, such as 0, N and/or S, and having at least one carboxyl function, 
 Phe is a residue of a phenylalanine derivative, of absolute configuration L or D, produced from coupling between the amine of the phenylalanine derivative and at least one acid carried by group R prior to attachment to Phe, 
 n represents the mole fraction of R substituted with Phe and is between 0.3 and 0.9, 
 i represents the average mole fraction of groups F-R-[Phe]n borne per saccharide unit and is between 0.5 and 2.5; 
 when R is not substituted with Phe, the acid or acids of group R are carboxylates with an alkaline cation, preferably such as Na+ or K+. 
 
       
     
     
         16 . The method as claimed in  claim 14 , wherein the anionic compound is selected from the group consisting of anionic molecules, anionic polymers and of compounds consisting of a skeleton formed from a discrete number p between 1 and 8 (1≦p≦8) of identical or different saccharide units, bound by identical or different glycosidic bonds that are naturally carriers of carboxyl groups or are substituted with carboxyl groups. 
     
     
         17 . A method of preparing a formulation of human insulin having an insulin concentration between 240 and 3000 μM (40 and 500 IU/mL), whose onset of in action in humans is less than that of the reference formulation at the same insulin concentration in the absence of oligosaccharide, wherein it comprises a step of adding, to said formulation, at least one oligosaccharide having partially substituted carboxyl functional groups. 
     
     
         18 . The method as claimed in  claim 17 , wherein it further comprises a step of adding at least one polyanionic compound to said formulation. 
     
     
         19 . The method as claimed in  claim 17 , for preparing a formulation of human insulin having an insulin concentration of 600 μM (100 IU/mL), whose onset of action in humans is less than 60 minutes, wherein it comprises a step of adding, to said formulation, at least one oligosaccharide having partially substituted carboxyl functional groups. 
     
     
         20 . The method as claimed in  claim 19 , wherein it further comprises a step of adding at least one polyanionic compound to said formulation. 
     
     
         21 . A method of preparing a formulation of insulin analog having an insulin concentration between 240 and 3000 μM (40 and 500 IU/mL), whose onset of action in humans is less than that of the reference formulation at the same insulin concentration in the absence of oligosaccharide, wherein it comprises a step of adding, to said formulation, at least one oligosaccharide having partially substituted carboxyl functional groups. 
     
     
         22 . The method as claimed in  claim 21 , wherein it further comprises a step of adding at least one polyanionic compound to said formulation. 
     
     
         23 . The method as claimed in  claim 21 , for preparing a formulation of insulin analog, having an insulin concentration of 600 μM (100 IU/mL), whose onset of action in humans is less than 30 minutes, wherein it comprises a step of adding, to said formulation, at least one oligosaccharide having partially substituted carboxyl functional groups. 
     
     
         24 . The method as claimed in  claim 23 , wherein it further comprises a step of adding at least one polyanionic compound to said formulation. 
     
     
         25 . The method as claimed in  claim 17 , wherein the oligosaccharide is selected from the oligosaccharides of the following general formula I: 
       
         
           
           
               
               
           
         
         In which:
 the oligosaccharide is a dextran, 
 F results from the coupling between linkage R and an —OH function of the oligosaccharide and being either an ester-carbamate or ether function, 
 R is a chain comprising between 1 and 15 carbons, optionally branched and/or unsaturated, comprising one or more heteroatoms, such as O, N and/or S, and having at least one carboxyl function, 
 Phe is a residue of a phenylalanine derivative, of absolute configuration L or D, produced from coupling between the amine of the phenylalanine derivative and at least one acid carried by group R prior to attachment to Phe, 
 n represents the mole fraction of R substituted with Phe and is between 0.3 and 0.9, 
 i represents the average mole fraction of groups F-R-[Phe]n borne per saccharide unit and is between 0.5 and 2.5; 
 when R is not substituted with Phe, the acid or acids of group R are carboxylates with an alkaline cation. 
 
       
     
     
         26 . The method as claimed in  claim 18 , wherein the anionic compound is selected from the group consisting of anionic molecules, anionic polymers and of compounds consisting of a skeleton formed from a discrete number p between 1 and 8 (1≦p≦8) of identical or different saccharide units, bound by identical or different glycosidic bonds that are naturally carriers of carboxyl groups or are substituted with carboxyl groups.