Rapid-acting insulin formulation comprising a substituted anionic compound

1. A composition comprising insulin in hexameric form, at least one substituted anionic compound and a polyanionic compound, in an aqueous solution:

wherein the insulin in hexameric form is human insulin or an insulin analog;

said substituted anionic compound being chosen from substituted anionic compounds, in isolated form or as a mixture, consisting of a backbone formed from a discrete number u of between 1 and 8 (1≦u≦8) of identical or different saccharide units, linked via identical or different glycoside bonds, wherein u is the same for all of the at least one substituted anionic compounds, said saccharide units being chosen from the group consisting of hexoses, in cyclic form or in open reduced form, wherein they are substituted with:

a) at least one substituent of general formula I:

—[R 1 ] a -[AA] m   Formula I

the substituents being identical or different when there are at least two substituents, in which:

the radical -[AA] denotes an amino acid residue,

the radical —R 1 — being:

either a bond and then a=0 and the amino acid residue -[AA] is directly linked to the backbone via a function G,

or a C2 to C15 carbon-based chain, and then a=1, optionally substituted and/or comprising at least one heteroatom chosen from O, N and S and at least one acid function before the reaction with the amino acid, said chain forming with the amino acid residue -[AA] an amide function, and is attached to the backbone by means of a function F resulting from a reaction between a hydroxyl function borne by the backbone and a function or substituent borne by the precursor of the radical —R 1 —,

F is an ether, ester or carbamate function,

G is a carbamate function,

m is equal to 1 or 2,

the degree of substitution of the saccharide units, j, with —[R 1 ] a -[AA] m being strictly greater than 0 and less than or equal to 6, 0≦j≦6;

b) and, optionally, one or more substituents —R′ 1 ,

the substituent —R′ 1 being a C2 to C15 carbon-based chain, which is optionally substituted and/or comprising at least one heteroatom chosen from O, N and S and at least one acid function in the form of an alkali metal cation salt, said chain being linked to the backbone via a function F′ resulting from a reaction between a hydroxyl function borne by the backbone and a function or substituent borne by the precursor of the substituent —R′ 1 ,

F′ is an ether, ester or carbamate function,

the degree of substitution of the saccharide units, i, with —R′ 1 , being between 0 and 6−j, 0≦i≦6−j, and

F, F′ and G are identical or different,

i+j≦6,

—R′ 1 is identical to or different from —R 1 —,

the free salifiable acid functions borne by the substituent —R′ 1 are in the form of alkali metal cation salts,

said glycoside bonds, which may be identical or different, being chosen from the group consisting of glycoside bonds of (1,1), (1,2), (1,3), (1,4) or (1,6) type, in an alpha or beta geometry,

and

said polyanionic compound is chosen from the group consisting of citric acid and Na + , K + , Ca 2+ or Mg 2+ salts thereof.

2. The composition as claimed in claim 1 , wherein the insulin is a human insulin.

3. The composition as claimed in claim 1 , wherein the insulin is an insulin analog.

4. The composition as claimed in claim 3 , wherein the insulin analog is chosen from the group consisting of the insulin lispro (Humalog®), the insulin aspart (Novolog®, Novorapid®) and the insulin glulisine (Apidra®).

5. The composition as claimed in claim 3 , wherein the insulin analog is the insulin lispro (Humalog®).

6. The composition as claimed in claim 1 , wherein the substituted anionic compound/insulin mass ratio is between 0.5 and 10.

7. The composition as claimed in claim 1 , wherein the concentration of substituted anionic compound is between 1.8 and 36 mg/mL.

8. A pharmaceutical formulation comprising the composition as claimed in claim 1 .

9. The pharmaceutical formulation as claimed in claim 8 , wherein the insulin concentration is between 240 and 3000 μM (40 to 500 IU/mL).

10. The pharmaceutical formulation as claimed in claim 9 , wherein the insulin concentration is between 600 and 1200 μM (100 and 200 IU/mL).

11. An insulin pharmaceutical formulation comprising insulin, at least one substituted anionic compound having a backbone formed from a discrete number u of between 1 and 8 (1≦u≦8) of identical or different saccharide units, linked via identical or different glycoside bonds, wherein u is the same for all of the at least one substituted anionic compounds, said saccharide units being chosen from the group consisting of hexoses, in cyclic form or in open reduced form, said substituted anionic compound comprising partially substituted carboxyl functional groups, the unsubstituted carboxyl functional groups being salifiable, and a polyanionic compound that is chosen from the group consisting of citric acid and Na + , K + , Ca 2+ or Mg 2+ salts thereof, wherein the insulin pharmaceutical formulation makes it possible, after administration, to accelerate the passage of the insulin into the blood and to reduce the glycemia more rapidly when compared with a formulation free of substituted anionic compound.

12. The insulin pharmaceutical formulation as claimed in claim 11 , wherein the substituted anionic compound is chosen from substituted anionic compounds consisting of a saccharide backbone formed from a discrete number u of between 1 and 8 (1≦u≦8) of identical or different saccharide units, linked via identical or different glycoside bonds, wherein u is the same for all of the at least one substituted anionic compounds, said saccharide units being chosen from hexoses, in cyclic form or in open reduced form, wherein they are substituted with:

a) at least one substituent of general formula I:

—[R 1 ] a -[AA] m   Formula I

the substituents being identical or different when there are at least two substituents, in which:

the radical -[AA] denotes an amino acid residue, said amino acid being chosen from the group consisting of phenylalanine, alpha-methylphenylalanine, 3,4-dihydroxyphenylalanine, tyrosine, alpha-methyltyrosine, O-methyltyrosine, alpha-phenylglycine, 4-hydroxyphenylglycine and 3,5-dihydroxyphenylglycine, and the alkali metal cation salts thereof, said derivatives being in L or D absolute configuration, -[AA]- is attached to the backbone of the molecule via a radical —R 1 — or directly attached to the backbone via a function G,

—R 1 — being:

either a bond G, and then a=0,

or a C2 to C15 carbon-based chain, and then a=1, which is optionally substituted and/or comprising at least one heteroatom chosen from O, N and S and at least one acid function before the reaction with the amino acid, said chain forming with the amino acid residue -[AA] an amide function, and is attached to the backbone by means of a function F resulting from a reaction between a hydroxyl function or a substituent borne by the backbone and a function or a substituent borne by the precursor of the radical —R 1 —,

F is an ether, ester or carbamate function,

G is a carbamate function,

m is equal to 1 or 2,

the degree of substitution, j, with —[R 1 ] a -[AA] m being strictly greater than 0 and less than or equal to 6, 0<j≦6,

b) and, optionally, one or more substituents —R′ 1 ;

the substituent —R′ 1 being a C2 to C15 carbon-based chain, which is optionally substituted and/or comprising at least one heteroatom chosen from O, N and S and at least one acid function in the form of an alkali metal cation salt, said chain being linked to the backbone via a function F′ resulting from a reaction between a hydroxyl function borne by the backbone and a function or substituent borne by the precursor of the substituent —R′ 1 ,

F′ is an ether, ester or carbamate function,

the degree of substitution of the saccharide units, i, with —R′ 1 , being between 0 and 6−j, 0≦i≦6−j, and

—R′ 1 — is identical to or different from —R 1 ,

F, F′ and G are identical or different,

the free salifiable acid functions are in the form of alkali metal cation salts,

said glycoside bonds, which may be identical or different, being chosen from the group consisting of glycoside bonds of (1,1), (1,2), (1,3), (1,4) or (1,6) type, in an alpha or beta geometry,

i+j≦6.

13. A composition comprising insulin in hexameric form, at least one substituted anionic compound and a polyanionic compound, in an aqueous solution:

wherein the insulin in hexameric form is human insulin or an insulin analog;

said substituted anionic compound being chosen from substituted anionic compounds, in isolated form or as a mixture, consisting of a backbone formed from a saccharide unit

 wherein R is selected from the group consisting of H, —[R 1 ] a -[AA] m , and —R′ 1 , wherein substituent —[R 1 ] a -[AA] m is

 and substituent —R′ 1 is

 with a degree of substitution of the saccharide unit, j, with —[R 1 ] a -[AA] m being 0.65 and a degree of substitution of the saccharide unit, i, with —R′ 1 , being 1.0, and

said polyanionic compound is chosen from the group consisting of citric acid and Na + , K + , Ca 2+ or Mg 2+ salts thereof.

14. A composition comprising insulin in hexameric form, at least one substituted anionic compound and a polyanionic compound, in an aqueous solution:

wherein the insulin in hexameric form is human insulin or an insulin analog;

said substituted anionic compound being chosen from substituted anionic compounds, in isolated form or as a mixture, consisting of a backbone formed from a saccharide unit

 wherein R is selected from the group consisting of H, —[R 1 ] a -[AA] m , and —R′ 1 , wherein substituent —[R 1 ] a -[AA] m is

 and substituent —R′ 1 is

 with a degree of substitution of the saccharide unit, j, with —[R 1 ] a -[AA] m being 0.4 and a degree of substitution of the saccharide unit, i, with —R′ 1 , being 1.25, and

said polyanionic compound is chosen from the group consisting of citric acid and Na + , K + , Ca 2+ or Mg 2+ salts thereof.