Rapid-acting insulin formulation comprising a substituted anionic compound

Patent metadata

Field	Value
Publication number	US-10583175-B2
Application number	US-201715609670-A
Country	US
Kind code	B2
Filing date	May 31, 2017
Priority date	Nov 13, 2012
Publication date	Mar 10, 2020
Grant date	Mar 10, 2020

Abstract

A composition in aqueous solution includes insulin and at least one substituted anionic compound chosen from substituted anionic compounds 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, the saccharide units being chosen from the group consisting of hexoses, in cyclic form or in open reduced form, said compound comprising partially substituted carboxyl functional groups, the unsubstituted carboxyl functional groups being salifiable. A pharmaceutical formulation including the composition is also set forth.

First claim

The invention claimed is:

1. A composition comprising insulin in hexameric form, at least one substituted anionic compound and a polyanionic compound in an aqueous solution:
wherein,
said substituted anionic compound is 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, in —[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, in —R′ 1 , being between 0 and 6-j, 0≤i≤6−j, and
F, F′ 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 polycarboxylic acids and the Na + , K + , Ca 2+ or Mg 2+ salts thereof, chosen from the group consisting of polyphosphoric acids and the Na + , K + , Ca 2+ or Mg 2+ salts thereof or is a compound consisting of a saccharide backbone formed from a discrete number of saccharide units.

2. The composition as claimed in claim 1 , wherein u is of between 1 and 3 (1≤u≤3).

3. The composition as claimed in claim 1 , wherein -[AA] is 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.

4. The composition as claimed in claim 3 , wherein -[AA] is phenylalanine.

5. The composition as claimed in claim 1 , wherein —R 1 —, before attachment to -[AA], is chosen from the following groups, in which * represents the site of attachment to F:

or the salts thereof with alkali metal cations chosen from the group consisting of Na + and K + .

6. The composition as claimed in claim 1 , wherein —R′ 1 is chosen from the following groups, in which * represents the site of attachment to F′:

or the salts thereof with alkali metal cations chosen from the group consisting of Na + and K + .

7. The composition as claimed in claim 1 , wherein the substituted anionic compound is represented by

wherein R is H, R′ 1 or R 1 -[AA],
wherein —R′ 1 represents

wherein the degree of substitution of the saccharide units, j, with —R 1 -[AA] is between 0.3 and 1.8 and
wherein the degree of substitution of the saccharide units, i, with —R′ 1 is between 0.3 and 3.

8. The composition as claimed in claim 1 , wherein the polycarboxylic acid is chosen from the group consisting of citric acid and tartaric acid, and the Na + , K + , Ca 2+ or Mg 2+ salts thereof.

9. The composition as claimed in claim 1 , wherein the polyphosphoric acid is triphosphate and the Na + , K + , Ca 2+ or Mg 2+ salts thereof.

10. The composition as claimed in claim 1 , wherein the polyanionic compound is a compound consisting of a saccharide backbone formed from a discrete number of saccharide units obtained from a disaccharide compound chosen from the group consisting of trehalose, maltose, lactose, sucrose, cellobiose, isomaltose, maltitol and isomaltitol.

11. The composition as claimed in claim 1 , wherein the polyanionic compound is chosen from the group consisting of compounds consisting of a backbone formed from a discrete number u of between 1 and 3 (1≤u≤3) of identical or different saccharide units, linked via identical or different glycoside bonds naturally bearing carboxyl groups or substituted with carboxyl groups.

12. The composition as claimed in claim 1 , wherein the polyanionic compound is chosen from the group consisting of compounds consisting of a backbone formed from a discrete number of saccharide units obtained from a compound consisting of a backbone formed from a discrete number of saccharide units chosen from the group consisting of maltotriose, maltotetraose, maltopentaose, maltohexaose, maltoheptaose, maltooctaose and isomaltotriose.

13. The composition as claimed in claim 12 , wherein the polyanionic compound is chosen from the group consisting of compounds consisting of a backbone formed from a discrete number of saccharide units chosen from the group consisting of carboxymethylmaltotriose, carboxymethylmaltotetraose, carboxymethylmaltopentaose, carboxymethylmaltohexaose, carboxymethylmaltoheptaose, carboxymethylmaltooctaose and carboxymethylisomaltotriose.

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

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

16. The composition as claimed in claim 15 , 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®).

17. The composition as claimed in claim 16 , wherein the insulin analog is the insulin lispro (Humalog®).

18. The composition as claimed in claim 1 , wherei

Assignees

• Adocia

Inventors

• Soula Olivier
• Soula Gerard
• Dauty Emmanuel
• Charvet Richard

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61K47/30

  Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates · CPC title

• A61K47/183

  Amino acids, e.g. glycine, EDTA or aspartame · CPC title

• C07H15/18

  Acyclic radicals, substituted by carbocyclic rings · CPC title

• A61K47/12

  Carboxylic acids; Salts or anhydrides thereof · CPC title