Anionic polysaccharides functionalized by a hydrophobic acid derivative

Patent metadata

Field	Value
Publication number	US-9493583-B2
Application number	US-97769010-A
Country	US
Kind code	B2
Filing date	Dec 23, 2010
Priority date	Dec 23, 2009
Publication date	Nov 15, 2016
Grant date	Nov 15, 2016

Abstract

A novel anionic polysaccharides functionalized by at least one hydrophobic acid derivative. These novel anionic polysaccharides including hydrophobic groups have good biocompatibility and their hydrophobicity can be easily adjusted without detrimentally affecting the biocompatibility or the stability. A method of synthesis which makes it possible to produce them and to pharmaceutical compositions including them.

First claim

What is claimed is:

1. An anionic polysaccharide comprising saccharide units including carboxyl functions and being monofunctionalized with a hydrophobic function -M-Ach according to Formula I,

in which:
n represents the degree of functionalization of the saccharide units by -M-Ach and is between 0.01 and 0.7;
Ach is a hydrophobic radical composed of a chain comprising between 4 and 50 carbons which is optionally branched and/or unsaturated, which optionally comprises one or more heteroatoms, and which optionally comprises one or more saturated, unsaturated or aromatic rings or heterocycles;
M is either —F 1 —R 1 -G or —F 2 -R 2 -G;
F 1 is an amide function, an ester function or a thioester function;
F 2 is a carbamate function;
R 1 is a divalent radical composed of a chain comprising between 1 and 15 carbons which is optionally branched and/or unsaturated, which optionally comprises one or more heteroatoms, and which optionally comprises one or more saturated, unsaturated or aromatic rings or heterocycles;
R 2 is a divalent radical composed of a chain comprising between 1 and 15 carbons which is optionally branched and/or unsaturated, which optionally comprises one or more heteroatoms, and which optionally comprises one or more saturated, unsaturated or aromatic rings or heterocycles; and
G is an amide function, an ester function or a thioester function, wherein:
said connecting arm R 1 is bonded to the polysaccharide via said bond F 1 resulting from the coupling between a reactive function of a precursor of the connecting arm R 1 ′ and a carboxyl function of the anionic polysaccharide and said hydrophobic radical Ach is bonded to the connecting arm R 1 via said function G resulting from the coupling between an acid function of a hydrophobic acid and a reactive function of the precursor of the connecting arm R 1 ′;
said connecting arm R 2 is bonded to the polysaccharide via said bond F 2 resulting from the coupling between a reactive function of a precursor of the connecting arm R2′ and a hydroxyl function of the anionic polysaccharide and said hydrophobic radical Ach is bonded to the connecting arm R 2 via said function G resulting from the coupling between an acid function of a hydrophobic acid and a reactive function of the precursor of the connecting arm R 2 ′;

the unfunctionalized carboxyl functions of the anionic polysaccharide are in salt form;
Ach results from the coupling between the acid function of the hydrophobic acid and the reactive function of the precursor of the connecting arm R 1 ′ or R 2 ′;
R 1 results from the reaction of the precursor R 1 ′ having at least two identical or different reactive functions selected from the group consisting of alcohol, amine and thiol functions; and
R 2 results from the reaction of the precursor R 2 ′ having at least two reactive functions, one being an amine and the other being selected from the group consisting of alcohol, amine and thiol functions.

2. The anionic polysaccharide as claimed in claim 1 , obtained from a precursor polysaccharide naturally comprising carboxyl functions before functionalization with the hydrophobic function -M-Ach, the precursor polysaccharide being selected from the group consisting of alginate, hyaluronan and galacturonan.

3. The anionic polysaccharide as claimed in claim 1 , obtained from a synthetic precursor polysaccharide of Formula II before functionalization with the hydrophobic function -M-Ach, wherein the synthetic precursor polysaccharide is obtained by converting hydroxyl functions to carboxylates in a polysaccharide naturally comprising hydroxyl and carboxyl functions or a neutral polysaccharide naturally comprising hydroxyl functions, for which the degree of conversion of hydroxyl functions to carboxylates per saccharide unit is equal to or greater than 0.15,

in which:
the polysaccharide is selected from the group consisting of the polysaccharides predominantly composed of monomers bonded via glycoside bonds of (1,6) and/or (1,4) and/or (1,3) and/or (1,2) type;
L is a bond resulting from the coupling between a precursor of the connecting arm Q and an a hydroxyl function of the polysaccharide and is an ester, carbamate or ether function;
i represents the degree of conversion of the hydroxyl functions to L-Q sequences per saccharide unit of the polysaccharide; and
Q is of Formula III:

in which:
1 ≦a +b +c ≦6, 0 ≦a ≦3, 0 ≦b ≦3 and 0 ≦c ≦3; and
R 3 and R 4 , which are identical or different, are selected from the group consisting of —H, linear or branched C 1 to C 3 alkyl groups, —COOH and the radical of Formula IV,

in which:
1≦d≦3; and
R′ 3 and R′ 4 , which are identical or different, are selected from the group consisting of —H and linear or branched C 1 to C 3 alkyl groups.

4. The anionic polysaccharide as claimed in claim 3 , wherein the polysaccharide is predominantly composed of monomers bonded via glycoside bonds of (1,6) type.

5. The anionic polysaccharide as claimed in claim 4 , wherein the polysaccharide predominantly composed of monomers bonded via glycoside bonds of (1,6) type is dextran.

6. The anionic polysaccharide as claimed in claim 3 , wherein the polysaccharide is predominantly composed of monomers bonded via glycoside bonds of (1,4) type.

7. The anionic polysaccharide as claimed in claim 6 , wherein the polysaccharide predominantly composed of monomers bonded via glycoside bonds of (1,4) type is selected from the group consisting of pullulan, alginate, hyaluronan, xylan, galacturonan and a water-soluble cellulose.

8. The anionic polysaccharide as claimed in claim 3 , wherein the polysaccharide is predominantly composed of monomers bonded via glycoside bonds of (1,3) type.

9. The anionic polysaccharide as claimed in claim 8 , wherein the polysaccharide predominantly composed of monomers bonded via glycoside bonds of (1,3) type is a curdlan.

10. The anionic polysaccharide as claimed in claim 3 , wherein the polysaccharide is predominantly composed of monomers bonded via glycoside bonds of (1,2) type.

11. The anionic polysaccharide as claimed in claim 10 , wherein the polysaccharide predominantly composed of monomers bonded via glycoside bonds of (1,2) type is an inulin.

12. The anionic polysaccharide as claimed in claim 3 , wherein the polysaccharide is predominantly composed of monomers bonded via glycoside bonds of (1,4) and (1,3) type.

13. The anionic polysaccharide as claimed in claim 12 , wherein the polysaccharide predominantly composed of monomers bonded via glycoside bonds of (1,4) and (1,3) type is a glucan.

14. The anionic polysaccharide as claimed in claim 3 , wherein the polysaccharide is predominantly composed of monomers bonded via glycoside bonds of (1,4) and (1,3) and (1,2) type.

15. The anionic polysaccharide as claimed in claim 14 , wherein the polysaccharide predominantly composed of monomers bonded via glycoside bonds of (1,4) and (1,3) and (1,2) type is mannan.

16. The anionic polysaccharide as claimed in claim 3 , wherein L-Q is selected from the group consisting of:

Assignees

• Charvet Richard
• Soula Remi
• Soula Olivier
• Adocia

Inventors

• Charvet Richard
• Soula Remi
• Soula Olivier

Classifications

• C08B37/0018

  Pullulan, i.e. (alpha-1,4)(alpha-1,6)-D-glucan; Derivatives thereof · CPC title

• A61K47/36

  Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin · CPC title

• C08B37/0021 Primary

  Dextran, i.e. (alpha-1,4)-D-glucan; Derivatives thereof, e.g. Sephadex, i.e. crosslinked dextran · CPC title

• C08B37/006

  Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof · CPC title

• C08B1/00

  Preparatory treatment of cellulose for making derivatives thereof {, e.g. pre-treatment, pre-soaking, activation} · CPC title