RU2575460C2 - Anionic polysaccharides, functionalised by at least two hydrophobic groups, bound with at least trivalent intermediate grouping - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of anionic polysaccharides, partly functionalised by at least two vicinal hydrophobic groups, with said hydrophobic groups, being similar or different, being connected with at least trivalent radical or intermediate grouping. Invention also relates to methods for their synthesis.

EFFECT: invention relates to application of polysaccharides, functionalised in accordance with claimed invention, for stabilisation of protein active substances, where active substance is selected from the group, including proteins, glycoproteins, peptides and non-peptide therapeutic compounds.

21 cl,15 ex

Description

 [0001] The present invention relates to new biocompatible polymers based on anionic polysaccharides functionalized with at least two hydrophobic groups associated with at least a trivalent intermediate group, which may be acceptable preferably for the introduction of one or more active substances (PA) to a person or animals for therapeutic and / or prophylactic purposes.

[0002] Anionic polysaccharides functionalized with at least two vicinal hydrophobic groups are of particular interest in pharmaceuticals and more preferably in the field of stabilization of protein active substances due to the formation of complexes due to their structure and biological compatibility.

[0003] Among the natural components of cell membranes are known, in particular, molecular compounds, such as phospholipids and triglycerides, which are associated with at least two vicinal hydrophobic chains, that is, associated with the same group. These compounds are very important, in particular, for the stabilization of transmembrane proteins. However, they are compounds with low molecular weight and strong hydrophobicity, which are solubilized only in complex structures such as vesicles.

[0004] The merit of the applicant is the synthesis of biocompatible polysaccharides functionalized with radicals linked to two vicinal hydrophobic chains. These polymeric compounds, the hydrophobicity of which can be controlled, are of particular interest in the composition of pharmaceutically active substances.

[0005] The present invention relates to new anionic polysaccharides functionalized with at least two vicinal hydrophobic groups, said hydrophobic groups being the same or different, linked to at least a trivalent radical or an intermediate moiety. In one embodiment, the carboxyl groups of the polysaccharide are partially replaced by at least two hydrophobic radicals, said hydrophobic radicals being the same or different, being bound to at least a trivalent radical or an intermediate moiety. In one embodiment, the hydroxyl groups of the polysaccharides are partially replaced by at least two hydrophobic radicals, said hydrophobic radicals being the same or different, being bound to at least a trivalent radical or an intermediate moiety. These new anionic polysaccharides containing hydrophobic groups have good biocompatibility, and their hydrophobicity is easily regulated without compromising biocompatibility and stability.

[0006] The invention also relates to methods for their synthesis.

[0007] In one embodiment, the polysaccharide is selected from polysaccharides containing carboxyl groups, said polysaccharides being selected from both natural polysaccharides containing carboxyl groups and synthetic polysaccharides obtained from natural polysaccharides containing carboxyl groups or from neutral polysaccharides whose hydroxyl groups have been converted to carboxyl groups, and from polysaccharides in which at least one of the carboxyl groups or at least the bottom of the hydroxyl groups substituted by at least two hydrophobic radicals denoted -Hy, being identical or different:

• wherein the hydrophobic radicals (-Hy) are connected or linked to the anionic polysaccharide via the R link arm, the R link arm carries at least three reactive functional groups and is connected to the polysaccharide by the F link formed by combining the reactive functional group of the shoulder precursor the bonds of R 'with the carboxyl or hydroxyl group of the anionic polysaccharide, and the hydrophobic radicals (-Hy) are connected to the R bond arm through at least one functional group G formed by the combination of The ability of the functional group of the hydrophobic compound (Hy ') with a reactive functional group precursor communication shoulder R';

• wherein the non-functionalized carboxyl groups of the anionic polysaccharide are in the form of carboxylates of cations, preferably alkali metal cations, such as Na ⁺ or K ⁺ ,

• wherein F is an amido group, an ester group or a carbamate group;

• wherein G is an amido group, an ester group or a carbamate group;

• wherein Hy means a radical formed by combining the reactive functional group of the hydrophobic compound (Hy ') with the reactive functional group of the shoulder precursor R', which is a chain containing from 4 to 50 carbon atoms, which is optionally branched and / or unsaturated, optionally containing one or more heteroatoms such as O, N and / or S, optionally containing one or more saturated, unsaturated or aromatic rings or heterocycles;

• wherein R is a trivalent radical, which is a chain containing from 1 to 15 carbon atoms, optionally branched and / or unsaturated, containing, if necessary, one or more heteroatoms, such as O, N and / or S, optionally containing one or several saturated, unsaturated or aromatic rings or heterocycles, and formed by the reaction of the precursor R 'having at least three reactive functional groups that are the same or different and selected from the group consisting of an alcohol group, an acid group and an amino group.

[0008] Thus, the present invention relates to anionic polysaccharides of the formula I selected from polysaccharides containing carboxyl groups, said polysaccharides being selected both from natural polysaccharides containing carboxyl groups and from synthetic polysaccharides derived from natural polysaccharides containing carboxyl groups, or starting from neutral polysaccharides whose hydroxyl groups have been converted to carboxyl groups, and from polysaccharides in which at least one of of the hydroxyl groups is substituted by at least two hydrophobic radicals denoted by -Hy _h , or at least one of the carboxyl groups is substituted by at least two hydrophobic radicals denoted by -Hy _c , which are the same or different:

Formula I

Where:

• n _c and n _h mean the degree of functionalization of the polysaccharide saccharide units with the chains —F _c —R _c - [G _c -Hy _c ] _rc and / or -F _h -R _h - [G _h -Hy _h ] _rh , with n _h ≥0 and n _c ≥0 s 0.01 ≤n _h + n _c ≤0.5;

• F _c means an amido group or an ester group;

• F _h means a carbamate group;

• non-functionalized carboxyl groups of the anionic polysaccharide are in the form of carboxylates of cations, preferably alkali metal cations, such as Na ⁺ or K ⁺ ;

• G _h or G _c means an amide group or an ester group, or a carbamate group formed by combining a reactive functional group of a hydrophobic compound (Hy _h 'or Hy _c ') with a reactive functional group of the link arm precursor R _h 'or R _c ';

• Hy _h or Hy _c means radicals that are the same or different, formed when the reactive functional group of the hydrophobic compound (Hy _h 'or Hy _c ') is combined with the reactive functional group of the link arm precursor R _h 'or R _c ', moreover, Hy _h or Hy _c is a chain containing from 4 to 50 carbon atoms, which is optionally branched and / or unsaturated, optionally containing one or more heteroatoms, such as O, N and / or S, optionally containing one or several of us saturated, unsaturated or aromatic cycles or heterocycles;

• R _c means a trivalent radical, which is a chain containing from 1 to 15 carbon atoms, which is optionally branched and / or unsaturated, optionally containing one or more heteroatoms, such as O, N and / or S, optionally containing one or more saturated, unsaturated or aromatic rings or heterocycles, and the precursor formed during the reaction, R _c ', having at least three reactive functional groups, which may be identical or different and are selected from g uppy, which includes an alcohol group, an acid group and an amino group;

• R _h means a trivalent radical, which is a chain containing from 1 to 15 carbon atoms, which is optionally branched and / or unsaturated, optionally containing one or more heteroatoms, such as O, N and / or S, optionally containing one or several saturated, unsaturated or aromatic rings or heterocycles, and formed by the reaction of the precursor R _h 'having at least three reactive functional groups, one of which is an amino group, and the other these groups are selected from the group consisting of an alcohol group, an acid group and an amino group;

• r _h is an integer representing the number of hydrophobic groups attached to at least the trivalent bond arm R _h , with 2≤r _h ≤4;

• r _c is an integer representing the number of hydrophobic groups attached to at least the trivalent bond arm R _c , with 2≤r _c ≤4.

[0009] In one embodiment, the implementation of the sum n _h + n _c is in the range from 0.02 to 0.4.

[00010] In one embodiment, the implementation of the sum of n _h + n _c is in the range from 0.03 to 0.3.

[00011] In one embodiment, the polysaccharide of the present invention is selected from the group of polysaccharides of formula II:

Formula II

Where:

- n _c means the degree of functionalization of the carboxyl groups of the polysaccharide by the chains -F _c -R _c - [G _c -Hy _c ] _rc and is in the range from 0.01 to 0.5;

- F _c , R _c , G _c , Hy _c and r _c correspond to the definitions given below;

- in the case where the carboxyl groups of the polysaccharide are not functionalized by the chains —F _c —R _c - [G _c -Hy _c ] _rc , one or more carboxyl groups of the polysaccharide are carboxylates of cations, preferably alkali metal cations, such as Na ⁺ or K ⁺ ;

- in the case when the unfunctionalized reactive functional group of the link arm R _c is an acid group, it is also in the form of a salt, in the form of a carboxylate of a cation, preferably an alkali metal cation, such as Na ⁺ or K ⁺ , and in the case when the unfunctionalized reactive functional group of the link arm R _c represents an amino group, it is in the form of a salt with an anion, and preferably with a halide ion.

[00012] In one embodiment, the polysaccharide of the present invention is selected from the group of polysaccharides of formula III:

Formula III

Where:

- n _c , F _c and R _c correspond to the following definitions;

- G _c1 and G _c2 , which are the same or different, correspond to the definition of G _c ;

- Hy _c1 and Hy _c2 , which are the same or different, correspond to the definition of Hy _c .

[00013] In one embodiment, the polysaccharide of the present invention is selected from the group of polysaccharides of formula IV:

Formula IV

Where:

- n _c , F _c and R _c correspond to the following definitions;

- G _c1 , G _c2 and G _c3 , which are the same or different, correspond to the definition of G _c ;

- Hy _c1 , Hy _c2 and Hy _c3 , which are the same or different, correspond to the definition of Hy _c .

[00014] In one embodiment, the polysaccharide of the present invention is selected from the group of polysaccharides of formula V:

Formula V

Where:

- n _h means the degree of functionalization of the hydroxyl groups of the polysaccharide with chains of -F _h -R _h - [G _h -Hy _h ] _rh and is in the range from 0.01 to 0.5;

- F _h , R _h , G _h , Hy _h and r _h correspond to the following definitions;

- the carboxyl groups of the polysaccharide are in the form of carboxylates of cations, preferably alkali metal cations, such as Na ⁺ or K ⁺ ;

- in the case when the unfunctionalized reactive functional group of the link arm R _h is an acid group, it is also in the form of a salt, in the form of a carboxylate of a cation, preferably an alkali metal cation, such as Na ⁺ or K ⁺ , and in the case when the unfunctionalized reactive functional group of the link arm R _h represents an amino group, it is in the form of a salt with an anion, and preferably with a halide ion.

[00015] In one embodiment, the polysaccharide of the present invention is selected from the group of polysaccharides of formula VI:

Formula VI

Where:

- n _h , F _h and R _h correspond to the following definitions;

- G _h1 and G _h2 , which are the same or different, correspond to the definition of G _h ;

- Hy _h1 and Hy _h2 , which are the same or different, correspond to the definition of Hy _h .

[00016] In one embodiment, the polysaccharide of the present invention is selected from the group of polysaccharides of formula VII:

Formula VII

Where:

- n _h , F _h and R _h correspond to the following definitions;

- G _h1 , G _h2 and G _h3 , which are the same or different, correspond to the definition of G _h ;

- Hy _h1 , Hy _h2 and Hy _h3 , which are the same or different, correspond to the definition of Hy _h .

[00017] By groups or derivatives or radicals, in particular, by Hy, R, Q groups, are meant mono- or multivalent chains formed during reactions between precursors or between precursors and polysaccharides.

[00018] Precursors, such as Hy ', R' and Q ', are certain compounds, which may be, for example, alcohols, amines, hydrophobic acids or amino acids, and may react to produce mono or multivalent groups or derivatives, or radicals Hy, R, and Q, as defined below.

[00019] By anionic polysaccharide is meant a polysaccharide containing carboxyl groups which are non-functionalized and can be converted to salt form.

[00020] The degree of functionalization is understood to mean the number of -F _c -R _c - [G _c -Hy _c ] _rc and / or -F _h -R _h - [G _h -Hy _h ] _rh groups per saccharide unit, or, in other words, the total number of -F _c -R _c - [G _c -Hy _c ] _rc and / or -F _h -R _h - [G _h -Hy _h ] _rh groups, referred to the total number of saccharide units. This indicator can also be expressed by the molar fraction of the hydroxyl or carboxyl groups of the polysaccharide functionalized by the chains —F _c —R _c - [G _c -Hy _c ] _rc and / or -F _h -R _h - [G _h -Hy _h ] _rh .

[00021] By the degree of conversion is meant the number of hydroxyl groups converted to carboxyl groups per saccharide unit, or, in other words, the total number of hydroxyl groups converted to carboxyl groups, related to the total number of saccharide units. This indicator can also be expressed in molar fraction. For example, polysaccharides in which the conversion of hydroxyl groups to carboxyl groups per saccharide unit is equal to or greater than 0.15, are polysaccharides in which at least 15 carboxyl groups per 100 saccharide units are linked.

[00022] By degree of polymerization m is meant the average number of repeating units (monomers) in a polymer chain. It is calculated by dividing the number average molecular weight by the average mass of the repeating unit.

[00023] By number average molecular weight (M _n ) is meant the arithmetic average of the masses of each of the polymer chains. Thus, for the number n _{i of} chains i with a molecular mass M _i , M _n = (Σ _i n _i M _i ) / (Σ _i n _i ) is obtained.

[00024] The weight average molecular weight (M _w ) is obtained by the formula M _w = (Σ _i n _i M _i ² ) / (Σ _i n _i M _i ), where n _i is the number of polymer chains i with a molecular weight M _i .

[00025] The polymers can also be characterized by the distribution of chain lengths, also called the polydispersity index (Ip), equal to M _w divided by M _n .

[00026] In one embodiment, the polysaccharides containing carboxyl groups are naturally occurring polysaccharides containing carboxyl groups and are selected from the group consisting of alginate, hyaluronan, and galacturonan.

[00027] In one embodiment, the polysaccharides containing carboxyl groups are synthetic polysaccharides of the general formula VIII, derived from naturally occurring polysaccharides containing carboxyl groups, or from neutral polysaccharides in which the degree of conversion of hydroxyl groups to carboxyl groups occurs in on a saccharide unit equal to or greater than 0.15:

Formula VIII

Where:

- natural polysaccharides are selected from the group of polysaccharides formed for the most part by monomers linked by glycosidic bonds of the type (1,6) and / or (1,4), and / or (1,3), and / or (1,2);

- L means a bond formed by combining a Q-link arm precursor with a —OH group of a polysaccharide and representing an ester group, a carbamate group or an ether group;

- i denotes the degree of conversion of hydroxyl groups in the L-Q chain attributable to the saccharide unit of the polysaccharide;

- Q is selected from radicals of the general formula IX:

Formula IX

Where:

1≤a + b + c≤6, 0≤a≤3, 0≤b≤3 and 0≤c≤3;

R ₃ and R ₄ , which are the same or different, are selected from the group consisting of —H, linear or branched alkyl C1-C3, —COOH and a radical of general formula X:

Formula X

Where:

1≤d≤3; and

R ′ ₃ and R ′ ₄ , which are the same or different, are selected from the group consisting of —H and linear or branched C1-C3 alkyl.

[00028] In one embodiment, a + b + c≤5.

[00029] In one embodiment, a + b + c≤4.

[00030] In one embodiment, i is in the range from 0.1 to 3.

[00031] In one embodiment, i is in the range of 0.2 to 2.5.

[00032] In one embodiment, i is in the range of 0.5 to 1.7.

[00033] In one embodiment, i is in the range of 0.8 to 1.2.

[00034] In one embodiment, the polysaccharide is formed predominantly by monomers linked by glycosidic bonds of type (1,6).

[00035] In one embodiment, the polysaccharide formed for the most part by monomers linked by glycosidic bonds of type (1,6) is dextran.

[00036] In one embodiment, the polysaccharide is formed predominantly by monomers linked by glycosidic bonds of type (1,4).

[00037] In one embodiment, the polysaccharide formed for the most part by monomers linked by glycosidic bonds of type (1,4) is selected from the group consisting of pullulan, alginate, hyaluronan, xylan, galacturonan or water soluble cellulose.

[00038] In one embodiment, the polysaccharide is pullulan.

[00039] In one embodiment, the polysaccharide is alginate.

[00040] In one embodiment, the polysaccharide is hyaluronan.

[00041] In one embodiment, the polysaccharide is xylan.

[00042] In one embodiment, the polysaccharide is galacturonan.

[00043] In one embodiment, the polysaccharide is a water soluble cellulose.

[00044] In one embodiment, the polysaccharide is formed predominantly by monomers linked by glycosidic bonds of type (1,3).

[00045] In one embodiment, the polysaccharide formed for the most part by monomers linked by glycosidic bonds of type (1,3) is Kurdlan.

[00046] In one embodiment, the polysaccharide is formed predominantly by monomers linked by glycosidic bonds of type (1,2).

[00047] In one embodiment, the polysaccharide formed for the most part by monomers linked by glycosidic bonds of type (1,2) is inulin.

[00048] In one embodiment, the polysaccharide is formed predominantly by monomers linked by glycosidic bonds of types (1,4) and (1,3).

[00049] In one embodiment, the polysaccharide formed for the most part by monomers linked by glycosidic bonds of types (1,4) and (1,3) is glucan.

[00050] In one embodiment, the polysaccharide is formed predominantly by monomers linked by glycosidic bonds of types (1,4), (1,3) and (1,2).

[00051] In one embodiment, the polysaccharide formed for the most part by monomers linked by glycosidic bonds of types (1,4), (1,3) and (1,2) is mannan.

[00052] In one embodiment, the polysaccharide of the present invention is characterized in that the L-Q chain is selected from the group consisting of the following chains, wherein L has the meaning defined below:

[00053] In one embodiment, the polysaccharide of the present invention is characterized in that the L-Q chain is selected from the group consisting of the following chains, wherein L has the meaning defined below:

[00054] In one embodiment, the polysaccharide of the present invention is characterized in that the L-Q chain is selected from the group consisting of the following chains, wherein L has the meaning defined below:

[00055] In one embodiment, the polysaccharide of the present invention is characterized in that the L-Q chain is the following chain, with L having the meaning defined below:

[00056] In one embodiment, the polysaccharide of the present invention is characterized in that the L-Q chain is the following chain, with L having the meaning defined below:

[00057] In one embodiment, the polysaccharides are selected from polysaccharides of the formulas II, III, or IV, in which —Hy _c is a radical derived from a hydrophobic alcohol formed when a hydroxyl group of a hydrophobic alcohol is combined with at least one reactive functional group, associated with the precursor R _c 'of at least the trivalent radical R _c , and:

- G _c means an ester group or a carbamate group;

- R _c and F _c correspond to the definitions below.

[00058] In one embodiment, the polysaccharides are selected from polysaccharides of the formulas V, VI, or VII, in which —Hy _h is a radical derived from a hydrophobic alcohol resulting from the combination of a hydroxyl group of a hydrophobic alcohol with at least one reactive functional group, bound to the precursor R _h ′ of at least the trivalent radical R _h , and:

- G _h means an ester group or a carbamate group;

- R _h and F _h correspond to the following definitions.

[00059] In one embodiment, the hydrophobic alcohol is selected from fatty alcohols.

[00060] In one embodiment, the hydrophobic alcohol is selected from alcohols formed by unsaturated or saturated, branched or unbranched alkyl chains containing from 4 to 18 carbon atoms.

[00061] In one embodiment, the hydrophobic alcohol is selected from alcohols formed by unsaturated or saturated, branched or unbranched alkyl chains containing more than 18 carbon atoms.

[00062] In one embodiment, the hydrophobic alcohol is octanol.

[00063] In one embodiment, the hydrophobic alcohol is dodecanol.

[00064] In one embodiment, the hydrophobic alcohol is 2-ethylbutanol.

[00065] In one embodiment, the hydrophobic alcohol is selected from myristyl, cetyl, stearyl, cetearyl, butyl, oleyl, lanolin.

[00066] In one embodiment, the hydrophobic alcohol is selected from cholesterol derivatives.

[00067] In one embodiment, the cholesterol derivative is cholesterol.

[00068] In one embodiment, the hydrophobic alcohol is selected from menthol derivatives.

[00069] In one embodiment, the hydrophobic alcohol is menthol in the form of a racemate.

[00070] In one embodiment, the hydrophobic alcohol is a menthol D isomer.

[00071] In one embodiment, the hydrophobic alcohol is the menthol L-isomer.

[00072] In one embodiment, the hydrophobic alcohol is selected from tocopherols.

[00073] In one embodiment, the tocopherol is alpha tocopherol.

[00074] In one embodiment, the alpha tocopherol is an alpha tocopherol racemate.

[00075] In one embodiment, the tocopherol is the D-isomer of alpha-tocopherol.

[00076] In one embodiment, the tocopherol is the L-isomer of alpha-tocopherol.

[00077] In one embodiment, the hydrophobic alcohol is selected from alcohols containing aryl groups.

[00078] In one embodiment, the alcohol containing an aryl group is selected from benzyl alcohol, phenylethyl alcohol.

[00079] In one embodiment, the hydrophobic alcohol is selected from unsaturated fatty alcohols.

[00080] In one embodiment, the unsaturated fatty alcohols are selected from the group consisting of geraniol, β-citronellol and farnesol.

[00081] In one embodiment, the hydrophobic alcohol is 3,7-dimethyl-1-octanol.

[00082] In one embodiment, the polysaccharides are selected from polysaccharides of the formulas II, III, or IV, wherein —Hy _c is a hydrophobic acid-derived radical formed by combining a carboxy group of a hydrophobic acid with at least one reactive functional group linked to with a precursor R _c 'of at least a trivalent radical R _c , and:

- G _c means an ester group or an amido group;

- R _c and F _c correspond to the definitions below.

[00083] In one embodiment, the polysaccharides are selected from polysaccharides of formulas V, VI, or VII, in which —Hy _h is a hydrophobic acid-derived radical formed by combining a carboxyl group of a hydrophobic acid with at least one reactive functional group, bound to the precursor R _h ′ of at least the trivalent radical R _h , and:

- G _h means an ester group or an amido group;

- R _h and F _h correspond to the following definitions.

[00084] In one embodiment, the hydrophobic acid is selected from fatty acids.

[00085] In one embodiment, the implementation of the fatty acids is selected from the group consisting of acids formed by unsaturated or saturated, branched or unbranched alkyl chains containing from 6 to 50 carbon atoms.

[00086] In one embodiment, the fatty acids are selected from the group consisting of linear fatty acids.

[00087] In one embodiment, the linear fatty acids are selected from the group consisting of caproic, enanthic, caprylic, capric, nonanoic, decanoic, undecanoic, dodecanoic, palmitic, stearic, arachidic, behenic, tricosanic, lignocacosanoic, heptane melissilic acid.

[00088] In one embodiment, the fatty acids are selected from the group consisting of unsaturated fatty acids.

[00089] In one embodiment, the unsaturated fatty acids are selected from the group consisting of myristoleic, palmitoleic, oleic, elaidic, linoleic, alpha-linoleic, arachidonic, eicosapentaenoic, erucic and docosahexaenoic acids.

[00090] In one embodiment, the fatty acids are selected from the group consisting of bile acids and their derivatives.

[00091] In one embodiment, the bile acids and their derivatives are selected from the group consisting of cholic, dehydrocholic, deoxycholic and chenodeoxycholic acids.

[00092] In one embodiment, fatty acids are selected from acids containing aryl groups.

[00093] In one embodiment, the implementation of the fatty acid containing an aryl group is phenylacetic acid.

[00094] In one embodiment, the polysaccharides are selected from polysaccharides of the formulas II, III, or IV, wherein —Hy _c is a radical derived from a hydrophobic amine formed by combining the amino group of a hydrophobic amine with at least one reactive functional group linked to with a precursor R _c 'of at least a trivalent radical R _c , and:

- G _c means an amide or carbamate group;

- R _c and F _c correspond to the definitions below.

[00095] In one embodiment, the polysaccharides are selected from polysaccharides of the formulas V, VI, or VII, in which —Hy _h is a radical derived from a hydrophobic amine formed by combining the amino group of a hydrophobic amine with at least one reactive functional group linked to with a precursor R _h ′ of at least a trivalent radical R _h , and:

- G _h means an amide or carbamate group;

- R _h and F _h correspond to the following definitions.

[00096] In one embodiment, the hydrophobic amine is selected from fatty amines.

[00097] In one embodiment, the hydrophobic amine is selected from amines formed by unsaturated or saturated, branched or linear alkyl chains containing from 6 to 18 carbon atoms.

[00098] In one embodiment, the fatty amine is dodecylamine.

[00099] In one embodiment, the fatty amine is selected from myristyl, cetyl, stearyl, cetearyl, butyl, oleyl.

[000100] In one embodiment, the hydrophobic amine is selected from amines containing aryl groups.

[000101] In one embodiment, an amine containing an aryl group is selected from benzylamine, phenylethylamine.

[000102] The precursors described below are classified depending on the type of their reactive functional groups, the number of which is at least three, but some of the precursors described below may contain four reactive functional groups or more.

[000103] In one embodiment, the at least trivalent precursors R _c 'and R _h ' are selected from amino acids containing two acid groups.

[000104] Amino acids containing two acid groups are selected from the group consisting of aspartic, glutamic, methylaspartic, gamma-carboxyglutamic, 2-aminopimelic, 2-aminoadipic and O-succinyl homoserine.

[000105] In one embodiment, the at least trivalent precursors R _c 'and R _h ' are aspartic acids.

[000106] In one embodiment, the at least trivalent precursors R _c 'and R _h ' are selected from amino acids containing two amino groups.

[000107] Amino acids containing two amino groups are selected from the group consisting of lysine, 5-hydroxylisine, 2,4-diaminobutyric acid, 2,3-diaminopropionic acid, ornithine and p-aminophenylalanine.

[000108] In one embodiment, the at least trivalent precursors R _c 'and R _h ' are lysines.

[000109] In one embodiment, the at least trivalent precursors R _c 'and R _h ' are selected from amino acids containing alcohol groups.

[000110] Amino acids containing alcohol groups are selected from the group consisting of serine, threonine, tyrosine, homoserine and alpha-methylserine.

[000111] In one embodiment, the at least trivalent precursors R _c 'and R _h ' are serines.

[000112] In one embodiment, the at least trivalent precursors R _c 'and R _h ' are selected from alkanolamines.

[000113] Alkanolamines are selected from the group consisting of tromethamine (Tris), 3-amino-1,2-propanediol, triethanolamine, hydroxymethyl tyrosine, tyrosinol, serine (2-amino-1,2-propanediol) and threoninol.

[000114] In one embodiment, the at least trivalent precursors R _c 'and R _h ' are tromethamines or 3-amino-1,2-propanediols.

[000115] In one embodiment, the at least trivalent precursor R _c 'is selected from dibasic hydroxy acids.

[000116] In one embodiment, the dibasic hydroxy acids are selected from the group consisting of 3-hydroxy-3-methylglutaric, malic, and N- (2-hydroxyethyl) iminodiacetic acids.

[000117] In one embodiment, the at least trivalent precursor R _c 'is selected from dihydric hydroxy acids.

[000118] In one embodiment, the dihydric hydroxy acids are selected from the group consisting of bicin, 2,2-bis- (hydroxymethyl) propionic, 2,4-dihydroxycinnamic, 3,4-dihydroxyhydrocinnamic and 4,4-bis- (4 -hydroxyphenyl) valerianic acid.

[000119] In one embodiment, the at least trivalent precursors R _c 'and R _h ' are selected from triamines.

[000120] In one embodiment, the triamines are selected from the group consisting of 2- (aminomethyl) -2-methyl-1,3-propanediamine and tris- (2-aminoethyl) amine.

[000121] In one embodiment, the triamines are prepared by the interaction between a dibasic amino acid and two diamines, resulting in a triamine containing two amido groups.

[000122] The dibasic amino acids are selected from the group consisting of aspartic, glutamic, methylaspartic, gamma-carboxyglutamic, 2-aminopimelic, 2-aminoadipic acids and O-succinyl homoserine.

[000123] In one embodiment, the dibasic amino acid is aspartic acid.

[000124] In one embodiment, the diamines are selected from the group consisting of ethylenediamine and decarboxylated lysine and its derivatives.

[000125] In one embodiment, the diamines are selected from the group consisting of diethylene glycol diamine and triethylene glycol diamine.

[000126] In one embodiment, the triamine is di (2-aminoethyl) aspartamide.

[000127] In one embodiment, the at least trivalent precursor R _c 'is selected from tribasic hydroxy acids.

[000128] In one embodiment, the tribasic hydroxy acids are selected from the group consisting of citric acid.

[000129] In one embodiment, the at least trivalent precursor R _c ′ is selected from trihydric alcohols.

[000130] In one embodiment, the trihydric alcohols are selected from the group consisting of 2-hydroxymethyl-1,3-propanediol, phloroglucin, and 1,1,1-tris- (hydroxymethylpropane).

[000131] In one embodiment, the at least trivalent precursor R _c 'is selected from triatomic hydroxy acids.

[000132] In one embodiment, the triatomic hydroxy acids are selected from the group consisting of silt acid.

[000133] In one embodiment, the at least trivalent precursor R _c 'is selected from polyols.

[000134] In one embodiment, the polyols are selected from the group consisting of glycerin, diglycerol, triglycerol, pentaerythritol, and alpha, alpha'-diglycerol.

[000135] In one embodiment, the polysaccharides of the present invention contain two groups —Hy _c1 and —Hy _c2 or —Hy _h1 and —Hy _h2 , which are the same or different but have the same reactive functional groups, with the bonds G _c1 and G _c2 or G _h1 and G _h2 are the same.

[000136] By way of example, the combinations given below are implemented.

[000137] In one embodiment, F _c is an ester group, G _c1 and G _{c2 are} ester groups, R _c 'is a dibasic hydroxy acid, and Hy _c1 and Hy _c2 are groups derived from a hydrophobic alcohol.

[000138] In one embodiment, F _c is an ester group, G _c1 and G _{c2 are} ester groups, R _c 'is a trihydric alcohol, and Hy _c1 and Hy _c2 are hydrophobic acid derived groups.

[000139] In one embodiment, F _c is an ester group, G _c1 and G _{c2 are} amido groups, R _c 'is alkanol diamine, and Hy _c1 and Hy _c2 are groups derived from hydrophobic acid.

[000140] In one embodiment, F _c is an ester group, G _c1 and G _{c2 are} carbamate groups, R _c 'is alkanol diamine, and Hy _c1 and Hy _c2 are groups derived from a hydrophobic alcohol.

[000141] In one embodiment, F _c is an ester group, G _c1 and G _{c2 are} amido groups, R _c 'is a dibasic hydroxy acid, and Hy _c1 and Hy _c2 are groups derived from a hydrophobic amine.

[000142] In one embodiment, F _c is an ester group, G _c1 and G _{c2 are} carbamate groups, R _c 'is a trihydric alcohol, and Hy _c1 and Hy _c2 are groups derived from a hydrophobic amine.

[000143] In one embodiment, F _c is an amido group, G _c1 and G _{c2 are} ester groups, R _c 'is a dibasic amino acid, and Hy _c1 and Hy _c2 are groups derived from a hydrophobic alcohol.

[000144] In one embodiment, F _c is an amido group, G _c1 and G _{c2 are} ester groups, R _c 'is dialkanolamine, and Hy _c1 and Hy _c2 are hydrophobic acid derived groups.

[000145] In one embodiment, F _c is an amido group, G _c1 and G _{c2 are} amido groups, R _c 'is triamine, and Hy _c1 and Hy _c2 are groups derived from hydrophobic acid.

[000146] In one embodiment, F _c is an amido group, G _c1 and G _{c2 are} amido groups, R _c 'is a dibasic amino acid, and Hy _c1 and Hy _c2 are groups derived from a hydrophobic amine.

[000147] In one embodiment, F _c is an amido group, G _c1 and G _{c2 are} carbamate groups, R _c 'is dialkanolamine, and Hy _c1 and Hy _c2 are groups derived from a hydrophobic amine.

[000148] In one embodiment, F _c is an amido group, G _c1 and G _{c2 are} carbamate groups, R _c 'is triamine, and Hy _c1 and Hy _c2 are groups derived from a hydrophobic alcohol.

[000149] In one embodiment, F _h is a carbamate group, G _h1 and G _{h2 are} ester groups, R _h 'is a dibasic amino acid, and Hy _h1 and Hy _h2 are groups derived from a hydrophobic alcohol.

[000150] In one embodiment, F _h is a carbamate group, G _h1 and G _{h2 are} ester groups, R _h 'is dialkanolamine, and Hy _h1 and Hy _h2 are groups derived from hydrophobic acid.

[000151] In one embodiment, F _h is a carbamate group, G _h1 and G _{h2 are} amido groups, R _h 'is triamine, and Hy _h1 and Hy _h2 are groups derived from a hydrophobic acid.

[000152] In one embodiment, F _h is a carbamate group, G _h1 and G _{h2 are} carbamate groups, R _h 'is triamine, and Hy _h1 and Hy _h2 are groups derived from a hydrophobic alcohol.

[000153] In one embodiment, F _h is a carbamate group, G _h1 and G _{h2 are} amido groups, R _h 'is a dibasic amino acid, and Hy _h1 and Hy _h2 are groups derived from a hydrophobic amine.

[000154] In one embodiment, F _h is a carbamate group, G _h1 and G _{h2 are} carbamate groups, R _h 'is dialkanolamine, and Hy _h1 and Hy _h2 are groups derived from a hydrophobic amine.

[000155] In one embodiment, the polysaccharides of the present invention contain two groups —Hy _c1 and —Hy _c2 or —Hy _h1 and —Hy _h2 , which are different, wherein the bonds G _c1 and G _c2 or G _h1 and G _h2 are the same .

[000156] By way of example, the combinations given below are implemented.

[000157] In one embodiment, F _c is an ester group, G _c1 and G _{c2 are} ester groups, R _c 'is a dihydric hydroxy acid, Hy _c1 is a radical derived from a hydrophobic alcohol, and Hy _c2 is a radical derived from hydrophobic acid.

[000158] In one embodiment, F _c is an ester group, G _c1 and G _{c2 are} amido groups, R _c 'is hydroxy amino acid, Hy _c1 is a radical derived from hydrophobic acid, and Hy _c2 is a radical derived from hydrophobic amine.

[000159] In one embodiment, F _c is an amido group, G _c1 and G _{c2 are} ester groups, R _c 'is hydroxy amino acid, Hy _c1 is a radical derived from hydrophobic alcohol, and Hy _c2 is a radical derived from hydrophobic acid.

[000160] In one embodiment, F _c is an amido group, G _c1 and G _{c2 are} amido groups, R _c 'is a diamino acid, Hy _c1 is a radical derived from a hydrophobic acid, and Hy _c2 is a radical derived from a hydrophobic amine.

[000161] In one embodiment, F _h is a carbamate group, G _h1 and G _{h2 are} ester groups, R _h 'is hydroxy amino acid, Hy _h1 is a radical derived from hydrophobic alcohol, and Hy _h2 is a radical derived from hydrophobic acid .

[000162] In one embodiment, F _h is a carbamate group, G _h1 and G _{h2 are} amido groups, R _h 'is a dibasic amino acid, Hy _h1 is a radical derived from a hydrophobic acid, and Hy _h2 is a radical derived from a hydrophobic amine.

[000163] In one embodiment, F _h is a carbamate group, G _h1 and G _{h2 are} carbamate groups, R _h 'is diaminoalkanol, Hy _h1 is a radical derived from a hydrophobic alcohol, and Hy _h2 is a radical derived from a hydrophobic amine.

[000164] In one embodiment, the polysaccharides of the present invention comprise two groups Hy _c1 and Hy _c2 or Hy _h1 and Hy _h2 that are the same or different but have the same reactive functional groups, and the bonds G _c1 and G _c2 or G _h1 and G _h2 are different.

[000165] By way of example, the combinations given below are implemented.

[000166] In one embodiment, F _c is an ester group, G _c1 is an ester group, R _c 'is dialkanolamine, G _c2 is an amido group, and Hy _c1 and Hy _c2 are hydrophobic acid derived groups.

[000167] In one embodiment, F _c is an ester group, G _c1 is an ester group, R _c 'is a hydroxy amino acid, G _c2 is a carbamate group, and Hy _c1 and Hy _c2 are groups derived from a hydrophobic alcohol.

[000168] In one embodiment, F _c is an amido group, G _c1 is an ester group, R _c 'is diaminoalkanol, G _c2 is an amido group, and Hy _c1 and Hy _c2 are hydrophobic acid derived groups.

[000169] In one embodiment, F _c is an amido group, G _c1 is an ester group, R _c 'is a diamino acid, G _c2 is a carbamate group, and Hy _c1 and Hy _c2 are groups derived from a hydrophobic alcohol.

[000170] In one embodiment, F _c is an ester group, G _c1 is an amido group, R _c 'is a dihydric hydroxy acid, G _c2 is a carbamate group, and Hy _c1 and Hy _c2 are groups derived from a hydrophobic amine.

[000171] In one embodiment, F _h is a carbamate group, G _h1 is an ester group, R _h 'is diaminoalkanol, G _h2 is an amido group, and Hy _h1 and Hy _h2 are hydrophobic acid derived groups.

[000172] In one embodiment, F _h is a carbamate group, G _h1 is an ester group, R _h 'is a diamino acid, G _h2 is a carbamate group, and Hy _h1 and Hy _h2 are groups derived from a hydrophobic alcohol.

[000173] In one embodiment, F _h is a carbamate group, G _h1 is an amido group, R _h 'is a hydroxy amino acid, G _h2 is a carbamate group, and Hy _h1 and Hy _h2 are groups derived from a hydrophobic amine.

[000174] In one embodiment, the polysaccharides of the present invention comprise two groups Hy _c1 and Hy _c2 or Hy _h1 and Hy _h2 , which are different, and the bonds G _c1 and G _c2 or G _h1 and G _h2 are also different.

[000175] By way of example, the combinations given below are implemented.

[000176] In one embodiment, F _c is an ester group, G _c1 is an ester group, R _c 'is dialkanolamine, Hy _c1 is a radical derived from a hydrophobic acid, G _c2 is a carbamate group, and Hy _c2 is a radical, derived from hydrophobic alcohol.

[000177] In one embodiment, F _c denotes an ester group, G _c1 denotes an ester group, R _c 'denotes a hydroxy amino acid, Hy _c1 denotes a radical derived from a hydrophobic alcohol, G _c2 denotes an amide group, and Hy _c2 denotes a radical originating from hydrophobic acid.

[000178] In one embodiment, F _c is an ester group, G _c1 is an amido group, R _c 'is an alkanol diamine, Hy _c1 is a radical derived from a hydrophobic acid, G _c2 is a carbamate group, and Hy _c2 is a radical derived from hydrophobic alcohol.

[000179] In one embodiment, F _c is an ester group, G _c1 is an ester group, R _c 'is a dibasic hydroxy acid, Hy _c1 is a radical derived from a hydrophobic alcohol, G _c2 is an amido group, and Hy _c2 is a radical, originating from a hydrophobic amine.

[000180] In one embodiment, F _c is an ester group, G _c1 is an ester group, R _c 'is a dihydric hydroxy acid, Hy _c1 is a radical derived from a hydrophobic acid, G _c2 is an amide group, and Hy _c2 is a radical, originating from a hydrophobic amine.

[000181] In one embodiment, F _c is an ester group, G _c1 is an amido group, R _c 'is dialkanolamine, Hy _c1 is a radical derived from a hydrophobic acid, G _c2 is a carbamate group, and Hy _c2 is a radical derived from hydrophobic amine.

[000182] In one embodiment, F _c is an ester group, G _c1 is an ester group, R _c 'is a trihydric alcohol, Hy _c1 is a radical derived from a hydrophobic acid, G _c2 is a carbamate group, and Hy _c2 is a radical originating from a hydrophobic amine.

[000183] In one embodiment, F _c is an ester group, G _c1 is an ester group, R _c 'is a dihydric hydroxy acid, Hy _c1 is a radical derived from a hydrophobic alcohol, G _c2 is a carbamate group, and Hy _c2 is a radical originating from a hydrophobic amine.

[000184] In one embodiment, F _c is an amido group, G _c1 is an ester group, R _c 'is a diamino acid, Hy _c1 is a radical derived from a hydrophobic alcohol, G _c2 is an amido group, and Hy _c2 is a radical derived from hydrophobic acids.

[000185] In one embodiment, F _c is an amido group, G _c1 is an ester group, R _c 'is alkanediamine, Hy _c1 is a radical derived from hydrophobic acid, G _c2 is a carbamate group, and Hy _c2 is a radical derived from hydrophobic alcohol.

[000186] In one embodiment, F _c is an amido group, G _c1 is an amido group, R _c 'is a triamine, Hy _c1 is a radical derived from hydrophobic acid, G _c2 is a carbamate group, and Hy _c2 is a radical derived from hydrophobic alcohol .

[000187] In one embodiment, F _c is an amido group, G _c1 is an ester group, R _c 'is a dibasic amino acid, Hy _c1 is a radical derived from a hydrophobic alcohol, G _c2 is an amido group, and Hy _c2 is a radical derived from hydrophobic amine.

[000188] In one embodiment, F _c is an amido group, Gc ₁ is an ester group, R _c 'is a hydroxy amino acid, Hy _c1 is a radical derived from hydrophobic acid, G _c2 is an amido group, and Hy _c2 is a radical derived from hydrophobic amine.

[000189] In one embodiment, F _c is an amido group, G _c1 is an amido group, R _c 'is an alkanol diamine, Hy _c1 is a radical derived from a hydrophobic acid, G _c2 is a carbamate group, Hy _c2 is a radical derived from a hydrophobic amine.

[000190] In one embodiment, F _c is an amido group, G _c1 is an ester group, R _c 'is dialkanolamine, Hy _c1 is a radical derived from hydrophobic acid, G _c2 is a carbamate group, and Hy _c2 is a radical derived from hydrophobic amine.

[000191] In one embodiment, F _c is an amido group, G _c1 is an ester group, R _c 'is a hydroxy amino acid, Hy _c1 is a radical derived from a hydrophobic alcohol, G _c2 is a carbamate group, and Hy _c2 is a radical derived from hydrophobic amine.

[000192] In one embodiment, F _h is a carbamate group, G _h1 is an ester group, R _h 'is a diamino acid, Hy _h1 is a radical derived from a hydrophobic alcohol, G _h2 is an amide group, and Hy _h2 is a radical derived from hydrophobic acid.

[000193] In one embodiment, F _h is a carbamate group, G _h1 is an ester group, R _h 'is alkanol diamine, Hy _h1 is a radical derived from hydrophobic acid, G _h2 is a carbamate group, and Hy _h2 is a radical derived from hydrophobic alcohol.

[000194] In one embodiment, F _h is a carbamate group, G _h1 is an amido group, R _h 'is a triamine, Hy _h1 is a radical derived from a hydrophobic acid, G _h2 is a carbamate group, and Hy _h2 is a radical derived from hydrophobic alcohol.

[000195] In one embodiment, F _h is a carbamate group, G _h1 is an ester group, R _h 'is a dibasic amino acid, Hy _h1 is a radical derived from a hydrophobic alcohol, G _h2 is an amide group, and Hy _h2 is a radical derived from hydrophobic amine.

[000196] In one embodiment, F _h is a carbamate group, G _c1 is an ester group, R _h 'is a hydroxy amino acid, Hy _h1 is a radical derived from a hydrophobic acid, G _h2 is an amide group, and Hy _h2 is a radical derived from hydrophobic amine.

[000197] In one embodiment, F _h is a carbamate group, G _h1 is an amido group, R _h 'is alkanediamine, Hy _h1 is a radical derived from hydrophobic acid, G _h2 is a carbamate group, and Hy _h2 is a radical derived from hydrophobic amine.

[000198] In one embodiment, F _h is a carbamate group, G _h1 is an ester group, R _h 'is dialkanolamine, Hy _h1 is a radical derived from a hydrophobic acid, G _h2 is a carbamate group, and Hy _h2 is a radical derived from hydrophobic amine.

[000199] In one embodiment, F _h is a carbamate group, G _h1 is an ester group, R _h 'is a hydroxy amino acid, Hy _h1 is a radical derived from a hydrophobic alcohol, G _h2 is a carbamate group, and Hy _h2 is a radical derived from hydrophobic amine.

[000200] The degree of polymerization m of the polysaccharide may be in the range from 5 to 10000.

[000201] In one embodiment, the degree of polymerization m of the polysaccharide is in the range from 10 to 1000.

[000202] In one embodiment, the degree of polymerization of the polysaccharide m is in the range from 10 to 500.

[000203] The invention also relates to the synthesis of polysaccharides of the present invention.

[000204] The invention also relates to the synthesis of polysaccharides containing carboxyl groups, of which at least one group is functionalized by at least two hydrophobic groups, denoted by Hy _c1 and Hy _c2 and / or Hy _h1 and Hy _h2 , which are the same or different.

[000205] In the case where the polysaccharides are selected from polysaccharides of the general formulas II, III, IV, said synthesis includes the step of preparing the intermediate amino compound [Hy _c —G _c ] _rc —R _c —NH ₂ or the ammonium salt [Hy _c —G _c ] _rc —R _c —NH ₃ ⁺ , wherein the counterion is an anion selected from halide ions, sulfate ions, sulfonate ions, carboxylate ions, and a step for attaching this intermediate amino compound to the carboxyl group of the polysaccharide, wherein R _c , G _c , Hy _c and r _c correspond to the definitions below.

[000206] In one embodiment, the step of converting the hydroxyl groups of the polysaccharide to at least 15 carboxyl groups per 100 saccharide units is carried out by attaching compounds of the formula QL ′ to at least 15 hydroxyl groups per 100 saccharide units of the polysaccharide, wherein QL 'represents the precursor of the QL chain, and Q and L correspond to the following definitions.

[000207] In a preferred embodiment, an intermediate amino compound of the formula [Hy _c —G _c ] _rc —R _c —NH ₂ or [Hy _c —G _c ] _rc —R _c —NH ₃ ^{+ is} prepared by reacting a compound of the formula [G ′] _rc - R _c —NH ₂ , where G ′ represents a functional group of a carboxylic acid, amine or alcohol, with a reactive functional group of a hydrophobic compound, wherein R _c , G _c , Hy _c and r _c correspond to the definitions given below.

[000208] Other methods of synthesis, such as methods that use carbodiimides, are well known to specialists in this field of technology and can also be used.

[000209] If necessary, methods for introducing and deprotecting, well known to those skilled in the art, are used in the preparation of the intermediate amino compound.

[000210] The step of attaching an intermediate amino compound to the carboxyl group of the polysaccharide is preferably carried out in an organic solvent medium.

[000211] In the case where the polysaccharides are selected from polysaccharides of the general formulas V, VI, VII, said synthesis includes the step of producing an intermediate amino compound [Hy _h —G _h ] _rh —R _h —NH ₂ or an ammonium salt [Hy _h —G _h ] _rh —R _h —NH ₃ ⁺ , wherein the counterion is an anion selected from halide ions, sulfate ions, sulfonate ions, carboxylate ions, and the step of attaching this intermediate amino compound to the hydroxyl group of the polysaccharide, wherein R _h , G _h , Hy _h and r _h correspond to the definitions below.

[000212] In one embodiment, the step of converting the hydroxyl groups of the polysaccharide to at least 15 carboxyl groups per 100 saccharide units is carried out by attaching compounds of the formula QL ′ to at least 15 hydroxyl groups per 100 saccharide units of the polysaccharide, wherein QL 'represents the precursor of the QL chain, and Q and L correspond to the following definitions.

[000213] In a preferred embodiment, an intermediate amino compound of the formula [Hy _h -G _h ] _rh -R _h -NH ₂ or [Hy _h -G _h ] _rh -R _h -NH ₃ ^{+ is} prepared by reacting a compound of the formula [G _h '] _rh —R _h —NH ₂ , where G _h ′ is a functional group of a carboxylic acid, amine or alcohol, with a reactive functional group of a hydrophobic compound, wherein R _h , G _h , Hy _h and r _h are as defined below.

[000214] Other synthetic methods, such as methods that use carbodiimides, are well known to those skilled in the art and can also be used.

[000215] If necessary, methods for introducing and deprotecting, well known to those skilled in the art, are used in the preparation of the intermediate amino compound.

[000216] The step of attaching an intermediate amino compound to the carboxyl group of the polysaccharide is preferably carried out in an organic solvent medium.

[000217] In one embodiment, the invention relates to a polysaccharide selected from the group consisting of the following polysaccharides:

- sodium dextranmethylcarboxylate modified with dihexyl aspartate;

- sodium dextranmethylcarboxylate modified with dibenzyl aspartate;

- sodium dextranmethylcarboxylate modified with dilauryl aspartate (10 kD dextran);

- sodium dextranmethylcarboxylate, modified with 3-amino-1,2-propanediol-di-laurate;

- sodium dextranmethylcarboxylate modified with dioctyl aspartate;

- sodium dextranmethylcarboxylate modified with dilauryl aspartate (5 kD dextran);

- sodium dextranmethylcarboxylate modified with 2 - [(2-dodecanoylamino-6-dodecanoylamino) hexanoylamino] ethanamine;

- sodium dextran succinate modified with dioctyl aspartate;

- sodium dextranmethylcarboxylate, modified 2,2 ', 2 "- (amino-bis- [methylphenyl acetate]) ethyl phenyl acetate;

- sodium dextranmethylcarboxylate, modified benzyl-2-amino-3-octanoyloxypropanoate;

- sodium N-methylcarboxylate dextrancarbamate modified with dioctyl aspartate;

- dextran modified with sodium N-methylcarboxylate carbamate and dihexyl aspartate carbamate;

- sodium dextranmethylcarboxylate modified with dilaurylglutamide;

- sodium dextranmethylcarboxylate, modified di (ethyl-2-dodecanamide) aspartamide.

Example 1. Dextranmethylcarboxylate of sodium modified with dihexyl aspartate

Polymer 1

[000218] 16 g (or 296 mmol of hydroxyl groups) of dextran with a weight average molecular weight of approximately 40 kg / mol (Pharmacosmos) are solubilized in water at a concentration of 42 g / l. To this solution, 30 ml of 10N are added. NaOH solution (296 mmol NaOH). The mixture is heated to 35 ° C. and then 46 g (396 mmol) of sodium chloroacetate are added. The temperature of the reaction mixture was brought to 60 ° C at a rate of 0.5 ° C / min and then the mixture was maintained at a temperature of 60 ° C for 100 minutes. The reaction mixture was diluted with 200 ml of water, neutralized with acetic acid and purified by ultrafiltration through a PES membrane with a threshold of 5 kD against 6 volumes of water. The final solution is metered by dry solids to determine the polymer concentration; then dosed by acid-base titration in a 50/50 (V / V) water / acetone mixture to determine the degree of conversion to methyl carboxylates.

[000219] Analysis of the dry residue: [polymer] = 31.5 mg / g.

[000220] The result of acid-base titration: the degree of conversion of hydroxyl groups to methyl carboxylate groups is 1.07 per saccharide unit.

[000221] A solution of sodium dextranmethylcarboxylate was passed through a Purolite resin (anion exchange resin) to obtain dextranmethylcarboxylic acid, which was then lyophilized for 18 hours.

[000222] Dihexyl aspartate in the form of a salt of para-toluenesulfonic acid is obtained by the method described in the patent (Kenji, M. et al., US 4826818).

[000223] 10 g of dextranmethylcarboxylic acid (47.76 mmol of methylcarboxylic acid) are solubilized in DMF at a concentration of 60 g / L and then cooled to 0 ° C. 2.0 g of dihexyl aspartate in the form of a salt of para-toluenesulfonic acid (4.46 mmol) are suspended in DMF at a concentration of 100 g / L. Then, 0.45 g of triethylamine (4.46 mmol) was added to this suspension. After the polymer solution was cooled to 0 ° C, a solution of NMM (1.35 g, 13.39 mmol) in DMF (530 g / L) and 1.45 g (13.39 mmol) EtOCOCl were added. After the reaction, a suspension of dihexyl aspartate is added over 10 minutes. Next, the mixture was kept at 10 ° C for 45 minutes. Then the mixture is heated to 30 ° C. A solution of imidazole (3.04 g in 9 ml of water) and 52 ml of water are added to the reaction mixture. The polymer solution is ultrafiltered through a PES membrane with a threshold of 10 kD against 15 volumes of 0.9% NaCl solution and 5 volumes of water. The concentration of the polymer solution is determined by solids. The fraction of the solution was lyophilized and analyzed by ¹ H NMR in D ₂ O to determine the content of carboxyl groups converted to dihexyl aspartate amide.

[000224] Analysis of the dry residue: [polymer 1] = 31.1 mg / g.

[000225] ¹ H NMR analysis: the degree of functionalization of acids with dihexyl aspartate per saccharide unit is 0.075.

Example 2. Sodium Dextran Methyl Carboxylate Modified with Dibenzyl Aspartate

Polymer 2

[000226] Dibenzyl aspartate in the form of a salt of para-toluenesulfonic acid is obtained by the method described in the patent (Kenji, M. et al., US 4826818).

[000227] In a manner analogous to the method described in example 1, sodium dibenzyl aspartate modified dextran methyl carboxylate is obtained.

[000228] Analysis of the dry residue: [polymer 2] = 35 mg / g.

[000229] ¹ H NMR Analysis: The degree of functionalization of acids with dibenzyl aspartate is 0.085.

Example 3. Sodium Dextranmethyl Carboxylate Modified with Dilauryl Aspartate (10 KD Dextran)

Polymer 3

[000230] Dilauryl aspartate in the form of a salt of para-toluenesulfonic acid is obtained by the method described in the patent (Kenji, M. et al., US 4826818).

[000231] In a similar manner to that described in Example 1, sodium dextranmethylcarboxylate modified by dilauryl aspartate was synthesized by the method described in Example 1 using dextran with a weight average molecular weight of about 10 kg / mol (Pharmacosmos).

[000232] Analysis of the dry residue: [polymer 3] = 17.8 mg / g

[000233] ¹ H NMR analysis: the degree of functionalization of acids with dilauryl aspartate is 0.05.

Example 4. Sodium dextranmethylcarboxylate modified with 3-amino-1,2-propanediol-di-laurate

Polymer 4

[000234] The 3-amino-1,2-propanediol-di-laurate ester in the form of a salt of p-toluenesulfonic acid is prepared by the method described in the patent (Kenji, M. et al., US 4826818).

[000235] In a manner analogous to the method described in Example 1, sodium dextranmethyl carboxylate modified with 3-amino-1,2-propanediol-di-laurate was obtained.

[000236] Analysis of the dry residue: [polymer 4] = 18.5 mg / g

[000237] ¹ H NMR Analysis: The degree of functionalization of acids by 3-amino-1,2-propanediol-dilaurate per saccharide unit is 0.045.

Example 5. Dioctyl Aspartate Modified Sodium Dextran Methyl Carboxylate

Polymer 5

[000238] Dioctyl aspartate in the form of a salt of para-toluenesulfonic acid is obtained by the method described in the patent (Kenji, M. et al., US 4826818).

[000239] In a similar manner to that described in Example 1, dioctyl aspartate-modified sodium dextran methyl carboxylate synthesized by the method described in Example 1 was prepared using dextran with a weight average molecular weight of about 10 kg / mol (Pharmacosmos).

[000240] Analysis of the dry residue: [polymer 5] = 22.2 mg / g

[000241] ¹ H NMR Analysis: The degree of functionalization of acids by dioctyl aspartate is 0.05.

Example 6. Sodium dextranmethylcarboxylate modified with dilauryl aspartate (5 kD dextran)

Polymer 6

[000242] Dilauryl aspartate in the form of a salt of para-toluenesulfonic acid is obtained by the method described in the patent (Kenji, M. et al., US 4826818).

[000243] In a manner analogous to the method described in example 1, sodium dextranmethylcarboxylate modified by dilauryl aspartate is synthesized by the method described in example 1 using dextran with a weight average molecular weight of about 5 kg / mol (Pharmacosmos).

[000244] Analysis of the dry residue: [polymer 6] = 8.9 mg / g.

[000245] ¹ H NMR Analysis: The degree of functionalization of acids with dilauryl aspartate is 0.05.

Example 7. Sodium dextranmethylcarboxylate modified with 2 - [(2-dodecanoylamino-6-dodecanoylamino) hexanoylamino] ethanamine

Polymer 7

[000246] N, N-bis- (dodecanoyl) lysine is prepared by the method described in (Pal, A. et al., Tetrahedron, 2007, 63, 7334-7348), starting from L-lysine ethyl ester in the form of hydrochloric salt acids (Bachem) and dodecanoic acid (Sigma).

[000247] 2 - [(2-Dodecanoylamino-6-dodecanoylamino) hexanoylamino)] ethanamine in the form of a salt of hydrochloric acid is obtained by the methods described in publications (Paul, R. et al., 3. Org. Chem. 1962, 27, 2094 -2099 and Dale, DJ et al., Org. Process. Res. Dev., 2002, 6, 767-772), starting from N, N-bis- (dodecanoyl) lysine and ethylenediamine (Roth).

[000248] In a similar manner to that described in Example 1, a modified 2 - [(2-dodecanoylamino-6-dodecanoylamino) hexanoylamino)] ethanamine sodium dextranmethylcarboxylate synthesized by the method described in Example 1 was prepared using dextran with a weight average molecular weight of approximately 10 kg / mol (Pharmacosmos).

[000249] Analysis of the dry residue: [polymer 7] = 16.9 mg / g.

[000250] ¹ H NMR analysis: the degree of functionalization of the acids 2 - [(2-dodecanoylamino-6-dodecanoylamino) hexanoylamino)] ethanamine is 0.02.

Example 8. Sodium dextran succinate modified with dioctyl aspartate

Polymer 8

[000251] Dioctyl aspartate in the form of a salt of para-toluenesulfonic acid is obtained by the method described in the patent (Kenji, M. et al., US 4826818).

[000252] Sodium dextran succinate is prepared starting from dextran 10 (Pharmacosmos) by the method described in Sanchez-Chaves et al. (Sanchez-Chaves, Manuel et al., Polymer, 1998, 39 (13), 2751-2757). The content of carboxyl groups per glycosidic link is 1.41 according to ¹ H NMR in D ₂ O / NaOD.

[000253] In a similar manner to that described in Example 1, sodium dioctyl aspartate modified dextran succinate was obtained.

[000254] Analysis of the dry residue: [polymer 8] = 19.3 mg / g.

[000255] ¹ H NMR analysis: the degree of functionalization of acids by dioctyl aspartate per saccharide unit is 0.05.

Example 9. Sodium Dextranmethyl Carboxylate Modified with 2,2 ', 2 "- (Amino-bis- [Methyl Phenyl Acetate]) Ethyl Phenyl Acetate

Polymer 9

[000256] 2,2 ', 2 "- (Amino-bis- [methylphenyl acetate]) ethyl phenyl acetate in the form of a salt of p-toluenesulfonic acid obtained by the method described in the patent (Kenji, M. et al., US 4826818), starting from 2 -amino-2- (hydroxymethyl) -1,3-propanediol (Tris) (Aldrich) and phenylacetic acid (Aldrich).

[000257] In a manner analogous to the method described in example 1, receive modified 2,2 ', 2 "- (amino-bis- [methylphenylacetate]) ethylphenylacetate sodium dextranmethylcarboxylate synthesized by the method described in example 1, using dextran with a weight average molecular weight weighing approximately 10 kg / mol (Pharmacosmos).

[000258] Analysis of the dry residue: [polymer 9] = 15.4 mg / g

[000259] ¹ H NMR Analysis: The degree of functionalization of the acids 2,2 ', 2 "- (amino-bis- [methylphenyl acetate]) ethyl phenyl acetate is 0.04.

Example 10. Sodium dextranmethylcarboxylate modified with benzyl-2-amino-3-octanoyloxypropanoate

Polymer 10

[000260] Benzyl-2-amino-3-octanoyloxypropanoate in the form of a salt of para-toluenesulfonic acid is obtained by the method described in the patent (Kenji, M. et al., US 4826818), starting from L-serine benzyl ester in the form of a hydrochloric acid salt and octanoic acid.

[000261] In a similar manner to that described in Example 1, a modified benzyl-2-amino-3-octanoyloxypropanoate dextran was prepared using dextran with a weight average molecular weight of about 10 kg / mol (Pharmacosmos).

[000262] Analysis of the dry residue: [polymer 10] = 21.2 mg / g

[000263] ¹ H NMR Analysis: The degree of functionalization of the acids with benzyl-2-amino-3-octanoyloxypropanoate per saccharide unit is 0.045.

Example 11. Dioctyl Aspartate Modified Sodium N-Methyl Carboxylate Dextran Carbamate

Polymer 11

[000264] Dioctyl aspartate in the form of a salt of para-toluenesulfonic acid is obtained by the method described in the patent (Kenji, M. et al., US 4826818).

[000265] 11.5 g (or 0.21 mol of hydroxyl groups) of dextran with a weight average molecular weight of about 10 kg / mol (Bachem) are solubilized in a mixture of DMF / DMSO. The mixture is heated to 130 ° C. with stirring and 13.75 g (0.11 mol) of ethyl isocyanatoacetate are gradually added. After the reaction was carried out for 1 h, the mixture was diluted with water and purified by diafiltration through a PES membrane with a threshold of 5 kD versus 0.1 n. NaOH solution, 0.9% NaCl solution and water. The final solution is metered by dry solids to determine the polymer concentration; then analyzed by the method of acid-base titration in a mixture of water / acetone 50/50 (V / V) to determine the degree of conversion of hydroxyl groups to N-methylcarboxylate groups of carbamates.

[000266] Analysis of the dry residue: [polymer] = 38.9 mg / g.

[000267] The result of acid-base titration: the degree of conversion of hydroxyl groups to N-methylcarboxylate groups of carbamates is 1.08 per saccharide unit.

[000268] A solution of sodium N-methylcarboxylate dextrancarbamate is passed through a Purolite resin (anion exchange resin) to obtain N-methylcarboxylic acid dextrancarbamate, which is then lyophilized for 18 hours.

[000269] 5 g of N-methylcarboxylic acid dextrancarbamate (20 mmol of N-methylcarboxylic acid) are solubilized in DMF at a concentration of 50 g / L and then cooled to 0 ° C. 0.95 g of dioctyl aspartate in the form of a salt of para-toluenesulfonic acid (0.18 mmol) is suspended in DMF at a concentration of 100 g / l. Then, 0.02 g of triethylamine (0.18 mmol) was added to this suspension. Next, 2.22 g (22 mmol) of NMM and 2.38 g (22 mmol) of EtOCOCl are added. After the reaction, a suspension of dioctyl aspartate is added over 10 minutes. Then the mixture was kept at 10 ° C for 45 minutes. The mixture is then heated to 50 ° C. An aqueous solution of imidazole with a concentration of 600 g / l and 25 ml of water is added at 30 ° C. After stirring for 1 h 30 min at 50 ° C, the resulting solution was ultrafiltered through a PES membrane with a threshold of 10 kD against 0.1 N. NaOH solution, 0.9% NaCl solution and water. The concentration of the polymer solution is determined by solids. The fraction of the solution was lyophilized and analyzed by ¹ H NMR in D ₂ O to determine the content of carboxyl groups converted to dioctyl aspartate amide.

[000270] Analysis of the dry residue: [polymer 11] = 21.2 mg / g

[000271] ¹ H NMR Analysis: The degree of functionalization of acids by dioctyl aspartate per saccharide unit is 0.09.

Example 12. Dextran modified with sodium carbamate N-methylcarboxylate and dihexyl aspartate carbamate

Polymer 12

[000272] Dihexyl aspartate in the form of a salt of p-toluenesulfonic acid is obtained by the method described in the patent (Kenji, M. et al., US 4826818).

[000273] Dihexyl-2-isocyanatobutanedioate is prepared by the method described in the publication (Knöckler, H.-J. et al., Synlett. 1997, 925-928) starting from dihexyl aspartate.

[000274] 2.7 g (or 50 mol of hydroxyl groups) of dextran with a weight average molecular weight of approximately 10 kg / mol (Bachem) are solubilized in a mixture of DMF / DMSO. The mixture is heated to 130 ° C. with stirring and 3.2 g (25 mmol) of ethyl isocyanatoacetate and then 3.9 g (8 mmol) of dihexyl-2-isocyanatobutanedioate are gradually added. After the reaction was carried out for 1 h, the mixture was diluted with water and purified by diafiltration through a PES membrane with a threshold of 5 kD against 0.1 N. NaOH solution, 0.9% NaCl solution and water. The final solution is metered by dry solids to determine the concentration of the polymer. The solution fraction is lyophilized and analyzed by ¹ H NMR in D ₂ O to determine the degree of conversion of hydroxyl groups to sodium N-methylcarboxylate carbamate and the degree of functionalization of hydroxyl groups with dihexyl aspartate carbamate.

[000275] Analysis of the dry residue: [polymer 12] = 8.2 mg / g

[000276] ¹ H NMR analysis: the degree of conversion of hydroxyl groups to sodium N-methylcarboxylate carbamate is 1.1, and the degree of functionalization of hydroxyl groups by dihexyl aspartate carbamate is 0.05.

Example 13. Sodium dextranmethylcarboxylate modified with dilauryl aspartate (5 kD dextran)

Polymer 13

[000277] Dilauryl aspartate in the form of a salt of para-toluenesulfonic acid is obtained by the method described in the patent (Kenji, M. et al., US 4826818).

[000278] By repeating twice the methyl carboxylation method of dextran described in Example 1, using dextran with a weight average molecular weight of about 5 kg / mol (Pharmacosmos), sodium dextranmethyl carboxylate is obtained with a conversion of hydroxyl groups to methyl carboxylate groups of 1.66 per saccharide unit. Based on this sodium dextranmethyl carboxylate, in a manner analogous to the method described in example 1, sodium dextran methyl carboxylate modified with dilauryl aspartate is obtained.

[000279] Analysis of the dry residue: [polymer 13] = 10.1 mg / g

¹ H NMR analysis: the degree of functionalization of acids with dilauryl aspartate is 0.05.

Example 14. Sodium dextranmethylcarboxylate modified with dilaurylglutamide

Polymer 14

[000280] Dilauryl-L-glutamamide, in which the alpha amino group is protected by the Fmoc group, is prepared from the Fmoc of L-glutamic acid (Bachem) and dodecylamine by the method described in the publication (Pal, A. et al., Tetrahedron, 2007, 63, 7334-7348). The Fmoc group is then cleaved by treatment in piperidine solution to obtain dilaurylglutamide.

[000281] In a similar manner to that described in Example 1, sodium dextranmethylcarboxylate modified dilaurylglutamide synthesized by the method described in Example 1 was prepared using dextran with a weight average molecular weight of about 10 kg / mol (Pharmacosmos).

[000282] Analysis of the dry residue: [polymer 14] = 15.6 mg / g

[000283] ¹ H NMR Analysis: The degree of functionalization of the acids with dilaurylglutamide is 0.07.

Example 15. Sodium dextranmethylcarboxylate modified with di (ethyl-2-dodecanamide) aspartamide

Polymer 15

N- (2-aminoethyl) dodecanamide is prepared by the method described in the patent (Weiner, N. et al., US 2387201) starting from dodecanoic acid methyl ester (Sigma) and ethylenediamine (Roth).

Di (ethyl-2-dodecanamide) -L-aspartamide in which the alpha amino group is protected by the Fmoc group is prepared from the Fmoc of L-aspartic acid (Bachem) and N- (2-aminoethyl) dodecanamide by the method described in the publication (Pal , A. et al., Tetrahedron, 2007, 63, 7334-7348). Then, the Fmoc group is cleaved by treatment in piperidine solution to obtain di (ethyl-2-dodecanamide) aspartamide.

[000284] In a similar manner to that described in Example 1, a modified sodium di-ethyl-2-dodecanamide aspartamide dextranmethylcarboxylate was synthesized, synthesized by the method described in Example 1, using dextran with a weight average molecular weight of about 5 kg / mol (Pharmacosmos) .

[000285] Analysis of the dry residue: [polymer 15] = 9.2 mg / g

[000286] ¹ H NMR Analysis: The degree of functionalization of di (ethyl-2-dodecanamide) aspartamide acids is 0.05.

[000287] The invention also relates to the use of polysaccharides functionalized according to the present invention for the preparation of pharmaceutical compositions.

[000288] The invention also relates to a pharmaceutical composition comprising one of the polysaccharides of the present invention described below and at least one active substance.

[000289] The invention also relates to the pharmaceutical composition of the present invention, described below and characterized in that the active substance is selected from the group consisting of proteins, glycoproteins, peptides and non-peptide therapeutic compounds.

[000290] By active substance is meant a substance in the form of a chemically individual compound or in the form of a combination having physiological activity. The specified active substance may be exogenous, that is, it is introduced by the composition of the present invention. It can also be endogenous, for example, growth factors that can be secreted in the wound during the first stage of healing and can be retained in the wound by the composition of the present invention.

[000291] Depending on the particular pathology, the composition is intended for topical or systemic treatment.

[000292] In the case of local and systemic release, the provided methods of administration include intravenous, subcutaneous, intradermal, transdermal, intramuscular, oral, nasal, vaginal, intraocular, buccal, pulmonary administration and the like.

[000293] The pharmaceutical compositions of the present invention are in the form of a liquid, an aqueous solution, or in the form of a powder, implant or film. In addition, they contain traditional pharmaceutical excipients well known to those skilled in the art.

[000294] Depending on the pathology and methods of administration, the pharmaceutical compositions may preferably also contain excipients which make it possible to obtain dosage forms in the form of a gel, sponge, injection, drinkable solution, lyophilized tablets and the like.

[000295] The invention also relates to the pharmaceutical composition of the present invention, described below and characterized in that it can be introduced in the form of a stent, film or “coating” of implantable biomaterials and implants.

Claims (21)

1. Anionic polysaccharide of formula VIII, characterized in that it is a dextran in which the degree of conversion of hydroxyl groups to carboxyl groups per saccharide unit is equal to or greater than 0.15:

Where:
- L means a bond formed by combining a Q-link arm precursor with a —OH group of a polysaccharide and representing an ester group, a carbamate group or an ether group;
- i means the degree of conversion of hydroxyl groups in the LQ chain attributable to the saccharide unit of the polysaccharide;
Q is a chain containing from 1 to 18 carbon atoms, which is optionally branched and / or unsaturated, optionally containing one or more heteroatoms, such as O, N and / or S, and containing at least one -CO ₂ carboxyl group H
moreover, at least one of the hydroxyl groups of the indicated polysaccharide is substituted by at least two hydrophobic radicals, denoted by Hy _h , or at least one of the carboxyl groups is substituted by at least two hydrophobic radicals Hy _c , which are the same or different:

Where:
- n _c and n _h mean the degree of functionalization of the saccharide units of the polysaccharide by the chains -F _c -R _c - [G _c -Hy _c ] _rc and / or -F _h -R _h - [G _h -Hy _h ] _rh , with n _h ≥0 and n _c ≥0 s 0.01 ≤n _h + n _c ≤0.5;
- F _c means an amido group or an ester group;
- F _h means a carbamate group;
- non-functionalized carboxyl groups of the anionic polysaccharide are in the form of carboxylates of cations, preferably alkali metal cations, such as Na ⁺ or K ⁺ ;
- G _h or G _c means an amide group or an ester group, or a carbamate group formed by combining a reactive functional group of a hydrophobic compound (Hy _h ′ or Hy _c ′) with a reactive functional group of the link arm precursor R _h ′ or R _c ′;
- Hy _h or Hy _c means radicals that are the same or different, formed when the reactive functional group of the hydrophobic compound (Hy _h ′ or Hy _c ′) is combined with the reactive functional group of the link arm precursor R _h ′ or R _c ′, moreover, Hy _h or Hy _c is a chain containing from 4 to 50 carbon atoms, which is optionally branched and / or unsaturated, optionally containing one or more heteroatoms, such as O, N and / or S, optionally containing one or some saturated, unsaturated or aromatic rings or heterocycles;
- R _c means a trivalent radical, which is a chain containing from 1 to 15 carbon atoms, which is optionally branched and / or unsaturated, optionally containing one or more heteroatoms, such as O, N and / or S, optionally containing one or more saturated, unsaturated or aromatic rings or heterocycles, and the precursor formed during the reaction, R _c ', having at least three reactive functional groups, which may be identical or different and are selected from g uppy, which includes an alcohol group, an acid group and an amino group;
- R _h means a trivalent radical, which is a chain containing from 1 to 15 carbon atoms, which is optionally branched and / or unsaturated, optionally containing one or more heteroatoms, such as O, N and / or S, optionally containing one or several saturated, unsaturated or aromatic rings or heterocycles, and formed by the reaction of the precursor R ′ _h having at least three reactive functional groups, one of which is an amino group, and the other these groups are selected from the group consisting of an alcohol group, an acid group and an amino group;
- r _h is an integer representing the number of hydrophobic groups attached to at least the trivalent bond arm R _h , with 2≤r _h ≤4;
- r _c is an integer denoting the number of hydrophobic groups attached to at least the trivalent bond arm R _c , with 2≤r _c ≤4. 2. The polysaccharide according to claim 1, characterized in that the polysaccharide is selected from the group of polysaccharides of the formula II:

Where:
- n _c means the degree of functionalization of the carboxyl groups of the polysaccharide by the chains -F _c -R _c - [G _c -Hy _c ] _rc and is in the range from 0.01 to 0.5;
- F _c , R _c , G _c , Hy _c and r _c correspond to the above definitions;
- in the case where the carboxyl groups of the polysaccharide are not functionalized by the chains —F _c —R _c - [G _c -Hy _c ] _rc , one or more carboxyl groups of the polysaccharide are carboxylates of cations, preferably alkali metal cations, such as Na ⁺ or K ⁺ ;
- in the case when the unfunctionalized reactive functional group of the link arm R _c is an acid group, it is also in the form of a salt, in the form of a carboxylate of a cation, preferably an alkali metal cation, such as Na ⁺ or K ⁺ , and in the case when the unfunctionalized reactive functional group of the link arm R _c represents an amino group, it is in the form of a salt with an anion, and preferably with a halide ion. 3. The polysaccharide according to claim 1, characterized in that the polysaccharide is selected from the group of polysaccharides of the formula III:

Where:
- n _c , F _c and R _c correspond to the above definitions;
- G _c1 and G _c2 , which are the same or different, correspond to the definition of G _c ;
- Hy _c1 and Hy _c2 , which are the same or different, correspond to the definition of Hy _c . 4. The polysaccharide according to claim 1, characterized in that the polysaccharide is selected from the group of polysaccharides of the formula V:

Where:
- n _h means the degree of functionalization of the hydroxyl groups of the polysaccharide with chains of -F _h -R _h - [G _h -Hy _h ] _rh and is in the range from 0.01 to 0.5;
- F _h , R _h , G _h , Hy _h and r _h correspond to the above definitions;
- the carboxyl groups of the polysaccharide are in the form of carboxylates of cations, preferably alkali metal cations, such as Na ⁺ or K ⁺ ;
- in the case where the unfunctionalized reactive functional group of the link arm R _h is an acidic group, it is also in the form of a salt, in the form of a carboxylate of a cation, preferably an alkali metal cation, such as Na ⁺ or K ⁺ , and in the case when the unfunctionalized reactive functional group of the link arm R _h represents an amino group, it is in the form of a salt with an anion, and preferably with a halide ion. 5. The polysaccharide according to claim 1, characterized in that the polysaccharide is selected from the group of polysaccharides of formula VI:

Where:
- n _h , F _h and R _h correspond to the above definitions;
- G _h1 and G _h2 , which are the same or different, correspond to the definition of G _h ;
- Hy _h1 and Hy _h2 , which are the same or different, correspond to the definition of Hy _h . 6. The polysaccharide according to claim 2, characterized in that
- Q is selected from radicals of the general formula IX:

Where:
1≤a + b + c≤6, 0≤a≤3, 0≤b≤3 and 0≤c≤3;
R ₃ and R ₄ , which are the same or different, are selected from the group consisting of —H, linear or branched alkyl C1-C3, —COOH and a radical of general formula X:

Where:
1≤d≤3; and
R ′ ₃ and R ′ ₄ , which are the same or different, are selected from the group consisting of —H and linear or branched alkyl C1-C3. 7. The polysaccharide according to claim 3, characterized in that
- Q is selected from radicals of the general formula IX:

Where:
1≤a + b + c≤6, 0≤a≤3, 0≤b≤3 and 0≤c≤3;
R ₃ and R ₄ , which are the same or different, are selected from the group consisting of —H, linear or branched alkyl C1-C3, —COOH and a radical of general formula X:

Where:
1≤d≤3; and
R ′ ₃ and R ′ ₄ , which are the same or different, are selected from the group consisting of —H and linear or branched alkyl C1-C3. 8. The polysaccharide according to claim 4, characterized in that
- Q is selected from radicals of the general formula IX:

Where:
1≤a + b + c≤6, 0≤a≤3, 0≤b≤3 and 0≤c≤3;
R ₃ and R ₄ , which are the same or different, are selected from the group consisting of —H, linear or branched alkyl C1-C3, —COOH and a radical of general formula X:

Where:
1≤d≤3; and
R ′ ₃ and R ′ ₄ , which are the same or different, are selected from the group consisting of —H and linear or branched alkyl C1-C3. 9. The polysaccharide according to claim 5, characterized in that
- Q is selected from radicals of the general formula IX:

Where:
1≤a + b + c≤6, 0≤a≤3, 0≤b≤3 and 0≤c≤3;
R ₃ and R ₄ , which are the same or different, are selected from the group consisting of —H, linear or branched alkyl C1-C3, —COOH and a radical of general formula X:

Where:
1≤d≤3; and
R ′ ₃ and R ′ ₄ , which are the same or different, are selected from the group consisting of —H and linear or branched alkyl C1-C3. 10. The polysaccharide according to claim 6, characterized in that it is selected from polysaccharides, characterized in that the LQ chain is selected from the group consisting of the following chains, and L has the meaning defined above:

11. The polysaccharide according to claim 7, characterized in that it is selected from polysaccharides, characterized in that the LQ chain is selected from the group consisting of the following chains, and L has the meaning defined above:

12. The polysaccharide according to claim 8, characterized in that it is selected from polysaccharides, characterized in that the LQ chain is selected from the group consisting of the following chains, and L has the meaning defined above:

13. The polysaccharide according to claim 9, characterized in that it is selected from polysaccharides, characterized in that the LQ chain is selected from the group consisting of the following chains, and L has the meaning defined above:

14. The polysaccharide according to claim 1, characterized in that it is selected from polysaccharides of the formulas II, III or IV, in which -Hy _c means a radical derived from a hydrophobic alcohol formed when a hydroxyl group of a hydrophobic alcohol is combined with at least one reaction capable functional group associated with the precursor R _c ′ of at least the trivalent radical R _c , and:
- G _c means an ester group or a carbamate group. 15. The polysaccharide according to claim 14, wherein the hydrophobic alcohol is selected from alcohols formed by unsaturated or saturated, branched or unbranched alkyl chains containing from 4 to 18 carbon atoms. 16. The polysaccharide according to claim 14, wherein the hydrophobic alcohol is selected from alcohols formed by unsaturated or saturated, branched or unbranched alkyl chains containing more than 18 carbon atoms. 17. The polysaccharide according to claim 1, characterized in that it is selected from polysaccharides of the formulas II, III or IV, in which -Hy _c means a radical derived from a hydrophobic acid, formed by combining the carboxyl group of a hydrophobic acid with at least one reaction capable functional group associated with the precursor R _c ′ of at least the trivalent radical R _c , and:
- G _c means an ester group or an amido group. 18. The polysaccharide according to claim 17, wherein the hydrophobic acid is selected from the group consisting of fatty acids formed by unsaturated or saturated, branched or unbranched alkyl chains containing from 6 to 50 carbon atoms. 19. The polysaccharide according to claim 1, characterized in that it is selected from polysaccharides of the formulas II, III or IV, in which -Hy _c means a radical derived from a hydrophobic amine formed by combining the amino group of a hydrophobic amine with at least one reactive a functional group associated with the precursor R _c ′ of at least the trivalent radical R _c , and:
- G _c means an amide or carbamate group. 20. The polysaccharide according to any one of paragraphs. 1-19 to stabilize protein active substances, where the active substance is selected from the group consisting of proteins, glycoproteins, peptides and non-peptide therapeutic compounds. 21. The use of the polysaccharide according to any one of paragraphs. 1-19 to stabilize protein active substances, where the active substance is selected from the group consisting of proteins, glycoproteins, peptides and non-peptide therapeutic compounds.