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  • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
  • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
  • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
  • C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
  • C08B37/0018—Pullulan, i.e. (alpha-1,4)(alpha-1,6)-D-glucan; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
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  • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
  • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
• • C—CHEMISTRY; METALLURGY
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  • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
  • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
  • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
  • C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
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  • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
  • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
  • C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
  • C08B37/0021—Dextran, i.e. (alpha-1,4)-D-glucan; Derivatives thereof, e.g. Sephadex, i.e. crosslinked dextran
• • C—CHEMISTRY; METALLURGY
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  • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
  • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
  • C08B37/0024—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid beta-D-Glucans; (beta-1,3)-D-Glucans, e.g. paramylon, coriolan, sclerotan, pachyman, callose, scleroglucan, schizophyllan, laminaran, lentinan or curdlan; (beta-1,6)-D-Glucans, e.g. pustulan; (beta-1,4)-D-Glucans; (beta-1,3)(beta-1,4)-D-Glucans, e.g. lichenan; Derivatives thereof
• • C—CHEMISTRY; METALLURGY
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  • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
  • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
  • C08B37/0045—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Galacturonans, e.g. methyl ester of (alpha-1,4)-linked D-galacturonic acid units, i.e. pectin, or hydrolysis product of methyl ester of alpha-1,4-linked D-galacturonic acid units, i.e. pectinic acid; Derivatives thereof
• • C—CHEMISTRY; METALLURGY
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  • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
  • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
  • C08B37/0051—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid beta-D-Fructofuranans, e.g. beta-2,6-D-fructofuranan, i.e. levan; Derivatives thereof
  • C08B37/0054—Inulin, i.e. beta-2,1-D-fructofuranan; Derivatives thereof
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
  • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
  • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
  • C08B37/0057—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid beta-D-Xylans, i.e. xylosaccharide, e.g. arabinoxylan, arabinofuronan, pentosans; (beta-1,3)(beta-1,4)-D-Xylans, e.g. rhodymenans; Hemicellulose; Derivatives thereof
• • C—CHEMISTRY; METALLURGY
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  • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
  • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
  • 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
  • C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
  • C08B37/0072—Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates
• • C—CHEMISTRY; METALLURGY
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  • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
  • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
  • 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
  • C08B37/0084—Guluromannuronans, e.g. alginic acid, i.e. D-mannuronic acid and D-guluronic acid units linked with alternating alpha- and beta-1,4-glycosidic bonds; Derivatives thereof, e.g. alginates

Definitions

• the present invention relates to novel biocompatible polymers based on polysaccharides.
• These polymers may be useful in particular for the administration of active principle (s) (PA) to humans or animals for therapeutic and / or prophylactic purposes.
• PA active principle
• Polysaccharides also called glycans or polysaccharides, are polymers formed of monosaccharide units, or osides, linked by glycosidic bonds.
• the polysaccharides have the general formula [C x (H 2 ⁇ ) x- i)] n . These macromolecules are complex due to variations in size, branching, monosaccharide unit nature and glycosidic bond nature.
• Homopolysaccharides consist of a single monosaccharide unit.
• the glycosidic bond is the bond formed between the hemi-acetal group of a saccharide and the hydroxyl function of another saccharide. This bond can be alpha or beta depending on the stereochemistry of the anomeric carbon but above all it can be (1, 2), (1, 3), (1, 4) or (1, 6) depending on the hydroxyl function 2, 3, 4 or 6 saccharide involved in the binding.
• Some polysaccharides are composed of the same units but vary by the bonds involved.
• dextran and pullulan are both polysaccharides composed of glucose units but, in the case of dextran, the glycosidic bonds are greater than 95% (1, 6) while in the case of pullulan, they are at 67% (1, 4) and 33% (1, 6).
• These structural differences lead to differences in physical properties. such as solubility in organic solvents, solubility in water, viscosity.
• amphiphilic polysaccharides numerous examples have been reported.
• Biodex in US Pat. No. 6,646,120 has described carboxymethyldextrans modified with benzylamine.
• This polysaccharide consists predominantly of glycosidic units linked by a bond 1, 6. This sequence leads to obtaining very fluid polymer solutions.
• Patent FR0702316 of the Applicant describes dextrans modified with hydrophobic amino acids including tryptophan.
• dextran consists mainly of sequences 1, 6 of a lycosidic ions.
• dextran is a singular polysaccharide because it is the only polysaccharide composed of more than 95% of bonds (1, 6) which gives it a very good solubility in water, a low viscosity in water and also a good solubility in polar organic solvents such as dimethylsulfoxide, DMSO.
• the polysaccharides can be used as carriers or excipients in pharmaceutical formulations.
• the low viscosity of dextran and its high solubility in water may have disadvantages such as too much diffusion from the site of administration, too rapid dilution by biological fluids.
• polysaccharides such as hyaluronans or alginates have different physical properties.
• Hyaluronan derivatives modified with fatty alkyl chains in C12 or C18 are described in particular in patent FR2794763.
• derivatives of alginate modified with fatty alkyl chains are also described derivatives of alginate modified with fatty alkyl chains.
• Akiyoski et al. J. Controlled Release 1998, 54, 313-320
• the hydrophobic groups that are grafted do not have sufficient affinity with certain active principles such as proteins when they are used as carriers in pharmaceutical compositions.
• the present invention relates to novel polysaccharide derivatives, predominantly comprising (1, 4), (1, 3) and / or (1, 2) glycoside linkages functionalized with at least one tryptophan derivative.
• novel amphiphilic polysaccharides have a biocompatibility comparable to the dextran derivatives but their viscosity is higher and makes it possible to obtain vehicles for pharmaceutical compositions having a viscosity sufficient to prevent diffusion from the site of administration. Nevertheless, their hydrophobicity can easily be modulated without altering their biocompatibility.
• the use as hydrophobic groups of tryptophan derivatives also makes it possible to obtain a good interaction with the active principles, in particular by the formation of complexes, which allows a modulation of their immobilization.
• the polysaccharides according to the invention consist mainly of glycoside bonds of (1,4) type, and / or (1,3) and / or (1,2) they may be neutral, that is to say not be carrying acid or anionic functions and carrying acid functions. They are functionalized by at least one derivative of tryptophan, noted Trp:
• Said tryptophan derivative being grafted or bound to the polysaccharides by coupling with an acid function, said acid function possibly being an acid function of an anionic polysaccharide and / or an acid function carried by a linker R linked to the polysaccharide by a function F, said function F resulting from the coupling between the linker R and a function -OH of the neutral or anionic polysaccharide,
• F being either an ester, thioester, amide, carbonate, carbamate, ether, thioether or amine function
• R being a chain comprising between 1 and 18 carbons, optionally branched and / or unsaturated comprising one or more heteroatoms, such as O, N or / and S, and having at least one acid function
• Trp being a residue of a tryptophan derivative, L and / or D, product of the coupling between the tryptophan amine and the at least one acid carried by the R group and / or an acid carried by the anionic polysaccharide.
• the functionalized polysaccharides may correspond to the following general formulas:
• polysaccharide consisting mainly of glycoside bonds of (1,4) type, and / or (1,3) and / or (1,2),
• R being a chain comprising between 1 and 18 carbons, optionally branched and / or unsaturated comprising one or more heteroatoms, such as O, N or / and S, and having at least one acid function
• Trp being a residue of a tryptophan derivative, L and / or D, produces coupling between the amine of the tryptophan derivative and at least one acid carried by the group R and / or an acid carried by the anionic polysaccharide.
• n represents the molar fraction of the Rs substituted by Trp and is between 0.05 and 0.7.
• o represents the molar fraction of the acid functions of the polysaccharides substituted with Trp and is between 0.05 and 0.7.
• i represents the mole fraction of acid functions carried by the group R per saccharide unit and is between 0 and 2
• j represents the mole fraction of acid functional groups carried by the anionic polysaccharide per saccharide unit and is between 0 and 1
• (i + j) represents the mole fraction of acid functions per saccharide unit and is between 0.1 and 2
• the acid or acids of the R group are cationic carboxylates, alkali preferably as
• polysaccharide when the polysaccharide is an anionic polysaccharide, when one or more acid functions of the polysaccharide are not substituted by Trp, then they are salified by a cation, alkaline preferably as Na or K. said polysaccharides being amphiphilic at neutral pH.
• F is either an ester, a carbonate, a carbamate or an ether.
• the polysaccharide consists predominantly of glycoside bonds of the type (1, 4).
• the polysaccharide predominantly composed of glycoside bonds of type (1, 4) is selected from the group consisting of pullulan, alginate, hyaluronan, xylan, galacturonan or a cellulose soluble in the water.
• the polysaccharide is a pullulan.
• the polysaccharide is an alginate. In one embodiment, the polysaccharide is a hyaluronan. In one embodiment, the polysaccharide is a xylan. In one embodiment, the polysaccharide is a galacturonan.
• the polysaccharide is a water-soluble cellulose.
• the polysaccharide consists predominantly of glycoside bonds of (1, 3) type.
• the polysaccharide consisting predominantly of glycoside bonds of type (1, 3) is a curdlane.
• the polysaccharide consists mainly of glycoside bonds of (1, 2) type.
• the polysaccharide consisting predominantly of glycoside bonds of type (1, 2) is an inulin.
• the polysaccharide consists mainly of glycoside bonds of (1,4) and (1,3) type.
• the polysaccharide predominantly composed of glycoside bonds of (1,4) and (1,3) type is a glucan.
• the polysaccharide consists predominantly of glycoside bonds of (1, 4) and (1, 3) and (1, 2) type.
• the polysaccharide predominantly composed of glycoside bonds of (1,4) and (1,3) and (1,2) type is mannan.
• the polysaccharide according to the invention is characterized in that the group R is chosen from the following groups:
• the polysaccharide according to the invention is characterized in that the tryptophan derivative is selected from the group consisting of tryptophan, tryptophanol, tryptophanamide, 2-indole ethylamine and their alkaline cation salts.
• the polysaccharide according to the invention is characterized in that the tryptophan derivative is chosen from the esters of tryptophan of formula II
• E being a group that can be:
• a linear or branched C1 to C8 alkyl A linear or branched C1 to C8 alkyl. "A linear or branched C 6 -C 20 alkylaryl or arylalkyl.
• the polysaccharide may have a degree of polymerization m of between 10 and 10,000.
• it has a degree of polymerization m of between 10 and 1000.
• the functionalized polysaccharides are pullulans which correspond to the following general formula III:
• R being a chain comprising between 1 and 18 carbons, optionally branched and / or unsaturated comprising one or more heteroatoms, such as O, N or / and S, and having at least one acid function; Trp being a residue of a derivative; tryptophan, L and / or D, product of the coupling between the amine of the tryptophan derivative and the at least one acid carried by the R.
• n group represents the molar fraction of the Rs substituted by Trp and is between 0.05 and 0.7.
• i represents the mole fraction of acid functional groups carried by the group R per saccharide unit and is between 0 and 2
• the acid or acids of the R group are cationic carboxylates, alkali preferably as Na or K, said pullulans being amphiphilic at neutral pH.
• F is either an ester, a carbonate, a carbamate or an ether.
• the pullulan according to the invention is characterized in that the group R is chosen from the following groups:
• the pullulan according to the invention is characterized in that the tryptophan derivative is chosen from the group consisting of tryptophan, tryptophanol, tryptophanamide, 2-indole ethylamine and their alkaline cation salts.
• the pullulan according to the invention is characterized in that the tryptophan derivative is chosen from the esters of tryptophan of formula II
• E being a group that can be:
• a linear or branched C1 to C8 alkyl A linear or branched C1 to C8 alkyl.
• a linear or branched C 6 -C 20 alkylaryl or arylalkyl is A linear or branched C 6 -C 20 alkylaryl or arylalkyl.
• the pullulan may have a degree of polymerization m of between 10 and 10,000.
• it has a degree of polymerization m of between 10 and 1000. In another embodiment, it has a degree of polymerization m of between 10 and 500.
• the functionalized polysaccharides are galacturonans which correspond to the following general formulas:
• linker R a function -OH of galacturonan, being either an ester, thioester, amide, carbonate, carbamate, ether, thioether or amine function
• R being a chain comprising between 1 and 18 carbons , optionally branched and / or unsaturated comprising one or more heteroatoms, such as O, N or / and S, and having at least one acid function
• Trp being a residue of a tryptophan derivative, L and / or D, produces a coupling between the amine of the tryptophan derivative and the at least one acid carried by the R group and / or an acid carried by galacturonan.
• n represents the molar fraction of the Rs substituted by Trp and is between 0.05 and 0.7.
• 0 represents the mole fraction of the acid functions of Trp-substituted galacturonans and is between 0.05 and 0.7.
• the acid or acids of the R group are cationic carboxylates, alkali preferably as
• galacturonan when one or more acid functions of galacturonan are not substituted by Trp, then they are salified by a cation, alkaline preferably as Na or K. said galacturonans being amphiphilic at neutral pH.
• F is either an ester, a carbonate, a carbamate or an ether.
• the galacturonan according to the invention is characterized in that the group R is chosen from the following groups:
• the galacturonan according to the invention is characterized in that the tryptophan derivative is selected from the group consisting of tryptophan, tryptophanol, tryptophanamide, 2-indole ethylamine and their alkali cation salts.
• the galacturonan according to the invention is characterized in that the tryptophan derivative is chosen from the esters of tryptophan of formula II Formula II
• E being a group that can be:
• a linear or branched C1 to C8 alkyl A linear or branched C 6 -C 20 alkylaryl or arylalkyl.
• Galacturonan may have a degree of polymerization m of between 10 and 10,000.
• it has a degree of polymerization m of between 10 and 1000.
• it has a degree of polymerization m of between 10 and 500.
• the functionalized polysaccharides are alginates which correspond to the following general formulas:
• linker R an -OH function of the alginate, being either an ester, thioester, amide, carbonate, carbamate, ether, thioether or amine function
• R being a chain comprising between 1 and 18 carbons, optionally branched and / or unsaturated comprising one or more heteroatoms, such as O, N or / and S, and having at least one acidic function
• Trp being a residue of a tryptophan derivative, L and / or D, product of the coupling between the amine of the tryptophan derivative and the at least one acid carried by the R group and / or an acid carried by the alginate .
• n represents the molar fraction of the Rs substituted by Trp and is between 0.05 and 0.7.
• 0 represents the mole fraction of the acid functions of Trp-substituted alaginates and is between 0.05 and 0.7.
• the acid or acids of the R group are cation carboxylates, alkali preferably as Na or K.
• F is either an ester, a carbonate, a carbamate or an ether.
• the alginate according to the invention is characterized in that the group R is chosen from the following groups:
• the alginate according to the invention is characterized in that the tryptophan derivative is selected from the group consisting of tryptophan, tryptophanol, tryptophanamide, 2-indole ethylamine and their alkaline cation salts.
• the alginate according to the invention is characterized in that the tryptophan derivative is chosen from the esters of tryptophan of formula II
• E being a group that can be: • linear or branched C1 to C8 alkyl.
• a linear or branched C 6 -C 20 alkylaryl or arylalkyl is A linear or branched C 6 -C 20 alkylaryl or arylalkyl.
• the alginate may have a degree of polymerization m of between 10 and 10,000.
• it has a degree of polymerization m of between 10 and 1000. In another embodiment, it has a degree of polymerization m of between 10 and 500.
• R groups may be grafted onto the alcohols functions of the polysaccharide and grafting of the tryptophan derivative may be carried out:
• the coupling reactions are followed by the neutralization of unreacted acid functional groups with a tryptophan derivative by salification by one of the methods well known to those skilled in the art, for obtain an alkaline cation salt, preferably Na or K.
• the invention also relates to a pharmaceutical composition
• a pharmaceutical composition comprising one of the polysaccharides according to the invention as described above and at least one active ingredient.
• Active ingredient means a product in the form of a single chemical entity or in the form of a combination having an activity physiological.
• Said active ingredient may be exogenous, ie it is provided by the composition according to the invention. It may also be endogenous, for example the growth factors that will be secreted in a wound during the first healing phase and that may be retained on said wound by the composition according to the invention.
• the invention also relates to a pharmaceutical composition according to the invention as described above characterized in that it is administrable orally, nasally, vaginally, orally.
• the invention also relates to a pharmaceutical composition according to the invention as described above, characterized in that it is obtained by drying and / or lyophilization.
• the invention also relates to a pharmaceutical composition according to the invention as described above, characterized in that it is administrable in stent form, film or "coating" of implantable biomaterials implant.
• the invention also relates to a pharmaceutical composition according to the invention as described above characterized in that the active ingredient is selected from the group consisting of proteins, glycoproteins, peptides and non-peptide therapeutic molecules.
• compositions are either in liquid form (nanoparticles or microparticles suspended in water or in solvent mixtures), or in powder, implant or film form.
• the modes of administration • considered are intravenous, subcutaneous, intradermal, intramuscular, oral, nasal, vaginal, ocular, oral, etc.
• the invention also relates to the use of the functionalized polysaccharides according to the invention for the preparation of pharmaceutical compositions as described above.
• the invention is illustrated by the following examples.
• the sodium pullulanemethylcarboxylate solution is passed through a Purolite resin (anionic) to obtain the acidic pullulanemethylcarboxylic acid which is then lyophilized for 18 hours.
• the solution of sodium pullulanesucciniccarboxylate is passed through a Purolite resin (anionic) to obtain the acidic pullulanesucciniccarboxylic acid which is then lyophilized for 18 hours.
• the solution is purified by dialysis on an 8 kD regenerated cellulose membrane in 3 times 8 liters of 0.9% NaCl solution and then twice 8 liters of water.
• the purified solution is lyophilized entirely.
• the lyophilizate is analyzed by 1 H NMR in D 2 O NaOD to determine the DS in grafted tryptophan.
• the lyophilizate is analyzed by 1 H NMR in D 2 O NaOD to determine the degree of substitution, DS, of tryptophan grafted per saccharide unit. According to 1 H NMR, the DS in tryptophan per saccharide unit is 0.25.
• the molar mass distribution of the final polymer is analyzed by Steric Exclusion Chromatography. The chromatogram makes it possible to validate the absence of a secondary reaction such as the coupling of chains or the breaking of chains.
• Example 4 Synthesis of Galacturonate Modified with Sodium Tryptophan
• RCOONa 9% RCOOMe, SigmaAIdrich P9135
• RCOONa 9% RCOOMe, SigmaAIdrich P9135
• the solution obtained is cooled to 4 ° C.
• 4.72 g (25 mmol) of N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (EDC, Fluka 03450) are added.
• EDC N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride
• TrpOEt.HCl tryptophan ethyl ester hydrochloride
• reaction medium After stirring for 30 minutes at 4 ° C., the reaction medium is brought to 25 ° C. and stirring is maintained for 24 hours. The reaction medium is then diluted in a sodium hydroxide solution such that the pH of the mixture is greater than 12. The mixture which has become clear is purified by ultrafiltration on a 50 KD cutoff membrane against 9 volumes of water and concentrated. A solids content of 17 mg / g is obtained.
• the DS in tryptophan per saccharide unit is 0.15.
• a fraction of the solution is lyophilized and then analyzed by NMR
• This polymer is a comparative example.
• the polymer 5 is a sodium dextranmethylcarboxylate modified with the sodium salt of L-tryptophan obtained from a dextran with a weight average molecular mass of 40 kg / mol (Pharmacosmos) according to the process described in the patent application FR07. 02316.
• the molar fraction of sodium methylcarboxylate, modified or not with tryptophan, per saccharide unit is 1.03.
• the molar fraction of tryptophan-modified sodium methylcarboxylates per saccharide unit is 0.36.
• Counterexample 1 Synthesis of a sodium pullulanemethylcarboxylate, polymer 6
• This polymer is obtained according to the process described in the first part of Example 1. The acidification and grafting steps of tryptophan are not carried out.
• the degree of substitution of the hydroxyl functions by methylcarboxylate functions is 1.17 per saccharide unit. This polymer serves as a counterexample to this invention.
• Preparation of the 1/500 protein / polymer complex 1 5 ⁇ g of protein are added to 750 ⁇ g of polymer, to 15 ⁇ l of 10X migration buffer (tris acetate pH 7). The solution is completed at 150 ⁇ l with hbO. This solution is incubated at room temperature for 20 minutes. 5 ⁇ l of this second solution containing 50 ng of protein and 25 ⁇ g of polymer are diluted in 5 .mu.l of 1X migration buffer. Similar solutions containing only the protein or polymer are prepared as a control.
• the protein / polymer solution (10 ⁇ l) is mixed with 3 ⁇ l of loading buffer (glycerol, tris-acetate and bromophenol blue in water). These 13 .mu.l containing 50 ng of protein and 25 .mu.g of polymer are deposited in a well of a 0.8% agarose gel. Control solutions (protein or polymer alone) are deposited in a similar manner.
• the electrophoresis tank is closed and the generator is set at 30V. The migration lasts
• the gel is transferred to a PVDF membrane by capillarity with an Apelex system for 2 hours at room temperature.
• the membrane is then saturated with skimmed milk for 1 hour at room temperature and then incubated with rabbit primary antibodies. directed against the protein (overnight at 4 0 C) and finally incubated with secondary antibodies rabbit anti goat HRP (1 hour at room temperature).
• the revelation is by reaction of I 1 HRP on Opti-4CN. The revelation is stopped by rinsing in water when the coloration is sufficient since the reaction product absorbs in the visible.
• the protein When the protein is alone or does not complex with the polymer, it can migrate if it is anionic or remain at the deposition site if it is cationic. The protein is then detected either at the loading wells or in the form of a single spot 0.3-0.4 cm from the deposit. When the protein forms a complex with the polymer, the complex is driven more strongly by the charges of the polymer and moves towards the anode. It is detected as a single spot 0.7 cm from the deposit. The intensity of this spot varies according to the amount of protein entrained by the polymer. The analysis is considered semi-quantitative since there is a link between spot intensity and the importance of affinity.
• the viscosity of the precursor polysaccharides was studied using a TA AR2000ex rheometer.
• the precursor pullulan of polymer 1 has a viscosity of 14 mPa.s at a concentration of 77 mg / mL.
• the precursor dextran of the polymer has a viscosity of 15 mPa.s at a concentration of 164 mg / mL.
• the pullulan used is about twice as viscous as the dextran used.

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