WO2003095597A1 - Novel amphiphilic copolymer-type biodegradable surface active agents comprising hydrophobic segments and oligo- and/or polysaccharides - Google Patents

Novel amphiphilic copolymer-type biodegradable surface active agents comprising hydrophobic segments and oligo- and/or polysaccharides Download PDF

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WO2003095597A1
WO2003095597A1 PCT/FR2003/001408 FR0301408W WO03095597A1 WO 2003095597 A1 WO2003095597 A1 WO 2003095597A1 FR 0301408 W FR0301408 W FR 0301408W WO 03095597 A1 WO03095597 A1 WO 03095597A1
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oligo
radical
polysaccharide
surfactant
copolymer according
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PCT/FR2003/001408
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French (fr)
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Cédric-Georges CHAUVIERRE
Patrick Couvreur
Denis Labarre
Christine Vauthier
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Centre National De La Recherche Scientifique (C.N.R.S.)
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Priority to AU2003251039A priority Critical patent/AU2003251039A1/en
Publication of WO2003095597A1 publication Critical patent/WO2003095597A1/en

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    • C—CHEMISTRY; METALLURGY
    • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
    • C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
    • C11D3/00—Other compounding ingredients of detergent compositions covered in group C11D1/00
    • C11D3/16—Organic compounds
    • C11D3/37—Polymers
    • C11D3/3788—Graft polymers
    • C—CHEMISTRY; METALLURGY
    • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
    • C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
    • C11D1/00—Detergent compositions based essentially on surface-active compounds; Use of these compounds as a detergent
    • C11D1/008—Polymeric surface-active agents

Definitions

  • the subject of the invention is the use as surfactants of a family of amphiphilic bioerodible copolymers consisting of hydrophobic segments and of oligo- and / or polysaccharides. They are particularly useful in sectors such as detergents and surface treatments and more generally in the fields of detergents, pharmacy, cosmetics, ecology, food ...
  • Surfactants or surfactants are generally charged or uncharged molecules and / or macromolecules of an amphiphilic nature, that is to say having on the one hand a hydrophilic region and on the other hand a hydrophobic region. This particular structure induces an orientation of these molecules when they are present at liquid / liquid, liquid / gas or liquid / solid type interfaces.
  • a surfactant is a molecule consisting of one or more hydrophilic group (s) ionic or not and one or more hydrophobic chain (s), most often hydrocarbon (s) insoluble ( s) in water.
  • the surfactant properties arise from the antagonism between these two parts.
  • Anionic surfactants comprising negatively charged hydrophilic groups such as carboxylate, sulfate or sulfonate functions, cationic surfactants comprising positively charged groups such as a quaternary ammonium function, amphoteric surfactants comprising positively and negatively charged groups and which, depending on the pH, behave in anionic or cationic surfactants such as, for example, betaines, the most widely used nonionic surfactants, the solubility of which in water results from the accumulation in the molecule of alcohol functions or of ether functions.
  • ionic agent of fatty acid salts, alkyl sulfates, quaternary ammonium salts, and on the other hand , ethoxylated alkylphenols (APE), poly (alkyl glucosides) (PGA), ethoxylated alcohols (AE), compounds comprising poly (ethylene glycol) (PEG) or poly (oxyethylene) (POE) sequences, non-ionic agent.
  • APE ethoxylated alkylphenols
  • PGA poly (alkyl glucosides)
  • AE ethoxylated alcohols
  • PEG poly (ethylene glycol)
  • POE poly (oxyethylene)
  • the present invention is based on the discovery of new surfactants, the polymer structure of which derives from the association of hydrophilic segments of natural or modified oligo- and / or polysaccharide nature and hydrophobic segments.
  • Oleaccharide is understood to mean, in the present description, any sugar composed of at least 5 saccharide units, at most 50 saccharide units.
  • Polysaccharide is understood to mean, in the present description, any sugar composed of more than 50 saccharide units.
  • the subject of the present invention is the use as surfactant of at least one linear and / or branched block amphiphilic block copolymer comprising at least one natural or modified oligo- and / or polysaccharide block and at least one hydrophobic sequence consisting of bioerodible polymers of general formula (I):
  • - X represents a CN or CONHR radical
  • - Y represents a COOR ′ or CONHR ′′ radical, with R, R ′ and R ′′ representing, independently of one another, a hydrogen atom, a linear or branched C 1 to C 20 alkyl group, a group C alkoxy . with linear or branched C 20 , an amino acid radical, a mono- or polyhydroxylated acid radical or an aryl or heteroaryl radical in C 5 to C ⁇ 2 .
  • Bioerodable polymer is understood to mean, in the present description, any polymer which can be degraded by living organisms, most often by the enzymes of these organisms.
  • the new family of claimed surfactant is bioerodible, due to the presence of hydrolyzable bonds in its structure.
  • Another advantageous aspect of these surfactants is their biocompatible character.
  • the surfactant properties of the copolymers according to the invention are modular.
  • their solubility can be adjusted by varying the proportion, the length and the nature of the segments of saccharide nature incorporated in the polymer structure.
  • their solubility is directly linked to the proportion, to the nature, and to the length of the hydrophobic segments.
  • the copolymers have surfactant properties such that they are neither soluble in water, or in an organic solvent, therefore necessarily placing itself at the interface of the two phases present.
  • X preferably represents a CN radical. More preferably, Y represents a radical COOR 'with R' as defined above. More preferably, R 'is chosen from the methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, isohexyl, octyl, 2-methoxyethyl groups.
  • the repeating unit of isobutyl cyanoacrylate may be more particularly cited by way of illustration of a unit capable of composing a segment of general formula (I).
  • sequenced structure is intended to denote a structure which derives from the establishment of a covalent bond between at least one of the ends of the segment of saccharide nature and one of the ends of the polymer chain of general formula (I).
  • the following are useful as surfactants: linear copolymer structures comprising either a single segment of general formula (I) linked to one end of the saccharide nature segment, or two segments of general formula (I), identical or different, linked respectively by part and on the other side of the saccharide segment; grafted copolymer structures having one or more lateral branching (s) of hydrophobic nature on the segment of saccharide nature.
  • the covalent bond, established between the two types of segment, is generally of C-C or C-O-C nature.
  • the covalent bond can be derived from radical or anionic polymerization of at least one molecule of a compound of formula (II).
  • the saccharide nature segment derives from an oligo- or polysaccharide of natural or synthetic origin, modified or not.
  • modified oligo- or polysaccharide means any oligo- or polysaccharide which has undergone a change in its skeleton, such as for example the introduction of reactive functions; grafting of chemical entities (molecules, aliphatic links, PEG chains, etc.); functionalization of one of the functions of the oligo- or polysaccharide, such as the substitution of one or more hydroxyl functions with functions such as the amino, amide, acylamine functions, by esterification or etherification of one or more hydroxyl functions , by amidification of one or more amino functions; the elimination of one or more functions, for example hydroxyl functions of the oligo- or polysaccharide; the salification of one or more functions of the oligo- or polysaccharide such as the hydroxyl, amino, sulfonic, carboxylic functions.
  • Other polysaccharides grafted with hydrophilic chains eg PEG
  • PEG polysaccharides modified like those described in the reference Jozefowicz and Jozefonvicz, Biomaterials, 18, 1633-1644 (1997), or polysaccharides modified by grafting of a ligand which can be an active principle, a recognition entity specific for a cell receptor or antigen, an antigen, a positively or negatively charged chemical entity.
  • oligo- or polysaccharide of natural origin means any oligo- or polysaccharide extracted from living organisms such as algae, plants, animals, microorganisms.
  • oligo- or polysaccharide of synthetic origin means any oligo- or polysaccharide produced by chemical synthesis or by a biotechnological process.
  • an anionic surfactant preference is given to the choice of an anionic oligo- and / or polysaccharide such as glycosaminoglycans, such as heparin, polysialic acids, carbohydrate parts of glycoproteins, neutral oligo- and / or polysaccharides substituted by carboxylic, sulphate or sulphonate groups such as dextran sulphate, dermatan sulphate, pentosan sulphate and natural anionic gums.
  • an anionic oligo- and / or polysaccharide such as glycosaminoglycans, such as heparin, polysialic acids, carbohydrate parts of glycoproteins, neutral oligo- and / or polysaccharides substituted by carboxylic, sulphate or sulphonate groups such as dextran sulphate, dermatan sulphate, pentosan sulphate and natural anionic gums.
  • the cationic or neutral surfactants are prepared by favoring the choice, respectively, of a cationic oligo- and / or polysaccharide comprising for example glucosamine sequences such as chitin and its derivatives or of an oligo- and / or neutral polysaccharide such as starch, glycogen, dextrins, cellulose, dextran and neutral natural gums.
  • a cationic oligo- and / or polysaccharide comprising for example glucosamine sequences such as chitin and its derivatives or of an oligo- and / or neutral polysaccharide such as starch, glycogen, dextrins, cellulose, dextran and neutral natural gums.
  • oligo- or polysaccharides which can be used in the context of the present invention, mention may more particularly be made of oligo- or polysaccharides comprising the D-glucose units such as cellulose, starch, dextran, glycogen, cyclodextrins, D-galactose, D-mannose, D-fructose units such as inulin, galactosan, manane, fructosan, fucose unit such as fucane and their derivatives for neutral polysaccharides.
  • D-glucose units such as cellulose, starch, dextran, glycogen, cyclodextrins, D-galactose, D-mannose, D-fructose units such as inulin, galactosan, manane, fructosan, fucose unit such as fucane and their derivatives for neutral polysaccharides.
  • anionic polysaccharides such as the carbohydrate parts of glycoproteins or glycolipids and their derivatives such as poly (sialic acid), also called colominic acid or poly (N-acetylneuraminic acid), neuraminic acid, carbohydrate parts of orosomucoid, glycosaminoglycans such as hyaluronic acid, heparin, chondroitin sulfate, or algae extracts such as marine algae such as carragheenane, or alginate.
  • cationic polysaccharides for example polymers of glucosamines or their derivatives. Chitosan is a preferred example.
  • oligo- and polysaccharides are more particularly preferred according to the invention: dextran, starch, amylose, glycogen, cellulose, inulin, chitin, cyclodextrins, xylan, xanthan, l arabinan, fucan, curdlan, pullulan, chitosan, hyaluronic acid, chondroitin sulfate, heparin, poly (N-acetylneuraminic acid), neuraminic acid, the carbohydrate parts of orosomucoid , pectin, alginate, agar, carragheenane, amylopectin, succinoglycan, poly (glucuronic) acid, poly (mannuronic) acid, and their derivatives such as, for example, dextran sulfate, heparans sulfates, amylose esters, cellulose acetate, pentosan sulfate.
  • oligo- and / or polysaccharide By “derivative” of an oligo- and / or polysaccharide is meant any “modified” oligo- and / or polysaccharide as defined above.
  • the polysaccharide sequence is preferred.
  • the oligo- and / or polysaccharide preferably has a molar mass greater than or equal to 6000 g / mol.
  • the copolymers have a controlled oligo- or polysaccharide content.
  • the preferred surfactants according to the invention are the copolymers consisting of heparin or dextran as a segment of saccharide nature and of poly (isobutyl cyanoacrylate) as a hydrophobic segment, resulting from anionic and / or radical polymerization.
  • the claimed copolymer may be in powder form. It can be directly introduced into the medium in the powder state and dissolve with stirring at liquid type interfaces.
  • the surfactant can be used in particular for preparing emulsions. It is then generally used at a rate of 0.1 to 10% of the total weight of the emulsion, preferably from 0.2% to 5%.
  • copolymers according to the invention which are in a linear form can be obtained according to the process described in application PCT / FR01 / 03619.
  • this process consists in a radical polymerization of at least one molecule of a compound of general formula (II):
  • - X represents a CN or CONHR radical
  • - Y represents a COOR 'or CONHR "radical with R, R' and R" representing, independently of one another, a hydrogen atom, a linear or branched C 1 -C 2 alkyl group, a group linear or branched C 1 -C 2 alkoxy, an amino acid radical, a mono- or polyhydroxylated acid radical or a C 5 to C12 aryl or heteroaryl radical, with said oligo- and / or polysaccharide segment being linked either by the one of these ends to a single segment of general formula (I), either by each of its two ends, to a segment of general formula (I), the two hydrophobic segments being identical or different, said radical polymerization being carried out in the presence of at least one molecule of an oligo- and / or polysaccharide, under pH and atmosphere conditions unfavorable to the presence and or to the generation of anions in the reaction medium and in presence of a sufficient amount of a suitable radical redox initiator.
  • the pH of the reaction medium is preferably adjusted to a value less than 2 and more preferably less than 1.5.
  • This reaction is also carried out under inert atmosphere conditions.
  • the solvent is advantageously chosen so that, while maintaining conditions favorable to radical polymerization and more particularly to the formation of the hydrophobic segment of formula (I), the solubility of the oligo- and / or polysaccharide is complete in the medium defined by this solvent.
  • the solvent is also chosen to be weakly or non-solubilizing with respect to the copolymer.
  • it is preferably chosen from aqueous, hydroalcoholic or hydroacetonic solvents.
  • the solvent chosen is acidified with an organic or inorganic acid and preferably a nitric acid to obtain an adequate pH during the course of the radical polymerization.
  • oligo- and / or polysaccharide and monomer of general formula (II) can vary widely, depending on the desired surfactant properties.
  • the process described in application PCT / FR01 / 03619 precisely has the advantage of allowing control of the structure of the copolymer which it is desired to prepare.
  • the amounts of reagents introduced also depend on their respective molecular weights and their degrees of solubility in the reaction medium.
  • Redox initiator these are generally mixtures of oxidizing and reducing agents, organic or inorganic, generating radicals during the electronic transfer step. This generation of radicals has the advantage of requiring a low activation energy unlike conventional radical initiators, which makes it possible to initiate radical polymerizations at relatively low temperatures (0-50 ° C).
  • the Redox initiator used preferably comprises at least one metal salt chosen from the salts of Ce 4+ , V 5+ , Cr 6+ , Mn 3+ . According to a preferred variant of the invention, it is Ce 4+ . It is generally introduced in the form of cerium and ammonium nitrate.
  • the concentration of radical initiator is liable to influence the course of the radical polymerization.
  • the composition of the copolymer and the length of the respective blocks of the oligo- and / or polysaccharide and of the polymer of general formula (I) can be adjusted as a function of the initiator concentration. Its adjustment is within the competence of a person skilled in the art.
  • reaction temperature it is adjusted to a value compatible with the initiation of the polymerization. Generally, this temperature is between 0 and 50 ° C.
  • the oligo- and / or polysaccharide is preferably dissolved in the chosen solvent, followed by the addition of the radical initiator Redox.
  • the monomer of formula (II) is then introduced into the mixture.
  • the copolymer can be obtained in a soluble form or in the form of micelles, aggregates or particles.
  • the pH of the reaction medium can be neutralized if necessary. Preferably, this is adjusted to a value that remains less than or equal to 7.5.
  • the copolymer is recovered by conventional techniques.
  • the copolymer is isolated beforehand, with a complexation of the metal salt resulting from the reaction of the radical initiator.
  • This complexation which is within the competence of a person skilled in the art, makes it possible to eliminate these metal salts.
  • the copolymers according to the invention which are in branched form, they are accessible by a separate process which involves anionic polymerization. This type of process is described in particular in patent EP0007895 (Couvreur et al., 1979) and in the publication by SJ Douglas, L. Illum, SS Davis, Journal of colloid and interface science, 103, 154 (1985).
  • the anionic polymerizations are carried out in the presence of a strong acid at a pH of less than 3 and preferably around 2.5.
  • the surfactants according to the invention can be used in particular for stabilizing cosmetic emulsions, such as, for example, make-up products comprising organic and inorganic pigments present in the aqueous and / or oily phase.
  • the surfactants according to the invention can also be used for the dispersion of finely divided solid particles of varied nature in fluids, in particular in a liquid aqueous medium, in particular colloids. These dispersed solid particles can be pigments for paints or inks, magnetic metal oxides, optical brighteners or agrochemicals (fungicides).
  • the surfactants according to the invention can be used in particular as emulsifiers (or emulsifiers), _ _ ⁇
  • suspending agents such as the paper, leather and textile industry (eg fabric softeners), the manufacture of fire extinguishers, of cosmetic and pharmaceutical products, mineral extraction, organic catalysis ...
  • Figure 1 Turbidity profiles obtained by measuring the transmission of a light ray as a function of the height of a tube containing the emulsions of Example 5: reference emulsion, emulsion prepared with the dextran-PIBCA copolymer (A) , emulsion prepared with the heparin-PIBCA copolymer (B).
  • FIG. 2 Micrographs of the emulsions of Example 5, obtained by optical microscopy: emulsion prepared with the dextran-PIBCA copolymer (A), emulsion prepared with the heparin-PIBCA copolymer (B).
  • Figure 3 Turbidity profiles presented by the emulsions of Example 6, the reference emulsion, the emulsion prepared with the dextran-PIBCA copolymer (A '), and the emulsion prepared with the heparin-PIBCA copolymer (B ').
  • Figure 4 Stability of latexes consisting of copolymers of poly (isobutyl cyanoacrylate) and dextran (white columns) and consisting of copolymers of poly (isobutyl cyanoacrylate) and heparin (black columns) evaluated by measuring the hydrodynamic diameter after preparation (time 0) and conservation in aqueous dispersion at + 4 ° C for several months. The error bars represent the distribution of the size dispersion. ND: not determined The hydrodynamic diameters and size distributions of the latex are unchanged during the storage period considered.
  • 0.1375 g of dextran is dissolved in 8 ml HNO 3 (0.2 mol / 1), with magnetic stirring at 40 ° C and with a light bubbling with argon. After 10 minutes, 2 ml of acid solution of cerium ions (8.10 "2 M of cerium IV ammonium nitrate in HN0 3 at 0.2 mol / l) then 0.5 ml of isobutyl cyanoacrylate are added. After 10 minutes , bubbling with argon is stopped and the glass tube is plugged. After at least 40 min, stirring is stopped and the glass tube cooled under tap water.
  • the pH is adjusted with NaOH (1 N ) so that after the addition of 1.25 ml of tri sodium citrate dihydrate (1.02 M) it comes directly to a value of 7 + 0.5 Finally, the suspension is stored in the refrigerator. a suspension of stable colloidal polymer particles is obtained.
  • the copolymers constituting the particles are purified as follows: Dialysis tubes (Spectra / Por ® CE MWCO: 100,000) are regenerated for 30 minutes with osmosis water, and the colloidal suspensions passed through a vortex and then introduced into the tubes.
  • copolymers thus purified and contained in the dialysis tubes are recovered then are dried by lyophilization without the addition of cryoprotective. To do this, the copolymers are aliquoted in pill organizers and then frozen (-18 ° C). Lyophilization is carried out with a Bioblock Scientific Christ alpha 1-4 device for 48 hours. The lyophilisates in the form of white powders are kept in the refrigerator until use.
  • Example 5 Surfactant properties of copolymers with a linear structure.
  • a reference emulsion is prepared from:
  • An emulsion containing the dextran-PIBCA copolymer prepared according to Example 1 is composed of:
  • An emulsion containing the heparin-PIBCA copolymer prepared according to Example 2 is composed of:
  • the emulsions are prepared in a glass tube with a round bottom and a screw cap of 12 ml at 28 ° C according to the following stirring sequence carried out continuously:
  • Figure 1 shows the turbidity profiles expressed in transmission over the height of the tube. They were recorded during the monitoring of the evolution of the three emulsions at times 0, 2, 10 and 30 minutes. An increase in the transmission at the bottom of the tube indicates a phase separation of the emulsion by expulsion of water. An increase in the transmission at the top of the tube indicates a phase separation of the emulsion by expulsion of ethyl acetate. A zero transmission means that the medium is turbid (cloudy) due to the presence of an emulsion.
  • Table 1 gives the phase migration speeds of the different emulsions obtained during the phase shift of the initial emulsion, measured at a height of 30% of the transmission peaks.
  • the speed of phase migration is greater the more the emulsion is unstable.
  • the emulsions prepared with the copolymer of dextran-PIBCA and heparin-PIBCA are much more stable than the reference emulsion, which indicates that the copolymers have surfactant properties.
  • FIG. 2 shows the globules of the emulsions by observation under an optical microscope after formation of the emulsion.
  • the globules obtained are larger in size for the emulsion prepared with the heparin-PIBCA copolymer than those of the emulsion prepared with the dextran-PIBCA copolymer.
  • a reference emulsion is prepared from:
  • An emulsion containing the dextran-PIBCA copolymer prepared according to Example 3 is composed of:
  • An emulsion containing the heparin-PIBCA copolymer prepared according to Example 4 is composed of:
  • Table 2 gives the phase migration speeds of the different emulsions obtained during the phase shift of the initial emulsion, measured at a height of 30% of the transmission peaks.
  • Figure 3 shows the turbidity profiles expressed in transmission over the height of the tube. They were recorded during the monitoring of the evolution of the three emulsions at times 0, 2, 10 and 30 minutes. An increase in the transmission at the bottom of the tube indicates a phase separation of the emulsion by expulsion of water. An increase in the transmission at the top of the tube indicates a phase separation of the emulsion by expulsion of ethyl acetate. A zero transmission means that the medium is turbid (cloudy) due to the presence of an emulsion.
  • Example 8 The same protocol as that described in example 1 is reproduced using 0.1375 g of gamma-cyclodextrins in place of dextran. The copolymer obtained is soluble in acetone.
  • Example 8 The same protocol as that described in example 1 is reproduced using 0.1375 g of gamma-cyclodextrins in place of dextran. The copolymer obtained is soluble in acetone.
  • Example 8 The same protocol as that described in example 1 is reproduced using 0.1375 g of gamma-cyclodextrins in place of dextran. The copolymer obtained is soluble in acetone.
  • Example 8 The same protocol as that described in example 1 is reproduced using 0.1375 g of gamma-cyclodextrins in place of dextran. The copolymer obtained is soluble in acetone.
  • Example 8 The same protocol as that described in example 1 is reproduced using 0.1375 g of gamma-cyclodext
  • the copolymers obtained self-organize into colloidal particles dispersed in water.
  • the hydrodynamic diameter of these particles varies according to the molar mass of the dextran sulfate used during the synthesis (see Table 3).
  • Table 3 gives the hydrodynamic diameter of the colloidal particles formed by self-organization of copolymers consisting of dextran sulfate and poly (isobutyl cyanoacrylate) with a linear structure prepared from dextran sulfate of different molar masses.
  • the latex is prepared according to the protocol described in Example 1 up to the included dialysis step. It is kept in a stoppered bottle at + 4 ° C in the form of an aqueous dispersion as it was prepared.
  • the hydrodynamic diameter of the particles is evaluated at different storage times by quasi-elastic light scattering at 90 ° using a COULTER ® N4Plus nanosizer after dilution in water.
  • the hydrodynamic diameter of the latex particles close to 300 nm remains unchanged during a storage period of 36 months in dispersion (see Figure 1).
  • Example 10 Stability of a latex consisting of copolymers of heparin and of poly (isobutyl cyanoacrylate) with a linear structure.
  • the latex is prepared according to the protocol described in Example 2 up to the included dialysis step. It is stored in a stoppered bottle at + 4 ° C in the form of an aqueous dispersion as it was prepared.
  • the hydrodynamic diameter of the particles is evaluated at different storage times by quasi-elastic light scattering at 90 ° using a COULTER N4Plus nanosizer after dilution in water.
  • the hydrodynamic diameter of the latex particles close to 95 nm remains unchanged during a storage period of 30 months in dispersion. (see Figure 4).
  • FIG. 4 shows the stability of latexes consisting of copolymers of poly (isobutyl cyanoacrylate) and dextran (white columns) and consisting of copolymers of poly (isobutyl cyanoacrylate) and heparin (black columns) evaluated by the measurement hydrodynamic diameter after preparation (time 0) and conservation in aqueous dispersion at + 4 ° C for several months.
  • the error bars represent the distribution of the size dispersion.
  • ND not determined The hydrodynamic diameters and size distributions of the latex are unchanged during the storage period considered.

Abstract

The invention relates to the use of at least one block copolymer as a surface active agent, said block copolymer having a linear and/or branched structure consisting of a segment comprising a natural or modified oligo- and/or polysaccharide sequence and at least one hydrophobic sequence made up of bioerodable polymers having general formula (I), wherein X denotes a CN or CONHR radical, Y denotes a COOR' or CONHR'' radical, with R, R' and R' denoting, independently of one another, a hydrogen atom, a linear or branched C1 to C20 alkyl group, a linear or branched C1 to C20 alkoxy group, an amino acid radical, a mono- or polyhydroxylated acid radical or a C5 to C12 heteroaryl or aryl radical.

Description

NOUVEAUX AGENTS TENSIOACTIFS BIODÉGRADABLES DE TYPE COPOLY ÈRES AMPHIPHILES CONSTITUÉS DE SEGMENTS HYDROPHOBES ET D'OLIGO ET/OU NOVEL BIODEGRADABLE SURFACTANTS OF THE AMPHIPHILIC COPOLY ERA TYPE, CONTAINING HYDROPHOBIC SEGMENTS AND OLIGO AND / OR
POLYSACCHARIDESPolysaccharides
L'invention a pour objet l'utilisation à titre d'agents tensioactifs d'une famille de copolymères bioérodables amphiphiles constitués de segments hydrophobes et d'oligo- et/ou polysaccharides. Ils sont particulièrement utiles dans des secteurs comme celui des détergents et des traitements de surface et de façon plus générale dans les domaines de la détergence, la pharmacie, les cosmétiques, l'écologie, l'agroalimentaire...The subject of the invention is the use as surfactants of a family of amphiphilic bioerodible copolymers consisting of hydrophobic segments and of oligo- and / or polysaccharides. They are particularly useful in sectors such as detergents and surface treatments and more generally in the fields of detergents, pharmacy, cosmetics, ecology, food ...
Les agents tensioactifs ou surfactifs sont généralement des molécules et/ou macromolécules chargées ou non chargées à caractère amphiphile, c'est-à-dire possédant d'une part une région hydrophile et d'autre part une région hydrophobe. Cette structure particulière induit une orientation de ces molécules lorsqu'elles sont présentes à des interfaces de type liquide / liquide, liquide / gaz ou liquide / solide. Typiquement, un agent tensioactif est une molécule constituée d'un ou plusieurs groupement(s) hydrophile(s) ionique(s) ou non et une ou plusieurs chaîne(s) hydrophobe(s), le plus souvent hydrocarbonée(s) insoluble(s) dans l'eau. Les propriétés tensioactives découlent de l'antagonisme entre ces deux parties. On distingue généralement 4 types de tensioactifs :Surfactants or surfactants are generally charged or uncharged molecules and / or macromolecules of an amphiphilic nature, that is to say having on the one hand a hydrophilic region and on the other hand a hydrophobic region. This particular structure induces an orientation of these molecules when they are present at liquid / liquid, liquid / gas or liquid / solid type interfaces. Typically, a surfactant is a molecule consisting of one or more hydrophilic group (s) ionic or not and one or more hydrophobic chain (s), most often hydrocarbon (s) insoluble ( s) in water. The surfactant properties arise from the antagonism between these two parts. There are generally 4 types of surfactants:
Les tensioactifs anioniques comprenant des groupements hydrophiles chargés négativement tels que des fonctions carboxylates, sulfates ou sulfonates, les tensioactifs cationiques comprenant des groupements chargés positivement tels qu'une fonction ammonium quaternaire, les tensioactifs amphotères comprenant des groupements chargés positivement et négativement et qui, selon le pH, se comportent en surfactifs anioniques ou cationiques comme par exemple les bétaïnes, les tensioactifs non ioniques, les plus employés, dont le caractère de solubilité dans l'eau résulte de l'accumulation dans la molécule de fonctions alcools ou de fonctions éthers. Parmi les familles de tensioactifs les plus connues, on peut citer notamment d'une part, à titre d'agent ionique, les sels d'acide gras, les sulfates d'alkyle, les sels d'ammonium quaternaires, et d'autre part, les alkylphénols éthoxylés (APE), les poly(glucosides d'alkyle) (PGA), les alcools éthoxylés (AE), les composés comportant des séquences poly(éthylèneglycols) (PEG) ou poly(oxyéthylènes) (POE), à titre d'agent non ionique.Anionic surfactants comprising negatively charged hydrophilic groups such as carboxylate, sulfate or sulfonate functions, cationic surfactants comprising positively charged groups such as a quaternary ammonium function, amphoteric surfactants comprising positively and negatively charged groups and which, depending on the pH, behave in anionic or cationic surfactants such as, for example, betaines, the most widely used nonionic surfactants, the solubility of which in water results from the accumulation in the molecule of alcohol functions or of ether functions. Among the most well-known families of surfactants, mention may be made on the one hand, as ionic agent, of fatty acid salts, alkyl sulfates, quaternary ammonium salts, and on the other hand , ethoxylated alkylphenols (APE), poly (alkyl glucosides) (PGA), ethoxylated alcohols (AE), compounds comprising poly (ethylene glycol) (PEG) or poly (oxyethylene) (POE) sequences, non-ionic agent.
La présente invention est basée sur la découverte de nouveaux agents tensioactifs dont la structure polymère dérive de l'association de segments hydrophiles de nature oligo- et/ou polysaccharides naturels ou modifiés et de segments hydrophobes.The present invention is based on the discovery of new surfactants, the polymer structure of which derives from the association of hydrophilic segments of natural or modified oligo- and / or polysaccharide nature and hydrophobic segments.
On entend par « oligosaccharide », dans le présent exposé, tout sucre composé d'au moins 5 unités saccharidiques, au plus 50 unités saccharidiques.“Oligosaccharide” is understood to mean, in the present description, any sugar composed of at least 5 saccharide units, at most 50 saccharide units.
On entend par « polysaccharide », dans le présent exposé, tout sucre composé de plus de 50 unités saccharidiques.“Polysaccharide” is understood to mean, in the present description, any sugar composed of more than 50 saccharide units.
Plus précisément, la présente invention a pour objet l'utilisation à titre d'agent tensioactif d'au moins un copolymère amphiphile bloc séquence linéaire et/ou branché comportant au moins une séquence oligo- et/ou polysaccharidique naturelle ou modifiée et au moins une séquence hydrophobe constituée de polymères bioérodables de formule générale (I) :
Figure imgf000004_0001
More specifically, the subject of the present invention is the use as surfactant of at least one linear and / or branched block amphiphilic block copolymer comprising at least one natural or modified oligo- and / or polysaccharide block and at least one hydrophobic sequence consisting of bioerodible polymers of general formula (I):
Figure imgf000004_0001
dans laquelle :in which :
- X représente un radical CN ou CONHR,- X represents a CN or CONHR radical,
- Y représente un radical COOR' ou CONHR", avec R, R' et R" représentant, indépendamment l'un de l'autre, un atome d'hydrogène, un groupement alkyle en Ci à C20 linéaire ou ramifié, un groupement alcoxy en C. à C20 linéaire ou ramifié, un radical acide aminé, un radical acide mono- ou polyhydroxylé ou un radical aryle ou hétéroaryle en C5 à Cι2. On entend par « polymère bioerodable », dans le présent exposé, tout polymère pouvant être dégradé par des organismes vivants, le plus souvent par les enzymes de ces organismes.- Y represents a COOR ′ or CONHR ″ radical, with R, R ′ and R ″ representing, independently of one another, a hydrogen atom, a linear or branched C 1 to C 20 alkyl group, a group C alkoxy . with linear or branched C 20 , an amino acid radical, a mono- or polyhydroxylated acid radical or an aryl or heteroaryl radical in C 5 to Cι 2 . “Bioerodable polymer” is understood to mean, in the present description, any polymer which can be degraded by living organisms, most often by the enzymes of these organisms.
Avantageusement, la nouvelle famille d'agent tensioactif revendiquée est bioerodable, de part la présence de liaisons hydrolysables dans sa structure.Advantageously, the new family of claimed surfactant is bioerodible, due to the presence of hydrolyzable bonds in its structure.
Un autre aspect avantageux de ces tensioactifs est leur caractère biocompatible.Another advantageous aspect of these surfactants is their biocompatible character.
D'autre part, les propriétés tensioactives des copolymères selon l'invention sont modulables. Ainsi, à concentration de monomère constante, leur solubilité peut être ajustée en jouant sur la proportion, la longueur et la nature des segments de nature saccharidique incorporés dans la structure polymère. De même, à concentration de chaînes saccharidiques constante, leur solubilité est directement liée à la proportion, à la nature, et à la longueur des segments hydrophobes. Selon un mode de réalisation particulier de l'invention, les copolymères possèdent des propriétés tensioactives telles qu'ils sont ni solubles dans l'eau, ni dans un solvant organique, se plaçant donc nécessairement à l'interface des deux phases en présence.On the other hand, the surfactant properties of the copolymers according to the invention are modular. Thus, at a constant monomer concentration, their solubility can be adjusted by varying the proportion, the length and the nature of the segments of saccharide nature incorporated in the polymer structure. Likewise, at constant concentration of saccharide chains, their solubility is directly linked to the proportion, to the nature, and to the length of the hydrophobic segments. According to a particular embodiment of the invention, the copolymers have surfactant properties such that they are neither soluble in water, or in an organic solvent, therefore necessarily placing itself at the interface of the two phases present.
Dans le segment de formule générale (I), X représente de préférence un radical CN. Plus préférentiellement, Y représente un radical COOR' avec R' tel que défini précédemment. De façon plus préférée, R' est choisi parmi les groupements méthyle, éthyle, propyle, isopropyle, n- butyle, sec-butyle, isobutyle, isohexyle, octyle, 2-méthoxyéthyle.In the segment of general formula (I), X preferably represents a CN radical. More preferably, Y represents a radical COOR 'with R' as defined above. More preferably, R 'is chosen from the methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, isohexyl, octyl, 2-methoxyethyl groups.
L'unité répétitive du cyanoacrylate d'isobutyle peut être plus particulièrement citée à titre d'illustration d'une unité susceptible de composer un segment de formule générale (I).The repeating unit of isobutyl cyanoacrylate may be more particularly cited by way of illustration of a unit capable of composing a segment of general formula (I).
Par structure séquencée, on entend désigner une structure qui dérive de l'établissement d'une liaison covalente entre au moins l'une des extrémités du segment de nature saccharidique et l'une des extrémités de la chaîne polymère de formule générale (I). Sont utiles à titre de tensioactifs : des structures copolymères linéaires comprenant soit un unique segment de formule générale (I) lié à une extrémité du segment de nature saccharidique, soit deux segments de formule générale (I), identiques ou différents, liés respectivement de part et d'autre du segment de nature saccharidique ; des structures copolymères greffées possédant une ou des ramification(s) latérale(s) de nature hydrophobe sur le segment de nature saccharidique.The term “sequenced structure” is intended to denote a structure which derives from the establishment of a covalent bond between at least one of the ends of the segment of saccharide nature and one of the ends of the polymer chain of general formula (I). The following are useful as surfactants: linear copolymer structures comprising either a single segment of general formula (I) linked to one end of the saccharide nature segment, or two segments of general formula (I), identical or different, linked respectively by part and on the other side of the saccharide segment; grafted copolymer structures having one or more lateral branching (s) of hydrophobic nature on the segment of saccharide nature.
La liaison covalente, établie entre les deux types de segment, est généralement de nature C-C ou C-O-C.The covalent bond, established between the two types of segment, is generally of C-C or C-O-C nature.
La liaison covalente peut dériver de la polymérisation radicalaire ou anionique d'au moins une molécule d'un composé de formule (II).The covalent bond can be derived from radical or anionic polymerization of at least one molecule of a compound of formula (II).
Figure imgf000005_0001
dans laquelle X et Y sont tels que définis précédemment, en présence d'un oligo- et/ou polysaccharide.
Figure imgf000005_0001
in which X and Y are as defined above, in the presence of an oligo- and / or polysaccharide.
Le segment de nature saccharidique dérive d'un oligo- ou polysaccharide d'origine naturelle ou synthétique, modifié ou non.The saccharide nature segment derives from an oligo- or polysaccharide of natural or synthetic origin, modified or not.
On entend par « oligo- ou polysaccharide modifié », tout oligo- ou polysaccharide ayant subi un changement sur son squelette, comme par exemple l'introduction de fonctions réactives ; le greffage d'entités chimiques (molécules, chaînons aliphatiques, chaînes de PEG, etc.) ; fonctionnalisation de l'une des fonctions de l'oligo- ou polysaccharide, telle que la substitution d'une ou plusieurs fonctions hydroxyles par des fonctions telles que les fonctions aminés, amides, acylamines, par estérification ou éthérification d'une ou plusieurs fonctions hydroxyles, par amidification d'une ou plusieurs fonctions aminés ; l'élimination d'une ou plusieurs fonctions, par exemple des fonctions hydroxyles de l'oligo- ou polysaccharide ; la salification d'une ou plusieurs fonctions de l'oligo- ou polysaccharide telles que les fonctions hydroxyles, aminés, sulfoniques, carboxyliques. Il existe dans le commerce des polysaccharides modifiés par greffage de la biotine, de composés fluorescents, etc.. D'autres polysaccharides greffés avec des chaînes hydrophiles (ex. PEG) ont été décrits dans la littérature. On peut également envisager d'utiliser dans le cadre de la présente invention des polysaccharides modifiés à l'image de ceux décrits dans la référence Jozefowicz and Jozefonvicz, Biomaterials, 18, 1633-1644 (1997), ou des polysaccharides modifiés par greffage d'un ligand qui peut être un principe actif, une entité de reconnaissance spécifique d'un récepteur ou d'un antigène cellulaire, un antigène, une entité chimique chargée positivement ou négativement. Bien sûr, cette modification ne doit pas affecter la polymérisation du monomère de formule générale (II) en présence de l'oligo- ou polysaccharide modifié. Tout oligo- ou polysaccharide « modifié » peut être également désigné par le terme « dérivé » de l'oligo- ou polysaccharide. Dans le présent exposé, on entend par « oligo- ou polysaccharide d'origine naturelle », tout oligo- ou polysaccharide extrait d'organismes vivants tels que les algues, les végétaux, les animaux, les microorganismes. Dans le présent exposé, on entend par « oligo- ou polysaccharide d'origine synthétique », tout oligo- ou polysaccharide produit par synthèse chimique ou par un procédé biotechnologique.The term “modified oligo- or polysaccharide” means any oligo- or polysaccharide which has undergone a change in its skeleton, such as for example the introduction of reactive functions; grafting of chemical entities (molecules, aliphatic links, PEG chains, etc.); functionalization of one of the functions of the oligo- or polysaccharide, such as the substitution of one or more hydroxyl functions with functions such as the amino, amide, acylamine functions, by esterification or etherification of one or more hydroxyl functions , by amidification of one or more amino functions; the elimination of one or more functions, for example hydroxyl functions of the oligo- or polysaccharide; the salification of one or more functions of the oligo- or polysaccharide such as the hydroxyl, amino, sulfonic, carboxylic functions. There are commercially available polysaccharides modified by grafting biotin, fluorescent compounds, etc. Other polysaccharides grafted with hydrophilic chains (eg PEG) have been described in the literature. It is also possible to envisage using, within the framework of the present invention, polysaccharides modified like those described in the reference Jozefowicz and Jozefonvicz, Biomaterials, 18, 1633-1644 (1997), or polysaccharides modified by grafting of a ligand which can be an active principle, a recognition entity specific for a cell receptor or antigen, an antigen, a positively or negatively charged chemical entity. Of course, this modification should not affect the polymerization of the monomer of general formula (II) in the presence of the modified oligo- or polysaccharide. Any “modified” oligo- or polysaccharide can also be designated by the term “derivative” of the oligo- or polysaccharide. In the present description, the term "oligo- or polysaccharide of natural origin" means any oligo- or polysaccharide extracted from living organisms such as algae, plants, animals, microorganisms. In the present description, the term "oligo- or polysaccharide of synthetic origin" means any oligo- or polysaccharide produced by chemical synthesis or by a biotechnological process.
En l'occurrence, il s'avère possible, à travers le choix d'un oligo- ou polysaccharide d'origine naturelle ou synthétique, d'ajuster la charge ionique d'un copolymère correspondant et donc de préparer des tensioactifs à ionicité spécifique.In this case, it is possible, through the choice of an oligo- or polysaccharide of natural or synthetic origin, to adjust the ionic charge of a corresponding copolymer and therefore to prepare surfactants with specific ionicity.
Par exemple, pour un tensioactif anionique, on privilégie le choix d'un oligo- et/ou polysaccharide anionique comme les glycosaminoglycanes, tels que l'héparine, les acides polysialiques, les parties glucidiques des glycoprotéines, les oligo- et/ou polysaccharides neutres substitués par des groupes carboxyliques, sulfates ou sulfonates tels que le sulfate de dextrane, le sulfate de dermatane, le sulfate de pentosane et les gommes naturelles anioniques.For example, for an anionic surfactant, preference is given to the choice of an anionic oligo- and / or polysaccharide such as glycosaminoglycans, such as heparin, polysialic acids, carbohydrate parts of glycoproteins, neutral oligo- and / or polysaccharides substituted by carboxylic, sulphate or sulphonate groups such as dextran sulphate, dermatan sulphate, pentosan sulphate and natural anionic gums.
De la même manière, les tensioactifs cationiques ou neutres sont préparés en privilégiant le choix, respectivement, d'un oligo- et/ou polysaccharide cationique comprenant par exemple des séquences glucosamines telles que la chitine et ses dérivés ou d'un oligo- et/ou polysaccharide neutre comme l'amidon, le glycogène, les dextrines, la cellulose, le dextrane et les gommes naturelles neutres. A titre illustratif des oligo- ou polysaccharides pouvant être mis en œuvre dans le cadre de la présente invention, on peut plus particulièrement citer les oligo- ou polysaccharides comprenant les motifs D-glucose tels que la cellulose, l'amidon, le dextrane, le glycogène, les cyclodextrines, les motifs D-galactose, D-mannose, D-fructose tels que l'inuline, le galactosane, le manane, le fructosane, le motif fucose tel que le fucane et leurs dérivés pour les polysaccharides neutres. On peut également utiliser des polysaccharides anioniques tels que les parties glucidiques des glycoprotéines ou des glycolipides et leurs dérivés comme le poly(acide sialique), encore dénommé acide colominique ou poly(acide N-acétylneuraminique), l'acide neuraminique, les parties glucidiques de l'orosomucoïde, les glycosaminoglycanes comme l'acide hyaluronique, l'héparine, le sulfate de chondroïtine, ou encore les extraits d'algues tels que les algues marines comme la carragheenane, ou l'alginate. Sont également avantageux, les polysaccharides cationiques, par exemple les polymères de glucosamines ou leurs dérivés. Le chitosane en est un exemple préféré.Similarly, the cationic or neutral surfactants are prepared by favoring the choice, respectively, of a cationic oligo- and / or polysaccharide comprising for example glucosamine sequences such as chitin and its derivatives or of an oligo- and / or neutral polysaccharide such as starch, glycogen, dextrins, cellulose, dextran and neutral natural gums. As an illustration of the oligo- or polysaccharides which can be used in the context of the present invention, mention may more particularly be made of oligo- or polysaccharides comprising the D-glucose units such as cellulose, starch, dextran, glycogen, cyclodextrins, D-galactose, D-mannose, D-fructose units such as inulin, galactosan, manane, fructosan, fucose unit such as fucane and their derivatives for neutral polysaccharides. We can also use anionic polysaccharides such as the carbohydrate parts of glycoproteins or glycolipids and their derivatives such as poly (sialic acid), also called colominic acid or poly (N-acetylneuraminic acid), neuraminic acid, carbohydrate parts of orosomucoid, glycosaminoglycans such as hyaluronic acid, heparin, chondroitin sulfate, or algae extracts such as marine algae such as carragheenane, or alginate. Also advantageous are cationic polysaccharides, for example polymers of glucosamines or their derivatives. Chitosan is a preferred example.
Sont plus particulièrement préférés selon l'invention, les oligo- et polysaccharides suivants : le dextrane, l'amidon, l'amylose, le glycogène, la cellulose, l'inuline, la chitine, les cyclodextrines, le xylane, la xanthane, l'arabinane, le fucane, le curdlan, le pullulane, le chitosane, l'acide hyaluronique, le sulfate de chondroïtine, l'héparine, le poly(acide N- acétylneuraminique), l'acide neuraminique, les parties glucidiques de l'orosomucoïde, la pectine, l'alginate, la gélose, la carragheenane, l'amylopectine, le succinoglycane, l'acide poly(glucuronique), l'acide poly(mannuronique), et leurs dérivés comme par exemple le sulfate de dextrane, les héparanes sulfates, les esters d'amylose, l'acétate de cellulose, le sulfate de pentosane.The following oligo- and polysaccharides are more particularly preferred according to the invention: dextran, starch, amylose, glycogen, cellulose, inulin, chitin, cyclodextrins, xylan, xanthan, l arabinan, fucan, curdlan, pullulan, chitosan, hyaluronic acid, chondroitin sulfate, heparin, poly (N-acetylneuraminic acid), neuraminic acid, the carbohydrate parts of orosomucoid , pectin, alginate, agar, carragheenane, amylopectin, succinoglycan, poly (glucuronic) acid, poly (mannuronic) acid, and their derivatives such as, for example, dextran sulfate, heparans sulfates, amylose esters, cellulose acetate, pentosan sulfate.
Par « dérivé » d'un oligo- et/ou polysaccharide, on entend tout oligo- et/ou polysaccharide « modifié » tel que défini précédemment.By “derivative” of an oligo- and / or polysaccharide is meant any “modified” oligo- and / or polysaccharide as defined above.
Selon une variante de l'invention, la séquence polysaccharidique est préférée.According to a variant of the invention, the polysaccharide sequence is preferred.
L'oligo- et/ou polysaccharide possède préférentiellement une masse molaire supérieure ou égale à 6000 g/mol.The oligo- and / or polysaccharide preferably has a molar mass greater than or equal to 6000 g / mol.
Avantageusement, les copolymères possèdent une teneur en oligo- ou polysaccharide contrôlée. Les tensioactifs préférés selon l'invention sont les copolymères constitués d'héparine ou de dextrane à titre de segment de nature saccharidique et de poly(cyanoacrylate d'isobutyle) à titre de segment hydrophobe, résultant d'une polymérisation anionique et/ou radicalaire. Le copolymère revendiqué peut se présenter sous une forme pulvérulente. Il peut être directement introduit dans le milieu à l'état de poudre et se solubiliser sous agitation à des interfaces de type liquide.Advantageously, the copolymers have a controlled oligo- or polysaccharide content. The preferred surfactants according to the invention are the copolymers consisting of heparin or dextran as a segment of saccharide nature and of poly (isobutyl cyanoacrylate) as a hydrophobic segment, resulting from anionic and / or radical polymerization. The claimed copolymer may be in powder form. It can be directly introduced into the medium in the powder state and dissolve with stirring at liquid type interfaces.
L'agent tensioactif peut être utilisé notamment pour préparer des émulsions. Il est alors généralement utilisé à raison de 0.1 à 10 % du poids total de l'émulsion, de préférence de 0.2% à 5%.The surfactant can be used in particular for preparing emulsions. It is then generally used at a rate of 0.1 to 10% of the total weight of the emulsion, preferably from 0.2% to 5%.
Les copolymères selon l'invention qui se présentent sous une forme linéaire peuvent être obtenus selon le procédé décrit dans la demande PCT/FR01/03619.The copolymers according to the invention which are in a linear form can be obtained according to the process described in application PCT / FR01 / 03619.
Plus précisément, ce procédé consiste en une polymérisation par voie radicalaire d'au moins une molécule d'un composé de formule générale (II) :More specifically, this process consists in a radical polymerization of at least one molecule of a compound of general formula (II):
Figure imgf000009_0001
dans laquelle :
Figure imgf000009_0001
in which :
- X représente un radical CN ou CONHR,- X represents a CN or CONHR radical,
- Y représente un radical COOR' ou CONHR" avec R, R' et R" représentant, indépendamment l'un de l'autre, un atome d'hydrogène, un groupement alkyle en Ci à C2o linéaire ou ramifié, un groupement alcoxy en Ci à C2o linéaire ou ramifié, un radical acide aminé, un radical acide mono- ou polyhydroxylé ou un radical aryle ou hétéroaryle en C5 à C12, avec ledit segment oligo- et/ou polysaccharidique étant lié soit par l'une de ces extrémités à un unique segment de formule générale (I), soit par chacune de ses deux extrémités, à un segment de formule générale (I), les deux segments hydrophobes étant identiques ou différents, ladite polymérisation radicalaire étant réalisée en présence d'au moins une molécule d'un oligo- et/ou polysaccharide, dans des conditions de pH et d'atmosphère défavorables à la présence et ou à la génération d'anions dans le milieu réactionnel et en présence d'une quantité suffisante en un amorceur Redox radicalaire convenable.- Y represents a COOR 'or CONHR "radical with R, R' and R" representing, independently of one another, a hydrogen atom, a linear or branched C 1 -C 2 alkyl group, a group linear or branched C 1 -C 2 alkoxy, an amino acid radical, a mono- or polyhydroxylated acid radical or a C 5 to C12 aryl or heteroaryl radical, with said oligo- and / or polysaccharide segment being linked either by the one of these ends to a single segment of general formula (I), either by each of its two ends, to a segment of general formula (I), the two hydrophobic segments being identical or different, said radical polymerization being carried out in the presence of at least one molecule of an oligo- and / or polysaccharide, under pH and atmosphere conditions unfavorable to the presence and or to the generation of anions in the reaction medium and in presence of a sufficient amount of a suitable radical redox initiator.
Comme énoncé précédemment, il s'avère possible de privilégier la polymérisation radicalaire, au détriment de la polymérisation anionique naturellement prépondérante, en réalisant notamment la réaction de polymérisation dans des conditions de pH défavorables à la génération d'anions libres, comme par exemple les ions OH".As stated previously, it turns out to be possible to favor radical polymerization, to the detriment of naturally preponderant anionic polymerization, in particular carrying out the polymerization reaction under pH conditions unfavorable to the generation of free anions, such as for example ions OH " .
Pour ce faire, le pH du milieu réactionnel est de préférence ajusté à une valeur inférieure à 2 et plus préférentiellement inférieure à 1 ,5.To do this, the pH of the reaction medium is preferably adjusted to a value less than 2 and more preferably less than 1.5.
Cette réaction est également réalisée dans des conditions d'atmosphère inerte. Le solvant est avantageusement choisi de façon à ce que, tout en maintenant des conditions favorables à la polymérisation radicalaire et plus particulièrement à la formation du segment hydrophobe de formule (I), la solubilité de l'oligo- et/ou polysaccharide soit complète dans le milieu défini par ce solvant. Dans la mesure où l'on souhaite privilégier la formation du copolymère directement sous la forme, de particules ou de micelles, le solvant est également choisi pour être faiblement ou non solubilisant vis- à-vis du copolymère.This reaction is also carried out under inert atmosphere conditions. The solvent is advantageously chosen so that, while maintaining conditions favorable to radical polymerization and more particularly to the formation of the hydrophobic segment of formula (I), the solubility of the oligo- and / or polysaccharide is complete in the medium defined by this solvent. Insofar as it is desired to favor the formation of the copolymer directly in the form of particles or micelles, the solvent is also chosen to be weakly or non-solubilizing with respect to the copolymer.
Avantageusement, il est choisi de préférence parmi les solvants aqueux, hydroalcooliques ou hydroacétoniques.Advantageously, it is preferably chosen from aqueous, hydroalcoholic or hydroacetonic solvents.
Le solvant choisi est acidifié avec un acide organique ou minéral et de préférence un acide nitrique pour obtenir un pH adéquat au déroulement de la polymérisation radicalaire.The solvent chosen is acidified with an organic or inorganic acid and preferably a nitric acid to obtain an adequate pH during the course of the radical polymerization.
En ce qui concerne les quantités respectives en oligo- et/ou polysaccharide et monomère de formule générale (II), elles peuvent varier largement, en fonction des propriétés tensioactives désirées. Le procédé décrit dans la demande PCT/FR01/03619 a précisément pour avantage de permettre un contrôle de la structure du copolymère que l'on souhaite préparer. Les quantités en réactifs introduits sont également fonction de leurs masses molaires respectives et de leurs degrés de solubilité dans le milieu réactionnel.As regards the respective amounts of oligo- and / or polysaccharide and monomer of general formula (II), they can vary widely, depending on the desired surfactant properties. The process described in application PCT / FR01 / 03619 precisely has the advantage of allowing control of the structure of the copolymer which it is desired to prepare. The amounts of reagents introduced also depend on their respective molecular weights and their degrees of solubility in the reaction medium.
En ce qui concerne l'amorceur Redox, il s'agit généralement de mélanges d'agents oxydants et réducteurs, organiques ou inorganiques, générant des radicaux durant l'étape de transfert électronique. Cette génération de radicaux a pour avantage de nécessiter une énergie d'activation faible contrairement aux amorceurs radicalaires classiques, ce qui permet d'amorcer des polymérisations radicalaires à des températures relativement basses (0-50°C).As regards the Redox initiator, these are generally mixtures of oxidizing and reducing agents, organic or inorganic, generating radicals during the electronic transfer step. This generation of radicals has the advantage of requiring a low activation energy unlike conventional radical initiators, which makes it possible to initiate radical polymerizations at relatively low temperatures (0-50 ° C).
L'amorceur Redox utilisé comprend de préférence au moins un sel métallique choisi parmi les sels de Ce4+, V5+, Cr6+, Mn3+. Selon une variante préférée de l'invention, il s'agit de Ce4+. Il est généralement introduit sous la forme de nitrate de cérium et d'ammonium.The Redox initiator used preferably comprises at least one metal salt chosen from the salts of Ce 4+ , V 5+ , Cr 6+ , Mn 3+ . According to a preferred variant of the invention, it is Ce 4+ . It is generally introduced in the form of cerium and ammonium nitrate.
La concentration en initiateur radicalaire est susceptible d'influencer le déroulement de la polymérisation radicalaire. C'est ainsi que la composition du copolymère et la longueur des séquences respectives de l'oligo- et/ou du polysaccharide et du polymère de formule générale (I) sont modulables en fonction de la concentration en amorceur. Son ajustement relève des compétences de l'homme de l'art.The concentration of radical initiator is liable to influence the course of the radical polymerization. Thus, the composition of the copolymer and the length of the respective blocks of the oligo- and / or polysaccharide and of the polymer of general formula (I) can be adjusted as a function of the initiator concentration. Its adjustment is within the competence of a person skilled in the art.
En ce qui concerne la température réactionnelle, elle est ajustée à une valeur compatible avec l'amorçage de la polymérisation. Généralement, cette température est comprise entre 0 et 50°C.As regards the reaction temperature, it is adjusted to a value compatible with the initiation of the polymerization. Generally, this temperature is between 0 and 50 ° C.
En ce qui concerne l'ordre d'introduction des différents réactifs, on procède de préférence à une solubilisation de l'oligo- et/ou polysaccharide au sein du solvant choisi, puis à l'ajout de l'amorceur radicalaire Redox. Le monomère de formule (II) est ensuite introduit dans le mélange. A l'issue de la réaction, le copolymère peut être obtenu sous une forme soluble ou sous la forme de micelles, d'agrégats ou particules. A la fin de la polymérisation, on peut procéder si nécessaire à une neutralisation du pH du milieu réactionnel. De préférence, celui-ci est ajusté à une valeur demeurant inférieure ou égale à 7,5. Le copolymère est récupéré par des techniques conventionnelles. Selon une variante préférée du procédé décrit, on procède préalablement à l'isolement du copolymère, à une complexation du sel métallique résultant de la réaction de l'amorceur radicalaire. Cette complexation qui relève des compétences de l'homme de l'art, permet d'éliminer ces sels métalliques. En ce qui concerne les copolymères selon l'invention se présentant sous une forme ramifiée, ils sont accessibles par un procédé distinct qui implique une polymérisation anionique. Ce type de procédé est notamment décrit dans le brevet EP0007895 (Couvreur et al., 1979) et dans la publication de S.J. Douglas, L. Illum, S. S. Davis, Journal of colloid and interface science, 103, 154 (1985).As regards the order of introduction of the various reagents, the oligo- and / or polysaccharide is preferably dissolved in the chosen solvent, followed by the addition of the radical initiator Redox. The monomer of formula (II) is then introduced into the mixture. At the end of the reaction, the copolymer can be obtained in a soluble form or in the form of micelles, aggregates or particles. At the end of the polymerization, the pH of the reaction medium can be neutralized if necessary. Preferably, this is adjusted to a value that remains less than or equal to 7.5. The copolymer is recovered by conventional techniques. According to a preferred variant of the process described, the copolymer is isolated beforehand, with a complexation of the metal salt resulting from the reaction of the radical initiator. This complexation, which is within the competence of a person skilled in the art, makes it possible to eliminate these metal salts. As regards the copolymers according to the invention which are in branched form, they are accessible by a separate process which involves anionic polymerization. This type of process is described in particular in patent EP0007895 (Couvreur et al., 1979) and in the publication by SJ Douglas, L. Illum, SS Davis, Journal of colloid and interface science, 103, 154 (1985).
Généralement les polymérisations anioniques sont réalisées en présence d'un acide fort à un pH inférieur à 3 et préférentiellement voisin de 2,5.Generally, the anionic polymerizations are carried out in the presence of a strong acid at a pH of less than 3 and preferably around 2.5.
Les agents tensioactifs selon l'invention peuvent être utilisés notamment pour stabiliser des émulsions cosmétiques, comme par exemple des produits de maquillage comprenant des pigments organiques et inorganiques présents en phase aqueuse et/ou huileuse.The surfactants according to the invention can be used in particular for stabilizing cosmetic emulsions, such as, for example, make-up products comprising organic and inorganic pigments present in the aqueous and / or oily phase.
Les agents tensioactifs selon l'invention peuvent être également utilisés pour la dispersion de particules solides finement divisées de nature variée dans des fluides, en particulier dans un milieu aqueux liquide, notamment les colloïdes. Ces particules solides dispersées peuvent être des pigments pour les peintures ou les encres, des oxydes métalliques magnétiques, des agents de brillance optique ou des produits agrochimiques (fongicides). De façon générale, les agents tensioactifs selon l'invention peuvent être employés notamment comme émulsionnants (ou émulsifiants), _ _ώThe surfactants according to the invention can also be used for the dispersion of finely divided solid particles of varied nature in fluids, in particular in a liquid aqueous medium, in particular colloids. These dispersed solid particles can be pigments for paints or inks, magnetic metal oxides, optical brighteners or agrochemicals (fungicides). In general, the surfactants according to the invention can be used in particular as emulsifiers (or emulsifiers), _ _ώ
agents de suspension, solubilisants, agents mouillants, moussants ou détergents. Ils peuvent entrer dans la composition de produits nettoyants (lessives, détergents) et être employés dans des domaines très variés tels que l'industrie du papier, du cuir et du textile (ex. les adoucisseurs de tissus), la fabrication d'extincteurs, de produits cosmétiques et pharmaceutiques, l'extraction des minerais, la catalyse organique ...suspending agents, solubilizers, wetting agents, foaming agents or detergents. They can be used in the composition of cleaning products (detergents, detergents) and can be used in a wide variety of fields such as the paper, leather and textile industry (eg fabric softeners), the manufacture of fire extinguishers, of cosmetic and pharmaceutical products, mineral extraction, organic catalysis ...
Les exemples et figures figurant ci-après sont présentés à titre illustratif et non limitatif de la présente invention.The examples and figures appearing below are presented by way of illustration and without limitation of the present invention.
FIGURESFIGURES
Figure 1 : Profils de turbidité obtenus par mesure de la transmission d'un rayon lumineux en fonction de la hauteur d'un tube contenant les émulsions de l'exemple 5 : émulsion de référence, émulsion préparée avec le copolymère dextrane-PIBCA (A), émulsion préparée avec le copolymère héparine-PIBCA (B).Figure 1: Turbidity profiles obtained by measuring the transmission of a light ray as a function of the height of a tube containing the emulsions of Example 5: reference emulsion, emulsion prepared with the dextran-PIBCA copolymer (A) , emulsion prepared with the heparin-PIBCA copolymer (B).
Figure 2 : Micrographies des émulsions de l'exemple 5, obtenues par microscopie optique : émulsion préparée avec le copolymère dextrane-PIBCA (A), émulsion préparée avec le copolymère héparine- PIBCA (B).Figure 2: Micrographs of the emulsions of Example 5, obtained by optical microscopy: emulsion prepared with the dextran-PIBCA copolymer (A), emulsion prepared with the heparin-PIBCA copolymer (B).
Figure 3 : Profils de turbidité présentés par les émulsions de l'exemple 6, l'émulsion de référence, l'émulsion préparée avec le copolymère dextrane-PIBCA (A'), et l'émulsion préparée avec le copolymère héparine-PIBCA (B').Figure 3: Turbidity profiles presented by the emulsions of Example 6, the reference emulsion, the emulsion prepared with the dextran-PIBCA copolymer (A '), and the emulsion prepared with the heparin-PIBCA copolymer (B ').
Figure 4 : Stabilité de latex constitués de copolymères de poly(cyanoacrylate d'isobutyle) et de dextrane (colonnes blanches) et constitués de copolymères de poly(cyanoacrylate d'isobutyle) et d'héparine (colonnes noires) évaluée par la mesure du diamètre hydrodynamique après préparation (temps 0) et conservation en dispersion aqueuse à +4°C pendant plusieurs mois. Les barres d'erreurs représentent la distribution de la dispersion en taille. ND : non déterminé Les diamètres hydrodynamique et les distributions en taille des latex sont inchangés pendant la période de conservation considérée.Figure 4: Stability of latexes consisting of copolymers of poly (isobutyl cyanoacrylate) and dextran (white columns) and consisting of copolymers of poly (isobutyl cyanoacrylate) and heparin (black columns) evaluated by measuring the hydrodynamic diameter after preparation (time 0) and conservation in aqueous dispersion at + 4 ° C for several months. The error bars represent the distribution of the size dispersion. ND: not determined The hydrodynamic diameters and size distributions of the latex are unchanged during the storage period considered.
EXEMPLESEXAMPLES
Exemple 1 :Example 1:
Préparation d'un copolymère constitué de dextrane et de poly(cyanoacrylate d'isobutyle) (PIBCA) à structure linéaire.Preparation of a copolymer consisting of dextran and poly (isobutyl cyanoacrylate) (PIBCA) with a linear structure.
Dans un tube en verre de 2 cm de diamètre, 0,1375 g de dextrane sont dissous dans 8 ml HNO3 (0,2 mol/1), sous agitation magnétique à 40°C et avec un léger bullage à l'argon. Après 10 minutes, 2 ml de solution acide d'ions cérium (8.10"2 M de cérium IV ammonium nitrate dans HN03 à 0,2 mol/l) puis 0,5 ml de cyanoacrylate d'isobutyle sont ajoutés. Après 10 minutes, le bullage à l'argon est arrêté et le tube en verre est bouché. Après au moins 40 min, l'agitation est arrêtée et le tube en verre refroidi sous l'eau du robinet. Le pH est ajusté avec NaOH (1 N) pour qu'après l'ajout de 1 ,25 ml de tri sodium citrate dihydrate (1 ,02 M) il arrive directement à une valeur de 7 + 0,5. Enfin, la suspension est stockée au réfrigérateur. A ce stade, une suspension de particules polymères colloïdales stables est obtenue.In a glass tube 2 cm in diameter, 0.1375 g of dextran is dissolved in 8 ml HNO 3 (0.2 mol / 1), with magnetic stirring at 40 ° C and with a light bubbling with argon. After 10 minutes, 2 ml of acid solution of cerium ions (8.10 "2 M of cerium IV ammonium nitrate in HN0 3 at 0.2 mol / l) then 0.5 ml of isobutyl cyanoacrylate are added. After 10 minutes , bubbling with argon is stopped and the glass tube is plugged. After at least 40 min, stirring is stopped and the glass tube cooled under tap water. The pH is adjusted with NaOH (1 N ) so that after the addition of 1.25 ml of tri sodium citrate dihydrate (1.02 M) it comes directly to a value of 7 + 0.5 Finally, the suspension is stored in the refrigerator. a suspension of stable colloidal polymer particles is obtained.
Les copolymères constituant les particules sont purifiés comme suit : Des boudins à dialyse (Spectra/Por® CE MWCO : 100000) sont régénérés 30 minutes avec de l'eau osmosée, et les suspensions colloïdales passées au vortex puis introduites dans les boudins.The copolymers constituting the particles are purified as follows: Dialysis tubes (Spectra / Por ® CE MWCO: 100,000) are regenerated for 30 minutes with osmosis water, and the colloidal suspensions passed through a vortex and then introduced into the tubes.
On réalise deux dialyses successives de 1 H30 contre 5 litres d'eau osmosée qui sont suivies d'une autre dialyse d'une nuit contre 5 litres d'eau osmosée.Two successive 1 h 30 dialyses are carried out against 5 liters of osmosis water which are followed by another overnight dialysis against 5 liters of osmosis water.
Les copolymères ainsi purifiés et contenus dans les boudins à dialyse sont récupérés puis sont séchés par lyophilisation sans addition de cryoprotecteur. Pour ce faire les copolymères sont aliquotés dans des piluliers puis congelés (-18°C). La lyophilisation est réalisée avec un appareil Bioblock Scientific Christ alpha 1-4 pendant 48 heures. Les lyophilisats sous forme de poudres blanches sont conservés au réfrigérateur jusqu'à usage.The copolymers thus purified and contained in the dialysis tubes are recovered then are dried by lyophilization without the addition of cryoprotective. To do this, the copolymers are aliquoted in pill organizers and then frozen (-18 ° C). Lyophilization is carried out with a Bioblock Scientific Christ alpha 1-4 device for 48 hours. The lyophilisates in the form of white powders are kept in the refrigerator until use.
Exemple 2 :Example 2:
Préparation d'un copolymère constitué d'héparine et de poly(cyanoacrylate d'isobutyle) à structure linéaire.Preparation of a copolymer consisting of heparin and poly (isobutyl cyanoacrylate) with a linear structure.
Le même protocole que celui décrit en exemple 1 est reproduit en utilisant 0,1375 g d'héparine à la place du dextrane.The same protocol as that described in example 1 is reproduced using 0.1375 g of heparin in place of dextran.
Exemple 3 :Example 3:
Préparation d'un copolymère constitué de dextrane et de poly(cyanoacrylate d'isobutyle) à structure ramifiée.Preparation of a copolymer consisting of dextran and poly (isobutyl cyanoacrylate) with branched structure.
Le même protocole que celui décrit en exemple 1 est reproduit en utilisant 2 ml d'acide nitrique 0,2 mol/l à la place des 2 ml de solution acide d'ions cérium.The same protocol as that described in example 1 is reproduced using 2 ml of 0.2 mol / l nitric acid in place of the 2 ml of acid solution of cerium ions.
Exemple 4 :Example 4:
Préparation d'un copolymère constitué d'héparine et de poly(cyanoacrylate d'isobutyle) à structure ramifiée. Le même protocole que celui décrit en exemple 3 est reproduit en utilisant 0,1375 g d'héparine à la place du dextrane.Preparation of a copolymer consisting of heparin and poly (isobutyl cyanoacrylate) with branched structure. The same protocol as that described in Example 3 is reproduced using 0.1375 g of heparin in place of dextran.
Exemple 5 : Propriétés tensioactives des copolymères à structure linéaire.Example 5: Surfactant properties of copolymers with a linear structure.
Pour contrôler les propriétés tensioactives des copolymères, des émulsions modèles volontairement instables ont été préparées. Leur instabilité a été évaluée à l'aide d'un Turbiscan® qui permet de suivre l'évolution du profil de turbidité exprimé en transmission sur la hauteur des tubes dans le temps.To control the surfactant properties of the copolymers, deliberately unstable model emulsions were prepared. Their instability was assessed using a Turbiscan ® which makes it possible to follow the evolution of the turbidity profile expressed in transmission over the height of the tubes over time.
Une émulsion de référence est préparée à partir de :A reference emulsion is prepared from:
- 3 ml d'eau- 3 ml of water
- 3 ml d'acétate d'éthyle- 3 ml of ethyl acetate
Une émulsion contenant le copolymère dextrane-PIBCA préparé selon l'exemple 1 est composée de :An emulsion containing the dextran-PIBCA copolymer prepared according to Example 1 is composed of:
- 12 mg de copolymère de dextrane-PIBCA purifié et lyophilisé.- 12 mg of purified and lyophilized dextran-PIBCA copolymer.
- 3 ml d'eau- 3 ml of water
- 3 ml d'acétate d'éthyle- 3 ml of ethyl acetate
Une émulsion contenant le copolymère héparine-PIBCA préparé selon l'exemple 2 est composée de :An emulsion containing the heparin-PIBCA copolymer prepared according to Example 2 is composed of:
- 12 mg de copolymère d'héparine-PIBCA purifié et lyophilisé.- 12 mg of purified and lyophilized heparin-PIBCA copolymer.
- 3 ml d'eau- 3 ml of water
- 3 ml d'acétate d'éthyle- 3 ml of ethyl acetate
Les émulsions sont préparées dans un tube en verre à fond rond et à bouchon à vis de 12 ml à 28°C selon la séquence d'agitation suivante réalisée en continu :The emulsions are prepared in a glass tube with a round bottom and a screw cap of 12 ml at 28 ° C according to the following stirring sequence carried out continuously:
Vortex, vitesse maximale : 15 secondes.Vortex, maximum speed: 15 seconds.
Retournements du tube : 2.Tube turns: 2.
Vortex, vitesse maximale : 15 secondes. Retournements du tube : 20.Vortex, maximum speed: 15 seconds. Tube turns: 20.
Vortex, vitesse maximale : 30 secondes. Retournements du tube : 2.Vortex, maximum speed: 30 seconds. Tube turns: 2.
Vortex, vitesse maximale : 30 secondes.Vortex, maximum speed: 30 seconds.
A la fin de la séquence d'agitation, 5 ml de l'émulsion sont immédiatement transférés à l'aide d'une pipette en verre graduée dans la cellule de mesure d'un Turbiscan® MA2000. La cellule est placée dans l'appareil afin d'enregistrer le profil de transmission sur la hauteur du tube.At the end of the stirring sequence, 5 ml of the emulsion are immediately transferred using a graduated glass pipette into the measuring cell of a Turbiscan ® MA2000. The cell is placed in the device in order to record the transmission profile over the height of the tube.
Des enregistrements sont effectués toutes les minutes pendant 30 min.Recordings are made every minute for 30 min.
A titre d'exemple, la figure 1 montre les profils de turbidité exprimés en transmission sur la hauteur du tube. Ils ont été enregistrés lors du suivi de l'évolution des trois émulsions aux temps 0, 2, 10 et 30 minutes. Une augmentation de la transmission en bas du tube indique une séparation de phase de l'émulsion par expulsion de l'eau. Une augmentation de la transmission en haut du tube indique une séparation de phase de l'émulsion par expulsion de l'acétate d'éthyle. Une transmission nulle signifie que le milieu est turbide (trouble) dû à la présence d'une émulsion.For example, Figure 1 shows the turbidity profiles expressed in transmission over the height of the tube. They were recorded during the monitoring of the evolution of the three emulsions at times 0, 2, 10 and 30 minutes. An increase in the transmission at the bottom of the tube indicates a phase separation of the emulsion by expulsion of water. An increase in the transmission at the top of the tube indicates a phase separation of the emulsion by expulsion of ethyl acetate. A zero transmission means that the medium is turbid (cloudy) due to the presence of an emulsion.
Le tableau 1 donne les vitesses de migration des phases des différentes émulsions obtenues lors du déphasage de l'émulsion initiale, mesurées à une hauteur de 30 % des pics de transmission.Table 1 gives the phase migration speeds of the different emulsions obtained during the phase shift of the initial emulsion, measured at a height of 30% of the transmission peaks.
Figure imgf000017_0001
Figure imgf000017_0001
La vitesse de migration des phases est d'autant plus grande que l'émulsion est instable. Les émulsions préparées avec le copolymère de dextrane-PIBCA et d'héparine-PIBCA sont beaucoup plus stables que l'émulsion de référence ce qui indique que les copolymères possèdent des propriétés tensioactives.The speed of phase migration is greater the more the emulsion is unstable. The emulsions prepared with the copolymer of dextran-PIBCA and heparin-PIBCA are much more stable than the reference emulsion, which indicates that the copolymers have surfactant properties.
La figure 2 montre les globules des émulsions par observation au microscope optique après formation de l'émulsion. Les globules obtenus sont de taille plus importante pour l'émulsion préparée avec le copolymère héparine-PIBCA que ceux de l'émulsion préparée avec le copolymère dextrane-PIBCA.FIG. 2 shows the globules of the emulsions by observation under an optical microscope after formation of the emulsion. The globules obtained are larger in size for the emulsion prepared with the heparin-PIBCA copolymer than those of the emulsion prepared with the dextran-PIBCA copolymer.
Exemple 6 :Example 6:
Propriétés tensioactives des copolymères à structure ramifiée.Surfactant properties of branched structure copolymers.
Le protocole d'étude des propriétés tensioactives des copolymères obtenus par polymérisation anionique selon les exemples 3 et 4 est identique à celui donné dans l'exemple 5.The protocol for studying the surfactant properties of the copolymers obtained by anionic polymerization according to Examples 3 and 4 is identical to that given in Example 5.
Une émulsion de référence est préparée à partir de :A reference emulsion is prepared from:
- 3 ml d'eau- 3 ml of water
- 3 ml d'acétate d'éthyle- 3 ml of ethyl acetate
Une émulsion contenant le copolymère de dextrane-PIBCA préparé selon l'exemple 3 est composée de :An emulsion containing the dextran-PIBCA copolymer prepared according to Example 3 is composed of:
- 12 mg de copolymère de dextrane-PIBCA purifié et lyophilisé.- 12 mg of purified and lyophilized dextran-PIBCA copolymer.
- 3 ml d'eau- 3 ml of water
- 3 ml d'acétate d'éthyle Une émulsion contenant le copolymère d'héparine-PIBCA préparé selon l'exemple 4 est composée de :- 3 ml of ethyl acetate An emulsion containing the heparin-PIBCA copolymer prepared according to Example 4 is composed of:
- 12 mg de copolymère d'héparine-PIBCA purifié et lyophilisé.- 12 mg of purified and lyophilized heparin-PIBCA copolymer.
- 3 ml d'eau- 3 ml of water
- 3 ml d'acétate d'éthyle. Le tableau 2 donne les vitesses de migration des phases des différentes émulsions obtenues lors du déphasage de l'émulsion initiale, mesurées à une hauteur de 30 % des pics de transmission.- 3 ml of ethyl acetate. Table 2 gives the phase migration speeds of the different emulsions obtained during the phase shift of the initial emulsion, measured at a height of 30% of the transmission peaks.
Figure imgf000019_0001
Figure imgf000019_0001
Tableau 2Table 2
Les mêmes phénomènes de vitesse de migration des phases sont observés avec ces émulsions, indiquant que les copolymères possèdent des propriétés tensioactives.The same phase migration speed phenomena are observed with these emulsions, indicating that the copolymers have surfactant properties.
La figure 3 montre les profils de turbidité exprimés en transmission sur la hauteur du tube. Ils ont été enregistrés lors du suivi de l'évolution des trois émulsions aux temps 0, 2, 10 et 30 minutes. Une augmentation de la transmission en bas du tube indique une séparation de phase de l'émulsion par expulsion de l'eau. Une augmentation de la transmission en haut du tube indique une séparation de phase de l'émulsion par expulsion de l'acétate d'éthyle. Une transmission nulle signifie que le milieu est turbide (trouble) dû à la présence d'une émulsion.Figure 3 shows the turbidity profiles expressed in transmission over the height of the tube. They were recorded during the monitoring of the evolution of the three emulsions at times 0, 2, 10 and 30 minutes. An increase in the transmission at the bottom of the tube indicates a phase separation of the emulsion by expulsion of water. An increase in the transmission at the top of the tube indicates a phase separation of the emulsion by expulsion of ethyl acetate. A zero transmission means that the medium is turbid (cloudy) due to the presence of an emulsion.
Exemple 7 :Example 7:
Préparation d'un copolymère constitué de gamma-cyclodextrines et de poly(cyanoacrylate d'isobutyle) à structure linéaire.Preparation of a copolymer consisting of gamma-cyclodextrins and poly (isobutyl cyanoacrylate) with a linear structure.
Le même protocole que celui décrit en exemple 1 est reproduit en utilisant 0,1375 g de gamma-cyclodextrines à la place du dextrane. Le copolymère obtenu est soluble dans l'acétone. Exemple 8 :The same protocol as that described in example 1 is reproduced using 0.1375 g of gamma-cyclodextrins in place of dextran. The copolymer obtained is soluble in acetone. Example 8:
Préparation d'un copolymère constitué de sulfate de dextrane et de poly(cyanoacrylate d'isobutyle) à structure linéaire.Preparation of a copolymer consisting of dextran sulfate and poly (isobutyl cyanoacrylate) with a linear structure.
Le même protocole que celui décrit en exemple 1 est reproduit jusqu'après l'étape de dialyse en utilisant 0.1375 g de sulfate de dextrane à la place du dextrane. La méthode est appliquée en utilisant des sulfates de dextrane de différentes masses molaires.The same protocol as that described in example 1 is reproduced until after the dialysis step using 0.1375 g of dextran sulfate in place of dextran. The method is applied using dextran sulfates of different molecular weights.
Les copolymères obtenus s'auto-organisent en particules colloïdales en dispersion dans l'eau. Le diamètre hydrodynamique de ces particules varie selon la masse molaire du sulfate de dextrane utilisé lors de la synthèse (voir tableau 3).The copolymers obtained self-organize into colloidal particles dispersed in water. The hydrodynamic diameter of these particles varies according to the molar mass of the dextran sulfate used during the synthesis (see Table 3).
Le tableau 3 donne le diamètre hydrodynamique des particules colloïdales formées par auto-organisation de copolymères constitués de sulfate de dextrane et de poly(cyanoacrylate d'isobutyle) à structure linéaire préparés à partir de sulfate de dextrane de masses molaires différentes.Table 3 gives the hydrodynamic diameter of the colloidal particles formed by self-organization of copolymers consisting of dextran sulfate and poly (isobutyl cyanoacrylate) with a linear structure prepared from dextran sulfate of different molar masses.
Figure imgf000020_0001
Figure imgf000020_0001
Tableau 3Table 3
Exemple 9 :Example 9:
Stabilité d'un latex constitué de copolymères de dextrane et de poly(cyanoacrylate d'isobutyle) à structure linéaire.Stability of a latex made up of dextran and poly (isobutyl cyanoacrylate) copolymers with a linear structure.
Le latex est préparé selon le protocole décrit dans l'exemple 1 jusqu'à l'étape de dialyse incluse. Il est conservé dans un flacon bouché à +4°C sous la forme d'une dispersion aqueuse tel qu'il a été préparé. Le diamètre hydrodynamique des particules est évalué à différent temps de conservation par diffusion quasi-élastique de la lumière à 90° à l'aide d'un nanosizer de type COULTER® N4Plus après dilution dans l'eau. Le diamètre hydrodynamique des particules de latex proche de 300 nm reste inchangé durant une période de conservation en dispersion de 36 mois, (voir Figure 1 ).The latex is prepared according to the protocol described in Example 1 up to the included dialysis step. It is kept in a stoppered bottle at + 4 ° C in the form of an aqueous dispersion as it was prepared. The hydrodynamic diameter of the particles is evaluated at different storage times by quasi-elastic light scattering at 90 ° using a COULTER ® N4Plus nanosizer after dilution in water. The hydrodynamic diameter of the latex particles close to 300 nm remains unchanged during a storage period of 36 months in dispersion (see Figure 1).
Exemple 10 : Stabilité d'un latex constitué de copolymères d'héparine et de poly(cyanoacrylate d'isobutyle) à structure linéaire.Example 10: Stability of a latex consisting of copolymers of heparin and of poly (isobutyl cyanoacrylate) with a linear structure.
Le latex est préparé selon le protocole décrit dans l'exemple 2 jusqu'à l'étape de dialyse incluse. Il est conservé dans un flacon bouché à +4°C sous la forme d'une dispersion aqueuse tel qu'il a été préparé. Le diamètre hydrodynamique des particules est évalué à différent temps de conservation par diffusion quasi-élastique de la lumière à 90° à l'aide d'un nanosizer de type COULTER N4Plus après dilution dans l'eau. Le diamètre hydrodynamique des particules de latex proche de 95 nm reste inchangé durant une période de conservation en dispersion de 30 mois. (voir Figure 4).The latex is prepared according to the protocol described in Example 2 up to the included dialysis step. It is stored in a stoppered bottle at + 4 ° C in the form of an aqueous dispersion as it was prepared. The hydrodynamic diameter of the particles is evaluated at different storage times by quasi-elastic light scattering at 90 ° using a COULTER N4Plus nanosizer after dilution in water. The hydrodynamic diameter of the latex particles close to 95 nm remains unchanged during a storage period of 30 months in dispersion. (see Figure 4).
La figure 4 montre la stabilité de latex constitués de copolymères de poly(cyanoacrylate d'isobutyle) et de dextrane (colonnes blanches) et constitués de copolymères de poly(cyanoacrylate d'isobutyle) et d'héparine (colonnes noires) évaluée par la mesure du diamètre hydrodynamique après préparation (temps 0) et conservation en dispersion aqueuse à +4°C pendant plusieurs mois. Les barres d'erreurs représentent la distribution de la dispersion en taille. ND : non déterminé Les diamètres hydrodynamique et les distributions en taille des latex sont inchangés pendant la période de conservation considérée. FIG. 4 shows the stability of latexes consisting of copolymers of poly (isobutyl cyanoacrylate) and dextran (white columns) and consisting of copolymers of poly (isobutyl cyanoacrylate) and heparin (black columns) evaluated by the measurement hydrodynamic diameter after preparation (time 0) and conservation in aqueous dispersion at + 4 ° C for several months. The error bars represent the distribution of the size dispersion. ND: not determined The hydrodynamic diameters and size distributions of the latex are unchanged during the storage period considered.

Claims

REVENDICATIONS
1. Utilisation à titre d'agent tensioactif d'au moins un copolymère bloc à structure séquencée linéaire et/ou ramifiée composé d'un segment comportant une séquence oligo- et ou polysaccharidique naturelle ou modifiée et au moins une séquence hydrophobe constituée de polymères bioérodables de formule générale (I) :1. Use as surfactant of at least one block copolymer with a linear and / or branched block structure composed of a segment comprising a natural or modified oligo- and or polysaccharide block and at least one hydrophobic block consisting of bioerodable polymers of general formula (I):
Figure imgf000022_0001
dans laquelle :
Figure imgf000022_0001
in which :
- X représente un radical CN ou CONHR,- X represents a CN or CONHR radical,
- Y représente un radical COOR' ou CONHR" avec R, R' et R" représentant, indépendamment l'un de l'autre, un atome d'hydrogène, un groupement alkyle en Ci à C2o linéaire ou ramifié, un groupement alcoxy en Ci à C2o linéaire ou ramifié, un radical acide aminé, un radical acide mono- ou polyhydroxylé ou un radical aryle ou hétéroaryle en C5 à C.2.- Y represents a COOR 'or CONHR "radical with R, R' and R" representing, independently of one another, a hydrogen atom, a linear or branched C 1 -C 2 alkyl group, a group linear or branched C 1 -C 2 alkoxy, an amino acid radical, a mono- or polyhydroxylated acid radical or a C 5 to C 2 aryl or heteroaryl radical.
2. Utilisation à titre d'agent tensioactif d'un copolymère selon la revendication 1 , caractérisée en ce que X représente en formule générale (I) un radical CN.2. Use as surfactant of a copolymer according to claim 1, characterized in that X represents in general formula (I) a CN radical.
3. Utilisation à titre d'agent tensioactif d'un copolymère selon l'une des revendications précédentes, caractérisée en ce que Y représente en formule générale (I) un radical COOR' avec R' tel que défini précédemment . 3. Use as surfactant of a copolymer according to one of the preceding claims, characterized in that Y represents in general formula (I) a radical COOR 'with R' as defined above.
4. Utilisation à titre d'agent tensioactif d'un copolymère selon la revendication 3, caractérisée en ce que Y représente en formule générale (I) un radical COOR' avec R' choisi parmi les groupements méthyle, éthyle, propyle, isopropyle, n-butyle, sec-butyle, isobutyle, isohexyle, octyle, 2-méthoxyéthyle. 4. Use as surfactant of a copolymer according to claim 3, characterized in that Y represents in general formula (I) a COOR 'radical with R' chosen from methyl, ethyl, propyl, isopropyl, n -butyl, sec-butyl, isobutyl, isohexyl, octyl, 2-methoxyethyl.
5. Utilisation à titre d'agent tensioactif d'un copolymère selon l'une quelconque des revendications 1 à 4, caractérisée en ce que l'oligo- ou polysaccharide est d'origine naturelle ou synthétique, modifié ou non.5. Use as surfactant of a copolymer according to any one of claims 1 to 4, characterized in that the oligo- or polysaccharide is of natural or synthetic origin, modified or not.
6. Utilisation à titre d'agent tensioactif d'un copolymère selon l'une quelconque des revendications 1 à 5, caractérisée en ce que l'oligo- ou polysaccharide contient des motifs choisis parmi le D-glucose, le D- galactose, le D-mannose, le D-fructose, et le fucose.6. Use as surfactant of a copolymer according to any one of claims 1 to 5, characterized in that the oligo- or polysaccharide contains units chosen from D-glucose, D-galactose, D-mannose, D-fructose, and fucose.
7. Utilisation à titre d'agent tensioactif d'un copolymère selon la revendication 5, caractérisée en ce que l'oligo- ou polysaccharide est choisi parmi la cellulose, l'amidon, le glycogène, les cyclodextrines, l'inuline, le galactosane, le manane, le fructosane, le fucane.7. Use as a surfactant of a copolymer according to claim 5, characterized in that the oligo- or polysaccharide is chosen from cellulose, starch, glycogen, cyclodextrins, inulin, galactosan , manane, fructosan, fucan.
8. Utilisation à titre d'agent tensioactif d'un copolymère selon l'une quelconque des revendications 1 à 5, caractérisée en ce que l'oligo- ou polysaccharide est choisi parmi les parties glucidiques des glycoprotéines, des glycolipides, les glycosaminoglycanes, et les glucosamines.8. Use as surfactant of a copolymer according to any one of claims 1 to 5, characterized in that the oligo- or polysaccharide is chosen from the carbohydrate parts of glycoproteins, glycolipids, glycosaminoglycans, and glucosamines.
9. Utilisation à titre d'agent tensioactif d'un copolymère selon l'une quelconque des revendications 1 à 5, caractérisée en ce que l'oligo- ou polysaccharide est extrait d'une algue, d'un végétal, d'un animal, d'un microorganisme ou obtenu par synthèse chimique ou par un procédé biotechnologique.9. Use as a surfactant of a copolymer according to any one of claims 1 to 5, characterized in that the oligo- or polysaccharide is extracted from an alga, from a plant, from an animal , a microorganism or obtained by chemical synthesis or by a biotechnological process.
10. Utilisation à titre d'agent tensioactif d'un copolymère selon l'une quelconque des revendications 1 à 5, caractérisée en ce que l'oligo- ou polysaccharide est choisi parmi le dextrane, l'héparine, ou l'un de leurs dérivés. 10. Use as surfactant of a copolymer according to any one of claims 1 to 5, characterized in that the oligo- or polysaccharide is chosen from dextran, heparin, or one of their derivatives.
PCT/FR2003/001408 2002-05-07 2003-05-06 Novel amphiphilic copolymer-type biodegradable surface active agents comprising hydrophobic segments and oligo- and/or polysaccharides WO2003095597A1 (en)

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