EP1521575A1 - Aqueous dispersions of nanometric or micrometric particles for encapsulating chemical compounds - Google Patents

Aqueous dispersions of nanometric or micrometric particles for encapsulating chemical compounds

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Publication number
EP1521575A1
EP1521575A1 EP03763923A EP03763923A EP1521575A1 EP 1521575 A1 EP1521575 A1 EP 1521575A1 EP 03763923 A EP03763923 A EP 03763923A EP 03763923 A EP03763923 A EP 03763923A EP 1521575 A1 EP1521575 A1 EP 1521575A1
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EP
European Patent Office
Prior art keywords
composition according
particles
polymers
compounds
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP03763923A
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German (de)
French (fr)
Inventor
Ruxandra Gref
Catherine Amiel Epouse Guenoun
Bernard Sebille
Patrick Couvreur
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Centre National de la Recherche Scientifique CNRS
Universite Paris Sud Paris 11
Original Assignee
Centre National de la Recherche Scientifique CNRS
Universite Paris Sud Paris 11
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Publication of EP1521575A1 publication Critical patent/EP1521575A1/en
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Definitions

  • the present invention relates to aqueous dispersions of particles of nanometric or micrometric dimensions, suitable for
  • vectorization consists in trapping an active principle within a particle of micrometric or submicrometric size, which can be administered to a subject to be treated (in particular by injection or ingestion) and by choosing said particle so that 'it ' releases the active ingredient at the level of a targeted cell or tissue.
  • the encapsulation of active principles has notably been developed by liposomes (lipid bilayers surrounding an aqueous core), or even by nanocapsules (polymer shells of submicrometric size containing a phase, generally oily, containing the active ingredient).
  • nanosphere or microsphere systems have also been developed, namely particles based on biocompatible and biodegradable polymers (for example polylactic acid or poly-caprolactone), playing the role of a matrix. able to immobilize active ingredients and gradually release them within an organism where this encapsulation system is introduced.
  • biocompatible and biodegradable polymers for example polylactic acid or poly-caprolactone
  • nanosphere or microsphere type systems generally have a fairly good capacity for vectorization of active principles.
  • solvents and / or surfactants generally remain in trace amounts, which is likely both to pose problems in terms of toxicity (for example if the solvent remaining in trace amounts is a solvent such as dichloromethane) and / or degrading the active principles immobilized in the particles (traces of organic solvents can, for example, denature fragile molecules of the peptide or protein type).
  • an aqueous medium a mixture of specific water-soluble compounds, namely (1) polymers comprising crosslinked cyclodextrin units and (2) macromolecules carrying groups capable of forming complexes inclusion with the cyclodextrins (such as, for example, polysaccharides substituted by aliphatic chains), one can observe, under certain conditions of particular concentrations, the spontaneous formation of a dispersion of particles of average hydrodynamic diameter between 50 and 5000 nm, provided that the pair of compounds (1) and (2) used is properly selected.
  • a mixture of specific water-soluble compounds namely (1) polymers comprising crosslinked cyclodextrin units and (2) macromolecules carrying groups capable of forming complexes inclusion with the cyclodextrins (such as, for example, polysaccharides substituted by aliphatic chains)
  • type associations polymers comprising cyclodextrin / polysaccharide units substituted by aliphatic chains
  • a system of type (I) whatever the concentrations. respective in polymers and in polysaccharides (associations said here of type ai).
  • the type (II) system can only be obtained for other particular associations, say here of type an.
  • these specific year-type associations will be designated by the generic term of self-associative system "of the type which can lead, under certain conditions of concentration, to an associative phase separation".
  • the present invention is based on the completely unexpected discovery of the possibility of forming a third type of system from type a associations.
  • the work of the inventors has indeed made it possible to demonstrate that there is a specific concentration domain in which a direct mixture of water, of polymers based on cyclodextrin units, and of polysaccharide grafted by aliphatic chains, leads to the formation of a dispersion of particles based on polymers and associated polysaccharides, of average hydrodynamic diameter at least equal to 50 nm, and most often having very good stability.
  • the inventors have discovered that such particle dispersions can be obtained by the direct mixture of water, polymers based on cyclodextrin units, and macromolecules carrying groups capable of forming inclusion complexes with cyclodextrins.
  • the inventors have established that the dispersion thus produced constitutes a metastable system, and that only the systems of type (I) and (II) are thermodynamically stable systems.
  • the dispersion discovered by the inventors is subjected to sufficiently high shear conditions, there is generally an evolution towards a type (II) system.
  • the inventors have however discovered in this context that the stability of the metastable dispersion produced is surprisingly important, which makes it possible in particular to envisage its storage, its dilution, or even its integration within complex compositions, for example in pharmaceutical or cosmetic compositions.
  • the work of the inventors has also made it possible to demonstrate that the particles formed within the metastable dispersion obtained are particularly suitable for the encapsulation of chemical compounds, and in particular for the vectorization of active principles, with efficient and quantitative integration of the chemical compounds.
  • the inventors have in particular demonstrated that these particles make it possible to achieve a release of the active ingredients in a more controlled manner than by using most of the particles of the nanosphere or microsphere type of the prior art, for which there is generally observed, after administration, an immediate release of a large fraction of the encapsulated active ingredients
  • the present invention aims to provide new compositions of particles of nanometric or micrometric dimensions allowing easy encapsulation of chemical compounds, and in particular of active principles.
  • Another object of the invention is to provide compositions comprising particles free of all traces of organic solvent and of surfactants, which can advantageously replace the particles known from the prior art for the vectorization of active principles.
  • the invention aims in particular to provide compositions for achieving a controlled release of active ingredients.
  • Another object of the invention is to provide compositions intended for administering active principles, by ensuring "stealth" in the body, that is to say an ability to circulate in a prolonged manner in the body, in particular in the blood system, avoiding recognition by the immune system.
  • the subject of the present invention is a composition
  • a composition comprising an aqueous dispersion of particles (p) of average hydrodynamic diameter between 50 and 5000 nm, said particles containing, in combination: (A) polymers based on 'cyclodextrin units, comprising on average at least 4 cyclodextrin units within their structure; and
  • composition comprising an aqueous dispersion of particles
  • a composition containing an aqueous medium for example water, physiological saline, or, more generally, an aqueous solution comprising one or more solutes (in particular one or more salt (s) and / or sugar (s) such as sucrose or glucose for example), at concentrations preferably less than or equal to 20 g / L, or a mixture of water / alcohol type), within which said particles are dispersed, these particles being preferably individualized, and advantageously having an agglomeration rate of less than 80%, preferably of less than 50%, and advantageously at most equal to 10% in number.
  • an aqueous medium for example water, physiological saline, or, more generally, an aqueous solution comprising one or more solutes (in particular one or more salt (s) and / or sugar (s) such as sucrose or glucose for example), at concentrations preferably less than or equal to 20 g / L, or a mixture of water / alcohol type
  • a composition according to the invention can advantageously essentially consist of a dispersion of the particles (p) in an aqueous medium, and preferably by a dispersion of these particles in water, in an aqueous solution of glucose (in in particular a glucose solution at a concentration of the order of 5% by mass), or alternatively in an injectable solution, at physiological pH, for example in physiological serum.
  • a composition according to the invention can also be a more complex composition, for example a composition of single or multiple emulsion type, in which the aqueous dispersion of the particles of the invention plays the role of a continuous phase or of a dispersed phase.
  • a composition according to the invention can also comprise, in addition to the particles based on the combination of polymers (A) and (B), other particles, of mineral or organic nature.
  • average hydrodynamic diameter designates the size of a particle within an aqueous medium, which takes into account the average diameter of the particle in its conformation in the medium aqueous, as well as its possible layer of solvation.
  • the average hydrodynamic diameter of a population of particles within an aqueous medium can in particular be determined by quasi-elastic light scattering within the medium under consideration, in particular by an apparatus of the Nanosizer type. This type of apparatus also makes it possible to determine for the population of particles a polydispersite index of the hydrodynamic diameter, which reflects the distribution of the hydrodynamic diameters, more or less tightened around the average value.
  • the average hydrodynamic diameter of the particles (p) is greater than or equal to 80 nm, and it is advantageously at least equal to 100 nm.
  • the particles (p) may have, for certain applications, an average hydrodynamic diameter of between 1 and 5 microns (preferably less than 3 microns, if necessary), but it is generally preferred that the average hydrodynamic diameter of the particles (p) either less than or equal to 500 nm. More preferably, the average hydrodynamic diameter of the particles (p) is less than or equal to 400 nm, and advantageously less than or equal to 300 nm.
  • the average hydrodynamic diameter of the particles (p) is between 100 and 300 nm, and even more advantageously between 150 and 250 nm.
  • the particles (p) are generally of substantially spherical morphology, and the polydispersite index of their hydrodynamic diameter, as measured using a device of the Nanosizer type, East generally between 0.1 and 0.3, and it is advantageously less than 0.2.
  • the compounds (A) and (B) present in association within the particles of the invention are compounds which form, in aqueous medium, an associative system (A + B) of the type of the associations defined above, namely a system associative (A + B) of the type which can lead, under certain conditions of concentration, to an associative phase separation.
  • the compounds (A) and (B) useful according to the invention are, in general, compounds such as a mixture of two aqueous solutions of these compounds at a concentration of 50 g / l in a proportion ranging from 1: 5 at 5: 1 in volume leads to the formation of a two-phase system of type (II) as defined above.
  • the compounds (A) and (B) present in a composition according to the invention are compounds such as a mixture of two aqueous solutions of these compounds at concentrations ranging from 1g / l to 10g / l, in a proportion ranging from 1: 9 to 9: 1 by volume, leads to the formation of particles with an average hydrodynamic diameter greater than 50 nm and less than 5000 nm.
  • concentrations ranging from 1g / l to 10g / l, in a proportion ranging from 1: 9 to 9: 1 by volume
  • the aqueous dispersion of particles (p) present in a composition according to the invention typically constitutes a metastable system. Consequently, if a composition according to the invention is subjected to a sufficient shear stress (typically a centrifugation at the rate of at least 3000 revolutions per minute for at least 20 minutes), there is generally observed an irreversible evolution of the dispersion towards a type (II) system as defined above. However, it should be noted that, despite its metastable nature, the aqueous dispersion of particles (p) present in a composition according to the invention generally exhibits significant stability.
  • a sufficient shear stress typically a centrifugation at the rate of at least 3000 revolutions per minute for at least 20 minutes
  • the stability of the particles (p) in aqueous dispersion can in particular be demonstrated by the conservation of the mean hydrodynamic diameter of the particles (p) after storage.
  • the average hydrodynamic diameter of the particles (p) of a composition according to the invention remains less than or equal to 5000.
  • the mean hydrodynamic diameter of the particles (p) of a composition according to the invention remains less than or equal to 400 nm, preferably less than or equal to 350 nm, advantageously less than or equal to 300 nm, and even more advantageously less than or equal to 200 nm.
  • the mean hydrodynamic diameter of the particles (p) remains less than or equal to 400 nm, and preferably less than or equal to 300 nm, following storage for 2 days, or even after storage for 5 days, and even, in some cases, after 15 days storage. It should however be emphasized that, in order to observe good conservation of the mean hydrodynamic diameter of the particles (p) following prolonged storage, it may sometimes be necessary to preserve the composition in a non-oxidizing atmosphere (under argon for example) so as to avoid an aging of the compounds (A) and / or (B), which is likely to call into question the stability of the metastable system formed.
  • a non-oxidizing atmosphere under argon for example
  • the polymers (A) based on cyclodextrin units are essential constituents of the particles (p) present in dispersion in the composition of the invention.
  • These polymers (A) comprise on average at least 4 cyclodextrin units, preferably at least 9 cyclodextrin units, and advantageously at least 15 cyclodextrin units.
  • it is preferred that the polymers (A) comprise on average at least 100 cyclodextrin units, and advantageously at least 200 cyclodextrin units.
  • the polymers (A) comprise on average at least 400 cyclodextrin units.
  • the average number of cyclodextrin units present in the polymers (A) of a composition of the invention can for example be established by steric exclusion chromatography and by nuclear magnetic resonance.
  • the cyclodextrin units present within the polymers (A) can, in general, be ⁇ -cyclodextrins, ⁇ -cyclodextrins, ⁇ -cyclodextrins, or alternatively mixtures of at least two of these types of cyclodextrins. Nevertheless, the cyclodextrin units present in the polymers (A) preferably comprise ⁇ -cyclodextrins. In a particularly advantageous manner, all the cyclodextrin units present in the polymers (A) are ⁇ -cyclodextrins.
  • the cyclodextrin units present in the polymers (A) are a mixture of ⁇ -cyclodextrins and ⁇ -cyclodextrin units. According to this variant, it is generally preferred that the ⁇ -cyclodextrins represent less than 50%, and preferably less than 30% of the cyclodextrins present.
  • the cyclodextrin units are generally linked together by hydrocarbon chains, linear or branched, optionally interrupted by one or more oxygen atoms, and these chains preferably being alkyl, alkenyl or alkynyl chains , or alternatively polyether chains, these chains possibly being substituted by hydrophilic groups (hydroxy groups for example).
  • the chains linking together the cyclodextrin units contain at least 3 carbon atoms and preferably from 4 to 50 carbon atoms, the the shortest path between two cyclodextrin units is preferably constituted by a chain comprising between 3 and 8 carbon atoms.
  • the hydrocarbon chains linking together two cyclodextrin units within a polymer (A) correspond to the general formula a group of formula -O - (- CH 2 -CHOR (n) -CH 2 ) nO-, where n is an integer ranging from 1 to 50 (generally between 2 and 10) and where, in each of the n units (-CH 2 -CHOR-CH 2 ), R (n) denotes either a hydrogen atom or a chain -CH 2 -CHOH-CH 2 -O- linked to a cyclodextrin unit of the polymer.
  • the polymers (A) can typically be obtained by a polycondensation of cyclodextrin and epichlorohydrin molecules, generally in basic medium (generally in an aqueous medium added with soda, at a mass concentration of 10 to 40%), the ratio cyclodextrins / epichlorohydrin molar preferably being between 1:15 and 1: 1, and advantageously between 1:15 and 1: 8.
  • basic medium generally in an aqueous medium added with soda, at a mass concentration of 10 to 40%
  • the ratio cyclodextrins / epichlorohydrin molar preferably being between 1:15 and 1: 1, and advantageously between 1:15 and 1: 8.
  • the total mass of the cyclodextrin units present within the polymers (A) represent at least 30%, advantageously at least 40%, and even more preferably at least 50%, of the total mass of the polymers (A), this total mass of the cyclodextrin units generally representing between 30 and 80%, and preferably between 40 and 60% of the total mass of the polymers (A).
  • the polymers (A) present in a composition generally have a number-average molar mass of between 10,000 and 3,000,000 g / mole, advantageously between 20,000 and 2,000,000, and preferably between 100,000 and 1,500,000. g / mol. It is preferred that the polymers (A) have a polydispersite index (that is to say a ratio of the average molar mass by weight to the average molar mass by number) the least high possible, preferably less than 3, and even more advantageously less than 2.
  • the macromolecules of polysaccharides (B) present in the particles of the compositions of the invention specifically comprise groups G capable of forming inclusion complexes with the cyclodextrin units of the polymers (A).
  • These groups G can in particular be aliphatic groups, linear or branched, comprising from 8 to 18 carbon atoms.
  • these are linear alkyl groups comprising from 8 to 18 carbon atoms. According to a particular variant, it can also be adamantyl groups.
  • the macromolecules (B) present in the composition according to the invention are polysaccharides grafted with groups G as defined above.
  • the groups G are aliphatic groups, and advantageously linear alkyl groups comprising from 8 to 18 carbon atoms, or alternatively adamantyl groups, these groups generally being linked to the polysaccharide via an ester bond -COO -.
  • the grafted polysaccharides (B) are substituted derivatives of polysaccharides chosen from dextran, chitosan, amilose, amilopectin, hyaluronic acid, cellulose derivatives, starch, pullulan, pectin, alginates, heparin, caragheenanes, fucan, curdlan, xylan, polyguluronic acid, xanthan, arabinan, polymannuronic acid, and their derivatives (such as dextran sulfate, esters of amilose, or alternatively cellulose acetate), these polysaccharides generally having a mass-average molar mass of between 5,000 and 2,000,000 g / mol, and preferably between 6,000 and 70,000 g / mol.
  • the macromolecules (B) are dextrans grafted, preferably by linear alkyl groups comprising from 8 to 18 carbon atoms, or else by adamantyl groups.
  • Substituted polysaccharides useful as macromolecules (B) according to the invention can, for example, be obtained by reaction of a polysaccharide and an acyl chloride ROCI (R denoting an aliphatic chain as defined above), in proportions corresponding to the average level of aliphatic chains R which it is desired to graft onto the polysaccharide.
  • the reaction of the polysaccharide of acyl chloride ROCI takes place at a temperature of between 30 and 90 ° C, preferably between 70 and 90 ° C (typically at 80 ° C), and advantageously in the presence a base such as an amine, in particular of the pyridine type.
  • a base such as an amine
  • the number and the exact nature of the groups G present on the macromolecules (B) are preferably adapted to the nature of the polymer (A) used.
  • the compounds (A) and (B) must be chosen from associative systems capable of being able to lead, under certain conditions of concentration, to an associative phase separation.
  • the groups G present on the macromolecules (B) are alkyl groups, preferably linear, having from 6 to 18 carbon atoms, and preferably 8 to 10 carbon atoms.
  • the groups G present on the macromolecules (B) are alkyl groups, preferably linear, having from 10 to 18 (preferably from 12 to 16) carbon atoms, or adamantyl groups. If the polymer (A) contains only cyclodextrin units of the ⁇ -cyclodextrin type, it is particularly advantageous that the groups G are linear alkyls having 10 to 16 (preferably 12 to 16) carbon atoms, or adamantyl groups, these groups then preferably being linear alkyls having 12 carbon atoms or adamantyl groups.
  • the groups G present on the macromolecules (B) are alkyl groups, preferably linear, having from 12 to 16 carbon atoms.
  • the average number of groups G present on the macromolecules (B) is typically at least equal to 3 chains per macromolecule. As a general rule, this average number of G groups is all the more important the larger the size of the macromolecule and the larger the number of cyclodextrin units in compound (A). It is most often advantageous that the average number of groups G present on the macromolecules (B) is at least equal to 5, and advantageously at least equal to 8. In general, the average number of groups G present on the macromolecules (B) ) remains less than or equal to 50, and advantageously less than or equal to 15.
  • a rate of grafting by G groups reflecting the quantity of G groups relative to the size of the polysaccharide chain, that is to say to the number of saccharide units of the polysaccharide chain.
  • This rate of grafting by the G groups is calculated on the basis of an NMR spectrum of the proton of the grafted polysaccharides, and it corresponds to the ratio of the integrations of the protons of the G groups, relative to the integrations of the protons of the polysaccharide skeleton. This rate is calculated according to the following formula:
  • the rate of grafting by the groups G of the macromolecules of grafted polysaccharides (B) is generally at least equal to 1%, and preferably at least equal to 2%.
  • this rate is greater than or equal to 3%.
  • the number of G groups present on the macromolecules (B), most often hydrophobic, is limited by the fact that the compounds (B) must typically be water-soluble. It is also desirable, as a general rule, to limit the number of G groups present on the macromolecules (B) so as to avoid self-association phenomena between the macromolecules (B), and this very particularly when the G groups are hydrophobic groups of aliphatic chain type. Therefore, the rate of grafting by the groups G is generally less than or equal to 8%, and preferably less than or equal to 6%. Thus, it is typically between 3 and 4%.
  • the macromolecules (B) have a weight-average molar mass at least equal to 20,000 g / mole, and preferably between 20,000 and 100,000 g / mole. It is preferred that the polymers (A) have a polydispersite index (that is to say a ratio of the average molar mass by weight to the average molar mass by number) as low as possible, preferably less than 3, and even more advantageously less than 2.
  • the compounds (A) and (B) present within the particles (p) of a composition according to the invention can be chosen from the following associations:
  • polymers (A) comprising from 18 to 1000, and preferably from 100 to
  • polymers (A) comprising from 100 to 600, and preferably from 200 to 500 ⁇ -cyclodextrin / polysaccharide units (B) of molecular mass between 6,000 and 70,000 (preferably dextrans) grafted by groups aliphatic C10 (preferably linear alkyl chains) and having a hydrophobic substitution rate of 5 to 7%.
  • polymers (A) comprising from 18 to 1000, and preferably from 100 to 600 ⁇ -cyclodextrin / polysaccharide units (B) of molecular mass between 6000 and 70000 (preferably dextrans) grafted by adamantyl groups and with a hydrophobic substitution rate of 3 to 4%.
  • the molar ratio of the total amount of cyclodextrin units present within the polymers (A), related to the total amount of group G present in the macromolecules of polysaccharides (B) is between 1: 3 and 3: 1.
  • this ratio is at least equal to 0 , 7, and advantageously at least equal to 0.8. It is moreover preferred that this ratio is less than or equal to 1.5, and advantageously less than or equal to 1.3.
  • this ratio can for example be between 0.9 and 1.1.
  • the concentration of compounds (A) and (B) in a composition according to the invention can vary to a fairly large extent.
  • the concentration of polymers (A) within the aqueous dispersion present in the composition of the invention is between 0.01 and 10 g / L, advantageously between 0.02 and 2 g / L, and even more advantageously between 0.2 and 2 g / L.
  • the concentration of macromolecules (B) within the aqueous dispersion is generally between 0.01 and 10 g / L, preferably between 0.08 and 9 g / L and, even more preferably, between 0 , 8 and 8 g / L. It is more generally preferred that the total concentration of polymers (A) and modified macromolecules (B) within the aqueous dispersion is between 0.01 and 20 g / L.
  • the polymers (A) and macromolecules (B) are located within the particles (p).
  • at least 80% by mass (preferably at least 85% by mass, and advantageously at least 90% by mass of the compounds (A) and (B) present in a composition according to the invention are contained in the particles (p).
  • the present invention also relates to a process for the preparation of a composition as described above.
  • This process comprises a step (E), which is extremely simple to carry out, which consists in mixing a aqueous solution (SA) comprising polymers (A) as defined above and an aqueous solution (SB) comprising macromolecules of polysaccharides (B) as defined above, by choosing the volumes and the concentrations of said solutions (SA) and (SB) so as to obtain, following mixing, an aqueous medium where the respective concentrations CA and CB in said Compounds (A) and (B) belong to the field of formation of a metastable dispersion for the self-associative system (A + B) implemented.
  • SA aqueous solution
  • SB aqueous solution
  • B macromolecules of polysaccharides
  • domain of formation of a metastable dispersion of a self-associative system means the domain of concentrations of compounds (A) and (B) whose existence has been discovered by the inventors for associations of the an type, in which a direct mixture of compounds (A) and (B) as defined above leads to the formation of a dispersion of particles of dimensions between 50 and 5000 nm.
  • concentration domain designates a set of couples (CA; C B ).
  • domain refers to the ternary water / compound (A) / compound (B) diagrams which can be established for a system (A + B), observing the system formed for the different water contents, compound (A ) and compound (B).
  • the set of couples ( ⁇ A; CB) in which the respective concentrations must be chosen in compounds (A) and (B) in the final medium to observe the formation of the metastable dispersion indeed appears in the form of a continuous zone, called "concentration range”.
  • a composition according to the invention can be obtained from most associative systems of type (A + B) as defined above if the medium obtained at the end of step (E) satisfies both following conditions: - the sum of the CA + CB concentrations is between 0.1 and 10 g / L, and preferably between 1g / L and 10g / L; and
  • the molar ratio of the total quantity of cyclodextrin units present in the polymers (A) introduced, relative to the total quantity of aliphatic chains present as substituents on the macromolecules of polysaccharides (B) introduced is between 1, 3 and 3.1, and preferably between 1, 2 and 2.1.
  • the solution (SA) used in step (E) generally has a concentration of between 0.01 g / L and 20 g / L, this concentration advantageously being between 0.1 and 10 g / L .
  • the solution (SB) most often has a concentration between 0.01 g / L and 20 g / L, this concentration preferably being between 0.1 and 10 g / L.
  • the ratio of the total volume of solution (SA) introduced to the total volume of solution (S B ) introduced is most often between 1: 9 and 9: 1, and preferably this volume ratio is between 1: 5 and 5: 1.
  • this ratio is between 1: 5 and 1: 1.25 and preferably between 1: 3 and 1: 0.75 .
  • step (E) of the process of the invention consists of a simple mixture, which is generally carried out at room temperature, that is to say most often between 15 ° C and 30 ° C. It should also be noted that the process for preparing the invention can be limited to the sole implementation of step (E).
  • step (E) In particular in order to achieve a mixture of solutions (SA) and (SB) as homogeneous as possible, it is often advantageous to carry out step (E) with stirring, but this stirring is most of the time not necessary to observe the formation of the metastable dispersion.
  • the inventors have demonstrated that, subject to placing themselves in the suitable concentration range and carrying out a direct mixture as quickly as possible of the solutions (S A ) and (S B ), the mixing of said solutions spontaneously leads to the formation of the metastable dispersion.
  • a composition according to the invention is, in general, free of any trace of organic solvent or surfactant.
  • a composition according to the invention can comprise water and compounds (A) and (B) as defined above, to the exclusion of any other compound.
  • the particles (p) present in a composition according to the invention are particularly suitable for carrying out the encapsulation of chemical compounds, and very particularly for carrying out The encapsulation of chemical compounds having groups of hydrophobic nature.
  • the particular use of the compositions of the invention for this purpose constitutes a particular object of the present invention.
  • the particles (p) present in the compositions according to the invention are capable of integrating, in encapsulated form, many types of neutral or charged chemical compounds.
  • the compounds capable of being able to be encapsulated within the particles (p) of a composition according to the invention include in particular the compounds having hydrophobic groups, in particular alkyl groups, generally comprising from 6 to 18 carbon atoms.
  • the particles (p) present in a composition according to the invention are particularly well suited for carrying out an encapsulation of compounds capable of forming inclusion complexes with the cyclodextrin units which they comprise.
  • the particles (p) present in a composition according to the invention are particularly well suited for carrying out an encapsulation of compounds capable of forming inclusion complexes with the cyclodextrin units which they comprise.
  • inclusion complexes between chemical compounds and cyclodextrins as well as on the nature of the compounds capable of forming such complexes
  • reference may in particular be made to "Cyclodextrins and their inclusion complexes” Szejtli J., Academia Kiado, Budapest, 1982.
  • a composition according to the invention can for example be used as an absorbent composition, in particular for trapping agents of toxic or pollutants present in a medium aqueous, and in particular for eliminating compounds of the hydrocarbon type (in particular polycyclic aromatic hydrocarbons), halogenated aromatic compounds (such as chlorobenzene or chlorophenols), phthalic esters, or alternatively iodine, in particular radioactive iodine, or pollutants such as pesticides or textile dyes.
  • the composition based on particle (p) within the medium to be purified.
  • the particles (p) can, in this type of application, absorb (encapsulate) a quantity of compounds to be eliminated at least equal to 0.1 mole of compound per mole of cyclodextrins included in the particles, and which can range up to 1 mole per mole of cyclodextrin, or even up to 2 moles per mole of cyclodextrin, in particular for pollutants of hydrocarbon type, in particular of polycyclic aromatic hydrocarbons.
  • compositions according to the invention having chemical compounds encapsulated within their particles (p) may moreover be advantageous as such.
  • the subject of the present invention is also such compositions according to the invention, in which the particles (p) comprise at least one chemical compound (C) other than the compounds (A) and (B).
  • said compound (C) is generally a compound having groups of hydrophobic nature, advantageously groups of the hydrocarbon chain type comprising from 8 to 18 carbon atoms, and preferably from 10 to 18 carbon atoms.
  • this compound (C) is a compound capable of forming an inclusion complex with one of the cyclodextrin units included in the polymers (A) present in the particles
  • composition comprising a compound
  • (p) represents at least 0.5% by mass relative to the total mass of said particles (p). It is often advantageous in such a composition that the mass ratio (C) / (A + B) of the total mass of the compounds (C) relative to the mass total of the compounds (A) and (B) is between 1% and 50%, this ratio preferably being greater than 2%, and advantageously greater than 3%.
  • a composition according to the invention additionally comprising a compound (C) as defined above can in particular be obtained by a simple contacting of said compound (C) with a composition according to the invention based on a preformed aqueous dispersion of particles (p) based on compounds (A) and (B).
  • the particles (p) are essentially based on the compounds (A) and (B), with the exclusion of the presence of another compound, in particular of a compound capable of forming an inclusion complex with the cyclodextrin units present in the polymers (A).
  • the total amount of compound (C) brought into contact with the composition during this or these stages preferably represents between 4 and 100% by mass, and preferably between 10 and 80% by mass relative to the total mass of particles (p) initially present in the composition.
  • This quantity of compound (C) brought into contact with the composition advantageously represents between 10 and 70% by mass, and more preferably between 20 and 50% by mass relative to the total mass of the polymers (A).
  • the incorporation of the compounds (C) within the particles (p) can be carried out by implementing in the preparation process of the invention a solution (SA) comprising, in addition to the polymers (A), the compounds (C) which it is desired to integrate into the particles (p), this compound (C) advantageously forming inclusion complexes with cyclodextrin units present in the polymers (A).
  • SA a solution
  • the mass ratio of compound (C) / polymer (A) is preferably between 10 and 100%, and more preferably between 20 and 50%.
  • the presence of compound (C) within the solution (S A ) does not modify generally not the field of formation of the metastable dispersion for the self-associative system (A + B) with respect to the conditions to be implemented in the absence of compound (C). Therefore, in the presence or absence of the compound (C), the volumes and the concentrations of the solutions (S A ) and (S B ) of steps (E) are chosen so as to obtain, following mixing, a medium aqueous where the respective concentrations C A and CB in said compounds (A) and (B) belong to the field of formation of a metastable dispersion for the self-associative system (A + B).
  • the exact nature of the compound (C) which can be encapsulated in a composition according to the invention, in particular according to one of the abovementioned methods, can vary to a fairly large extent.
  • the polymers (A) and the macromolecules (B) can be chosen from non-toxic and biocompatible compounds, and that the presence of traces of organic solvents or surfactants can be avoided, one of the main applications that can be envisaged for a composition according to the invention is the vectorization of active principles, in particular compounds having a therapeutic or cosmetic effect.
  • a composition according to the invention can comprise, as compound (C) within its particles (p) at least one active compound as a medicament, this compound (C) active drug title preferably being capable of forming an inclusion complex with one of the cyclodextrin units included within the particles (p).
  • composition according to the invention is generally usable as a pharmaceutical composition for administration, by injection or by oral route, or alternatively by dermal or subcutaneous route, by nasal route, by pulmonary route or by ocular route and , more broadly, for any administration at the level of a mucosa, or at the level of a specific site (tumor, lumen of certain blood vessels ).
  • the composition consists essentially of water and of the compounds (A), (B) and (C), possibly in combination with a or several pharmacologically acceptable excipients suitable for the intended route of administration.
  • the composition according to the invention can, in this type of application, take the form of any pharmaceutical formulation incorporating an aqueous dispersion of the particles (p) comprising the active compound (C) as a medicament.
  • the particles (p) integrating the compound (C) have an average hydrodynamic diameter at most equal to 200 nm.
  • the particles (p) integrating the compound (C) have an average hydrodynamic diameter of between 200 and 5000 nm, preferably less than 1000 nm.
  • compositions of the invention which incorporate particles (p) based on polysaccharides grafted as compounds (B), are particularly advantageous in terms of bioadhesiveness, which makes them extremely advantageous for application to the mucous membranes.
  • the compounds (B) present in the particles (p) are grafted hyaluronic acids.
  • compositions of the invention comprising a compound (C) active as a medicament within their particles (p) generally induce, following their administration, a gradual release of the encapsulated compound (C), in particular when said compound ( C) is a compound capable of forming an inclusion complex with one of the cyclodextrin units included in the particles (p), in particular when the said composition is administered to a patient by the intravenous route. It is thus possible to carry out, using such a composition, the prolonged administration of the active compound (C), in particular when this compound is chosen from tamoxifen or its derivatives, or alternatively from piroxicam and its derivatives.
  • active agents are capable of being encapsulated in the particles (p) of the compositions of the invention for the purpose of prolonged release, and in particular anti-infectious, anti-inflammatory, antibacterial, anti-parasitic agents, opioids, enzymes, or even polypeptides.
  • active compounds (C) as drugs which can be encapsulated in the particles (p), mention may in particular be made of molsidomine, ketoconazole, gliclazide, diclofenac, levonorgestrel, paclitaxel, Phydrocortisone, pancratistatin, ketoprofen, diazepam, ibuprofen, nifedipine, testosterone, tamoxifen, furosemide, tolbutamide, chloramphenicol, benzodiazepine, naproxen, dexamethasone, diflunisal, anadamide, pilocarpine, daunorubicin, doxorubicin and diazepam.
  • a compound (C) active as a medicament contained in the particles (p) of a composition according to the invention is most often released preferentially in the cells or tissues where this compound is consumed, that is to say, most often, where it plays an effective therapeutic role.
  • compositions of the invention comprising a compound (C) active as a medicament
  • the particles (p) can generally be administered as such by the oral route.
  • they can make it possible to carry out the oral administration of a compound (C) of unpleasant taste or odor (the encapsulation is generally capable of masking this taste or this odor) or even of a compound (C) fragile and / or difficult to absorb by the oral route, such as for example a compound chosen from anti-inflammatory drugs such as piroxicam, ibuprofene and ketoprofen, hypoglycemic agents such as glicazide, contraceptive agents such than D-norgestrel, or still antifungal or antiparasitic compounds such as ketoconazole or albendazole.
  • anti-inflammatory drugs such as piroxicam, ibuprofene and ketoprofen
  • hypoglycemic agents such as glicazide
  • contraceptive agents such than D-norgestrel
  • the structure of the particles (p) is generally such that the outer layer of the particles (p) consists essentially of polysaccharides.
  • the particles (p) in particular when the polysaccharides (B) are dextrans, the particles (p) generally have a tendency to adhere to the surface of certain mucous membranes, at the level of which they then deliver, generally gradually, the principle active (c) they contain.
  • composition according to the invention comprising a compound (C) with a therapeutic effect on a given mucosa (nasal mucosa, ocular ...) to effect a selective administration of the compound at the level of this mucosa.
  • a composition according to the invention comprising a compound (C) with a therapeutic effect on a given mucosa (nasal mucosa, ocular ...) to effect a selective administration of the compound at the level of this mucosa.
  • the specific structure of the particles (p) promotes their translocation through the digestive epithelium, and their passage to the intact state in the blood network. , where they can then allow a prolonged release of the compound (C).
  • the particles (p) are intended for the vectorization of compounds of the drug type, it is generally advantageous for the compounds (A) and / or (B) to be substituted by groups allowing cell targeting. In this context, it may be advantageous, for example, for the compounds (A) and / or (B) to be complexed with ligands of the folic acid type. The particles (p) then constitute specific ligands called "third generation".
  • the particles (p) of the invention may be advantageous for the particles (p) of the invention to have external groups of propylene glycol (PEG) type.
  • PEG propylene glycol
  • compounds (B) macromolecules of polysaccharides (preferably dextrans) carrying both G groups as defined above, and PEG chains.
  • particles grafted by PEG groups consists in adding to the system compounds (A) and (B) in addition to compounds (C), compounds of the PEG- [Alk] type where Alk represents an alkyl group in C10 to C-i ⁇ , preferably from C 12 to Ci 6 , or else an adamantyl group.
  • the addition of the compounds of the PEG- [Alk] type can be carried out before or after formation of the particles from the associative system (A + B). In general, however, it is preferred that this addition is carried out after formation of the particles.
  • (p) prove capable of ensuring, for example, the vectorization of compounds with a reduced plasma half-life, or with high toxicity, in particular in the mononuclear phagocyte system.
  • the compounds (C) optionally present in the particles (p) can also be cosmetic active agents, and the composition according to the invention can then be advantageously used as a cosmetic composition.
  • the compounds (C) may for example be odorous compounds, for example of the terpene type, or else a mixture of such compounds (perfumes, essences ).
  • the odorous compounds generally have a lower irritant power than in the non-encapsulated state, and they are released in a delayed manner, which improves the resistance of the perfume.
  • other types of cosmetic agents preferably having a hydrophobic character, can be immobilized as compound (C) within the particles (p) of a composition according to the invention, then released in a manner progressive.
  • a composition according to the invention can for example allow the controlled release of antiperspirant agents or even antibacterial agents.
  • the compound (C) can also be an irritant dye or having a certain toxicity, the encapsulation of which makes it possible to reduce the undesirable effects.
  • compositions of the invention incorporating compounds (C) can be used to achieve a gradual release of said compounds (C) in a medium in which they are introduced or else to limit the contact of the compounds (C) with said medium, for example with a view to their protection, when they are molecules which are fragile with respect to the medium considered, or else to isolate compounds which may be pollutants (toxic agents , irritants, reagents ...) for this medium.
  • This general use of the compositions of the invention comprising compounds (C) within the particles (p) constitutes another object of the present invention.
  • compositions of the invention may in general be subjected to a lyophilization step, in particular when it is a composition essentially constituted by an aqueous dispersion of the particles (p). If necessary, this lyophilization step is generally carried out by abruptly cooling the composition (generally in liquid air or liquid nitrogen), then by subliming the water under high depression.
  • a lyophilization step is generally carried out by abruptly cooling the composition (generally in liquid air or liquid nitrogen), then by subliming the water under high depression.
  • the compositions obtained at the end of such a lyophilization step which are generally in the form of a compact powder with a cottony appearance, and which can be dispersed in water to lead to the reconstitution of a dispersion of particles of the type of particles (p), constitute another particular object of the present invention.
  • the reaction was then stopped by adding acetone which dissolves the excess of epichlorohydrin. The supernatant acetone solution was then removed.
  • the polymer (precipitate) is dissolved in distilled water and the solution was brought to pH12, and was stirred for 24 h. The pH value was then brought back to 7 (by adding 6N hydrochloric acid), then the mixture was ultrafiltered with a cutoff threshold membrane.
  • polymer P1 As for polymer P1, 5 g of ⁇ -CD were dissolved in a bicol in a 33% by mass aqueous sodium hydroxide solution. This mixture was allowed to stir, at room temperature (20 ° C), for 24 h, so as to deprotonate the hydroxyl groups.
  • the reaction was then stopped by adding acetone which dissolves the excess of epichlorohydrin. The supernatant acetone solution was then removed.
  • the polymer (precipitate) is dissolved in distilled water and the solution was brought to pH12, and was stirred for 24 h. The pH value was then brought back to 7 (by adding 6N hydrochloric acid), then the mixture was ultrafiltered with a cut-off membrane of 1000 Dalton, in order to remove the salts. A second ultrafiltration was then carried out with a 100,000 Dalton cutoff threshold membrane so as to eliminate the fractions of low molar mass.
  • the polymer P2 obtained following these various stages was then lyophilized and then stored in the freezer.
  • dextran with a molecular mass equal to 40,000 was reacted with different alkyl chlorides (nature and quantity specified in table 2 below), in the presence of pyridine (proton sensor) and dimethylaminipyridyne DMAP (catalyst).
  • the polymer obtained was then purified by precipitation in isopropanol, then by dialysis after solubilization in water. During this step, the polymer is fractionated according to its rate of modification by difference in solubility in water.
  • the solution was poured into a test tube and it was left to stand for 4 h. Following this decantation, three fractions (upper, middle and lower) of equal volumes were then separated. In each of the syntheses, one or more of these fractions (as indicated in Table 2 below) were dialyzed against pure water on cut-off threshold membranes. 6000-8000 Dalton. Following dialysis of the fraction considered, the modified dextran obtained was characterized by NMR to determine the rate of substitution by the alkyl chains, then it was lyophilized.
  • Example 3 preparations of aqueous dispersions of particles according to the invention.
  • Various aqueous dispersions were produced according to the invention by mixing a volume V (A) of an aqueous solution of polymers (A) at a concentration C (A), with a volume V (B) of an aqueous solution of dextrans modified (B) at a concentration C (B).
  • the conditions of the mixtures produced are reported below:
  • a mixture of 1 ml of a solution of modified dextran DM3 (10 mg / ml in milliQ water) was produced with 1 ml of a solution of two polymers (A) of distinct molar masses (polymers P1 and P2 such as defined in Example 1, of respective molecular weights 40,000 g / mole or 2,600,000 g / mole) also at 10 mg / ml in milliQ water.
  • A polymers of distinct molar masses
  • Table 5 represents the changes in the average diameters of the particles obtained in the two cases: Table 5: Comparative evolution of the average particle diameters for two polymers (A) of different molecular weights
  • the particles obtained with a polymer (A) of low molar mass are less stable than those obtained with a polymer (A) of higher molar mass (for P2, the diameter tends to stabilize after 5 days).
  • An aqueous solution of polymer P2 was produced as defined in Example 1 (0.44 g / L) to which benzophenone was added with an added benzophenone: cyclodextrin molar ratio equal to 1: 1. This solution was left stirring for 24 hours.
  • a particle composition was prepared by mixing 1 ml of the solution thus obtained with 1 ml of a DM3 modified dextran solution as defined in Example 1 (0.44 g / L).
  • the particles produced were ultracentrifuged (30 minutes at 40,000 rpm in a Beckman L7-55 centrifuge).
  • the non-encapsulated benzophenone present in the supernatant was assayed by spectrophotometry (absorption line at 261 nm).
  • the experiment was reproduced using a benzophenone: cyclodextrin molar ratio added equal to 1: 3 for the polymer solution P2.
  • the encapsulation yield of the benzophenone is between 30 and 40% (less than 70% of the benzophenone initially introduced is found in the supernatant).
  • Particle compositions were prepared by mixing two identical volumes (1 mL) of a polymer solution (A) and a modified dextran solution (B) under the conditions set out in Table 6 below.
  • the particles were then lyophilized (Christ LDC-1) for 24 hours, with or without the presence of cryoprotective (sucrose) as appropriate. It has been demonstrated in this context that the use of glucose and maltose is a cryoprotective ill-suited to this type of particles.
  • the lyophilizates obtained were then mixed with milliQ water, so as to reconstitute particle compositions.
  • Table 6 lyophilization tests and demonstration of the redispersibility of the lyophilisates obtained.
  • Example 7 Stability of the compositions of the invention under shear
  • a particle composition according to the invention was prepared by mixing 5 ml of solution of polymer P2 at 10 mg / ml in milliQ water and 5 ml of solution of modified dextran DM3 at 10 mg / ml in water milliQ.
  • the average diameter of the particles obtained is 178 nm.

Abstract

The invention concerns a composition comprising an aqueous dispersion of particles (p) of hydrodynamic mean diameter ranging between 50 and 5000 nm, said particles containing, in combination: (A) polymers based on cyclodextrin units, including on the average at least 4 cyclodextrin units inside their structure; and (B) polysaccharide macromolecules including groups G capable of forming inclusion complexes with the cyclodextrins present in the structure of said polymers (A), the average number of groups G per polysaccharide molecule being not less than 3, said compounds (A) and (B) being water-soluble in isolated state. The invention also concerns the method for preparing said compositions, and their use for encapsulating compounds such as active principles.

Description

Dispersions aqueuses de particules nanométriques ou micrométriques pour i'encapsulation de composés chimiques Aqueous dispersions of nanometric or micrometric particles for the encapsulation of chemical compounds
La présente invention a trait à des dispersions aqueuses de particules de dimensions nanométriques ou micrométriques, adaptées àThe present invention relates to aqueous dispersions of particles of nanometric or micrometric dimensions, suitable for
I'encapsulation de composés chimiques, et utilisables en particulier pour réaliser la vectorisation de principes actifs au niveau de cellules ou de tissus cibles, notamment dans des applications pharmaceutiques ou cosmétiques.The encapsulation of chemical compounds, and which can be used in particular to carry out the vectorization of active principles at the level of target cells or tissues, in particular in pharmaceutical or cosmetic applications.
Au cours des vingt dernières années, de nombreux systèmes de vectorisation de principes actifs ont été développés. De façon générale, le principe de la vectorisation consiste à emprisonner un principe actif au sein d'une particule de taille micrométrique ou submicrométrique, administrable chez un sujet à traiter (notamment par injection ou ingestion) et en choisissant ladite particule de façon à ce qu'elle" libère le principe actif au niveau d'une cellule ou d'un tissu ciblé.Over the past twenty years, numerous vectorization systems for active ingredients have been developed. In general, the principle of vectorization consists in trapping an active principle within a particle of micrometric or submicrometric size, which can be administered to a subject to be treated (in particular by injection or ingestion) and by choosing said particle so that 'it ' releases the active ingredient at the level of a targeted cell or tissue.
Dans ce cadre, on a notamment mis au point I'encapsulation de principes actifs par des liposomes (bicouches lipidiques entourant un cœur aqueux), ou bien encore par des nanocapsules (coquilles de polymère de taille submicrométrique contenant une phase, généralement huileuse, renfermant le principe actif).In this context, the encapsulation of active principles has notably been developed by liposomes (lipid bilayers surrounding an aqueous core), or even by nanocapsules (polymer shells of submicrometric size containing a phase, generally oily, containing the active ingredient).
De façon plus spécifique, on a également développé des systèmes de type nanosphères ou microsphères, à savoir des particules à base de polymères biocompatibles et biodégradables (par exemple de l'acide polylactique ou du poly-caprolactone), jouant le rôle d'une matrice capable d'immobiliser des principes actifs et de les libérer progressivement au sein d'un organisme où ce système d'encapsulation est introduit.More specifically, nanosphere or microsphere systems have also been developed, namely particles based on biocompatible and biodegradable polymers (for example polylactic acid or poly-caprolactone), playing the role of a matrix. able to immobilize active ingredients and gradually release them within an organism where this encapsulation system is introduced.
Ces systèmes de type nanosphères ou microsphères présentent en général une assez bonne capacité de vectorisation de principes actifs.These nanosphere or microsphere type systems generally have a fairly good capacity for vectorization of active principles.
Toutefois, ces vecteurs de principes actifs présentent actuellement un inconvénient majeur. En effet, les procédés de préparation des systèmes de ce type qui sont actuellement connus mettent en œuvre des étapes intermédiaires, qui nécessitent, en général, l'utilisation de solvants organiques ou d'agents tensioactifs non biocompatibles qu'il est nécessaire d'éliminer. Or, l'élimination de ces solvants et/ou tensioactifs est généralement longue et onéreuse (mise en œuvre de dialyse, d'ultracentrifugation ...), et elle est rarement totale. De ce fait, à l'issue de telles étapes de purification, des solvants et/ou tensioactifs subsistent en général à l'état de traces, ce qui est susceptible à la fois de poser des problèmes en terme de toxicité (par exemple si le solvant subsistant à l'état de trace est un solvant tel que le dichlorométhane) et/ou de dégrader les principes actifs immobilisés dans les particules (des traces de solvants organiques peuvent par exemple dénaturer des molécules fragiles de type peptides ou protéines).However, these vectors of active principles presently present a major drawback. Indeed, the processes for preparing the systems of this type which are currently known implement intermediate steps, which generally require the use of organic solvents or non-biocompatible surfactants which must be eliminated. However, the elimination of these solvents and / or surfactants is generally long and expensive (implementation of dialysis, ultracentrifugation, etc.), and it is rarely complete. Therefore, at the end of such purification steps, solvents and / or surfactants generally remain in trace amounts, which is likely both to pose problems in terms of toxicity (for example if the solvent remaining in trace amounts is a solvent such as dichloromethane) and / or degrading the active principles immobilized in the particles (traces of organic solvents can, for example, denature fragile molecules of the peptide or protein type).
Or, de façon inattendue, les inventeurs ont maintenant découvert qu'il est possible de réaliser des dispersions aqueuses de particules de type nanosphères ou microsphères, adaptées à une vectorisation de principes actifs, sans avoir pour cela à mettre en œuvre de solvants organiques ou d'agents tensioactifs.However, unexpectedly, the inventors have now discovered that it is possible to produce aqueous dispersions of particles of the nanosphere or microsphere type, suitable for vectorization of active principles, without having to use organic solvents or d surfactants.
Plus précisément, les inventeurs ont découvert que, si on effectue, en milieu aqueux, un mélange de composés hydrosolubles spécifiques, à savoir (1 ) des polymères comprenant des unités cyclodextrines réticulées et (2) des macromolécules porteuses de groupements susceptibles de former des complexes d'inclusion avec les cyclodextrines (tels que, par exemple, des polysaccharides substitués par des chaînes aliphatiques), on peut observer, dans certaines conditions de concentrations particulières, la formation spontanée d'une dispersion de particules de diamètre hydrodynamique moyen compris entre 50 et 5000 nm, sous réserve de choisir de façon adéquate le couple de composés (1 ) et (2) mis en oeuvre.More specifically, the inventors have discovered that, if an aqueous medium is used, a mixture of specific water-soluble compounds, namely (1) polymers comprising crosslinked cyclodextrin units and (2) macromolecules carrying groups capable of forming complexes inclusion with the cyclodextrins (such as, for example, polysaccharides substituted by aliphatic chains), one can observe, under certain conditions of particular concentrations, the spontaneous formation of a dispersion of particles of average hydrodynamic diameter between 50 and 5000 nm, provided that the pair of compounds (1) and (2) used is properly selected.
Des associations de polymères comprenant des unités cyclodextrines et de polysaccharides substitués par des chaînes aliphatiques en milieu aqueux ont déjà été décrites. A ce sujet, il est en particulier connu que si on met en présence en milieu aqueux des polymères comprenant des unités cyclodextrines et des polysaccharides substitués par des chaînes aliphatiques, on observe la formation de complexes d'inclusions entre les chaînes aliphatiques des polysaccharides substitués et les unités cyclodextrines des polymères, ce qui conduit à une association des polymères et des polysaccharides.Associations of polymers comprising cyclodextrin units and of polysaccharides substituted by aliphatic chains in an aqueous medium have already been described. In this regard, it is known in particular that if polymers comprising units are present in an aqueous medium cyclodextrins and polysaccharides substituted by aliphatic chains, the formation of inclusion complexes is observed between the aliphatic chains of the substituted polysaccharides and the cyclodextrin units of the polymers, which leads to an association of the polymers and polysaccharides.
Toutefois, jusqu'à présent, cette association en milieu aqueux a toujours été spécifiquement décrite comme ne pouvant conduire qu'à la formation de deux types de systèmes associatifs, à savoir :However, until now, this association in an aqueous medium has always been specifically described as being capable of only leading to the formation of two types of associative systems, namely:
(I) un système monophasique homogène comprenant des polymères et des polysaccharides associés, dissous dans le milieu aqueux; ou(I) a homogeneous monophasic system comprising polymers and associated polysaccharides, dissolved in the aqueous medium; or
(II) un système biphasique non émulsifiable, comprenant une première phase riche en polymères, dense et visqueuse (dite "gel") et une seconde phase homogène moins dense et visqueuse (dite "surnageant"), qui est obtenu par un mécanisme dit de "séparation de phase associative", qui a notamment été décrit dans une publication de l'ACS, éditée par C. McCormick (Symposium Séries, No 780, chapitre 4,"Stimuli-Responsive Water-Soluhle and Amphiphatic Polymers", C. Amiel et al. , 2000).(II) a biphasic non-emulsifiable system, comprising a first phase rich in polymers, dense and viscous (called "gel") and a second homogeneous less dense and viscous phase (called "supernatant"), which is obtained by a mechanism called "associative phase separation", which has in particular been described in an ACS publication, edited by C. McCormick (Symposium Series, No 780, chapter 4, "Stimuli-Responsive Water-Soluhle and Amphiphatic Polymers", C. Amiel et al., 2000).
A ce sujet, il est connu que certaines associations de type (polymères comprenant des unités cyclodextrines / polysaccharides substitués par des chaînes aliphatiques) conduisent, en milieu aqueux, exclusivement à la formation d'un système de type (I) quelles que soient les concentrations respectives en polymères et en polysaccharides (associations dites ici de type ai). Le système de type (II) ne peut être obtenu que pour d'autres associations particulières, dites ici de type an. Dans la suite de la description, ces associations spécifiques de type an seront désignées par le terme génériquede système auto-associatif "de type pouvant mener, dans certaines conditions de concentration, à une séparation de phase associative".In this regard, it is known that certain type associations (polymers comprising cyclodextrin / polysaccharide units substituted by aliphatic chains) lead, in aqueous medium, exclusively to the formation of a system of type (I) whatever the concentrations. respective in polymers and in polysaccharides (associations said here of type ai). The type (II) system can only be obtained for other particular associations, say here of type an. In the following description, these specific year-type associations will be designated by the generic term of self-associative system "of the type which can lead, under certain conditions of concentration, to an associative phase separation".
En ce qui concerne les associations de type an définies ci-dessus, il faut souligner que la séparation de phase associative ne peut être observée que dans des conditions de concentrations spécifiques, correspondant à un domaine relativement limité sur un diagramme ternaire eau/polymère/polysaccharide. Il était jusqu'à présent généralement admis que, dans ce domaine de concentrations spécifiques, il était uniquement possible d'observer des phénomènes de type séparation de phase associative conduisant à la formation d'un système de type (II), et qu'en dehors de ce domaine, on pouvait uniquement observer la formation d'un système de type (I).With regard to the year-type associations defined above, it should be emphasized that the associative phase separation can only be observed under specific concentration conditions, corresponding to a relatively limited domain on a ternary water / polymer / polysaccharide diagram. It has hitherto been generally accepted that, in this area of specific concentrations, it was only possible to observe phenomena of the associative phase separation type leading to the formation of a type (II) system, and that in outside this domain, one could only observe the formation of a type (I) system.
La présente invention repose sur la découverte tout à fait inattendue de la possibilité de former un troisième type de système à partir des associations de type a . En ce qui concerne ces associations spécifiques, les travaux des inventeurs ont en effet permis de mettre en évidence qu'il existe un domaine de concentrations spécifique dans lequel un mélange direct d'eau, de polymères à base d'unités cyclodextrine, et de polysaccharide greffés par des chaînes aliphatiques, conduit à la formation d'une dispersion de particules à base de polymères et de polysaccharides associés, de diamètre hydrodynamique moyen au moins égal à 50 nm, et présentant le plus souvent une très bonne stabilité. De façon plus générale, les inventeurs ont découvert que de telles dispersions de particules peuvent être obtenues par le mélange direct d'eau, de polymères à base d'unités cyclodextrine, et de macromolécules porteuses de groupements susceptibles de former des complexes d'inclusion avec les cyclodextrines.The present invention is based on the completely unexpected discovery of the possibility of forming a third type of system from type a associations. With regard to these specific associations, the work of the inventors has indeed made it possible to demonstrate that there is a specific concentration domain in which a direct mixture of water, of polymers based on cyclodextrin units, and of polysaccharide grafted by aliphatic chains, leads to the formation of a dispersion of particles based on polymers and associated polysaccharides, of average hydrodynamic diameter at least equal to 50 nm, and most often having very good stability. More generally, the inventors have discovered that such particle dispersions can be obtained by the direct mixture of water, polymers based on cyclodextrin units, and macromolecules carrying groups capable of forming inclusion complexes with cyclodextrins.
Dans ce cadre, les inventeurs ont établi que la dispersion ainsi réalisée constitue un système métastable, et que seuls les systèmes de type (I) et (II) sont des systèmes thermodynamiquement stables. Ainsi, si on soumet la dispersion découverte par les inventeurs à des conditions de cisaillement suffisamment importantes, on observe généralement une évolution vers un système de type (II). De façon surprenante, les inventeurs ont toutefois découvert dans ce cadre que la stabilité de la dispersion métastable réalisée est étonnamment importante, ce qui permet notamment d'envisager son stockage, sa dilution, ou bien encore son intégration au sein de compositions complexes, par exemple dans des compositions pharmaceutiques ou cosmétiques. Les travaux des inventeurs ont en outre permis de mettre en évidence que les particules formées au sein de la dispersion métastable obtenue sont particulièrement adaptées à I'encapsulation de composés chimiques, et notamment pour la vectorisation de principes actifs, avec une intégration efficace et quantitative des composés chimiques. Dans ce cadre, les inventeurs ont en particulier mis en évidence que ces particules permettent de réaliser une libération des principes actifs de façon plus contrôlée qu'en utilisant la plupart des particules de type nanosphères ou microsphères de l'état de la technique, pour lesquelles on observe généralement, après administration, une libération immédiate d'une fraction importante des principes actifs encapsulésIn this context, the inventors have established that the dispersion thus produced constitutes a metastable system, and that only the systems of type (I) and (II) are thermodynamically stable systems. Thus, if the dispersion discovered by the inventors is subjected to sufficiently high shear conditions, there is generally an evolution towards a type (II) system. Surprisingly, the inventors have however discovered in this context that the stability of the metastable dispersion produced is surprisingly important, which makes it possible in particular to envisage its storage, its dilution, or even its integration within complex compositions, for example in pharmaceutical or cosmetic compositions. The work of the inventors has also made it possible to demonstrate that the particles formed within the metastable dispersion obtained are particularly suitable for the encapsulation of chemical compounds, and in particular for the vectorization of active principles, with efficient and quantitative integration of the chemical compounds. In this context, the inventors have in particular demonstrated that these particles make it possible to achieve a release of the active ingredients in a more controlled manner than by using most of the particles of the nanosphere or microsphere type of the prior art, for which there is generally observed, after administration, an immediate release of a large fraction of the encapsulated active ingredients
Sur la base de ces découvertes, la présente invention a pour but de fournir de nouvelles compositions de particules de dimensions nanométriques ou micrométriques permettant une encapsulation facile de composés chimiques, et notamment de principes actifs. Un autre but de l'invention est de fournir des compositions comprenant des particules exemptes de toutes traces de solvant organique et de tensioactifs, pouvant avantageusement se substituer aux particules connues de l'état de la technique pour la vectorisation de principes actifs. Dans ce cadre, l'invention a en particulier pour but de fournir des compositions permettant de réaliser une libération contrôlée de principes actifs.On the basis of these discoveries, the present invention aims to provide new compositions of particles of nanometric or micrometric dimensions allowing easy encapsulation of chemical compounds, and in particular of active principles. Another object of the invention is to provide compositions comprising particles free of all traces of organic solvent and of surfactants, which can advantageously replace the particles known from the prior art for the vectorization of active principles. In this context, the invention aims in particular to provide compositions for achieving a controlled release of active ingredients.
Un autre but de l'invention est de fournir des compositions destinées à administrer des principes actifs, en assurant une "furtivité" dans l'organisme, c'est-à-dire une capacité à circuler de façon prolongée dans l'organisme, notamment dans le système sanguin, en évitant la reconnaissance par le système immunitaire.Another object of the invention is to provide compositions intended for administering active principles, by ensuring "stealth" in the body, that is to say an ability to circulate in a prolonged manner in the body, in particular in the blood system, avoiding recognition by the immune system.
L'invention a également pour but de fournir des dispersions de particules exemptes de tensioactifs et présentant néanmoins une stabilité suffisante pour pouvoir être stockées pendant une durée au moins de l'ordre de quelques jours. Ainsi, selon un premier aspect, la présente invention a pour objet une composition comprenant une dispersion aqueuse de particules (p) de diamètre hydrodynamique moyen compris entre 50 et 5000 nm, lesdites particules contenant, en association : (A) des polymères à base d'unités cyclodextrines, comprenant en moyenne au moins 4 unités cyclodextrines au sein de leur structure ; etThe invention also aims to provide dispersions of particles free of surfactants and nevertheless having sufficient stability to be able to be stored for a period of at least of the order of a few days. Thus, according to a first aspect, the subject of the present invention is a composition comprising an aqueous dispersion of particles (p) of average hydrodynamic diameter between 50 and 5000 nm, said particles containing, in combination: (A) polymers based on 'cyclodextrin units, comprising on average at least 4 cyclodextrin units within their structure; and
(B) des macromolécules de polysaccharides comprenant des groupements G susceptibles de former des complexes d'inclusion avec les cyclodextrines présentes dans la structure desdits polymères (A), avec un nombre moyen de groupements G par macromolécule de polysaccharide au moins égal à 3, lesdits composés (A) et (B) étant hydrosolubles à l'état isolé, c'est à dire possédant de préférence une solubilité au moins égale à 1 g/L, et avantageusement au moins égale à 3 g/L, à 25°C.(B) macromolecules of polysaccharides comprising groups G capable of forming inclusion complexes with the cyclodextrins present in the structure of said polymers (A), with an average number of groups G per macromolecule of polysaccharide at least equal to 3, said said compounds (A) and (B) being water-soluble in the isolated state, that is to say preferably having a solubility at least equal to 1 g / L, and advantageously at least equal to 3 g / L, at 25 ° C. .
Par "composition comprenant une dispersion aqueuse de particules", on entend, au sens de la présente invention, une composition contenant un milieu aqueux (par exemple de l'eau, du sérum physiologique, ou bien, de façon plus générale, une solution aqueuse comprenant un ou plusieurs solutés (notamment un ou plusieurs sel(s) et/ou sucre(s) comme le sucrose ou le glucose par exemple), à des concentrations de préférence inférieures ou égales à 20 g/L, ou encore un mélange de type eau/alcool), au sein duquel sont dispersées lesdites particules, ces particules étant de préférence individualisées, et présentant avantageusement un taux d'agglomération inférieur à 80 %, de préférence inférieur à 50 %, et avantageusement au plus égal à 10% en nombre. Une composition selon l'invention peut avantageusement être essentiellement constituée par une dispersion des particules (p) au sein d'un milieu aqueux, et de préférence par une dispersion de ces particules dans de l'eau, dans une solution aqueuse de glucose (en particulier une solution de glucose à une concentration de l'ordre de 5% en masse), ou bien encore dans une solution injectable, à pH physiologique, par exemple dans du sérum physiologique. Cependant, une composition selon l'invention peut également être une composition plus complexe, par exemple une composition de type émulsion simple ou multiple, où la dispersion aqueuse des particules de l'invention joue le rôle d'une phase continue ou d'une phase dispersée. Une composition selon l'invention peut également comprendre, en plus des particules à base de l'association des polymères (A) et (B), d'autres particules, de nature minérale ou organique.By “composition comprising an aqueous dispersion of particles” is meant, within the meaning of the present invention, a composition containing an aqueous medium (for example water, physiological saline, or, more generally, an aqueous solution comprising one or more solutes (in particular one or more salt (s) and / or sugar (s) such as sucrose or glucose for example), at concentrations preferably less than or equal to 20 g / L, or a mixture of water / alcohol type), within which said particles are dispersed, these particles being preferably individualized, and advantageously having an agglomeration rate of less than 80%, preferably of less than 50%, and advantageously at most equal to 10% in number. A composition according to the invention can advantageously essentially consist of a dispersion of the particles (p) in an aqueous medium, and preferably by a dispersion of these particles in water, in an aqueous solution of glucose (in in particular a glucose solution at a concentration of the order of 5% by mass), or alternatively in an injectable solution, at physiological pH, for example in physiological serum. However, a composition according to the invention can also be a more complex composition, for example a composition of single or multiple emulsion type, in which the aqueous dispersion of the particles of the invention plays the role of a continuous phase or of a dispersed phase. A composition according to the invention can also comprise, in addition to the particles based on the combination of polymers (A) and (B), other particles, of mineral or organic nature.
Le terme de "diamètre hydrodynamique moyen", au sens où il est employé dans la présente description, désigne la taille d'une particule au sein d'un milieu aqueux, qui prend en compte le diamètre moyen de la particule dans sa conformation en milieu aqueux, ainsi que son éventuelle couche de solvatation. Le diamètre hydrodynamique moyen d'une population de particules au sein d'un milieu aqueux peut notamment être déterminé par diffusion quasi élastique de la lumière au sein du milieu considéré, notamment par un appareil de type Nanosizer. Ce type d'appareil permet également de déterminer pour la population de particules un indice de polydispersite du diamètre hydrodynamique, qui reflète la distribution des diamètres hydrodynamiques, plus ou moins resserrée autour de la valeur moyenne.The term "average hydrodynamic diameter", in the sense used in the present description, designates the size of a particle within an aqueous medium, which takes into account the average diameter of the particle in its conformation in the medium aqueous, as well as its possible layer of solvation. The average hydrodynamic diameter of a population of particles within an aqueous medium can in particular be determined by quasi-elastic light scattering within the medium under consideration, in particular by an apparatus of the Nanosizer type. This type of apparatus also makes it possible to determine for the population of particles a polydispersite index of the hydrodynamic diameter, which reflects the distribution of the hydrodynamic diameters, more or less tightened around the average value.
De préférence, au sein d'une composition selon l'invention, le diamètre hydrodynamique moyen des particules (p) est supérieur ou égal à 80 nm, et il est avantageusement au moins égal à 100 nm. Les particules (p) peuvent posséder, pour certaines applications, un diamètre hydrodynamique moyen compris entre 1 et 5 microns (de préférence inférieur à 3 microns, le cas échéant), mais on préfère en général que le diamètre hydrodynamique moyen des particules (p) soit inférieur ou égal à 500 nm. Plus préférentiellement, le diamètre hydrodynamique moyen des particules (p) est inférieur ou égal à 400 nm, et avantageusement inférieur ou égal à 300 nm. Ainsi, de façon particulièrement avantageuse, le diamètre hydrodynamique moyen des particules (p) est compris entre 100 et 300 nm, et encore plus avantageusement entre 150 et 250 nm. Par ailleurs, dans une composition selon l'invention, les particules (p) sont en général de morphologie sensiblement sphérique, et l'indice de polydispersite de leur diamètre hydrodynamique, tel que mesuré à l'aide d'un appareil de type Nanosizer, est généralement compris entre 0,1 et 0,3 , et il est avantageusement inférieur à 0,2.Preferably, within a composition according to the invention, the average hydrodynamic diameter of the particles (p) is greater than or equal to 80 nm, and it is advantageously at least equal to 100 nm. The particles (p) may have, for certain applications, an average hydrodynamic diameter of between 1 and 5 microns (preferably less than 3 microns, if necessary), but it is generally preferred that the average hydrodynamic diameter of the particles (p) either less than or equal to 500 nm. More preferably, the average hydrodynamic diameter of the particles (p) is less than or equal to 400 nm, and advantageously less than or equal to 300 nm. Thus, particularly advantageously, the average hydrodynamic diameter of the particles (p) is between 100 and 300 nm, and even more advantageously between 150 and 250 nm. Furthermore, in a composition according to the invention, the particles (p) are generally of substantially spherical morphology, and the polydispersite index of their hydrodynamic diameter, as measured using a device of the Nanosizer type, East generally between 0.1 and 0.3, and it is advantageously less than 0.2.
Les composés (A) et (B) présents en association au sein des particules de l'invention sont des composés qui forment, en milieu aqueux, un système associatif (A+B) du type des associations a définies précédemment, à savoir un système associatif (A+B) de type pouvant mener, dans certaines conditions de concentrations, à une séparation de phase associative.The compounds (A) and (B) present in association within the particles of the invention are compounds which form, in aqueous medium, an associative system (A + B) of the type of the associations defined above, namely a system associative (A + B) of the type which can lead, under certain conditions of concentration, to an associative phase separation.
Ainsi, les composés (A) et (B) utiles selon l'invention sont, en général, des composés tels qu'un mélange de deux solutions aqueuses de ces composés à une concentration de 50g/l dans une proportion allant de 1 :5 à 5:1 en volume conduit à la formation d'un système biphasique de type (II) tel que défini précédemment.Thus, the compounds (A) and (B) useful according to the invention are, in general, compounds such as a mixture of two aqueous solutions of these compounds at a concentration of 50 g / l in a proportion ranging from 1: 5 at 5: 1 in volume leads to the formation of a two-phase system of type (II) as defined above.
L'homme du métier peut facilement vérifier que des composés (A) et des composés (B) candidats sont aptes à former un tel système biphasique, par simple mélange des solutions aqueuses à température ambiante. Pour sélectionner un candidat de type (A), il est préférable de mélanger une solution de ce composé avec une solution d'un composé (B) tel que décrit ci-après dans les exemples, et, de même, pour un candidat de type (B), de faire le mélange avec une solution d'un composé (A) tel que décrit ci-après dans les exemples. D'une façon générale, on peut tester des candidats potentiels avec des composés complémentaires ayant démontré leur capacité à former un système de type (II).Those skilled in the art can easily verify that compounds (A) and candidate compounds (B) are capable of forming such a two-phase system, by simple mixing of the aqueous solutions at room temperature. To select a candidate of type (A), it is preferable to mix a solution of this compound with a solution of compound (B) as described below in the examples, and, similarly, for a candidate of type (B), to mix with a solution of a compound (A) as described below in the examples. In general, we can test potential candidates with complementary compounds that have demonstrated their ability to form a type (II) system.
De préférence, les composés (A) et (B) présents dans une composition selon l'invention sont des composés tels qu'un mélange de deux solutions aqueuses de ces composés à des concentrations allant de 1g/l à 10g/l, dans une proportion allant de 1 :9 à 9:1 en volume, conduit à la formation de particules de diamètre hydrodynamique moyen supérieur à 50 nm et inférieur à 5000 nm. Ces mélanges sont extrêmement faciles à réaliser et il suffit ensuite de vérifier, par l'une des méthodes d'analyse classique mentionnés ici, l'apparition des particules selon l'invention.Preferably, the compounds (A) and (B) present in a composition according to the invention are compounds such as a mixture of two aqueous solutions of these compounds at concentrations ranging from 1g / l to 10g / l, in a proportion ranging from 1: 9 to 9: 1 by volume, leads to the formation of particles with an average hydrodynamic diameter greater than 50 nm and less than 5000 nm. These mixtures are extremely easy to carry out and it then suffices to verify, by one of the conventional analysis methods mentioned here, the appearance of the particles according to the invention.
La dispersion aqueuse de particules (p) présente au sein d'une composition selon l'invention constitue de façon caractéristique un système métastable. Par conséquent, si on soumet une composition selon l'invention à une contrainte de cisaillement suffisante (typiquement une centrifugation à raison d'au moins 3000 tours par minutes pendant au moins 20 minutes), on observe en général une évolution irréversible de la dispersion vers un système de type (II) tels que défini précédemment. Néanmoins, il est à noter que, malgré son caractère métastable, la dispersion aqueuse de particules (p) présente au sein d'une composition selon l'invention présente généralement une stabilité importante.The aqueous dispersion of particles (p) present in a composition according to the invention typically constitutes a metastable system. Consequently, if a composition according to the invention is subjected to a sufficient shear stress (typically a centrifugation at the rate of at least 3000 revolutions per minute for at least 20 minutes), there is generally observed an irreversible evolution of the dispersion towards a type (II) system as defined above. However, it should be noted that, despite its metastable nature, the aqueous dispersion of particles (p) present in a composition according to the invention generally exhibits significant stability.
La stabilité des particules (p) en dispersion aqueuse peut notamment être mise en évidence par la conservation du diamètre hydrodynamique moyen des particules (p) suite à un stockage. Ainsi, en général, suite à un stockage de 24 heures, le diamètre hydrodynamique moyen des particules (p) d'une composition selon l'invention reste inférieur ou égal à 5000. Le plus souvent, suite à un stockage de 24 heures, le diamètre hydrodynamique moyen des particules (p) d'une composition selon l'invention reste inférieur ou égal à 400 nm, de préférence inférieur ou égal à 350 nm, avantageusement inférieur ou égal à 300 nm, et encore plus avantageusement inférieur ou égal à 200 nm. De préférence, le diamètre hydrodynamique moyen des particules (p) reste inférieur ou égal à 400 nm, et de préférence inférieur ou égal à 300 nm, suite à un stockage de 2 jours, voire suite à un stockage de 5 jours, et même, dans certains cas, après un stockage de 15 jours. Il est toutefois à souligner que, pour observer une bonne conservation du diamètre hydrodynamique moyen des particules (p) suite à un stockage prolongé, il peut parfois être nécessaire de conserver la composition en atmosphère non oxydante (sous argon par exemple) de façon à éviter un vieillissement des composés (A) et/ou (B), qui est susceptible de remettre en cause la stabilité du système métastable formé. Les polymères (A) à base d'unités cyclodextrines sont des constituants essentiels des particules (p) présentes en dispersion dans la composition de l'invention. Ces polymères (A) comportent en moyenne au moins 4 unités cyclodextrines, de préférence au moins 9 unités cyclodextrines, et avantageusement au moins 15 unités cyclodextrines. De façon particulièrement avantageuse, on préfère que les polymères (A) comprennent en moyenne au moins 100 unités cyclodextrines, et avantageusement au moins 200 unités cyclodextrines. Typiquement, les polymères (A) comprennent en moyenne au moins 400 unités cyclodextrines. Le nombre moyen d'unités cyclodextrines présentes dans les polymères (A) d'une composition de l'invention peut par exemple être établi par chromatographie d'exclusion stérique et par résonance magnétique nucléaire.The stability of the particles (p) in aqueous dispersion can in particular be demonstrated by the conservation of the mean hydrodynamic diameter of the particles (p) after storage. Thus, in general, following a 24 hour storage, the average hydrodynamic diameter of the particles (p) of a composition according to the invention remains less than or equal to 5000. Most often, following a 24 hour storage, the mean hydrodynamic diameter of the particles (p) of a composition according to the invention remains less than or equal to 400 nm, preferably less than or equal to 350 nm, advantageously less than or equal to 300 nm, and even more advantageously less than or equal to 200 nm. Preferably, the mean hydrodynamic diameter of the particles (p) remains less than or equal to 400 nm, and preferably less than or equal to 300 nm, following storage for 2 days, or even after storage for 5 days, and even, in some cases, after 15 days storage. It should however be emphasized that, in order to observe good conservation of the mean hydrodynamic diameter of the particles (p) following prolonged storage, it may sometimes be necessary to preserve the composition in a non-oxidizing atmosphere (under argon for example) so as to avoid an aging of the compounds (A) and / or (B), which is likely to call into question the stability of the metastable system formed. The polymers (A) based on cyclodextrin units are essential constituents of the particles (p) present in dispersion in the composition of the invention. These polymers (A) comprise on average at least 4 cyclodextrin units, preferably at least 9 cyclodextrin units, and advantageously at least 15 cyclodextrin units. Particularly advantageously, it is preferred that the polymers (A) comprise on average at least 100 cyclodextrin units, and advantageously at least 200 cyclodextrin units. Typically, the polymers (A) comprise on average at least 400 cyclodextrin units. The average number of cyclodextrin units present in the polymers (A) of a composition of the invention can for example be established by steric exclusion chromatography and by nuclear magnetic resonance.
Les unités cyclodextrines présentes au sein des polymères (A) peuvent, de façon générale, être des α-cyclodextrines, des β-cyclodextrines, des γ-cyclodextrines, ou bien des mélanges d'au moins deux de ces types de cyclodextrines. Néanmoins, les unités cyclodextrines présentes dans les polymères (A) comprennent de préférence des β-cyclodextrines. De façon particulièrement avantageuse, toutes les unités cyclodextrines présentes dans les polymères (A) sont des β-cyclodextrines. Selon une variante particulière, les unités cyclodextrines présentes dans les polymères (A) sont un mélange de β-cyclodextrines et d'unités α-cyclodextrines. Selon cette variante, on préfère en général que les α-cyclodextrines représentent moins de 50%, et de préférence moins de 30% des cyclodextrines présentes.The cyclodextrin units present within the polymers (A) can, in general, be α-cyclodextrins, β-cyclodextrins, γ-cyclodextrins, or alternatively mixtures of at least two of these types of cyclodextrins. Nevertheless, the cyclodextrin units present in the polymers (A) preferably comprise β-cyclodextrins. In a particularly advantageous manner, all the cyclodextrin units present in the polymers (A) are β-cyclodextrins. According to a particular variant, the cyclodextrin units present in the polymers (A) are a mixture of β-cyclodextrins and α-cyclodextrin units. According to this variant, it is generally preferred that the α-cyclodextrins represent less than 50%, and preferably less than 30% of the cyclodextrins present.
Au sein des polymères (A), les unités cyclodextrines sont généralement liées entre elles par des chaînes hydrocarbonées, linéaires ou ramifiées, éventuellement interrompues par un ou plusieurs atomes d'oxygène, et ces chaînes étant de préférence des chaînes alkyles, alcényles, ou alcynyles, ou bien encore des chaînes polyéthers, ces chaînes pouvant être substituées par des groupements hydrophiles (groupements hydroxy par exemple). Les chaînes liant entre elles les unités cyclodextrines comportent au moins 3 atomes de carbone et de préférence de 4 à 50 atomes de carbone, le chemin le plus court entre deux unités cyclodextrines étant de préférence constitué par une chaîne comportant entre 3 et 8 atomes de carbone. Avantageusement, les chaînes hydrocarbonées liant entre elles deux unités cyclodextrines au sein d'un polymère (A) répondent à la formule générale un groupement de formule -O-(-CH2-CHOR(n)-CH2)n-O-, où n est un entier allant de 1 à 50 (généralement compris entre 2 et 10) et où, dans chacun des n unités (-CH2-CHOR-CH2), R(n) désigne soit un atome d'hydrogène, soit une chaîne -CH2-CHOH-CH2-O- reliée à une unité cyclodextrine du polymère.Within the polymers (A), the cyclodextrin units are generally linked together by hydrocarbon chains, linear or branched, optionally interrupted by one or more oxygen atoms, and these chains preferably being alkyl, alkenyl or alkynyl chains , or alternatively polyether chains, these chains possibly being substituted by hydrophilic groups (hydroxy groups for example). The chains linking together the cyclodextrin units contain at least 3 carbon atoms and preferably from 4 to 50 carbon atoms, the the shortest path between two cyclodextrin units is preferably constituted by a chain comprising between 3 and 8 carbon atoms. Advantageously, the hydrocarbon chains linking together two cyclodextrin units within a polymer (A) correspond to the general formula a group of formula -O - (- CH 2 -CHOR (n) -CH 2 ) nO-, where n is an integer ranging from 1 to 50 (generally between 2 and 10) and where, in each of the n units (-CH 2 -CHOR-CH 2 ), R (n) denotes either a hydrogen atom or a chain -CH 2 -CHOH-CH 2 -O- linked to a cyclodextrin unit of the polymer.
Ainsi, les polymères (A) peuvent typiquement être obtenus par une polycondensation de molécules de cyclodextrines et d'épichlorhydrine, généralement en milieu basique (généralement dans un milieu aqueux additionné de soude, à une concentration massique de 10 à 40%), le ratio molaire cyclodextrines/épichlorhydrine étant de préférence compris entre 1 : 15 et 1 : 1 , et avantageusement entre 1 : 15 et 1 : 8. Pour plus de détails concernant cette synthèse et contrôle du nombre moyen d'unités cyclodextrines intégrées au sein des polymères (A) obtenus selon ce procédé, on pourra notamment se référer à l'article de E. Renard et al., publié dans l'European Polymer Journal, vol. 33, No 1, pp 49-57 (1997).Thus, the polymers (A) can typically be obtained by a polycondensation of cyclodextrin and epichlorohydrin molecules, generally in basic medium (generally in an aqueous medium added with soda, at a mass concentration of 10 to 40%), the ratio cyclodextrins / epichlorohydrin molar preferably being between 1:15 and 1: 1, and advantageously between 1:15 and 1: 8. For more details concerning this synthesis and control of the average number of cyclodextrin units integrated within the polymers ( A) obtained according to this process, reference may in particular be made to the article by E. Renard et al., Published in the European Polymer Journal, vol. 33, No 1, pp 49-57 (1997).
Quelle que soit la nature exacte des chaînes hydrocarbonées liant entre elles les unités cyclodextrines, on préfère, en général, que la masse totale des motifs cyclodextrines présents au sein des polymères (A) représentent au moins 30%, avantageusement au moins 40 %, et encore plus préférentiellement au moins 50%, de la masse totale des polymères (A), cette masse totale des motifs cyclodextrines représentant généralement entre 30 et 80%, et de préférence entre 40 et 60% de la masse totale des polymères (A).Whatever the exact nature of the hydrocarbon chains linking together the cyclodextrin units, it is generally preferred that the total mass of the cyclodextrin units present within the polymers (A) represent at least 30%, advantageously at least 40%, and even more preferably at least 50%, of the total mass of the polymers (A), this total mass of the cyclodextrin units generally representing between 30 and 80%, and preferably between 40 and 60% of the total mass of the polymers (A).
Par ailleurs les polymères (A) présents dans une composition possèdent en général une masse molaire moyenne en nombre comprise entre 10 000 et 3000 000 g/mole, avantageusement entre 20 000 et 2 000 000, et de préférence entre 100 000 et 1 500 000 g/mole. On préfère que les polymères (A) possèdent un indice de polydispersite (c'est à dire un rapport de la masse molaire moyenne en poids sur la masse molaire moyenne en nombre) le moins élevé possible, de préférence inférieur à 3, et encore plus avantageusement inférieur à 2.Furthermore, the polymers (A) present in a composition generally have a number-average molar mass of between 10,000 and 3,000,000 g / mole, advantageously between 20,000 and 2,000,000, and preferably between 100,000 and 1,500,000. g / mol. It is preferred that the polymers (A) have a polydispersite index (that is to say a ratio of the average molar mass by weight to the average molar mass by number) the least high possible, preferably less than 3, and even more advantageously less than 2.
Les macromolécules de polysaccharides (B) présentes dans les particules des compositions de l'invention comportent de façon spécifique des groupements G susceptibles de former des complexes d'inclusion avec les unités cyclodextrines des polymères (A).The macromolecules of polysaccharides (B) present in the particles of the compositions of the invention specifically comprise groups G capable of forming inclusion complexes with the cyclodextrin units of the polymers (A).
Ces groupements G peuvent notamment être des groupements aliphatiques, linéaires ou ramifiés, comportant de 8 à 18 atomes de carbone.These groups G can in particular be aliphatic groups, linear or branched, comprising from 8 to 18 carbon atoms.
Avantageusement, il s'agit de groupements alkyles linéaires comportant de 8 à 18 atomes de carbone. Selon une variante particulière, il peut également s'agir de groupements adamantyle.Advantageously, these are linear alkyl groups comprising from 8 to 18 carbon atoms. According to a particular variant, it can also be adamantyl groups.
Ainsi, les macromolécules (B) présentes dans la composition selon l'invention sont des polysaccharides greffés par des groupements G tels que définis ci-dessus. De préférence, les groupements G sont des groupements aliphatiques, et avantageusement des groupements alkyles linéaires comportant de 8 à 18 atomes de carbone, ou bien des groupements adamantyle, ces groupements étant généralement liés au polysaccharide par l'intermédiaire d'une liaison ester -COO-.Thus, the macromolecules (B) present in the composition according to the invention are polysaccharides grafted with groups G as defined above. Preferably, the groups G are aliphatic groups, and advantageously linear alkyl groups comprising from 8 to 18 carbon atoms, or alternatively adamantyl groups, these groups generally being linked to the polysaccharide via an ester bond -COO -.
De préférence, les polysaccharides greffés (B) sont des dérivés substitués de polysaccharides choisis parmi le dextrane, le chitosane, l'amilose, l'amilopectine, l'acide hyaluronique, les dérivés de la cellulose, l'amidon, le pullulane, la pectine, les alginates, l'héparine, les caragheenanes, le fucane, le curdlan, le xylane, l'acide polyguluronique, le xanthane, l'arabinane, l'acide polymannuronique, et leurs dérivés (comme par exemple le sulfate de dextrane, les esters de l'amilose, ou bien, encore l'acétate de cellulose), ces polysaccharides possédant en général une masse molaire moyenne en masse comprise entre 5 000 et 2 000 000 g/mol, et de préférence entre 6 000 et 70 000 g/mol. Avantageusement, les macromolécules (B) sont des dextranes greffés, de préférence par des groupements alkyles linéaires comprenant de 8 à 18 atomes de carbone, ou bien par des groupements adamantyle.Preferably, the grafted polysaccharides (B) are substituted derivatives of polysaccharides chosen from dextran, chitosan, amilose, amilopectin, hyaluronic acid, cellulose derivatives, starch, pullulan, pectin, alginates, heparin, caragheenanes, fucan, curdlan, xylan, polyguluronic acid, xanthan, arabinan, polymannuronic acid, and their derivatives (such as dextran sulfate, esters of amilose, or alternatively cellulose acetate), these polysaccharides generally having a mass-average molar mass of between 5,000 and 2,000,000 g / mol, and preferably between 6,000 and 70,000 g / mol. Advantageously, the macromolecules (B) are dextrans grafted, preferably by linear alkyl groups comprising from 8 to 18 carbon atoms, or else by adamantyl groups.
Des polysaccharides substitués utiles à titre de macromolécules (B) selon l'invention, peuvent par exemple être obtenus par réaction d'un polysaccharide et d'un chlorure d'acyle ROCI (R désignant une chaîne aliphatique telle que définie ci-dessus), dans des proportions correspondant au taux moyen de chaînes aliphatiques R qu'on souhaite greffer sur le polysaccharide. De préférence, dans ce cas, la réaction du polysaccharide du chlorure d'acyle ROCI a lieu à une température comprise entre 30 et 90°C, de préférence entre 70 et 90°C (typiquement à 80°C), et avantageusement en présence d'une base telle qu'une aminé, notamment de type pyridine. Un exemple de synthèse de ce type est notamment décrit dans un article de F. Arranz et al. paru dans Polymer, vol. 29, pp 507-51 1 (1988).Substituted polysaccharides useful as macromolecules (B) according to the invention can, for example, be obtained by reaction of a polysaccharide and an acyl chloride ROCI (R denoting an aliphatic chain as defined above), in proportions corresponding to the average level of aliphatic chains R which it is desired to graft onto the polysaccharide. Preferably, in this case, the reaction of the polysaccharide of acyl chloride ROCI takes place at a temperature of between 30 and 90 ° C, preferably between 70 and 90 ° C (typically at 80 ° C), and advantageously in the presence a base such as an amine, in particular of the pyridine type. An example of a synthesis of this type is notably described in an article by F. Arranz et al. published in Polymer, vol. 29, pp 507-51 1 (1988).
Le nombre et la nature exacte des groupements G présents sur les macromolécules (B) sont de préférence adaptés à la nature du polymère (A) mis en œuvre. A ce sujet, il est en effet à souligner que les composés (A) et (B) doivent être choisis parmi les systèmes associatifs susceptibles de pouvoir mener, dans certaines conditions de concentration, à une séparation de phase associative.The number and the exact nature of the groups G present on the macromolecules (B) are preferably adapted to the nature of the polymer (A) used. In this regard, it should indeed be emphasized that the compounds (A) and (B) must be chosen from associative systems capable of being able to lead, under certain conditions of concentration, to an associative phase separation.
Ainsi, lorsque le polymère (A) comprend des unités α-cyclodextrines, il est en général préférable que les groupements G présents sur les macromolécules (B) soient des groupement alkyles, de préférence linéaires, ayant de 6 à 18 atomes de carbone, et de préférence de 8 à 10 atomes de carbone.Thus, when the polymer (A) comprises α-cyclodextrin units, it is generally preferable for the groups G present on the macromolecules (B) to be alkyl groups, preferably linear, having from 6 to 18 carbon atoms, and preferably 8 to 10 carbon atoms.
Lorsque le polymère (A) comprend des unités β-cyclodextrines, il est le plus souvent avantageux que les groupements G présents sur les macromolécules (B) soient des groupements alkyles, de préférence linéaires, ayant de 10 à 18 (de préférence de 12 à 16) atomes de carbone, ou bien des groupes adamantyle. Si le polymère (A) contient uniquement des unités cyclodextrines de type β-cyclodextrines, il est particulièrement avantageux que les groupements G soient des alkyles linéaires ayant de 10 à 16 (de préférence de 12 à 16) atomes de carbone, ou des groupement adamantyle, ces groupements étant alors de préférence des alkyles linéaires ayant 12 atomes de carbone ou des groupes adamantyle.When the polymer (A) comprises β-cyclodextrin units, it is most often advantageous for the groups G present on the macromolecules (B) to be alkyl groups, preferably linear, having from 10 to 18 (preferably from 12 to 16) carbon atoms, or adamantyl groups. If the polymer (A) contains only cyclodextrin units of the β-cyclodextrin type, it is particularly advantageous that the groups G are linear alkyls having 10 to 16 (preferably 12 to 16) carbon atoms, or adamantyl groups, these groups then preferably being linear alkyls having 12 carbon atoms or adamantyl groups.
Dans le cas où le polymère (A) comprend des unités γ-cyclodextrines, il est en général préférable que les groupements G présents sur les macromolécules (B) soient des groupements alkyles, de préférence linéaires, ayant de 12 à 16 atomes de carbone.In the case where the polymer (A) comprises γ-cyclodextrin units, it is generally preferable for the groups G present on the macromolecules (B) to be alkyl groups, preferably linear, having from 12 to 16 carbon atoms.
Par ailleurs, le nombre moyen de groupements G présents sur les macromolécules (B) est, de façon caractéristique, au moins égal à 3 chaînes par macromolécule. En règle générale, ce nombre moyen de groupements G est d'autant plus important que la taille de la macromolécule est élevée et que le nombre d'unités cyclodextrines dans le composé (A) est important. Il est le plus souvent avantageux que le nombre moyen de groupements G présents sur les macromolécules (B) soit au moins égal à 5, et avantageusement au moins égal à 8. En général, le nombre moyen de groupements G présents sur les macromolécules (B) reste inférieur ou égal à 50, et avantageusement inférieur ou égal à 15.Furthermore, the average number of groups G present on the macromolecules (B) is typically at least equal to 3 chains per macromolecule. As a general rule, this average number of G groups is all the more important the larger the size of the macromolecule and the larger the number of cyclodextrin units in compound (A). It is most often advantageous that the average number of groups G present on the macromolecules (B) is at least equal to 5, and advantageously at least equal to 8. In general, the average number of groups G present on the macromolecules (B) ) remains less than or equal to 50, and advantageously less than or equal to 15.
En ce qui concerne les macromolécules de polysaccharides greffés, on peut déterminer un "taux de greffage par les groupements G", reflétant la quantité de groupements G rapportée à la taille de la chaîne polysaccharidique, c'est à dire au nombre de motifs saccharidique de la chaîne polysaccharidique. Ce taux de greffage par les groupements G est calculé sur la base d'un spectre RMN du proton des polysaccharides greffés, et il correspond au ratio des intégrations des protons des groupements G, rapporté aux intégrations des protons du squelette polysaccharidique. Ce taux est calculé selon la formule suivante :As regards the macromolecules of grafted polysaccharides, it is possible to determine a "rate of grafting by G groups", reflecting the quantity of G groups relative to the size of the polysaccharide chain, that is to say to the number of saccharide units of the polysaccharide chain. This rate of grafting by the G groups is calculated on the basis of an NMR spectrum of the proton of the grafted polysaccharides, and it corresponds to the ratio of the integrations of the protons of the G groups, relative to the integrations of the protons of the polysaccharide skeleton. This rate is calculated according to the following formula:
taux de greffage par les groupements G (%) = (intégration des massifs correspondant aux protons des groupements G/ nombre de protons sur les groupements G) / (intégration des massifs correspondant aux protons des squelettes polysaccharidiques / nombre de protons sur les squelettes polysaccharidiques)grafting rate by groups G (%) = (integration of massifs corresponding to the protons of the G groups / number of protons on the G groups) / (integration of the masses corresponding to the protons of the skeletons polysaccharides / number of protons on polysaccharide backbones)
Le taux de greffage par les groupements G des macromolécules de polysaccharides greffés (B) est en général au moins égal à 1%, et de préférence au moins égal à 2%. Avantageusement, ce taux est supérieur ou égal à 3%.The rate of grafting by the groups G of the macromolecules of grafted polysaccharides (B) is generally at least equal to 1%, and preferably at least equal to 2%. Advantageously, this rate is greater than or equal to 3%.
Toutefois, dans le cas le plus général, le nombre de groupements G présents sur les macromolécules (B), le plus souvent hydrophobes, est limité par le fait que les composés (B) doivent, de façon caractéristique, être hydrosolubles. Il est également souhaitable.en règle générale, de limiter le nombre de groupements G présents sur les macromolécules (B) de façon à éviter des phénomènes d'auto-association entre les macromolécules (B), et ce tout particulièrement lorsque les groupements G sont des groupements hydrophobes de type chaînes aliphatiques. De ce fait, le taux de greffage par les groupements G est en général inférieur ou égal à 8 %, et de préférence inférieur ou égal à 6%. Ainsi, il est typiquement compris entre 3 et 4%.However, in the most general case, the number of G groups present on the macromolecules (B), most often hydrophobic, is limited by the fact that the compounds (B) must typically be water-soluble. It is also desirable, as a general rule, to limit the number of G groups present on the macromolecules (B) so as to avoid self-association phenomena between the macromolecules (B), and this very particularly when the G groups are hydrophobic groups of aliphatic chain type. Therefore, the rate of grafting by the groups G is generally less than or equal to 8%, and preferably less than or equal to 6%. Thus, it is typically between 3 and 4%.
De façon générale, on préfère que les macromolécules (B) possèdent une masse molaire moyenne en poids au moins égale à 20 000 g/mole, et de préférence comprise entre 20 000 et 100 000 g/mole. On préfère que les polymères (A) possèdent un indice de polydispersite (c'est à dire un rapport de la masse molaire moyenne en poids sur la masse molaire moyenne en nombre) le moins élevé possible, de préférence inférieur à 3, et encore plus avantageusement inférieur à 2.In general, it is preferred that the macromolecules (B) have a weight-average molar mass at least equal to 20,000 g / mole, and preferably between 20,000 and 100,000 g / mole. It is preferred that the polymers (A) have a polydispersite index (that is to say a ratio of the average molar mass by weight to the average molar mass by number) as low as possible, preferably less than 3, and even more advantageously less than 2.
De façon particulièrement préférentielle, les composés (A) et (B) présents au sein des particules (p) d'une composition selon l'invention peuvent être choisis parmi les associations suivantes :In a particularly preferred manner, the compounds (A) and (B) present within the particles (p) of a composition according to the invention can be chosen from the following associations:
- famille 1 : polymères (A) comportant de 18 à 1000, et de préférence de 100 à- family 1: polymers (A) comprising from 18 to 1000, and preferably from 100 to
600 unités β-cyclodextrines / polysaccharides (B) de masse moléculaire comprise entre 6 000 et 70 000 (de préférence des dextranes) greffés par des groupes aliphatiques en C12 (de préférence des chaînes alkyles linéaires) et présentant un taux de substitution hydrophobe de 3 à 5 %, de préférence inférieur à 4%.600 β-cyclodextrin / polysaccharide units (B) of molecular mass between 6,000 and 70,000 (preferably dextrans) grafted with C12 aliphatic groups (preferably linear alkyl chains) and having a hydrophobic substitution rate of 3 to 5%, preferably less than 4%.
- famille 2 : polymères (A) comportant de 100 à 600, et de préférence de 200 à 500 unités β-cyclodextrines / polysaccharides (B) de masse moléculaire comprise entre 6 000 et 70 000 (de préférence des dextranes) greffés par des groupes aliphatiques en C10 (de préférence des chaînes alkyles linéaires) et présentant un taux de substitution hydrophobe de 5 à 7 %.- family 2: polymers (A) comprising from 100 to 600, and preferably from 200 to 500 β-cyclodextrin / polysaccharide units (B) of molecular mass between 6,000 and 70,000 (preferably dextrans) grafted by groups aliphatic C10 (preferably linear alkyl chains) and having a hydrophobic substitution rate of 5 to 7%.
- famille 3 : polymères (A) comportant de 18 à 1000, et de préférence de 100 à 600 unités β-cyclodextrines / polysaccharides (B) de masse moléculaire comprise entre 6000 et 70000 (de préférence des dextranes) greffés par des groupements adamantyles et présentant un taux de substitution hydrophobe de 3 à 4 %.family 3: polymers (A) comprising from 18 to 1000, and preferably from 100 to 600 β-cyclodextrin / polysaccharide units (B) of molecular mass between 6000 and 70000 (preferably dextrans) grafted by adamantyl groups and with a hydrophobic substitution rate of 3 to 4%.
Quelle que soit la nature exacte des composés (A) et (B) mis en œuvre, on préfère en général qu'au sein des particules (p) d'une composition selon l'invention, le ratio molaire de la quantité totale d'unités cyclodextrines présentes au sein des polymères (A), rapportée à la quantité totale de groupement G présents dans les macromolécules de polysaccharides (B) soit compris entre 1 : 3 et 3 : 1. De préférence, ce ratio est au moins égal à 0,7, et avantageusement au moins égal à 0,8. On préfère par ailleurs que ce ratio soit inférieur ou égal à 1 ,5, et avantageusement inférieur ou égal à 1 ,3. Typiquement, ce ratio peut par exemple être compris entre 0,9 et 1 ,1.Whatever the exact nature of the compounds (A) and (B) used, it is generally preferred that, within the particles (p) of a composition according to the invention, the molar ratio of the total amount of cyclodextrin units present within the polymers (A), related to the total amount of group G present in the macromolecules of polysaccharides (B) is between 1: 3 and 3: 1. Preferably, this ratio is at least equal to 0 , 7, and advantageously at least equal to 0.8. It is moreover preferred that this ratio is less than or equal to 1.5, and advantageously less than or equal to 1.3. Typically, this ratio can for example be between 0.9 and 1.1.
En règle générale, la concentration en composés (A) et (B) au sein d'une composition selon l'invention peut varier en une assez large mesure. Toutefois, le plus souvent, la concentration en polymères (A) au sein de la dispersion aqueuse présente dans la composition de l'invention est comprise entre 0,01 et 10 g/L, avantageusement entre 0,02 et 2 g/L, et encore plus avantageusement entre 0,2 et 2g/L. La concentration en macromolécules (B) au sein de la dispersion aqueuse est quant à elle généralement comprise entre 0,01 et 10 g/L, de préférence entre 0,08 et 9 g/L et, de façon encore plus préférentielle, entre 0,8 et 8 g/L. On préfère de plus, en général, que la concentration totale en polymères (A) et en macromolécules modifiés (B) au sein de la dispersion aqueuse soit comprise entre 0,01 et 20 g/L.In general, the concentration of compounds (A) and (B) in a composition according to the invention can vary to a fairly large extent. However, most often, the concentration of polymers (A) within the aqueous dispersion present in the composition of the invention is between 0.01 and 10 g / L, advantageously between 0.02 and 2 g / L, and even more advantageously between 0.2 and 2 g / L. The concentration of macromolecules (B) within the aqueous dispersion is generally between 0.01 and 10 g / L, preferably between 0.08 and 9 g / L and, even more preferably, between 0 , 8 and 8 g / L. It is more generally preferred that the total concentration of polymers (A) and modified macromolecules (B) within the aqueous dispersion is between 0.01 and 20 g / L.
Le plus souvent, au sein d'une composition selon l'invention, l'essentiel des polymères (A) et des macromolécules (B) est localisé au sein des particules (p). Ainsi, en général, au moins 80% en masse (de préférence au moins 85% en masse, et avantageusement au moins 90% en masse des composés (A) et (B) présents dans une composition selon l'invention sont contenus dans les particules (p).Most often, within a composition according to the invention, most of the polymers (A) and macromolecules (B) are located within the particles (p). Thus, in general, at least 80% by mass (preferably at least 85% by mass, and advantageously at least 90% by mass of the compounds (A) and (B) present in a composition according to the invention are contained in the particles (p).
Selon un autre aspect, la présente invention a également pour objet un procédé de préparation d'une composition telle que décrite précédemment. Ce procédé comprend une étape (E), extrêmement simple à mettre en œuvre, qui consiste à effectuer un mélange d'une solution aqueuse (SA) comprenant des polymères (A) tels que définis précédemment et d'une solution aqueuse (SB) comprenant des macromolécules de polysaccharides (B) telles que définies plus haut, en choisissant les volumes et les concentrations desdites solutions (SA) et (SB) de façon à obtenir, suite au mélange, un milieu aqueux où les concentrations respectives C-A et CB en lesdits composés (A) et (B) appartiennent au domaine de formation d'une dispersion métastable pour le système auto-associatif (A+B) mis en œuvre.According to another aspect, the present invention also relates to a process for the preparation of a composition as described above. This process comprises a step (E), which is extremely simple to carry out, which consists in mixing a aqueous solution (SA) comprising polymers (A) as defined above and an aqueous solution (SB) comprising macromolecules of polysaccharides (B) as defined above, by choosing the volumes and the concentrations of said solutions (SA) and (SB) so as to obtain, following mixing, an aqueous medium where the respective concentrations CA and CB in said Compounds (A) and (B) belong to the field of formation of a metastable dispersion for the self-associative system (A + B) implemented.
Au sens de la présente invention, on entend par "domaine de formation d'une dispersion métastable d'un système auto-associatif (A+B)", le domaine de concentrations en composés (A) et (B) dont l'existence a été découverte par les inventeurs pour les associations de type an, dans lequel un mélange direct de composés (A) et (B) tels que définis précédemment conduit à la formation d'une dispersion de particules de dimensions comprises entre 50 et 5000 nm. Le terme "domaine de concentrations" tel qu'il est employé ici désigne un ensemble de couples (C-A ; CB ). Ce terme de "domaine" fait référence aux diagrammes ternaires eau/composé(A)/composé(B) qui peuvent être établi pour un système (A+B), en observant le système formé pour les différentes teneurs en eau, composé (A) et composé (B). Sur un tel diagramme ternaire, l'ensemble des couples (ÇA ; CB ) dans lequel il faut choisir les concentrations respectives en composés (A) et (B) dans le milieu final pour observer la formation de la dispersion métastable apparaît en effet sous la forme d'une zone continue, dite "domaine de concentrations". En ce qui concerne l'établissement de diagrammes ternaires pour des systèmes de type (A+B), on pourra notamment se reporter à l'article "Macromolecular assemblies generated by inclusion complexes between amphiphatic polymers and b-cyclodextrin polymers in aqueous média" (C. Amiel et al., ACS : Symposium Séries, N° 780, Edité par C. McCormik "Stimuli-Responsive Water-Soluble and Amphiphatic Polymers, chapître 4 (2000).For the purposes of the present invention, the term "domain of formation of a metastable dispersion of a self-associative system (A + B)" means the domain of concentrations of compounds (A) and (B) whose existence has been discovered by the inventors for associations of the an type, in which a direct mixture of compounds (A) and (B) as defined above leads to the formation of a dispersion of particles of dimensions between 50 and 5000 nm. The term "concentration domain" as used herein designates a set of couples (CA; C B ). This term "domain" refers to the ternary water / compound (A) / compound (B) diagrams which can be established for a system (A + B), observing the system formed for the different water contents, compound (A ) and compound (B). On such a ternary diagram, the set of couples (ÇA; CB) in which the respective concentrations must be chosen in compounds (A) and (B) in the final medium to observe the formation of the metastable dispersion indeed appears in the form of a continuous zone, called "concentration range". With regard to the establishment of ternary diagrams for systems of type (A + B), reference may in particular be made to the article "Macromolecular assemblies generated by inclusion complexes between amphiphatic polymers and b-cyclodextrin polymers in aqueous media" ( C. Amiel et al., ACS: Symposium Séries, N ° 780, Edited by C. McCormik "Stimuli-Responsive Water-Soluble and Amphiphatic Polymers, chapter 4 (2000).
De façon générale, sur un diagramme ternaire eau/composé(A)/composé(B) du type précité, le domaine de formation de la dispersion métastable qui a été découvert par les inventeurs se situe à la frontière entre les domaines de formation des deux systèmes thermodynamiquement stables connus de l'état de la technique, à savoir les systèmes de type (I) et (II) précités.In general, on a ternary water / compound (A) / compound (B) diagram of the aforementioned type, the area of formation of the metastable dispersion which has been discovered by the inventors is situated at the border between the areas of formation of the two thermodynamically stable systems known from the state of the art, namely the aforementioned type (I) and (II) systems.
Le plus souvent, une composition selon l'invention peut être obtenue à partir de la plupart des systèmes associatifs de type (A+B) tels que définis précédemment si le milieu obtenu à l'issue de l'étape (E) vérifie les deux conditions suivantes : - la somme des concentrations CA+CB est comprise entre 0,1 et 10 g/L, et de préférence entre 1g/L et 10g/L; etMost often, a composition according to the invention can be obtained from most associative systems of type (A + B) as defined above if the medium obtained at the end of step (E) satisfies both following conditions: - the sum of the CA + CB concentrations is between 0.1 and 10 g / L, and preferably between 1g / L and 10g / L; and
- le ratio molaire de la quantité totale d'unités cyclodextrines présentes au sein des polymères (A) introduits , rapportée à la quantité totale de chaînes aliphatiques présentes à titre de substituants sur les macromolécules de polysaccharides (B) introduites est compris entre 1 ,3 et 3,1 , et de préférence entre 1 ,2 et 2,1.the molar ratio of the total quantity of cyclodextrin units present in the polymers (A) introduced, relative to the total quantity of aliphatic chains present as substituents on the macromolecules of polysaccharides (B) introduced is between 1, 3 and 3.1, and preferably between 1, 2 and 2.1.
La solution (SA) mise en œuvre dans l'étape (E) possède, en général, une concentration comprise entre 0,01 g/L et 20 g/L, cette concentration étant avantageusement comprise entre 0,1 et 10 g/L. La solution (SB) possède quant à elle le plus souvent une concentration comprise entre 0,01 g/L et 20 g/L, cette concentration étant de préférence comprise entre 0,1 et 10 g/L.The solution (SA) used in step (E) generally has a concentration of between 0.01 g / L and 20 g / L, this concentration advantageously being between 0.1 and 10 g / L . The solution (SB) most often has a concentration between 0.01 g / L and 20 g / L, this concentration preferably being between 0.1 and 10 g / L.
En règle générale, et en particulier lorsque les solutions (SA) et (SB) ont les concentrations précitées, le rapport du volume total de solution (SA) introduite sur le volume total de solution (SB) introduite est le plus souvent compris entre 1 :9 et 9:1 , et de préférence ce rapport volumique est compris entre 1 :5 et 5:1. En particulier lorsque les macromolécules (B) sont des polysaccharides greffés, de type dextrane modifié, on préfère que ce rapport soit compris entre 1 :5 et 1 :1 ,25 et, de préférence, entre 1 :3 et 1 :0,75.As a general rule, and in particular when the solutions (SA) and (SB) have the abovementioned concentrations, the ratio of the total volume of solution (SA) introduced to the total volume of solution (S B ) introduced is most often between 1: 9 and 9: 1, and preferably this volume ratio is between 1: 5 and 5: 1. In particular when the macromolecules (B) are grafted polysaccharides, of the modified dextran type, it is preferred that this ratio is between 1: 5 and 1: 1.25 and preferably between 1: 3 and 1: 0.75 .
En règle générale, le procédé de la présente invention est extrêmement simple de mise en œuvre. Ainsi, l'étape (E) du procédé de l'invention consiste en un simple mélange, qui est généralement conduit à température ambiante, c'est-à-dire le plus souvent entre 15°C et 30°C. Il est par ailleurs à noter que le procédé de préparation de l'invention peut se limiter à la seule mise en œuvre de l'étape (E).In general, the method of the present invention is extremely simple to carry out. Thus, step (E) of the process of the invention consists of a simple mixture, which is generally carried out at room temperature, that is to say most often between 15 ° C and 30 ° C. It should also be noted that the process for preparing the invention can be limited to the sole implementation of step (E).
Notamment de façon à réaliser un mélange des solutions (SA) et (SB) le plus homogène possible, il est souvent avantageux de conduire l'étape (E) sous agitation, mais cette agitation n'est la plupart du temps pas nécessaire pour observer la formation de la dispersion métastable.In particular in order to achieve a mixture of solutions (SA) and (SB) as homogeneous as possible, it is often advantageous to carry out step (E) with stirring, but this stirring is most of the time not necessary to observe the formation of the metastable dispersion.
De façon plus générale, les inventeurs ont mis en évidence que, sous réserve de se placer dans le domaine de concentrations adapté et de réaliser un mélange direct le plus rapide possible des solutions (SA) et (SB), le mélange desdites solutions conduit spontanément à la formation de la dispersion métastable.More generally, the inventors have demonstrated that, subject to placing themselves in the suitable concentration range and carrying out a direct mixture as quickly as possible of the solutions (S A ) and (S B ), the mixing of said solutions spontaneously leads to the formation of the metastable dispersion.
A ce sujet, il faut bien souligner que le procédé de l'invention ne nécessite pas la mise en œuvre de solvants ou de tensioactifs. De ce fait, une composition selon l'invention est, en général, exempte de toute trace de solvant organique ou d'agent tensioactif. Ainsi, selon un mode de réalisation particulier, une composition selon l'invention peut comprendre de l'eau et des composés (A) et (B) tels que définis précédemment, à l'exclusion de tout autre composé. Cela étant, compte tenu de la présence de motifs cyclodextrines au sein de leur structure, les particules (p) présentes au sein d'une composition selon l'invention sont particulièrement adaptées pour réaliser I'encapsulation de composés chimiques, et tout particulièrement pour réaliser I'encapsulation de composés chimiques présentant des groupements de nature hydrophobe. L'utilisation particulière des compositions de l'invention à cet effet constitue un objet particulier de la présente invention.In this regard, it should be emphasized that the process of the invention does not require the use of solvents or surfactants. Therefore, a composition according to the invention is, in general, free of any trace of organic solvent or surfactant. Thus, according to a particular embodiment, a composition according to the invention can comprise water and compounds (A) and (B) as defined above, to the exclusion of any other compound. However, given the presence of cyclodextrin units within their structure, the particles (p) present in a composition according to the invention are particularly suitable for carrying out the encapsulation of chemical compounds, and very particularly for carrying out The encapsulation of chemical compounds having groups of hydrophobic nature. The particular use of the compositions of the invention for this purpose constitutes a particular object of the present invention.
Les particules (p) présentes dans les compositions selon l'invention sont à même d'intégrer, sous forme encapsulée, de nombreux types de composés chimiques neutres ou chargés. Les composés susceptibles de pouvoir être encapsulés au sein des particules (p) d'une composition selon l'invention comprennent en particulier les composés présentant des groupement hydrophobes, notamment des groupements alkyles, comportant en général de 6 à 18 atomes de carbone.The particles (p) present in the compositions according to the invention are capable of integrating, in encapsulated form, many types of neutral or charged chemical compounds. The compounds capable of being able to be encapsulated within the particles (p) of a composition according to the invention include in particular the compounds having hydrophobic groups, in particular alkyl groups, generally comprising from 6 to 18 carbon atoms.
De façon plus spécifique, les particules (p) présentes dans une composition selon l'invention sont particulièrement bien adaptées pour réaliser une encapsulation de composés susceptibles de former des complexes d'inclusion avec les unités cyclodextrines qu'elles comprennent. Pour plus de détails en ce qui concerne la formation de complexes d'inclusion entre des composés chimiques et des cyclodextrines, ainsi que sur la nature des composés susceptibles de former de tels complexes, on pourra notamment se reporter à "Cyclodextrins and their inclusion complexes", Szejtli J., Academia Kiado, Budapest, 1982.More specifically, the particles (p) present in a composition according to the invention are particularly well suited for carrying out an encapsulation of compounds capable of forming inclusion complexes with the cyclodextrin units which they comprise. For more details with regard to the formation of inclusion complexes between chemical compounds and cyclodextrins, as well as on the nature of the compounds capable of forming such complexes, reference may in particular be made to "Cyclodextrins and their inclusion complexes" , Szejtli J., Academia Kiado, Budapest, 1982.
De façon générale, une simple mise en contact des composés chimiques précités avec une composition selon l'invention suffit pour réaliserIn general, a simple contacting of the abovementioned chemical compounds with a composition according to the invention is sufficient to produce
I'encapsulation de composés chimiques par les particules (p), en particulier lorsque ladite composition est essentiellement à base d'eau et des particulesThe encapsulation of chemical compounds by the particles (p), in particular when said composition is essentially based on water and particles
(A) et (B).(A) and (B).
Dans ce cadre, une composition selon l'invention peut par exemple être utilisée à titre de composition absorbante, notamment pour emprisonner des agents de toxiques ou polluants présents dans un milieu aqueux, et en particulier pour éliminer des composés de type hydrocarbures (notamment les hydrocarbures aromatiques polycycliques), composés aromatiques halogènes (comme le chlorobenzène ou les chlorophénols), esters phtaliques, ou bien encore l'iode, notamment l'iode radioactif, ou des polluants de type pesticides ou colorants textiles. Pour ce faire, il suffit en général d'introduire la composition à base de particule (p) au sein du milieu à purifier. Les particules (p) peuvent, dans ce type d'application, absorber (encapsuler) une quantité de composés à éliminer au moins égale à 0,1 mole de composé par mole de cyclodextrines incluses dans les particules, et pouvant aller jusqu'à 1 mole par mole de cyclodextrine, voire jusqu'à 2 mole par mole de cyclodextrine, notamment pour des polluants de type hydrocarbures, notamment de type hydrocarbures aromatiques polycycliques.In this context, a composition according to the invention can for example be used as an absorbent composition, in particular for trapping agents of toxic or pollutants present in a medium aqueous, and in particular for eliminating compounds of the hydrocarbon type (in particular polycyclic aromatic hydrocarbons), halogenated aromatic compounds (such as chlorobenzene or chlorophenols), phthalic esters, or alternatively iodine, in particular radioactive iodine, or pollutants such as pesticides or textile dyes. To do this, it is generally sufficient to introduce the composition based on particle (p) within the medium to be purified. The particles (p) can, in this type of application, absorb (encapsulate) a quantity of compounds to be eliminated at least equal to 0.1 mole of compound per mole of cyclodextrins included in the particles, and which can range up to 1 mole per mole of cyclodextrin, or even up to 2 moles per mole of cyclodextrin, in particular for pollutants of hydrocarbon type, in particular of polycyclic aromatic hydrocarbons.
Les compositions selon l'invention possédant des composés chimiques encapsulés au sein de leurs particules (p) peuvent par ailleurs être intéressantes en tant que telles. Selon un aspect particulier, la présente invention a aussi pour objet de telles compositions selon l'invention, où les particules (p) comprennent au moins un composé chimique (C) autre que les composé (A) et (B).The compositions according to the invention having chemical compounds encapsulated within their particles (p) may moreover be advantageous as such. According to a particular aspect, the subject of the present invention is also such compositions according to the invention, in which the particles (p) comprise at least one chemical compound (C) other than the compounds (A) and (B).
Dans ce type de compositions, ledit composé (C) est en général un composé présentant des groupements de nature hydrophobe, avantageusement des groupements de type chaînes hydrocarbonées comportant de 8 à 18 atomes de carbone, et de préférence de 10 à 18 atomes de carbone. De façon avantageuse, ce composé (C) est un composé susceptible de former un complexe d'inclusion avec l'une des unités cyclodextrines comprises dans les polymères (A) présents dans les particulesIn this type of composition, said compound (C) is generally a compound having groups of hydrophobic nature, advantageously groups of the hydrocarbon chain type comprising from 8 to 18 carbon atoms, and preferably from 10 to 18 carbon atoms. Advantageously, this compound (C) is a compound capable of forming an inclusion complex with one of the cyclodextrin units included in the polymers (A) present in the particles
(P).(P).
On préfère que, dans une composition comprenant un composéIt is preferred that in a composition comprising a compound
(C) du type précité, la quantité de composé (C) intégré au sein des particules(C) of the aforementioned type, the amount of compound (C) integrated within the particles
(p) représente au moins 0,5 % en masse par rapport à la masse totale desdites particules (p). Il est souvent avantageux dans une telle composition que le ratio massique (C)/(A+B) de la masse totale des composés (C) rapportée à la masse totale des composés (A) et (B) soit compris entre 1 % et 50 %, ce ratio étant de préférence supérieur à 2 %, et avantageusement supérieur à 3 %.(p) represents at least 0.5% by mass relative to the total mass of said particles (p). It is often advantageous in such a composition that the mass ratio (C) / (A + B) of the total mass of the compounds (C) relative to the mass total of the compounds (A) and (B) is between 1% and 50%, this ratio preferably being greater than 2%, and advantageously greater than 3%.
Comme cela a déjà été souligné, une composition selon l'invention comprenant de façon additionnelle un composé (C) tel que défini ci-dessus peut notamment être obtenue par une simple mise en contact dudit composé (C) avec une composition selon l'invention à base d'une dispersion aqueuse préformée de particules (p) à base des composés (A) et (B). Dans ce cadre, il est naturellement préférable que les particules (p) soient essentiellement à base des composés (A) et (B), à l'exclusion de la présence d'un autre composé, en particulier d'un composé susceptible de former un complexe d'inclusions avec les unités cyclodextrines présentes dans les polymères (A). Toutefois, on peut envisager plusieurs étapes successives de mise en contact avec différents type de composés (C). La quantité totale de composé (C) mise en contact avec la composition au cours de cette ou de ces étapes représente de préférence entre 4 et 100 % en masse, et de préférence entre 10 et 80 % en masse par rapport à la masse totale des particules (p) présente initialement dans la composition. Cette quantité de composé (C) mise en contact avec la composition représente avantageusement entre 10 et 70 % en masse, et plus préférentiellement entre 20 et 50 % en masse par rapport à la masse totale des polymères (A).As already pointed out, a composition according to the invention additionally comprising a compound (C) as defined above can in particular be obtained by a simple contacting of said compound (C) with a composition according to the invention based on a preformed aqueous dispersion of particles (p) based on compounds (A) and (B). In this context, it is naturally preferable that the particles (p) are essentially based on the compounds (A) and (B), with the exclusion of the presence of another compound, in particular of a compound capable of forming an inclusion complex with the cyclodextrin units present in the polymers (A). However, it is possible to envisage several successive stages of contacting with different types of compounds (C). The total amount of compound (C) brought into contact with the composition during this or these stages preferably represents between 4 and 100% by mass, and preferably between 10 and 80% by mass relative to the total mass of particles (p) initially present in the composition. This quantity of compound (C) brought into contact with the composition advantageously represents between 10 and 70% by mass, and more preferably between 20 and 50% by mass relative to the total mass of the polymers (A).
De façon avantageuse, notamment lorsqu'on souhaite préparer une composition selon l'invention comprenant à titre additionnel des composés (C) susceptibles de former un complexe d'inclusion avec l'une des unités cyclodextrines comprises dans les polymères (A), l'incorporation des composés (C) au sein des particules (p) peut être réalisée en mettant en œuvre dans le procédé de préparation de l'invention une solution (SA) comprenant, en plus des polymères (A) les composés (C) qu'on souhaite intégrer dans les particules (p), ce composé (C) formant avantageusement des complexes d'inclusion avec des unités cyclodextrines présentes dans les polymères (A). Dans ce cadre, au sein de la solution (SA), le ratio massique composé (C)/polymère (A) est de préférence compris entre 10 et 100 %, et plus préférentiellement entre 20 et 50 %. La présence du composé (C) au sein de la solution (SA) ne modifie en général pas le domaine de formation de la dispersion métastable pour le système auto-associatif (A+B) par rapport aux conditions à mettre en œuvre en l'absence du composé (C). De ce fait, en présence ou non du composé (C), les volumes et les concentrations des solutions (SA) et (SB) de l'étapes (E) sont choisis de façon à obtenir, suite au mélange, un milieu aqueux où les concentrations respectives CA et CB en lesdits composés (A) et (B) appartiennent au domaine de formation d'une dispersion métastable pour le système auto-associatif (A+B).Advantageously, in particular when it is desired to prepare a composition according to the invention comprising, in addition, compounds (C) capable of forming an inclusion complex with one of the cyclodextrin units included in the polymers (A), the incorporation of the compounds (C) within the particles (p) can be carried out by implementing in the preparation process of the invention a solution (SA) comprising, in addition to the polymers (A), the compounds (C) which it is desired to integrate into the particles (p), this compound (C) advantageously forming inclusion complexes with cyclodextrin units present in the polymers (A). In this context, within the solution (SA), the mass ratio of compound (C) / polymer (A) is preferably between 10 and 100%, and more preferably between 20 and 50%. The presence of compound (C) within the solution (S A ) does not modify generally not the field of formation of the metastable dispersion for the self-associative system (A + B) with respect to the conditions to be implemented in the absence of compound (C). Therefore, in the presence or absence of the compound (C), the volumes and the concentrations of the solutions (S A ) and (S B ) of steps (E) are chosen so as to obtain, following mixing, a medium aqueous where the respective concentrations C A and CB in said compounds (A) and (B) belong to the field of formation of a metastable dispersion for the self-associative system (A + B).
La nature exacte du composé (C) qui peut être encapsulé dans une composition selon l'invention, notamment selon l'un des procédés précités, peut varier en une assez large mesure. Toutefois, notamment dans la mesure où les polymères (A) et les macromolécules (B) peuvent être choisis parmi des composés non toxiques et biocompatibles, et que la présence de traces de solvants organiques ou de tensioactifs peut être évitée, une des applications principales envisageable pour une composition selon l'invention est la vectorisation de principes actifs, notamment des composés présentant un effet thérapeutique ou cosmétique.The exact nature of the compound (C) which can be encapsulated in a composition according to the invention, in particular according to one of the abovementioned methods, can vary to a fairly large extent. However, in particular to the extent that the polymers (A) and the macromolecules (B) can be chosen from non-toxic and biocompatible compounds, and that the presence of traces of organic solvents or surfactants can be avoided, one of the main applications that can be envisaged for a composition according to the invention is the vectorization of active principles, in particular compounds having a therapeutic or cosmetic effect.
Ainsi, selon un mode de réalisation particulièrement avantageux, une composition selon l'invention peut comprendre à titre de composé (C) au sein de ses particules (p) au moins un composé actif à titre de médicament, ce composé (C) actif à titre de médicament étant de préférence susceptible de former un complexe d'inclusion avec l'une des unités cyclodextrines comprises au sein des particules (p).Thus, according to a particularly advantageous embodiment, a composition according to the invention can comprise, as compound (C) within its particles (p) at least one active compound as a medicament, this compound (C) active drug title preferably being capable of forming an inclusion complex with one of the cyclodextrin units included within the particles (p).
Une telle composition selon l'invention est en général utilisable à titre de composition pharmaceutique pour une administration, par injection ou par voie orale, ou bien encore par voie dermique ou sous-cutanée, par voie nasale, par voie pulmonaire ou par voie oculaire et, de façon plus large, pour toute administration au niveau d'une muqueuse, ou au niveau d'un site précis (tumeur, lumière de certains vaisseaux sanguins ...). Dans ce cadre, on préfère, le plus souvent, que la composition soit essentiellement constituée d'eau et des composés (A), (B) et (C), éventuellement en association avec un ou plusieurs excipient pharmacologiquement acceptables et adaptés à la voie d'administration envisagée. Toutefois, de façon large, la composition selon l'invention peut, dans ce type d'application, prendre la forme de toute formulation pharmaceutique intégrant une dispersion aqueuse des particules (p) comprenant le composé (C) actif à titre de médicament. Dans le cas d'une composition spécifiquement destinée à une administration par injection intraveineuse, on préfère en général que les particule (p) intégrant le composé (C) présentent un diamètre hydrodynamique moyen au plus égal à 200 nm. Pour ce qui est des compositions destinées à une administration par injection intramusculaire, on préfère que les particules (p) intégrant le composé (C) présentent un diamètre hydrodynamique moyen compris entre 200 et 5000 nm, de préférence inférieur à 1000 nm.Such a composition according to the invention is generally usable as a pharmaceutical composition for administration, by injection or by oral route, or alternatively by dermal or subcutaneous route, by nasal route, by pulmonary route or by ocular route and , more broadly, for any administration at the level of a mucosa, or at the level of a specific site (tumor, lumen of certain blood vessels ...). In this context, it is most often preferred that the composition consists essentially of water and of the compounds (A), (B) and (C), possibly in combination with a or several pharmacologically acceptable excipients suitable for the intended route of administration. However, broadly speaking, the composition according to the invention can, in this type of application, take the form of any pharmaceutical formulation incorporating an aqueous dispersion of the particles (p) comprising the active compound (C) as a medicament. In the case of a composition specifically intended for administration by intravenous injection, it is generally preferred that the particles (p) integrating the compound (C) have an average hydrodynamic diameter at most equal to 200 nm. As regards compositions intended for administration by intramuscular injection, it is preferred that the particles (p) integrating the compound (C) have an average hydrodynamic diameter of between 200 and 5000 nm, preferably less than 1000 nm.
Les compositions de l'invention, qui intègrent des particules (p) à base de polysaccharides greffés à titre de composés (B), sont particulièrement intéressantes en terme de bioadhésivité, ce qui les rend extrêmement avantageuses pour une application sur les muqueuses. Pour une application par voie oculaire, il s'avère particulièrement intéressant que les composés (B) présents dans les particules (p) soient des acides hyaluroniques greffés.The compositions of the invention, which incorporate particles (p) based on polysaccharides grafted as compounds (B), are particularly advantageous in terms of bioadhesiveness, which makes them extremely advantageous for application to the mucous membranes. For an application by ocular route, it turns out to be particularly advantageous that the compounds (B) present in the particles (p) are grafted hyaluronic acids.
Les compositions de l'invention comprenant un composé (C) actif à titre de médicament au sein de leurs particules (p) induisent en général, suite à leur administration, une libération progressive du composé (C) encapsulé, en particulier lorsque ledit composé (C) est un composé susceptible de former un complexe d'inclusion avec l'une des unités cyclodextrines comprises dans les particules (p), en particulier lorsque ladite composition est administrée chez un patient par voie intraveineuse. On peut ainsi réaliser à l'aide d'une telle composition l'administration prolongée du composé actif (C), en particulier lorsque ce composé est choisi parmi le tamoxifène ou ses dérivés, ou bien encore parmi le piroxicame et ses dérivés. De nombreux autres actifs sont susceptibles d'être encapsulés dans les particules (p) des compositions de l'invention dans le but d'un relargage prolongé, et notamment des agents antiinfectieux, anti-inflammatoires, antibactériens, anti-parasitaires, des opioïdes, des enzymes, ou encore des polypeptides. Ainsi, à titre de composés (C) actifs à titre de médicaments encapsulables dans les particules (p), on peut notamment citer la molsidomine, le ketoconazole, le gliclazide, le diclofénac, le levonorgestrel, le paclitaxel, Phydrocortisone, la pancratistatine, le kétoprofène, le diazépam, l'ibuprofene, la nifédipine, la testostérone, le tamoxifène, le furosémide, le tolbutamide, le chloramphénicol, la benzodiazépine, le naproxène, le déxaméthasone, le diflunisal, l'anadamide, la pilocarpine, la daunorubicine, la doxorubicine et la diazépame.The compositions of the invention comprising a compound (C) active as a medicament within their particles (p) generally induce, following their administration, a gradual release of the encapsulated compound (C), in particular when said compound ( C) is a compound capable of forming an inclusion complex with one of the cyclodextrin units included in the particles (p), in particular when the said composition is administered to a patient by the intravenous route. It is thus possible to carry out, using such a composition, the prolonged administration of the active compound (C), in particular when this compound is chosen from tamoxifen or its derivatives, or alternatively from piroxicam and its derivatives. Many other active agents are capable of being encapsulated in the particles (p) of the compositions of the invention for the purpose of prolonged release, and in particular anti-infectious, anti-inflammatory, antibacterial, anti-parasitic agents, opioids, enzymes, or even polypeptides. Thus, as active compounds (C) as drugs which can be encapsulated in the particles (p), mention may in particular be made of molsidomine, ketoconazole, gliclazide, diclofenac, levonorgestrel, paclitaxel, Phydrocortisone, pancratistatin, ketoprofen, diazepam, ibuprofen, nifedipine, testosterone, tamoxifen, furosemide, tolbutamide, chloramphenicol, benzodiazepine, naproxen, dexamethasone, diflunisal, anadamide, pilocarpine, daunorubicin, doxorubicin and diazepam.
Dans ce cadre, sans vouloir être lié en aucune façon à une théorie particulière, il semble pouvoir être avancé que la libération du composé (C) s'effectue avec un équilibre de partage entre les particules (p) et le milieu extérieur. Ainsi, il semble que la cavité hydrophobe interne de chaque cyclodextrine constitue un site potentiellement accepteur des molécules de principes actifs ou de leurs fragments lipophiles. Plus grande sera l'affinité du principe actif pour les cyclodextrines, plus sa libération sera ralentie. Ce concept a notamment pu être mis en évidence avec une molécule modèle, la benzophénone, possédant une forte affinité pour les cyclodextrines. De ce fait, un composé (C) actif à titre de médicament contenu dans les particules (p) d'une composition selon l'invention est le plus souvent libéré de façon préférentielle au niveau des cellules ou des tissus où ce composé est consommé, c'est-à-dire, le plus souvent, là où il joue un rôle thérapeutique effectif.In this context, without wishing to be linked in any way to a particular theory, it seems to be possible to suggest that the release of the compound (C) takes place with a sharing equilibrium between the particles (p) and the external medium. Thus, it seems that the internal hydrophobic cavity of each cyclodextrin constitutes a potentially acceptor site for the molecules of active principles or their lipophilic fragments. The greater the affinity of the active ingredient for cyclodextrins, the more its release will be slowed down. This concept was notably demonstrated with a model molecule, benzophenone, which has a strong affinity for cyclodextrins. As a result, a compound (C) active as a medicament contained in the particles (p) of a composition according to the invention is most often released preferentially in the cells or tissues where this compound is consumed, that is to say, most often, where it plays an effective therapeutic role.
Toujours en ce qui concerne les compositions de l'invention comprenant un composé (C) actif à titre de médicament, il est à noter que les particules (p) sont en général administrables en tant que telles par voie orale. Dans ce cas, elles peuvent permettre de réaliser l'administration par voie orale d'un composé (C) de goût ou d'odeur désagréable (I'encapsulation est généralement à même de masquer ce goût ou cette odeur) ou bien encore d'un composé (C) fragile et/ou difficilement absorbable par voie orale, comme par exemple un composé choisi parmi des anti-inflammatoires tels que le piroxicame, l'ibuprofene et le kétoprofène, des agents hypoglycémiques tels que le glicazide, des agents contraceptifs tels que le D-norgestrel, ou bien encore des composés antifongiques ou antiparasitaires tels que le ketoconazole ou l'albendazole.Still with regard to the compositions of the invention comprising a compound (C) active as a medicament, it should be noted that the particles (p) can generally be administered as such by the oral route. In this case, they can make it possible to carry out the oral administration of a compound (C) of unpleasant taste or odor (the encapsulation is generally capable of masking this taste or this odor) or even of a compound (C) fragile and / or difficult to absorb by the oral route, such as for example a compound chosen from anti-inflammatory drugs such as piroxicam, ibuprofene and ketoprofen, hypoglycemic agents such as glicazide, contraceptive agents such than D-norgestrel, or still antifungal or antiparasitic compounds such as ketoconazole or albendazole.
Par ailleurs, sans vouloir être lié en aucune façon à une théorie particulière, il semble pouvoir être avancé que, dans la mesure où les composés (B) sont des polysaccharides porteurs de groupements G, la structure des particules (p) est en règle générale telle que la couche externe des particules (p) est essentiellement constituée de polysaccharides. En tout état de cause, en particulier lorsque les polysaccharides (B) sont des dextranes, les particules (p) présentent en général tendance à adhérer à la surface de certaines muqueuses, au niveau desquelles elles délivrent ensuite, généralement de façon progressive, le principe actif (c) qu'elles contiennent. On peut ainsi, en appliquant une composition selon l'invention comprenant un composé (C) à effet thérapeutique sur une muqueuse donnée (muqueuse nasale, oculaire ...) réaliser une administration sélective du composé au niveau de cette muqueuse. Par ailleurs, il semble également pouvoir être avancé que, lors d'une administration par voie orale, la structure spécifique des particules (p) favorise leur translocation à travers l'épithélium digestif, et leur passage à l'état intact dans le réseau sanguin, où elles peuvent ensuite permettre une libération prolongée du composé (C).Furthermore, without wishing to be linked in any way to a particular theory, it seems to be possible to argue that, in so far as the compounds (B) are polysaccharides carrying groups G, the structure of the particles (p) is generally such that the outer layer of the particles (p) consists essentially of polysaccharides. In any event, in particular when the polysaccharides (B) are dextrans, the particles (p) generally have a tendency to adhere to the surface of certain mucous membranes, at the level of which they then deliver, generally gradually, the principle active (c) they contain. It is thus possible, by applying a composition according to the invention comprising a compound (C) with a therapeutic effect on a given mucosa (nasal mucosa, ocular ...) to effect a selective administration of the compound at the level of this mucosa. Furthermore, it also seems to be possible to suggest that, during oral administration, the specific structure of the particles (p) promotes their translocation through the digestive epithelium, and their passage to the intact state in the blood network. , where they can then allow a prolonged release of the compound (C).
Dans le cas où les particules (p) sont destinées à la vectorisation de composés de type médicaments, il est en général avantageux que les composés (A) et/ou (B) soient substitués par des groupements permettant un ciblage cellulaire. Dans ce cadre, il peut être intéressant par exemple que les composés (A) et/ou (B) soient complexés par des ligands de type acide folique. Les particules (p) constituent alors des ligands spécifiques dits "de troisième génération".In the case where the particles (p) are intended for the vectorization of compounds of the drug type, it is generally advantageous for the compounds (A) and / or (B) to be substituted by groups allowing cell targeting. In this context, it may be advantageous, for example, for the compounds (A) and / or (B) to be complexed with ligands of the folic acid type. The particles (p) then constitute specific ligands called "third generation".
Par ailleurs, de façon à améliorer le caractère "furtif" des particules (p) de l'invention (c'est-à-dire leur capacité à circuler de façon prolongée dans l'organisme tout en évitant une détection par le système immunitaire), il peut être avantageux que les particules (p) de l'invention présentent des groupements externes de type propylèneglycol (PEG). Pour ce faire, on peut par exemple mettre en œuvre à titre de composés (B) des macromolécules de polysaccharides (de préférence des dextranes) porteuses à la fois de groupements G tels que définis précédemment, et de chaînes PEG. Un autre mode de réalisation de particules greffées par des groupements PEG consiste à additionner au système des composés (A) et (B) en plus des composés (C), des composés de type PEG-[Alk] où Alk représente un groupement alkyle en C10 à C-iβ, de préférence de C12 à Ci6, ou bien un groupement adamantyle. Le cas échéant, comme pour le composés (C), l'addition des composés de type PEG-[Alk] peut être effectuée avant ou après formation des particules à partir du système associatif (A + B). En général, on préfère toutefois que cette addition soit réalisée après formation des particules.Furthermore, in order to improve the "stealthy" nature of the particles (p) of the invention (that is to say their ability to circulate in a prolonged manner in the body while avoiding detection by the immune system) , it may be advantageous for the particles (p) of the invention to have external groups of propylene glycol (PEG) type. For this to do, it is possible for example to use, as compounds (B), macromolecules of polysaccharides (preferably dextrans) carrying both G groups as defined above, and PEG chains. Another embodiment of particles grafted by PEG groups consists in adding to the system compounds (A) and (B) in addition to compounds (C), compounds of the PEG- [Alk] type where Alk represents an alkyl group in C10 to C-iβ, preferably from C 12 to Ci 6 , or else an adamantyl group. Where appropriate, as for the compounds (C), the addition of the compounds of the PEG- [Alk] type can be carried out before or after formation of the particles from the associative system (A + B). In general, however, it is preferred that this addition is carried out after formation of the particles.
Toutefois, en règle générale, la présence de groupements PEG n'est pas nécessaire pour assurer la furtivité et, le plus souvent, les particulesHowever, as a general rule, the presence of PEG groups is not necessary to ensure stealth and, more often than not, particles
(p) s'avèrent capables d'assurer par exemple la vectorisation des composés à demi-vie plasmatique réduite, ou à forte toxicité, notamment au niveau du système des phagocytes mononuclés.(p) prove capable of ensuring, for example, the vectorization of compounds with a reduced plasma half-life, or with high toxicity, in particular in the mononuclear phagocyte system.
Selon un autre mode de réalisation, les composés (C) éventuellement présents au sein des particules (p) peuvent également être des actifs cosmétiques, et la composition selon l'invention peut alors être avantageusement utilisée à titre de composition cosmétique.According to another embodiment, the compounds (C) optionally present in the particles (p) can also be cosmetic active agents, and the composition according to the invention can then be advantageously used as a cosmetic composition.
Dans ce cadre, les composés (C) peuvent par exemple être des composés odorants, par exemple de type terpènes, ou bien un mélange de tels composés (parfums, essences ...). Dans une telle composition les composés odorants présentent en général un pouvoir irritant plus faible qu'à l'état non encapsulé, et ils sont libérés de façon retardée, ce qui améliore la tenue du parfum. De la même façon, d'autres types d'agents cosmétiques présentant de préférence un caractère hydrophobe, peuvent être immobilisés à titre de composé (C) au sein des particules (p) d'une composition selon l'invention, puis libéré de façon progressive. Ainsi, une composition selon l'invention peut par exemple permettre la libération contrôlée d'agents antiperspirants ou bien encore antibactériens. Dans une composition selon l'invention destinée à un usage cosmétique, le composé (C) peut également être un colorant irritant ou présentant une certaine toxicité, dont I'encapsulation permet de réduire les effets indésirables.In this context, the compounds (C) may for example be odorous compounds, for example of the terpene type, or else a mixture of such compounds (perfumes, essences ...). In such a composition, the odorous compounds generally have a lower irritant power than in the non-encapsulated state, and they are released in a delayed manner, which improves the resistance of the perfume. In the same way, other types of cosmetic agents preferably having a hydrophobic character, can be immobilized as compound (C) within the particles (p) of a composition according to the invention, then released in a manner progressive. Thus, a composition according to the invention can for example allow the controlled release of antiperspirant agents or even antibacterial agents. In a composition according to the invention intended for a cosmetic use, the compound (C) can also be an irritant dye or having a certain toxicity, the encapsulation of which makes it possible to reduce the undesirable effects.
De façon plus générale, les compositions de l'invention intégrant des composés (C) peuvent être mises en œuvre pour réaliser une libération progressive desdits composés (C) au sein d'un milieu dans lequel elles sont introduites ou bien pour limiter la mise en contact des composés (C) avec ledit milieu, par exemple en vue de leur protection, lorsqu'il s'agit de molécules fragiles vis-à-vis du milieu considéré, ou bien pour isoler des composés qui peuvent être des polluants (agents toxiques, irritants, réactifs ...) pour ce milieu. Cette utilisation générale des compositions de l'invention comprenant des composés (C) au sein des particules (p) constitue un autre objet de la présente invention.More generally, the compositions of the invention incorporating compounds (C) can be used to achieve a gradual release of said compounds (C) in a medium in which they are introduced or else to limit the contact of the compounds (C) with said medium, for example with a view to their protection, when they are molecules which are fragile with respect to the medium considered, or else to isolate compounds which may be pollutants (toxic agents , irritants, reagents ...) for this medium. This general use of the compositions of the invention comprising compounds (C) within the particles (p) constitutes another object of the present invention.
Qu'elles comprennent ou non un composé (C) à titre additionnel, les compositions de l'invention peuvent en général être soumises à une étape de lyophilisation, en particulier lorsqu'il s'agit de composition essentiellement constituées par une dispersion aqueuse des particules (p). Le cas échéant, cette étape de lyophilisation est généralement conduite en refroidissant brutalement la composition (généralement dans l'air liquide ou l'azote liquide), puis en sublimant l'eau sous forte dépression Les compositions obtenues à l'issue d'une telle étape de lyophilisation, qui se présentent en général sous la forme d'une poudre compacte d'aspect cotonneux, et qui peuvent être dispersées dans l'eau pour conduire à la reconstitution d'une dispersion de particules du type des particules (p), constituent un autre objet particulier de la présente invention.Whether or not they comprise a compound (C) in addition, the compositions of the invention may in general be subjected to a lyophilization step, in particular when it is a composition essentially constituted by an aqueous dispersion of the particles (p). If necessary, this lyophilization step is generally carried out by abruptly cooling the composition (generally in liquid air or liquid nitrogen), then by subliming the water under high depression. The compositions obtained at the end of such a lyophilization step, which are generally in the form of a compact powder with a cottony appearance, and which can be dispersed in water to lead to the reconstitution of a dispersion of particles of the type of particles (p), constitute another particular object of the present invention.
Les caractéristiques et avantages de la présente invention apparaîtront de façon encore plus nette au vu des exemples illustratifs exposés ci-après. La figure unique jointe en annexe représente une vue agrandie de particules selon l'invention.The characteristics and advantages of the present invention will appear even more clearly in the light of the illustrative examples set out below. The single figure attached in the appendix represents an enlarged view of particles according to the invention.
EXEMPLESEXAMPLES
Exemple 1 : synthèse de polymères (A) à base d'unités de β-cyclodextrineEXAMPLE 1 Synthesis of Polymers (A) Based on β-Cyclodextrin Units
On a préparé deux polymères P1 et P2 à base d'unités cyclodextrines en faisant réagir de la β-cyclodextrine (notée β-CD) avec de l'épichlorhydrine en milieu basique, selon le mode opératoire décrit dans F Européen Polymer Journal, vol 33, No 1 , pp 49-57 (1997).Two polymers P1 and P2 based on cyclodextrin units were prepared by reacting β-cyclodextrin (denoted β-CD) with epichlorohydrin in basic medium, according to the procedure described in F European Polymer Journal, vol 33 , No 1, pp 49-57 (1997).
1.1 - Synthèse du polymère PI1.1 - Synthesis of the PI polymer
Dans un bicol, on a dissous 5g de β-CD dans une solution aqueuse de soude à 33% en masse. On a laissé ce mélange sous agitation, à température ambiante (20°C), pendant 24 h, de façon à réaliser la déprotonation des groupes hydroxyles.In a bicol, 5 g of β-CD were dissolved in an aqueous sodium hydroxide solution at 33% by mass. This mixture was allowed to stir, at room temperature (20 ° C), for 24 h, so as to deprotonate the hydroxyl groups.
On a ensuite introduit 2,7 mL d'épichlorhydrine dans le milieu (rapport molaire β-CD/épichlorhydrine = 1/7), et le mélange a été agité vigoureusement et porté à 30°C. On a laissé le milieu dans ces conditions pendant 3 heures.2.7 ml of epichlorohydrin were then introduced into the medium (β-CD / epichlorohydrin molar ratio = 1/7), and the mixture was stirred vigorously and brought to 30 ° C. The medium was left under these conditions for 3 hours.
La réaction a alors été arrêtée, par addition d'acétone qui dissout l'excès d'épichlorhydrine. La solution d'acétone surnageante a ensuite été éliminée.The reaction was then stopped by adding acetone which dissolves the excess of epichlorohydrin. The supernatant acetone solution was then removed.
Le polymère (précipité) est dissous dans de l'eau distillée et la solution a été portée à pH12, et a été placée sous agitation pendant 24 h. La valeur du pH a ensuite été ramenée à 7 (par ajout d'acide chlorhydrique 6N), puis le mélange a été ultrafiltré avec une membrane de seuil de coupure deThe polymer (precipitate) is dissolved in distilled water and the solution was brought to pH12, and was stirred for 24 h. The pH value was then brought back to 7 (by adding 6N hydrochloric acid), then the mixture was ultrafiltered with a cutoff threshold membrane.
1000 Dalton, afin d'éliminer les sels.1000 Dalton, to remove the salts.
Le polymère P1 obtenu suite à ces différentes étapes a ensuite été lyophilisé puis conservé au congélateur. 1-2 Synthèse du polymère P2The polymer P1 obtained following these various steps was then lyophilized and then stored in the freezer. 1-2 Synthesis of polymer P2
Comme pour le polymère P1 , on a dissous dans un bicol 5g de β- CD dans une solution aqueuse de soude à 33% en masse. On a laissé ce mélange sous agitation, à température ambiante (20°C), pendant 24 h, de façon à réaliser la déprotonation des groupes hydroxyles.As for polymer P1, 5 g of β-CD were dissolved in a bicol in a 33% by mass aqueous sodium hydroxide solution. This mixture was allowed to stir, at room temperature (20 ° C), for 24 h, so as to deprotonate the hydroxyl groups.
On a ensuite introduit 3,8 mL d'épichlorhydrine dans le milieu3.8 ml of epichlorohydrin were then introduced into the medium.
(rapport molaire β-CD/épichlorhydrine = 1/10), et le mélange a été agité vigoureusement et porté à 30°C. On a laissé le milieu évoluer jusqu'au voisinage immédiat de la gélification du milieu reactionnel, c'est-à-dire jusqu'à obtention d'un milieu de haute viscosité.(β-CD / epichlorohydrin molar ratio = 1/10), and the mixture was stirred vigorously and brought to 30 ° C. The medium was left to evolve to the immediate vicinity of the gelling of the reaction medium, that is to say until a medium of high viscosity is obtained.
La réaction a alors été arrêtée, par addition d'acétone qui dissout l'excès d'épichlorhydrine. La solution d'acétone surnageante a ensuite été éliminée.The reaction was then stopped by adding acetone which dissolves the excess of epichlorohydrin. The supernatant acetone solution was then removed.
Le polymère (précipité) est dissous dans de l'eau distillée et la solution a été portée à pH12, et a été placée sous agitation pendant 24 h. La valeur du pH a ensuite été ramenée à 7 (par ajout d'acide chlorhydrique 6N), puis le mélange a été ultrafiltré avec une membrane de seuil de coupure de 1000 Dalton, afin d'éliminer les sels. Une deuxième ultrafiltration a ensuite été réalisée avec une membrane de seuil de coupure 100 000 Dalton de façon à éliminer les fractions de faible masse molaire.The polymer (precipitate) is dissolved in distilled water and the solution was brought to pH12, and was stirred for 24 h. The pH value was then brought back to 7 (by adding 6N hydrochloric acid), then the mixture was ultrafiltered with a cut-off membrane of 1000 Dalton, in order to remove the salts. A second ultrafiltration was then carried out with a 100,000 Dalton cutoff threshold membrane so as to eliminate the fractions of low molar mass.
Le polymère P2 obtenu suite à ces différentes étapes a ensuite été lyophilisé puis conservé au congélateur.The polymer P2 obtained following these various stages was then lyophilized and then stored in the freezer.
Les caractéristiques des polymères P1 et P2 sont regroupés dans le tableau ci-après (les masses moléculaires reportées dans ce tableau sont telles que mesurées par chromatographie SEC, avec un étalonnage pullulan, et le nombre moyen d'unités β-cyclodextrine par copolymère a été calculé à partir de cette masse moléculaire) Tableau 1 : caractéristiques des polymères P1 et P2The characteristics of polymers P1 and P2 are grouped in the table below (the molecular weights reported in this table are as measured by SEC chromatography, with pullulan calibration, and the average number of β-cyclodextrin units per copolymer has been calculated from this molecular weight) Table 1: characteristics of polymers P1 and P2
Exemple 2 : synthèse de dextranes modifiées par des chaînes alkyles (B)EXAMPLE 2 Synthesis of Dextrans Modified by Alkyl Chains (B)
On a préparé différents dextranes modifiées par des chaînes alkyles, en faisant réagir du dextrane et différents chlorures d'acyle, selon le mode opératoire décrit dans Polymer, vol 29, pp507-511 (1988).Different dextrans modified with alkyl chains were prepared by reacting dextran and different acyl chlorides, according to the procedure described in Polymer, vol 29, pp507-511 (1988).
Plus précisément, on a fait réagir du dextrane de masse moéculaire égale à 40 000 (dextrane T40) avec différents chlorures d'alkyle (nature et quantité précisées dans le tableau 2 ci-dessous), en présence de pyridine (capteur de protons) et diméthylaminipyridyne DMAP (catalyseur).More specifically, dextran with a molecular mass equal to 40,000 (dextran T40) was reacted with different alkyl chlorides (nature and quantity specified in table 2 below), in the presence of pyridine (proton sensor) and dimethylaminipyridyne DMAP (catalyst).
Dans chacune des synthèses effectuées, 4g de dextrane ont été solubilisés dans 100 mL de diméthylformamide préalablement distillé, en présence de 1g de chlorure de lithium LiCI. La réaction a été conduite en additionnant au milieu obtenu 0,5 g de DMAP, 0,031 mL de pyridine et le chlorure d'alkyle, et en laissant réagir à 80 °C pendant 3 heures.In each of the syntheses carried out, 4 g of dextran were dissolved in 100 ml of dimethylformamide previously distilled, in the presence of 1 g of lithium chloride LiCl. The reaction was carried out by adding to the medium obtained 0.5 g of DMAP, 0.031 ml of pyridine and the alkyl chloride, and allowing to react at 80 ° C for 3 hours.
Le polymère obtenu a ensuite été purifié par précipitation dans l'isopropanol, puis par dialyse après solubilisation dans de l'eau. Lors de cette étape, le polymère est fractionné en fonction de son taux de modification par différence de solubilité dans l'eau.The polymer obtained was then purified by precipitation in isopropanol, then by dialysis after solubilization in water. During this step, the polymer is fractionated according to its rate of modification by difference in solubility in water.
A cet effet, après solubilisation dans l'eau, la solution a été versée dans une éprouvette et elle a été laissée au repos pendant 4 h. Suite à cette décantation, trois fractions (supérieure, médiane et inférieure) de volumes égaux ont alors été séparées. Dans chacune des synthèse, une ou plusieurs de ces fractions (telles qu'indiquées dans le tableau 2 ci-dessous) ont été dialysées contre de l'eau pure sur des membranes de seuil de coupure de 6000-8000 Dalton. Suite à la dialyse de la fraction considérée, le dextrane modifié obtenu a été caractérisés par RMN pour déterminer le taux de substitution par les chaînes alkyles, puis il a été lyophilisé.For this purpose, after solubilization in water, the solution was poured into a test tube and it was left to stand for 4 h. Following this decantation, three fractions (upper, middle and lower) of equal volumes were then separated. In each of the syntheses, one or more of these fractions (as indicated in Table 2 below) were dialyzed against pure water on cut-off threshold membranes. 6000-8000 Dalton. Following dialysis of the fraction considered, the modified dextran obtained was characterized by NMR to determine the rate of substitution by the alkyl chains, then it was lyophilized.
Les caractéristiques des dextranes modifiés DM1 -DM5 ainsi préparés sont regroupées dans le tableau 2 ci-dessous.The characteristics of the DM1 -DM5 modified dextrans thus prepared are collated in Table 2 below.
Tableau 2 : caractéristiques des dextranes modifiés DM1 -DM5Table 2: characteristics of the DM1 -DM5 modified dextrans
Exemple 3 : préparations de dispersions aqueuses de particules selon l'invention. On a réalisé différentes dispersions aqueuses selon l'invention en mélangeant un volume V(A) d'une solution aqueuse de polymères (A) à une concentration C(A), avec un volume V(B) d'une solution aqueuse de dextranes modifiés (B) à une concentration C(B). Les conditions des mélanges réalisés sont reportées ci-dessous :Example 3: preparations of aqueous dispersions of particles according to the invention. Various aqueous dispersions were produced according to the invention by mixing a volume V (A) of an aqueous solution of polymers (A) at a concentration C (A), with a volume V (B) of an aqueous solution of dextrans modified (B) at a concentration C (B). The conditions of the mixtures produced are reported below:
Tableau 3 : conditions de mélangesTable 3: mixing conditions
Les diamètres moyens des particules observées dans les dispersions C1 à C4, obtenues immédiatement après le mélange et suite à 2 à 15 jours de stockage, sont reportés dans le tableau 4 ci-dessous :The average particle diameters observed in dispersions C1 to C4, obtained immediately after mixing and after 2 to 15 days of storage, are shown in Table 4 below:
Tableau 4 : évolution des diamètres moyens des particules présentes dans les compositions C1 à C4Table 4: Evolution of the average diameters of the particles present in the compositions C1 to C4
(*J Au bout de 1 jour de stockage, le diamètre moyen des particules de la composition C5 est de 330 nm. (* J After 1 day of storage, the average diameter of the particles of composition C5 is 330 nm.
Exemple 4 : influence de la masse molaire du polymère (A)EXAMPLE 4 Influence of the Molar Mass of the Polymer (A)
On a réalisé le mélange de 1 ml d'une solution de dextrane modifié DM3 (10 mg/ml dans l'eau milliQ) avec 1 ml d'une solution de deux polymères (A) de masses molaires distinctes (polymères P1 et P2 tels que définis dans l'exemple 1 , de masses moléculaires respectives 40 000 g/mole ou 2 600 000 g/mole) également à 10 mg/ml dans l'eau milliQ.A mixture of 1 ml of a solution of modified dextran DM3 (10 mg / ml in milliQ water) was produced with 1 ml of a solution of two polymers (A) of distinct molar masses (polymers P1 and P2 such as defined in Example 1, of respective molecular weights 40,000 g / mole or 2,600,000 g / mole) also at 10 mg / ml in milliQ water.
Le tableau 5 ci-dessous suivant représente les évolutions des diamètres moyens des particules obtenues dans les deux cas : Tableau 5 : évolution comparée des diamètres moyens des particules pour deux polymères (A) de masses molaires différentesTable 5 below represents the changes in the average diameters of the particles obtained in the two cases: Table 5: Comparative evolution of the average particle diameters for two polymers (A) of different molecular weights
Ainsi, on note que les particules obtenues avec un polymère (A) de faible masse molaire sont moins stables que celles obtenues avec un polymère (A) de masse molaire supérieure (pour P2, le diamètre tend à se stabiliser après 5 jours).Thus, it is noted that the particles obtained with a polymer (A) of low molar mass are less stable than those obtained with a polymer (A) of higher molar mass (for P2, the diameter tends to stabilize after 5 days).
Dans le cas de P1 , il est cependant à noter que les évolutions de diamètre sont moins importantes lorsque les concentrations des polymères de départ sont plus faibles.In the case of P1, it should however be noted that the changes in diameter are less significant when the concentrations of the starting polymers are lower.
Exemple 5 : Encapsulation d'un composé modèle : la benzophénoneEXAMPLE 5 Encapsulation of a Model Compound: Benzophenone
On a réalisé une solution aqueuse de polymère P2 tel que défini dans l'exemple 1 (0,44 g/L) auxquelles on a additionné de la benzophénone avec un rapport molaire benzophénone ajoutée : cyclodextrine égal à 1 : 1. Cette solution a été laissée sous agitation pendant 24 heures.An aqueous solution of polymer P2 was produced as defined in Example 1 (0.44 g / L) to which benzophenone was added with an added benzophenone: cyclodextrin molar ratio equal to 1: 1. This solution was left stirring for 24 hours.
Une compositions de particules a été préparée par mélange de 1 ml de la solution ainsi obtenue avec 1 mL d'une solution de dextrane modifié DM3 tel que défini dans l'exemple 1 (0,44 g/L).A particle composition was prepared by mixing 1 ml of the solution thus obtained with 1 ml of a DM3 modified dextran solution as defined in Example 1 (0.44 g / L).
Après mélange, les particules réalisées ont été ultracentrifugées (30 minutes à 40000 tours/minutes dans une centrifugeuse Beckman L7-55). La benzophénone non encapsulée, présente dans le surnageant, a été dosée par spectrophotométrie (raie d'absorption à 261 nm). L'expérience à été reproduite en utilisant un rapport molaire benzophénone ajoutée : cyclodextrine égal à 1 : 3 pour la solution de polymère P2.After mixing, the particles produced were ultracentrifuged (30 minutes at 40,000 rpm in a Beckman L7-55 centrifuge). The non-encapsulated benzophenone present in the supernatant was assayed by spectrophotometry (absorption line at 261 nm). The experiment was reproduced using a benzophenone: cyclodextrin molar ratio added equal to 1: 3 for the polymer solution P2.
L'expérience a également été reproduite en utilisant le dextrane modifié DM4 au lieu de DM3.The experiment was also repeated using modified DM4 dextran instead of DM3.
Enfin, on a aussi reproduit l'expérience en en utilisant à la fois un rapport molaire benzophénone ajoutée : cyclodextrine égal à 1 : 3 pour la solution de polymère P2, et en remplaçant le dextrane modifié DM3 par DM4Finally, the experiment was also reproduced by using at the same time an added benzophenone: cyclodextrin molar ratio equal to 1: 3 for the solution of polymer P2, and by replacing the dextran modified DM3 by DM4.
Dans les 4 cas, les rendement d'encapsulation de la benzophénone sont compris entre 30 et 40% (moins de 70% de la benzophénone initialement introduite se retrouve dans le surnageant).In the 4 cases, the encapsulation yield of the benzophenone is between 30 and 40% (less than 70% of the benzophenone initially introduced is found in the supernatant).
Avec un rapport molaire benzophénone : cyclodextrine égal à 1 : 1 dans la solution initiale de P2, on réalise des particules comprenant 1 % en masse de benzophénone. Avec un rapport molaire benzophénone : cyclodextrine égal à 1 : 3, on réalise des particules comprenantWith a benzophenone: cyclodextrin molar ratio equal to 1: 1 in the initial solution of P2, particles comprising 1% by mass of benzophenone are produced. With a benzophenone: cyclodextrin molar ratio equal to 1: 3, particles are produced comprising
3% en masse de benzophénone.3% by mass of benzophenone.
Exemple 6 : Préparation de compositions de particules lyophiliséesExample 6 Preparation of Lyophilized Particle Compositions
Des compositions de particules ont été préparées par mélange de deux volumes identiques (1 mL) d'une solution de polymère (A) et d'une solution de dextrane modifié (B) dans les conditions exposées dans le tableau 6 ci- dessous.Particle compositions were prepared by mixing two identical volumes (1 mL) of a polymer solution (A) and a modified dextran solution (B) under the conditions set out in Table 6 below.
Les récipients les contenant ont ensuite été plongés dans l'air liquide.The containers containing them were then immersed in liquid air.
Les particules ont été ensuite lyophilisées (Christ LDC-1) pendant 24 heures, avec ou sans présence de cryoprotecteur (saccharose) selon les cas. Il a été mis en évidence dans ce cadre que l'utilisation du glucose et du maltose est un cryoprotecteur mal adapté à ce type de particules. Les lyophilisais obtenus ont ensuite été mélangés avec de l'eau milliQ, de façon à reconstituer des compositions de particules.The particles were then lyophilized (Christ LDC-1) for 24 hours, with or without the presence of cryoprotective (sucrose) as appropriate. It has been demonstrated in this context that the use of glucose and maltose is a cryoprotective ill-suited to this type of particles. The lyophilizates obtained were then mixed with milliQ water, so as to reconstitute particle compositions.
Les diamètres avant et après lyophilisation sont regroupés dans le tableau 6 ci-dessous :The diameters before and after freeze-drying are grouped in Table 6 below:
Tableau 6 : essais de lyophilisation et mise en évidence de la redispersabilite des lyophilisats obtenus.Table 6: lyophilization tests and demonstration of the redispersibility of the lyophilisates obtained.
Exemple 7 : Stabilité des compositions de l'invention sous cisaillementExample 7: Stability of the compositions of the invention under shear
On a préparé un composition de particules selon l'invention par mélange de 5 ml de solution de polymère P2 à 10 mg/ml dans l'eau milliQ et de 5 ml de solution de dextrane modifié DM3 à 10 mg/ml dans l'eau milliQ. Le diamètre moyen des particules obtenues est de 178 nm.A particle composition according to the invention was prepared by mixing 5 ml of solution of polymer P2 at 10 mg / ml in milliQ water and 5 ml of solution of modified dextran DM3 at 10 mg / ml in water milliQ. The average diameter of the particles obtained is 178 nm.
6,3 ml de la composition de particules réalisée ont été soumis à un cisaillement en géométrie cône-godel (DG41) sur un rheomètre Rhéo Stress6.3 ml of the particle composition produced were subjected to shear in cone-godel geometry (DG41) on a Rhéo Stress rheometer
100 (Haake/Fisons). L'étude a été effectuée à 20°C avec une contrainte de cisaillement passant de 0 à 2000 mPa en 300 secondes, maintenue à 2000 mPa pendant 300 sec, puis descendue de 2000 à 0 mPa en 300 sec. Suite à ce traitement, le diamètre final des particules a été mesuré égal à 183 nm. On n'a donc pas noté d'évolution significative. 100 (Haake / Fisons). The study was carried out at 20 ° C with a shear stress passing from 0 to 2000 mPa in 300 seconds, maintained at 2000 mPa for 300 sec, then lowered from 2000 to 0 mPa in 300 sec. Following this treatment, the final particle diameter was measured equal to 183 nm. No significant development was therefore noted.

Claims

REVENDICATIONS
1. Composition comprenant une dispersion aqueuse de particules (p) de diamètre hydrodynamique moyen compris entre 50 et 5000 nm, lesdites particules contenant, en association : (A) des polymères à base d'unités cyclodextrines, comprenant en moyenne au moins 4 unités cyclodextrines au sein de leur structure ; et1. Composition comprising an aqueous dispersion of particles (p) of average hydrodynamic diameter between 50 and 5000 nm, said particles containing, in combination: (A) polymers based on cyclodextrin units, comprising on average at least 4 cyclodextrin units within their structure; and
(B) des macromolécules de polysaccharides comprenant des groupements G susceptibles de former des complexes d'inclusion avec les cyclodextrines présentes dans la structure desdits polymères (A), avec un nombre moyen de groupements G par macromolécule de polysaccharide au moins égal à 3, lesdits composés (A) et (B) étant hydrosolubles à l'état isolé.(B) polysaccharide macromolecules comprising G groups capable of forming inclusion complexes with the cyclodextrins present in the structure of said polymers (A), with an average number of G groups per polysaccharide macromolecule at least equal to 3, said compounds (A) and (B) being water-soluble in the isolated state.
2. Composition selon la revendication 1 , caractérisée en ce que les particules (p) possèdent un diamètre hydrodynamique moyen supérieur ou égal à 80 nm et inférieur ou égal à 500 nm.2. Composition according to claim 1, characterized in that the particles (p) have an average hydrodynamic diameter greater than or equal to 80 nm and less than or equal to 500 nm.
3. Composition selon la revendication 1 ou selon la revendication 2, caractérisée en ce que les polymères (A) comportent en moyenne au moins 9 unités cyclodextrines au sein de leur structure.3. Composition according to claim 1 or according to claim 2, characterized in that the polymers (A) comprise on average at least 9 cyclodextrin units within their structure.
4. Composition selon l'une quelconque des revendications 1 à 3, caractérisée en ce que les unités cyclodextrines présentes dans les polymères (A) comprennent des β-cyclodextrines.4. Composition according to any one of claims 1 to 3, characterized in that the cyclodextrin units present in the polymers (A) comprise β-cyclodextrins.
5. Composition selon l'une quelconque des revendications 1 à 4, caractérisée en ce que les polymères (A) sont obtenus par une polycondensation de molécules de cyclodextrines et d'épichlorhydrines. 5. Composition according to any one of claims 1 to 4, characterized in that the polymers (A) are obtained by a polycondensation of cyclodextrin and epichlorohydrin molecules.
6. Composition selon l'une quelconque des revendications 1 à 5, caractérisée en ce que les polymères (A) possèdent une masse molaire moyenne en nombre comprise entre 10 000 et 3 000 000 g/mole.6. Composition according to any one of claims 1 to 5, characterized in that the polymers (A) have a number-average molar mass of between 10,000 and 3,000,000 g / mole.
7. Composition selon l'une quelconque des revendications 1 à 6, caractérisée en ce que les groupements G sont des groupements aliphatiques, linéaires ou ramifiés, comportant de 8 à 18 atomes de carbone.7. Composition according to any one of claims 1 to 6, characterized in that the groups G are aliphatic groups, linear or branched, comprising from 8 to 18 carbon atoms.
8. Composition selon l'une quelconque des revendications 1 à 7, caractérisée en ce que le taux de greffage des polysaccharides (B) par les groupements G est compris entre 1 et 8 %.8. Composition according to any one of claims 1 to 7, characterized in that the degree of grafting of the polysaccharides (B) by the groups G is between 1 and 8%.
9. Composition selon l'une quelconque des revendications 1 à9. Composition according to any one of claims 1 to
8, caractérisée en ce que les composés (A) et (B) sont choisis parmi les associations suivantes :8, characterized in that the compounds (A) and (B) are chosen from the following associations:
- polymères (A) comportant de 18 à 1000 unités β-cyclodextrines / polysaccharides (B) de masse moléculaire comprise entre 6 000 et 70 000 greffés par des groupes aliphatiques en C12 et présentant un taux de substitution hydrophobe de 3 à 5 % ;- polymers (A) comprising from 18 to 1000 β-cyclodextrin / polysaccharide units (B) of molecular mass between 6,000 and 70,000 grafted with C12 aliphatic groups and having a hydrophobic substitution rate of 3 to 5%;
- polymères (A) comportant de 100 à 600 unités β-cyclodextrines / polysaccharides (B) de masse moléculaire comprise entre 6 000 et 70 000 greffés par des groupes aliphatiques en C10 et présentant un taux de substitution hydrophobe de 5 à 7 % ;- polymers (A) comprising from 100 to 600 β-cyclodextrin / polysaccharide units (B) of molecular mass between 6,000 and 70,000 grafted with C10 aliphatic groups and having a hydrophobic substitution rate of 5 to 7%;
- polymères (A) comportant de 18 à 1000, β-cyclodextrines / polysaccharides (B) de masse moléculaire comprise entre 6000 et 70000 greffés par des groupements adamantyles et présentant un taux de substitution hydrophobe de 3 à 4 %. - polymers (A) comprising from 18 to 1000, β-cyclodextrins / polysaccharides (B) of molecular mass between 6000 and 70,000 grafted by adamantyl groups and having a hydrophobic substitution rate of 3 to 4%.
10. Composition selon l'une quelconque des revendications 1 à 9, caractérisée en ce que le ratio molaire de la quantité totale d'unités cyclodextrines présentes au sein des polymères (A), rapportée à la quantité totale de chaînes aliphatiques présentes à titre de substituants sur les macromolécules de polysaccharides (B) est compris entre 1 :3 et 3:1. 10. Composition according to any one of claims 1 to 9, characterized in that the molar ratio of the total amount of cyclodextrin units present in the polymers (A), relative to the total amount of aliphatic chains present as substituents on the macromolecules of polysaccharides (B) is between 1: 3 and 3: 1.
11. Composition selon l'une quelconque des revendications 1 à 10, caractérisée en ce qu'au moins 80% en masse des composés (A et B) présents dans la composition sont contenus dans les particules (p).11. Composition according to any one of claims 1 to 10, characterized in that at least 80% by mass of the compounds (A and B) present in the composition are contained in the particles (p).
12. Composition selon l'une quelconque des revendications 1 à 11 , caractérisée en ce que les particules (p) comprennent au moins un composé chimique (C) supplémentaire, autre que les composé (A) et (B).12. Composition according to any one of claims 1 to 11, characterized in that the particles (p) comprise at least one additional chemical compound (C), other than the compounds (A) and (B).
13. Composition selon la revendication 12, caractérisée en ce que ledit composé (C) est un composé susceptible de former un complexe d'inclusion avec l'une des unités cyclodextrines comprises dans les polymères (A) présents dans les particules (p).13. Composition according to claim 12, characterized in that said compound (C) is a compound capable of forming an inclusion complex with one of the cyclodextrin units included in the polymers (A) present in the particles (p).
14. Composition selon la revendication 12 ou la revendication 13, caractérisée en ce que la quantité de composé (C) intégré au sein des particules (p) représente au moins 0,5 % en masse par rapport à la masse totale desdites particules (p).14. Composition according to claim 12 or claim 13, characterized in that the amount of compound (C) integrated within the particles (p) represents at least 0.5% by mass relative to the total mass of said particles (p ).
15. Composition selon l'une quelconque des revendications 12 à 14, caractérisée en ce que le composé (C) est un composé présentant un effet thérapeutique ou cosmétique et en ce que ladite composition est une composition pharmaceutique ou cosmétique.15. Composition according to any one of claims 12 to 14, characterized in that the compound (C) is a compound having a therapeutic or cosmetic effect and in that said composition is a pharmaceutical or cosmetic composition.
16. Procédé de préparation d'une composition selon l'une quelconque des revendications 1 à 11 , caractérisé en ce qu'il comprend une étape (E) consistant à effectuer un mélange d'une solution aqueuse (SA) comprenant des polymère (A) tels que définis dans la revendication 1 et d'une solution aqueuse (SB) comprenant des macromolécules de polysaccharide (B) telles que définies dans la revendication 1 , les volumes et les concentrations desdites solutions (SA) et (SB) étant choisis de façon à obtenir, suite au mélange, un milieu aqueux où les concentrations respectives C-A et CB en lesdits composés (A) et (B) appartiennent au domaine de formation d'une dispersion métastable pour le système auto-associatif (A+B). 16. A method of preparing a composition according to any one of claims 1 to 11, characterized in that it comprises a step (E) consisting in carrying out a mixing of an aqueous solution (SA) comprising polymers (A ) as defined in claim 1 and an aqueous solution (SB) comprising macromolecules of polysaccharide (B) as defined in claim 1, the volumes and concentrations of said solutions (SA) and (SB) being chosen from so as to obtain, following mixing, an aqueous medium where the respective concentrations CA and C B in said compounds (A) and (B) belong to the field of formation of a metastable dispersion for the self-associative system (A + B) .
17. Procédé selon la revendication 16, caractérisé en ce que dans le milieu obtenu à l'issue de l'étape (E) :17. Method according to claim 16, characterized in that in the medium obtained at the end of step (E):
- la somme des concentrations CA+CB est comprise entre 0,01g/L et 20g/L ; et - le ratio molaire de la quantité totale d'unités cyclodextrines présentes au sein des polymères (A) introduits, rapportée à la quantité totale de chaînes aliphatiques présentes à titre de substituants sur les1 macromolécules (B) introduites est compris entre 1 :3 et 3:1.- the sum of the CA + C B concentrations is between 0.01g / L and 20g / L; and the molar ratio of the total amount of cyclodextrin units present in the polymers (A) introduced, relative to the total amount of aliphatic chains present as substituents on the 1 macromolecules (B) introduced is between 1: 3 and 3: 1.
18. Procédé selon la revendication 16 ou selon la revendication 17, caractérisé en ce que la concentration de la solution (SA) est comprise entre18. Method according to claim 16 or according to claim 17, characterized in that the concentration of the solution (S A ) is between
0,01 g/L et 20 g/L, en ce que la concentration de la solution (SB) est comprise entre 0,01 g/L et 20 g/L, et en ce que le rapport du volume total de solution (SA) introduite sur le volume total de solution (SB) introduite est compris entre 1 :9 et 9:1.0.01 g / L and 20 g / L, in that the concentration of the solution (SB) is between 0.01 g / L and 20 g / L, and in that the ratio of the total volume of solution ( SA) introduced on the total volume of solution (SB) introduced is between 1: 9 and 9: 1.
19. Procédé de préparation d'une composition selon l'une quelconque des revendications 12 à 15, caractérisé en ce qu'il consiste à mettre en contact ledit composé (C) avec une composition selon l'une quelconque des revendications 1 à 14.19. A method of preparing a composition according to any one of claims 12 to 15, characterized in that it consists in bringing said compound (C) into contact with a composition according to any one of claims 1 to 14.
20. Procédé de préparation d'une composition selon l'une quelconque des revendications 12 à 15, caractérisé en ce qu'il comprend une étape consistant à effectuer un mélange d'une solution aqueuse (SA) comprenant des polymère (A) tels que définis dans la revendication 1 et ledit composé additionnel (C), et d'une solution aqueuse (SB) comprenant des polysaccharides modifiés (B) tels que définis dans la revendication 1 , les volumes et les concentrations desdites solutions (SA) et (SB) étant choisis de façon à obtenir, suite au mélange, un milieu aqueux où les concentrations respectives ÇA et CB en lesdits composés (A) et (B) appartiennent au domaine de formation d'une dispersion métastable pour le système auto-associatif (A+B). 20. A method of preparing a composition according to any one of claims 12 to 15, characterized in that it comprises a step consisting in carrying out a mixing of an aqueous solution (SA) comprising polymers (A) such as defined in claim 1 and said additional compound (C), and of an aqueous solution (SB) comprising modified polysaccharides (B) as defined in claim 1, the volumes and the concentrations of said solutions (S A ) and ( S B ) being chosen so as to obtain, after mixing, an aqueous medium in which the respective concentrations ÇA and CB in said compounds (A) and (B) belong to the field of formation of a metastable dispersion for the self-associative system (A + B).
21. Utilisation d'une composition selon l'une quelconque des revendications 1 à 11 pour réaliser une encapsulation de composés chimiques.21. Use of a composition according to any one of claims 1 to 11 for carrying out an encapsulation of chemical compounds.
22. Utilisation d'une composition selon l'une quelconque des revendications 12 à 15, pour réaliser une libération progressive de composés (C) présents au sein des particules (p) au sein d'un milieu dans lequel ladite composition est introduite, ou pour limiter la mise en contact desdits composés (C) avec ledit milieu.22. Use of a composition according to any one of claims 12 to 15, for producing a gradual release of compounds (C) present within the particles (p) in a medium into which said composition is introduced, or to limit the contacting of said compounds (C) with said medium.
23. Utilisation d'une composition selon la revendication 15, où le composé (C) est un composé actif à titre de médicament, pour la fabrication d'une composition pharmaceutique destinée à délivrer ledit composé (C) de façon progressive et/ou à délivrer ce composé (C) de façon sélective au niveau d'une muqueuse donnée.23. Use of a composition according to claim 15, in which the compound (C) is an active compound as a medicament, for the manufacture of a pharmaceutical composition intended for delivering said compound (C) gradually and / or to deliver this compound (C) selectively to a given mucosa.
24. Composition susceptible d'être obtenue à l'issue de la lyophilisation d'une composition selon l'une quelconque des revendications 1 à 15. 24. Composition capable of being obtained at the end of the lyophilization of a composition according to any one of claims 1 to 15.
EP03763923A 2002-07-11 2003-07-01 Aqueous dispersions of nanometric or micrometric particles for encapsulating chemical compounds Withdrawn EP1521575A1 (en)

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