Classifications

• • C—CHEMISTRY; METALLURGY
  • C01—INORGANIC CHEMISTRY
  • C01G—COMPOUNDS CONTAINING METALS NOT COVERED BY SUBCLASSES C01D OR C01F
  • C01G23/00—Compounds of titanium
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
  • A61K8/84—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions otherwise than those involving only carbon-carbon unsaturated bonds
  • A61K8/88—Polyamides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B82—NANOTECHNOLOGY
  • B82B—NANOSTRUCTURES FORMED BY MANIPULATION OF INDIVIDUAL ATOMS, MOLECULES, OR LIMITED COLLECTIONS OF ATOMS OR MOLECULES AS DISCRETE UNITS; MANUFACTURE OR TREATMENT THEREOF
  • B82B3/00—Manufacture or treatment of nanostructures by manipulation of individual atoms or molecules, or limited collections of atoms or molecules as discrete units
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
  • C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
  • C08G69/02—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids
  • C08G69/08—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids derived from amino-carboxylic acids
  • C08G69/10—Alpha-amino-carboxylic acids
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
  • C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
  • C08G69/48—Polymers modified by chemical after-treatment
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
  • C08L77/00—Compositions of polyamides obtained by reactions forming a carboxylic amide link in the main chain; Compositions of derivatives of such polymers
  • C08L77/04—Polyamides derived from alpha-amino carboxylic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
  • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
  • A61K2800/57—Compounds covalently linked to a(n inert) carrier molecule, e.g. conjugates, pro-fragrances

Definitions

• the present invention relates to novel biodegradable materials based on copolyamino acids, useful in particular for the vectorization of active principle (s) (PA).
• PA active principle
• the invention also relates to novel pharmaceutical, cosmetic, dietetic or phytosanitary compositions based on these modified polyamino acids.
• These compositions may be of the type of those allowing the vectorization of AP and are preferably in the form of emulsions, micelles, particles, gels, implants or films.
• the PAs considered are, advantageously, biologically active compounds that can be administered to an animal or human organism orally, parenterally, nasally, vaginally, ocularly, subcutaneously, intravenously, intramuscularly, intradermally, intraperitoneally, intracerebrally, orally, etc.
• PAs more particularly, but not exclusively, concerned by the invention are proteins, glycoproteins, peptides, polysaccharides, lipopolysaccharides, oligo or polynucleotides, and organic molecules. But it can also be cosmetic products or phytosanitary products, such as herbicides, insecticides, fungicides, etc.
• polymers of the polylactic, polylactic-glycolic, polyoxyethylene-oxypropylene, polyamino acid or polysaccharide type are raw materials for manufacturing, for example, mass implants, microparticles, nanoparticles, vesicles, micelles or gels.
• these polymers must be suitable for the manufacture of such systems, they must also be biocompatible, non-toxic, non-immunogenic, economical and they must be easily removed from the body and / or be biodegradable. On this last aspect, it is moreover essential that the biodegradation in the organism generates non-toxic products.
• an associative polymer Another equally important aspect in the development of an associative polymer is its solubility in water.
• the possibility of solubilizing a high amount of polymer makes it possible to have a polymer / active ingredient ratio adapted to the desired release profile.
• US-B-4,652,441 discloses polylactide microcapsules encapsulating the hormone LH-RH. These microcapsules are produced by preparing a water-in-oil-in-water emulsion and comprise an aqueous inner layer containing the hormone, a substance (gelatin) fixing the latter, an oily layer of polylactide, and an aqueous outer layer. (polyvinyl alcohol). The release of the AP can be done over a period of more than two weeks after subcutaneous injection.
• compositions based on amphiphilic poly (oxyethylene) -poly (oxypropylene) micelles for the vectorization of anticancer drugs such as adriamycin.
• US Pat. No. 4,888,398 describes polymers based on polyglutamate or polyaspartate, and optionally polyleucine, with pendent groups of alkyloxycarbonylmethyl type, randomly placed on the polyamino acid chain. These polyamino acids, grafted with side groups eg methoxycarbonylmethyl, can be used in the form of biodegradable implants containing a sustained release PA.
• US Pat. No. 5,904,936 describes nanoparticles obtained from a polyleucine-polyglutamate block polymer capable of forming stable colloidal suspensions capable of associating spontaneously with biologically active proteins without denaturing them. These can then be released in vivo in a controlled manner over a long period.
• the patent application WO-A-99/61512 describes polylysines and polyornithines functionalized with a hydrophobic group (palmitic acid connected to polylysine or ornithine) and a hydrophilic group (polyoxyethylene).
• These polymers for example polylysine grafted with polyoxyethylene and palmitoyl chains form, in the presence of cholesterol, vesicles capable of encapsulating doxorubicin or DNA.
• These polymers based on polylysines are cationic in a physiological medium.
• US-B-6,630,171 of the Applicant describes block polymers or random poly (sodium glutamate) -poly (methyl, ethyl, hexadecyl or dodecyl glutamate), capable of forming stable colloidal suspensions and capable of associating spontaneously with biologically active proteins without denaturing them. These can then be released in vivo in a controlled manner over a long period.
• These linear amphiphilic copolyamino acids are modified by the presence of a hydrophobic alkyl side chain. These alkyl groups are grafted covalently on the polymer via an ester function.
• These polymers are anionic in a physiological medium.
• WO-A-03/104303 discloses anionic polyamino acids functionalized with alpha-tocopherol.
• the application WO-A-2004/013206 describes anionic polyamino acids having hydrophobic groups and characterized in that these groups are connected to the polymer via a ball joint containing two amide functions, and more specifically via a lysine-type spacer. or ornithine.
• the application WO-A-2004/060968 describes polyamino acids functionalized with at least one oligoamino acid group based on leucine and / or isoleucine and / or valine and / or phenylalanine.
• Patent applications WO-A-02/098951 and WO-A-02/098952 disclose polyalkylglutamines having one or two hydrophobic groups at one end of the polymer. These polymers are capable of forming liposomes and encapsulating water-soluble small molecules (active ingredient).
• PV biocompatible particles for vectorization
• PA active principles
• PV are based on a hydrophilic neutral polyamino acid diblock copolymer (polyAANI) / hydrophobic neutral polyamino acid (polyAANO), for example POLY [(LEU) -BLOC- (GLN-N-HYDROXYETHYL)] X #
• polyAANI / polyAANO particles are capable of associating in a colloidal suspension in the undissolved state, at least one PA and to release it, in particular in vivo, in a prolonged and / or delayed manner.
• the invention also provides a powdery solid from which the PVs are derived as well as the preparation of this solid and this PV suspension based on polyAANI / polyAANO. These new PVs form spontaneously and without the aid of surfactants or organic solvents, stable aqueous suspensions.
• the invention also relates to PV in dry form, process for their preparation, and pharmaceutical compositions (dry form or suspension) comprising these PVs associated with an active principle.
• the invention relates to known biodegradable polyamino acids that can be converted into nano- or micro-colloidal vector particles capable of reversibly associating with active principles.
• one of the essential objectives of the present invention is to provide novel amphiphilic copolyamino acids, linear or branched and substantially neutral, soluble in a wide pH range
• These polymers represent an improvement over those described in patents or patent applications cited above, in terms of vectorization of an active ingredient such as a therapeutic protein.
• Another essential objective of the present invention is that these polymers are capable of being used for the AP vectorization and make it possible to optimally satisfy all the specifications of the specifications, namely in particular: o capacity:
• the term "multiplicity" means that the copolhydroxyalkylglutamine comprises, on average, at least two pendant GH per molecule. It is possible according to the invention that the copolhydroxyalkylglutamine has, in addition to the pendant GH, GH attached to at least one end of the copolymer chains.
• this copolhydroxyalkylglutamine comprises on average at least 3 hydrophobic groups (GH) per copolymer chain.
• Copolyhydroxyalkylglutamine also carries hydroxyalkylamine groups. These hydroxyalkylamine groups are preferably linked to the copolymer via an amide bond. It is the merit of the applicant to have developed a new family of copolymers based on polyhydroxyalkylglutamines "substantially neutral” and functionalized by a multiplicity of hydrophobic groups and capable of forming stable colloidal systems.
• the ability to modify the number of anionic charges on the surface of a colloid makes it possible to modify, in particular, their interaction with the proteins and / or living cells, thus making it possible to vary their biodisposition (see, for example, the article by Furumoto et al. J. Controlled Release 2004, 97, 133-141).
• association or “associating” used to qualify the relations between one or more active ingredients and copolyhydroxyalkylglutamines, mean in particular that the active ingredient (s) are related to ( x) copolyhydroxyalkylglutamine (s) in particular by a hydrophobic interaction, and / or are encapsulated by the copolyhydroxyalkylglutamine (s).
• hydroxyalkylamine groups that can be used to functionalize the glutamate units of the copolyhydroxyalkylglutamine are identical to or different from each other and are, for example, chosen from the following groups: 2-hydroxyethylamine, 3-hydroxypropylamine, 2,3-dihydroxypropylamine, tris (hydroxymethyl) aminomethane and 6-hydroxyhexylamine.
• At least one of the hydrophobic groups GH is included in a hydrophobic graft comprising at least one spacer (or "spacer") balloon (or pattern) for connecting the hydrophobic group GH to a chain of copolyglutamates (for example a main chain - skeleton-copolyglutamates).
• This patella may comprise, e.g., at least one direct covalent bond and / or at least one amide bond and / or at least one ester bond.
• the patella may be of the type belonging to the group comprising in particular: the "amino acid" units different from the constituent monomeric unit of the copolyglutamates, the aminoalcohol derivatives, the polyamine derivatives (for example the diamines), the derivatives of polyols (for example diols) and derivatives of hydroxy acids.
• the grafting of GH on the chain copolyglutamates or polyalkylglutamine may go through the implementation of GH precursors, able to bind to the chain copolyglutamates or copolyhydroxyalkylglutamines.
• the precursors of GH are, in practice and without being limited to, selected from the group comprising alcohols and amines, these compounds being easily functionalized by those skilled in the art.
• the grafting of GH is explained in more detail below in the description of the process for obtaining modified polyamino acids according to the invention.
• the hydrophobic group GH of the hydrophobic graft comprises from 8 to 30 carbon atoms.
• Linear or branched C8 to C30 alkyls which may optionally comprise at least one unsaturation and / or at least one heteroatom,
• the (poly) cyclic C8 to C30 may optionally comprise at least one unsaturation and / or at least one heteroatom.
• the GH-forming patellae of the hydrophobic grafts may be di-, tri- or tetravalent (or even pentavalent and more).
• the hydrophobic graft comprises a single GH group
• a trivalent patella gives the hydrophobic graft a bifid character, that is to say that the graft has two "legs" GH.
• a trivalent patella mention may be made, inter alia, of "amino acid” units, for example "glutamic acid” or polyol residues, for example glycerol.
• two advantageous but non-limiting examples of hydrophobic grafts comprising bifid GHs are dialkyl glycerol and dialkyl glutamate.
• the hydrophobic groups GH can be, for example, derived from groups selected from the group comprising: octanol, dodecanol, tetradecanol, hexadecanol, octadecanol, oleyl alcohol, tocopherol or cholesterol.
• the backbone of the copolyglutamate according to the present invention comprises alpha-L-glutamate and / or alpha-L-glutamic units.
• copolyhydroxyalkylglutamines according to the invention correspond to one of the following general formulas (I):
• R 2 represents an H, a C 2 to C 10 linear or branched C 3 to C 10 alkyl or a benzyl
• B is a divalent, trivalent or tetravalent linking group, preferably chosen from the following radicals:
• C is a mono, di or trihydroxy (C 1 -C 6) alkyl group, preferably hydroxyethyl, hydroxypropyl or trishydroxymethylmethane
• D is H, a linear acyl group of 2 to 6 carbon atoms, ClO or branched in C3 to
• hydrophobic groups GH each independently represent a radical selected from:
• linear or branched C8 to C30 alkyls which may optionally comprise at least one unsaturation and / or at least one heteroatom (preferably O and / or N and / or S), or
• C 8 -C 30 alkylaryls or arylalkyls which may optionally comprise at least one unsaturation and / or at least one heteroatom (preferably O and / or N and / or S), or C8 to C30 (poly) cyclic compounds possibly comprising at least one unsaturation and / or at least one heteroatom (preferably O and / or N and / or S);
• R represents an H or a cationic entity, preferably selected from the group comprising:
• metal cations advantageously chosen from the subgroup comprising: sodium, potassium, calcium, magnesium;
• cations based on amino acid (s) advantageously chosen from the class comprising cations based on lysine or arginine,
• cationic polyamino acids advantageously chosen from the subgroup comprising polylysine or oligolysine;
• the hydrophobic groups GH are arranged randomly.
• the hydrophobic mole ratio of the copolyhydroxyalkylglutamines according to the invention is between 2 and 100%, and preferably between 5 and 50% provided that each polymer chain has on average at least 3 hydrophobic grafts.
• the (q) / (m + q + n) ratio of the copolyhydroxyalkylglutamines according to the invention means that they may contain from 0 to about 60 mole% of carboxylic or carboxylate functional groups.
• the polymers according to the invention have a molar mass which is between 2,000 and 200,000 g / mol, and preferably between 5,000 and 100,000 g / mol.
• the copolyhydroxyalkylglutamine according to the invention may carry at least one graft of polyalkylene (preferably ethylene) glycol type linked to a glutamate unit.
• copolyhydroxyalkylglutamines of the invention are likely to be used in several ways depending on the nature of the hydrophobic groups and the degree of polymerization of copolyglutamate.
• Methods for shaping a polymer for the encapsulation of an active ingredient in the various forms contemplated by the invention are known to those skilled in the art. For more details, we can refer, for example to these few particularly relevant references:
• Microspheres, Microcapsules and Liposomes, vol 1. Preparations and chemical applications Ed R. Arshady, Citus Books 1999. ISBN: 0-9532187-1-6.
• copolyhydroxyalkylglutamines are also extremely interesting because, depending on the length of the copolymer (degree of polymerization) and the nature of the hydrophobic groups, they are dispersed in water at pH 7.4 (for example with a phosphate buffer) to give colloidal solutions or suspensions or structured or unstructured gels, depending on the concentration of copolymers.
• copolyhydroxyalkylglutamines in the form of particles or not
• the preferred shaping is that described in US-B-6,630,171 of the applicant and which consists in dispersing the copolymer in water and incubating the solution in the presence of an active ingredient (PA).
• PA active ingredient
• the copolymer can then form microparticles capable of associating or encapsulating PAs.
• the shaping of the microparticles can be done by co-solubilizing the PA and the polymer in a suitable organic solvent and then the mixture precipitated in water.
• the particles are then recovered by filtration and can then be used for oral administration (in capsule form, in compacted form and / or coated or even in dispersed form in an oil) or parenterally after redispersion in the water.
• the copolymer may be solubilized in a biocompatible solvent such as N-methylpyrrolidone ethanol or an appropriate oil such as Mygliol® and then injected intramuscularly or subcutaneously or into a tumor.
• a biocompatible solvent such as N-methylpyrrolidone ethanol or an appropriate oil such as Mygliol®
• the diffusion of the solvent or of the oil leads to the precipitation of the copolymer at the injection site and thus forms a deposit.
• These deposits then provide controlled release by diffusion and / or erosion and / or hydrolytic or enzymatic degradation of the copolymer.
• the copolymers of the invention in neutral or ionized form, are more generally usable alone or in a liquid, solid or gel composition and in a medium aqueous or organic.
• the copolymer based on copolyglutamines containing carboxylic residual functions are either neutral (COOH form) or ionized (COO anion "), depending on pH and composition.
• the counter cation may be a metal cation such as sodium, calcium or magnesium, or an organic cation such as triethanolamine, tris (hydroxymethyl) aminomethane or a polyamine such as polyethyleneimine.
• the copolymers of the invention are for example obtained by methods known to those skilled in the art.
• N-carboxy-amino acid anhydrides NCA
• polymers that can be used according to the invention, for example of the poly (alpha-L-glutamic), poly (alpha-D-glutamic), poly (alpha-D, L-glutamate) and poly (gamma-L) type can be used.
• -glutamic) of variable masses are commercially available.
• the copolymers of the invention are synthesized according to 2 routes.
• the hydroxyalkylamine (e.g. ethanolamine) and B-GH (e.g., dodecylamine) groups are first grafted simultaneously or sequentially onto a poly (L-glutamic acid).
• This reaction can be carried out in a solvent such as DMF, DMSO or NMP according to the following scheme.
• the poly (L-glutamic acid) can be synthesized according to the route described in the patent application FR-A-2 801 226.
• the HB-GH group is linked via an ester function, it is easier to first grafting the B-GH group by a conventional coupling reaction using a carbodiimide before grafting the alkylamine.
• a poly (alkyl-L-glutamine) is first produced according to a route described in the literature (see, for example, WO-A-02/098951) and the hydrophobic group GH is grafted onto the OH groups of the alkylamide of the polymer.
• Polymerization chemistry and coupling reactions of conventional groups are well known to those skilled in the art (see for example the patents or patent applications of the applicant mentioned above). These methods will be better understood through the description of the examples.
• the degree of polymerization is defined by the molar ratio of the initiator to that of the monomer.
• the coupling of the hydrophobic graft to GH with an acidic function of the polymer is easily achieved by reacting the polyamino acid in the presence of a carbodiimide as a coupling agent and optionally a catalyst such as 4-dimethylaminopyridine and in a suitable solvent such as dimethylformamide. (DMF), N-methyl pyrrolidone (NMP) or dimethylsulfoxide (DMSO).
• a carbodiimide is, for example, dicyclohexylcarbodiimide or diisopropylcarbodiimide.
• Coupling reagents such as chloroformates can also be used for the formation of amide bonds (see, for example, Bodanszky's “Principles of Peptide Synthesis” Springer Verlag 1984 for examples of coupling agents).
• the degree of grafting is chemically controlled by the stoichiometry of the constituents and reactants or the reaction time.
• Hydrophobic grafts functionalized with an amino acid other than that of the polymer are obtained by conventional peptide coupling or by direct condensation by acid catalysis. These techniques are well known to those skilled in the art.
• the invention relates to a pharmaceutical, cosmetic, dietetic or phytosanitary composition
• a pharmaceutical, cosmetic, dietetic or phytosanitary composition comprising at least one copolyhydroxyalkylglutamine as defined above and optionally at least one active ingredient, which may be therapeutic, cosmetic, dietetic or phytosanitary.
• the active principle is associated with (x) polyamino acid (s) modified by one or more bonds other than (or that) chemical bond (s) covalent (s) ( s).
• a colloidal suspension of PV particles optionally prepared extemporaneously by the dispersion of dry PV in a suitable solvent, such as water.
• the active ingredient is a protein, a glycoprotein, a protein linked to one or more polyalkylene glycol chains (preferably polyethylene glycol (PEG): "protein-PEGylated”), a polysaccharide, a liposaccharide, an oligonucleotide, a polynucleotide or a peptide.
• PEG polyethylene glycol
• the active principle is a "small" hydrophobic, hydrophilic or amphiphilic organic molecule.
• a "small" molecule is especially a small nonprotein molecule.
• PA that may be associated with the polyamino acids according to the invention, whether or not in the form of (nano or micro) particles, mention may be made of: o proteins such as insulin, interferons, hormones growth, interleukins, erythropoietin or cytokines; peptides such as leuprolide or cyclosporine; o small molecules such as those belonging to the family of anthracyclines, taxoids or camptothecins; o and their mixtures.
• proteins such as insulin, interferons, hormones growth, interleukins, erythropoietin or cytokines
• peptides such as leuprolide or cyclosporine
• small molecules such as those belonging to the family of anthracyclines, taxoids or camptothecins
• o and their mixtures o proteins such as insulin, interferons, hormones growth, interleukins, erythropoietin or cytokines
• the composition of the invention is in the form of a gel, a solution, a suspension, an emulsion, micelles, nanoparticles, microparticles, an implant, a d a powder or a film.
• the composition whether loaded or not with active ingredient (s), is a stable colloidal suspension of nanoparticles and / or microparticles and / or polyamino acid micelles, in an aqueous phase.
• the composition of the invention is in the form of a solution in a biocompatible solvent and can be injected subcutaneously, intramuscularly or into a tumor.
• the composition according to the invention since it is pharmaceutical, can be administered orally, parenterally, nasally, vaginally, ocularly, subcutaneously, intravenously, intramuscularly, intradermally, intraperitoneally, intracerebrally or buccally.
• composition is in the form of a solution in a solvent or a mixture of biocompatible solvents that can be injected subcutaneously, intramuscularly or into a tumor.
• the composition may optionally contain an excipient for adjusting the pH and / or the osmolarity and / or to improve the stability (antioxidants) and / or as anti-microbial agent.
• excipients are well known to those skilled in the art (see Injectable Drug Development, P.K. Gupta et al., Interpharm Press, Denver, Colorado 1999).
• the composition according to the invention is formulated so that it is capable of forming a deposit on the injection site.
• the deposition may, for example, be at least partly caused by a physiological protein present in vivo.
• compositions which comprise polyamino acids according to the invention and active principles and which may be used for the preparation:
• Medicaments in particular for oral, nasal, vaginal, ocular, subcutaneous, intravenous, intramuscular, intradermal, intraperitoneal or intracerebral administration, the active principles of these medicinal products being, in particular, proteins, glycoproteins, proteins bound to one or more polyalkylene glycol chains (for example PolyEthyleneGlycol (PEG), referred to as "PEGylated” proteins ⁇ , peptides, polysaccharides, liposaccharides, oligonucleotides, polynucleotides and hydrophobic, hydrophilic or amphiphilic organic small molecules;
• PEG PolyEthyleneGlycol
• the invention aims at a method of preparation:
• Medicaments in particular for oral, nasal, vaginal, ocular, subcutaneous, intravenous, intramuscular, intradermal, intraperitoneal or intracerebral administration, the active principles of these medicinal products being, in particular, proteins, glycoproteins, protein linked to one or more polyalkylene glycol chains (eg PolyEthyleneGlycol (PEG), so-called "PEGylated” proteins ⁇ , peptides, polysaccharides, liposaccharides, oligonucleotides, polynucleotides and hydrophobic, hydrophilic or amphiphilic organic small molecules;
• PEG PolyEthyleneGlycol
• the invention also relates to a method of therapeutic treatment consisting essentially of administering the composition as described herein, orally, parenterally, nasally, vaginally, ocularly, subcutaneously, intravenously, intramuscularly, intradermally, intraperitoneally, intracerebrally or oral.
• this method of therapeutic treatment essentially consists of putting the composition as described above in the form of a solution in a biocompatible solvent and then injecting it subcutaneously, intramuscularly or into a tumor, preferably so that it forms a deposit on the injection site.
• the reaction medium is stirred for 30 minutes allowing to rise to 0 ° C.
• the reaction medium is again cooled to -15 ° C. before adding the 9.5 g of ethanolamine.
• the temperature rises to ambient in 1.5 hours.
• the reaction medium is diluted in 920 ml of water before proceeding with diafiltration against 5 volumes of salt water (0.9% NaCl) and 8 volumes of water.
• the polymer solution is then frozen and lyophilized. 5.2 g of the polymer (2) are obtained, ie 68% yield.
• the percentage of Cl 2 graft determined by 1 H NMR in TFA-d is 14.4%.
• the percentage of hydroxyethylglutamine determined by 1 H NMR in TFA-d is 86.0%.
• the Mn (determined by GPC NMP) is 22.7 kg / mol in PMMA equivalents.
• Comparative polymer C1 was synthesized according to Example 4 of patent application WO-A-02/098952.
• the polymer contains an end-of-the-chain distearylamine group consisting of 40 units of polyhydroxyethylglutamine.
• aqueous solution containing 10 mg of polymer per milliliter at pH 7.4 and 200 IU insulin (7.4 mg) is prepared.
• the solutions are incubated for two hours at room temperature and the free insulin is separated from the associated insulin by ultrafiltration. (threshold at 100 KDa, 15 minutes under 10000G at 18 ° C).
• the free insulin recovered in the filtrate is then assayed by HPLC (High Performance Liquid Chromatography) and the amount of insulin associated is deduced.
• HPLC High Performance Liquid Chromatography
• the polymer C1 having a distearyl hydrophobe at the end of the chain is less effective.
• the combination capacity of these polymers makes them suitable for use as targeting agents.

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