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  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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  • C08G18/08—Processes
  • C08G18/0804—Manufacture of polymers containing ionic or ionogenic groups
  • C08G18/0819—Manufacture of polymers containing ionic or ionogenic groups containing anionic or anionogenic groups
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  • C08G18/30—Low-molecular-weight compounds
  • C08G18/32—Polyhydroxy compounds; Polyamines; Hydroxyamines
  • C08G18/3271—Hydroxyamines
  • C08G18/3275—Hydroxyamines containing two hydroxy groups
• • C—CHEMISTRY; METALLURGY
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  • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
  • C08G18/00—Polymeric products of isocyanates or isothiocyanates
  • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
  • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
  • C08G18/30—Low-molecular-weight compounds
  • C08G18/34—Carboxylic acids; Esters thereof with monohydroxyl compounds
  • C08G18/348—Hydroxycarboxylic acids
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  • C08G18/00—Polymeric products of isocyanates or isothiocyanates
  • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
  • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
  • C08G18/40—High-molecular-weight compounds
  • C08G18/48—Polyethers
  • C08G18/4833—Polyethers containing oxyethylene units
  • C08G18/4837—Polyethers containing oxyethylene units and other oxyalkylene units
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  • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
  • C08G18/40—High-molecular-weight compounds
  • C08G18/48—Polyethers
  • C08G18/4833—Polyethers containing oxyethylene units
  • C08G18/4837—Polyethers containing oxyethylene units and other oxyalkylene units
  • C08G18/4841—Polyethers containing oxyethylene units and other oxyalkylene units containing oxyethylene end groups
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  • C08G18/65—Low-molecular-weight compounds having active hydrogen with high-molecular-weight compounds having active hydrogen
  • C08G18/66—Compounds of groups C08G18/42, C08G18/48, or C08G18/52
  • C08G18/6666—Compounds of group C08G18/48 or C08G18/52
  • C08G18/667—Compounds of group C08G18/48 or C08G18/52 with compounds of group C08G18/32 or polyamines of C08G18/38
  • C08G18/6681—Compounds of group C08G18/48 or C08G18/52 with compounds of group C08G18/32 or polyamines of C08G18/38 with compounds of group C08G18/32 or C08G18/3271 and/or polyamines of C08G18/38
  • C08G18/6688—Compounds of group C08G18/48 or C08G18/52 with compounds of group C08G18/32 or polyamines of C08G18/38 with compounds of group C08G18/32 or C08G18/3271 and/or polyamines of C08G18/38 with compounds of group C08G18/3271
• • C—CHEMISTRY; METALLURGY
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  • C08G18/00—Polymeric products of isocyanates or isothiocyanates
  • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
  • C08G18/70—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the isocyanates or isothiocyanates used
  • C08G18/72—Polyisocyanates or polyisothiocyanates
  • C08G18/74—Polyisocyanates or polyisothiocyanates cyclic
  • C08G18/75—Polyisocyanates or polyisothiocyanates cyclic cycloaliphatic
  • C08G18/758—Polyisocyanates or polyisothiocyanates cyclic cycloaliphatic containing two or more cycloaliphatic rings
• • C—CHEMISTRY; METALLURGY
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  • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
  • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
  • C08G65/32—Polymers modified by chemical after-treatment
  • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
  • C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
  • C08G65/33344—Polymers modified by chemical after-treatment with organic compounds containing nitrogen containing carbamate group
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  • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
  • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
  • C08G65/32—Polymers modified by chemical after-treatment
  • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
  • C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
  • C08G65/33348—Polymers modified by chemical after-treatment with organic compounds containing nitrogen containing isocyanate group
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  • C08G2210/00—Compositions for preparing hydrogels
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  • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
  • C08G2650/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
  • C08G2650/28—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule characterised by the polymer type
  • C08G2650/58—Ethylene oxide or propylene oxide copolymers, e.g. pluronics

Definitions

• thermosensitive polymers and thermoreversible gels obtained from these polymers.
• the present invention relates to a thermosensitive polymer capable of forming thermoreversible gels with a high viscosity index as well as their preparation. It also relates to applications of these gels.
• thermoreversible gels are in particular, but not exclusively, therapeutic or non-therapeutic compositions, in particular cosmetic, for the treatment of the human or animal body.
• Reversible gelation compositions are defined as solutions whose variation in viscosity is linked to a change in environmental conditions.
• thermoreversible gels and the constituent polymers of the formulation are identified as “thermo-gelling polymers” or even “thermosensitive polymers”.
• thermosensitive polymers These polymers are formed of hydrophobic, thermosensitive parts, and hydrophilic parts. Gel formation is explained by the self-association of the heat-sensitive portions into hydrophobic micro-domains; all of the polymer being kept in solution by the hydrophilic segments.
• the viscosity and gel properties are then controlled by the respective length of the different segments and by the hydrophobic / hydrophilic ratio (L.E. Bromberg, Adv. Dmg Delivery Reviews 31 (1998) 197-221).
• thermosensitive polymers which are intended to form thermoreversible gels in aqueous solution, the viscosity of said gels changing reversibly as a function of their temperature.
• thermosensitive polymers have hydrophobic portions capable of aggregating together to form micelles when the temperature of the medium is high to reach that of their critical solution temperature; the hydrophilic portions interconnecting said said micelles. In this way, an increase in the temperature of the aqueous medium in which these heat-sensitive polymers are dissolved is capable of transforming it from a liquid state to a viscous state forming a gel.
• Such polymers are well known under the generic name of poloxamer.
• thermosensitive polymers capable of being synthesized in particular according to the methods described in patents US 4,188,373 and US 4,478,822.
• the heat-sensitive polymers thus obtained allow formulating aqueous compositions have critical solution temperatures of between 24 and 40 ° C.
• such formulations necessarily contain from 15 to 50% of thermosensitive polymers in order to obtain a significant variation in viscosity so that they are initially extremely viscous.
• these formulations only exhibit variations in viscosity of less than a decade at their critical solution temperature.
• thermo-gelling polymer polymer
• Carbopol polycarboxylic acids
• polyacrylic acid segments have been chemically associated with poloxamer segments. Besides the character biadhesive and "sensitive pH", the polyacid acrylic part gives the material greater solubility in water. The presence of the hydrophilic segment promotes the solubilization of the copolymer and thus limits the phase separation. It appears that the alternating copolymers of thermo- and pH-sensitive monomers rapidly lose their thermo-gelling property when the level of pH-sensitive monomer increases; block copolymers are preferred.
• thermosensitive component of the material is provided by Pluronics® polymers or poly (isopropylacrylamide) (NIPAm).
• Pluronics® polymers or poly (isopropylacrylamide) (NIPAm) poly (isopropylacrylamide)
• the copolymerization is carried out either by condensation reaction of the acid functions of the PAA with the modified reactive end of the Pluronic (monoamination of the hydroxy- ends) - the Pluronic-g-poly (acrylic acid) copolymer has heat-sensitive grafts -, or by condensation reaction between the polyacrylic acid and the poly (isopropylacrylamide), both modified at one end by inter-condensable functions (amine and acid) - the Pluronic-b-poly copolymer (NlPAm) is formed by two chemically linked blocks.
• thermoreversible gelation of Hoffman's copolymers (WO95 / 24430) is obtained with compositions of lower polymer concentrations: the formulations containing from 1 to 3% by mass of copolymer have a range of well defined critical gelation temperature, between 20 ° C and 40 ° C, for a pH range from 4 to 8.
• critical gelation temperature between 20 ° C and 40 ° C
• pH range from 4 to 8.
• the variation in viscosity for these compositions does not reach a decade and a phase separation in micro- domains is observed at the critical gelation temperature, which results in a clouding of the medium.
• the syntheses are carried out in several stages: controlled modification of the terminal functions of the polymers employed, condensation or chain copolymerization and finally separation / purification of the desired products.
• Bromberg et al. have described comb copolymers of polyacrylic acid and poloxamer and their new route of production (WO 9700275).
• a first step radicals are created on the poloxamer chain by pulling hydrogen from the poly (propylene oxide) segment.
• the radical chain polymerization of acrylic acid is then initiated from the poloxamer macroradicals.
• Smart Hydrogel TM presents perfect clarity before and at the point of gelation; the sol-gel transition of aqueous solutions with low concentration of copolymers (1 to 5% by mass) occurs in a narrow temperature range (10 ° C), between 25 and 40 ° C and results in an increase in viscosity of approximately at least 30 times the initial viscosity.
• the gel thus formed behaves like a viscoelastic solid and retains its viscosity regardless of the shear rate applied.
• Two drawbacks concerning this system have been noted by the inventors of the present invention: the bioadhesiveness of the hydrogel is
• Bromberg et al. have developed new linear block copolymers keeping the poloxamer and poly (acrylic acid), respectively as thermosensitive and hydrophilic compounds.
• the originality of these copolymers is that they are composed of a central block of poloxamer modified at its two ends by polyacid blocks. To obtain them, the two ends of the poloxamer are functionalized beforehand by acrylic or thiol groups allowing the initiation of the radical polymerization of the acid. acrylic.
• thermosensitive polymers which make it possible not only to obtain thermoreversible physical gels with a low polymer concentration, but also thermoreversible physical gels with a high viscosity index, the viscosity of which increases sharply at their critical solution temperature.
• an object of the present invention is also to provide thermosensitive polymers making it possible to obtain thermoreversible gels at temperatures substantially equal to body temperatures for formulating effective cosmetic and pharmaceutical compositions.
• the invention relates to polymers comprising polymer chains of terpolymer type consisting of polyethylene oxide (POE) and propylene polyoxide (PPO) of the form POE- PPO-POE modified at their ends by groups which may be essentially other POE-PPO-POE chains, acid segments, amino groups or POEs, these chains being linked to the terpolymer chains by chemical bridges which are consisting of urethane bridges, urea bridges, allophanate bridges and biuret bridges. All these bridges can be present either in the same chain of polymers, or in different chains and, as appears from the description which follows, the proportion of these different bonds essentially depends on the operating conditions.
• POE polyethylene oxide
• PPO propylene polyoxide
• the present invention provides a water-soluble thermosensitive polymer capable of forming thermoreversible physical gels with a high viscosity index, characterized in that it comprises both sequences comprising at least one linear chain of polyoxyalkylene type thermosensitive triblocks constituted of polyethylene oxide (POE) blocks and of propylene polyoxide (PPO) blocks, said chain being of the POE-PPO-POE form and being elongated at at least one of its ends by an organic group via a carbamate bond and sequences comprising at least one linear chain of polyoxyalkylene type POE-PPO-POE triblock elongated at at least one of its ends by an organic grouping via a urea bond.
• POE polyethylene oxide
• PPO propylene polyoxide
• thermosensitive polymer according to the invention lies in the elongation of the linear chain of thermosensitive polyoxyalkylenes and in the introduction of urea groups into the polymer chain, so as to give them a higher molecular weight and to provide new functions capable of inducing additional interactions of the hydrogen bond type.
• the extension is then carried out by connecting the organic groups to the linear chains by carbamate and urea bonds.
• thermosensitive polymers of higher molecular weight, containing urea bridges the viscosity of the gels which they make it possible to formulate, at their critical solution temperature, is increased.
• thermosensitive polymer comprises at least one linear chain of thermosensitive polyoxyalkylene type consisting of three blocks (polyethylene oxide-propylene polyoxide-polyethylene oxide) elongated at each of its two ends by an organic group via a bond. carbamate or urea.
• thermosensitive polyoxyalkylene type consisting of three blocks (polyethylene oxide-propylene polyoxide-polyethylene oxide) elongated at each of its two ends by an organic group via a bond. carbamate or urea.
• said linear chains of heat-sensitive triblock polyoxyalkylene type correspond to the formula:
• the polyoxyalkylene chain has a linear propylene oxide block each end of which is connected to a block of ethylene oxide.
• the polyoxyalkylene linear chain is symmetrical, m being equal to 1 and x being substantially equal to z. These are the ends of the chain which are linked to the organic group by carbamate and / or urea bonds.
• said organic groups contain radicals capable of being linked to the polyoxyalkylene chains by a carbamate or urea bond and are chosen from:
• the organic groups contain at least one of said radicals, in particular at one of its ends.
• the radical is linked, on the one hand to the polyoxyalkylene chain by a carbamate or urea bond, and on the other hand to another molecule, also by a carbamate or urea group.
• the organic groups contain at least one of said radicals and acid units linked together by carbamate or urea bonds.
• the acid unit is spaced from the polyoxyalkylene chain by one of said radicals, which is linked to the polyoxyalkylene chain and to the acid unit by two separate carbamate or urea bonds.
• the organic group is capable of being constituted alternately by said radicals and by the acid units and that it is capable of extending to each of the ends of said polyoxyalkylene chain or that it is capable of gathering between they two of the so-called poloxyalkylene chains.
• thermosensitive polymer which is the subject of the invention is capable of seeing its rheological properties, not only varied depending on the temperature but also depending on the pH of the environment in which it is found.
• the presence of an acid group gives the thermosensitive polymer the property of bioadhesiveness.
• said organic group contains said radicals and tertiary amine units linked together by carbamate or urea bonds.
• the amine functions which are capable of capturing a proton, make it possible to vary the properties of the polymer as a function of the acidity of the medium.
• the organic group alternately contains at least one sequence: radical, amine motif, radical and acid motif, the elements of this sequence being linked in pairs by a carbamate or urea bond.
• said organic group contains a chain of the polyethylene oxide type.
• This polyethylene oxide chain can be spaced from the thermosensitive polyoxyalkylene chain by one of said radicals and connected to the latter by a carbamate or urea bond.
• the polyethylene oxide chain which advantageously has a molecular weight of less than 1000 may be associated with acid or amine units in the organic group.
• said organic group has ramifications constituted by allophanate or biuret bonds.
• bonds formed, as will be explained in more detail in the description of the synthesis process, by the reaction of an isocyanate function on a carbamate or urea bond, generate ramifications thanks to the tri-substituted nitrogen of the bond carbamate or urea.
• the radicals are capable of being linked to one another thanks to the allophanate or biuret bonds.
• the improved thermosensitive polymer comprises a plurality of linear chains of the thermosensitive polyoxyalkylene triblock type linked together by one or more organic groups via carbamate or urea bonds, either linearly, polyoxyalkylene linear chains being spaced from each other by organic groups, either in a branched manner thanks to the allophanate or biuret bonds.
• organic groups can contain acid, amine or polyoxyethylene chains.
• the present invention provides a process for the synthesis of an improved thermosensitive polymer capable of forming thermoreversible physical gels with a high viscosity index and, very particularly of the polymers defined above, which process comprises the reaction of at least one linear polymer P of polyoxyalkylene type thermosensitive triblocks having at least one terminal hydroxy function with at least one organic molecule carrying at least one isocyanate function so as to link them together by carbamate or urea bonds.
• This synthesis is carried out in a particularly simple manner in a solvent medium in a single step and without intermediate purification of the polymers P which generally contain at least traces of water, the presence of which makes it possible to introduce, during the reaction, urea-type bonds. in the chains formed.
• a characteristic of the invention is to lengthen a polymer
• Linear P of thermo-sensitive polyoxyalkylene triblock type having at least one terminal hydroxy function by reacting isocyanate functions on the hydroxy functions of the polymer P in the presence of water.
• said polymer P has at least two terminal hydroxy functions so that it can be extended at each of its ends.
• said polymer P has the generic formula:
• m is equal to 1 and x equals z.
• the organic molecule comprises two isocyanate functions, so that a single organic molecule can link together two molecules comprising hydroxy groups via two carbamate or urea bonds obtained by condensation reaction of the isocyanate functions and of the hydroxy functions, in presence of water.
• the organic molecule is chosen from:
• said reaction is carried out in the presence of at least one other organic molecule carrying at least one hydroxy function, advantageously two, in the presence of water.
• said other molecule organic is capable of being linked to the organic molecule by a carbamate or urea bond, which itself is linked to said chain of said linear polymer P of thermosensitive polyoxyalkylene type.
• said other molecule has two hydroxy functions, it is understood that one can extend said heat-sensitive polymer at each of its ends, alternately, by an organic molecule having two isocyanate functions and another molecule, the organic molecules being linked to other organic molecules by carbamate or urea bonds.
• said other organic molecule further comprises at least one carboxylic acid function, advantageously two.
• said other organic molecule further comprises at least one carboxylic acid function, advantageously two.
• said other molecule has the formula:
• said other organic molecule advantageously comprises at least one tertiary amine function which also provides the gels formulated with the improved thermosensitive polymer with sensitivity to variations in pH.
• said other molecule has the formula:
• said other molecule is a monohydroxylated polyethylene oxide capable of increasing the stability and the viscosification properties of the gel containing said improved thermosensitive polymer.
• the present invention provides an improved thermosensitive polymer having a solution in low viscosity at room temperature and capable of forming thermoreversible physical gels with high viscosity index for temperatures above 25 ° C. Its structure comprises at least one linear chain of thermosensitive polyoxyalkylene triblock type elongated at one of its ends at least by an organic group via a carbamate or urea bond.
• thermosensitive polyoxyalkylene triblock type having at least one terminal hydroxy function
• organic molecule carrying at least one isocyanate function in the presence of water, so as to connect them together by said carbamate or urea bond.
• the present invention provides a thermoreversible gel, comprising at least one thermosensitive polymer in accordance with the first object or at least one thermosensitive polymer obtained according to a synthesis process in accordance with the second object.
• the gel formed is a physical gel.
• the thermoreversible gel of the invention contains from 1 to 10% by weight of said improved thermosensitive polymer and more advantageously from 1 to 5% of said improved thermosensitive polymer obtained in the presence of water and thus containing urea groups.
• the present invention provides a pharmaceutical or non-pharmaceutical composition, in particular a cosmetic composition, intended for the treatment or care of the human body comprising a product in solution of low viscosity at temperature and capable of forming a thermoreversible physical gel of high viscosity at temperatures above 25 ° C according to said fourth object.
• the invention relates to a prosthetic element capable of being inserted into an organ of the human body, characterized in that it comprises a thermoreversible gel according to said fourth object.
• FIG. 1 illustrates the viscosity curve of a gel obtained according to Example 1.
• FIG. 3 shows the viscosity curve of a gel obtained according to example 4.
• FIG. 4 shows the viscosity curve of a gel obtained according to Example 5.
• the invention relates to improved water-soluble thermosensitive copolymers, linear or branched which have a low viscosity solution at room temperature and which are capable of forming thermoreversible gels with high viscosity index at temperatures above 26 ° C and a process for the synthesis of such polymers.
• it also relates to the application of such a thermoreversible gel.
• thermosensitive polymers are synthesized, making it possible to obtain thermoreversible gels whose viscosity increases by at least a factor of 1000 when the temperature exceeds 25 ° C. for concentrations of thermosensitive polymers in water below 10%.
• the synthesis of improved heat-sensitive polymers is carried out from well-known heat-sensitive copolymers: polyoxyalkylenes or poloxamers, with hydroxy functions, terminal.
• the copolymers chosen are triblocks and have the generic formula: in which, 20 ⁇ x ⁇ 120 and 20 ⁇ y ⁇ 120.
• heat-sensitive polymers marketed for example under the name of Pluronics, contain 25% by mole of propylene oxide motif and allow an increase in viscosity of only a factor of 10 when the temperature goes from 20 ° C to 30 ° C for concentrations higher than 15% in water.
• the inventive concept of the invention lies in particular in the coupling of well-known heat-sensitive polymers with organic groups whose size is smaller than that of said polymers. These couplings are capable of being obtained by reaction of organic compounds of the di-isocyanate type with the hydroxy functions of the heat-sensitive polymer in the presence of water to form urethane and / or urea bonds as well as allophanate and / or biuret groups.
• the POE-PPO-POE triblock polymer is dissolved in a solvent, preferably in butanone at a temperature of around 70 ° C.
• a solvent preferably in butanone
• the di-isocyanate is introduced dropwise.
• the catalyst is added. The reaction continues at 70 ° C with stirring until complete disappearance of the isocyanates.
• the advantage of the synthesis is that it is carried out, in a single step, in a single reactor.
• the second advantage of this synthesis is that it is produced from commercial constituents, without any additional purification treatment.
• the POE-PPO-POE triblock copolymer is used without being dried. It then generally contains 0.3% +/- 0.05% by mass of water and this water leads during synthesis to the formation of urea bridges.
• the thermogelling polymers obtained are the most effective because there are, in addition to the urethane and allophanate bridges, urea and biuret bridges which can give rise to interactions of the hydrogen bond type which add up to the interactions. hydrophobic PPOs.
• the amount of water acceptable for forming thermogelling polymers is advantageously from 0.1 to 0.6% by mass relative to the terpolymer. At 0.6% water, the viscosity of our polymer solution is slightly higher than that of other improved polymer solutions, but the viscosity of the corresponding gel is also higher than that of other gels. There is therefore a beneficial effect of water (and thereby urea groups) on the ability of polymers to gel aqueous solutions at temperatures above 25 ° C.
• the most effective polymers are those obtained with 0.3 to 0.6% of water, introduced at the start of the synthesis into the reaction medium via the constituents and / or by adding water.
• polymers can then be used alone, preferably at a rate of 3.5 to 5% by mass in aqueous solutions.
• the improved polymer can be used at less than 3% and preferably between 1% and 2.5%. This synergistic effect is obtained with 0.05% to 1% of crosslinked polyacid.
• the quantity of polymer to be used would be at least 10% by mass to achieve the same gain in viscosity.
• the viscosity increasing properties with temperature can be adjusted as a function of the water concentration in the reaction medium and therefore as a function of the proportion of urea, biuret, allophanate and urethane groups.
• di-isocyanates which can be used for the synthesis of improved heat-sensitive polymers are in particular the following compounds:
• one of the important advantages of di-isocyanates is to be able to introduce branches into the organic groups linking the heat-sensitive polymers and also urea groups capable of forming additional interactions by hydrogen bonding. between chains of heat-sensitive polymers.
• the polymers of the invention are either linear or branched.
• a first type of improved heat-sensitive polymer has the general formula:
• H the form: H H-, H, if it is at the end of the chain or of the form:
• the group L and the heat-sensitive polymers P are linked together by carbamate functions, and more particularly urethane,
• thermosensitive polymer synthesis corresponding to the first type of polymer described above is given in Example 1.
• the proportions of the various constituents and the implementation conditions are given for laboratory syntheses, but they are likely to be adapted to industrial conditions by increasing the proportions and by adapting the implementation. This will be the case for all the synthesis examples described below.
• Example 2 A second example of synthesis of an improved heat-sensitive polymer corresponding to this first type of polymer is described in Example 2.
• a second type of improved thermosensitive polymer has the general formula: (AL) r ⁇ - (PL) m , - (AL) r2, or, (AL) r1 - [(PL) m , - ( AL) r2 ] n - (PL) m , - (AL), in which m ', r1, r2> 1.
• P and L correspond to the structures previously described.
• r1 and r2 are independently of one another between 1 and 1000.
• the symbol A corresponds either to acid blocks or to tertiary amine blocks or alternatively to polyethylene oxide.
• This second type of polymer can also contain two or all three of these different blocks.
• the organic group connecting the heat-sensitive polymers is capable of being constituted by a chain of molecules of type L and A linked to each other by carbamate functions.
• An advantage of these organic groups is that they are ionizable and that the viscosity of the gel formulated with this second type of polymer varies with the pH of the medium. Examples 3 and 4 below correspond to examples of synthesis of improved heat-sensitive polymers corresponding to this second type of polymer.
• thermosensitive polymer having ramifications is obtainable according to the invention. These branches are formed by the reaction of isocyanate functions with carbamate and / or urea functions to form allophanate bonds having the following structure: HN ⁇ O
• M is likely to correspond to the first or to the second type of improved heat-sensitive polymers as described in the examples corresponding to the two preceding types of polymers.
• R corresponds to the radical of the di-isocyates previously described and Y can correspond to an ethyl or methyl terminal function, to an amino group or even to another improved heat-sensitive polymer. It is thus understood that not only are these polymers capable of being branched by virtue of the allophanate or biuret bonds, but also that they can comprise a plurality of polyoxyalkylene linked together by organic groups capable of comprising di-isocyanates alone or of di-isocyanate coupled with acid, basic or other blocks.
• the improved heat-sensitive polymers which are the subject of the present invention have the double advantage of forming thermoreversible gels having a large increase in their viscosity for relatively low concentrations, advantageously of the order of 5%.
• the temperature ranges in which the viscosity increases are can be adjusted and they can be adjusted depending on the pH.
• the gels are obtained from a solution containing from 1 to 10% of the polymer according to the invention, preferably from 1 to 5%, preferably from 3.5 to 5%.
• the aqueous solution of the polymer can be obtained in two ways: from the precipitated polymer or by means of a solvent exchange at the end of synthesis of said polymer.
• the precipitated and dried polymer is added in water at a pH preferably of the order of 7 and the dissolution is carried out at temperature close to ambient (15-23 ° C) for 12 to 24 hours.
• Antifoaming agents can be added to limit foaming and thus accelerate dissolution.
• Aqueous solutions of improved thermogelling polymers so prepared are liquid at room temperature • (dynamic viscosity between 35 and 100CP) and gel when their temperature is between 25 ° C and 40 ° C.
• the gelling of the solution results in an increase in viscosity of at least 3 decades (measurement carried out under a shear of 0.3 s "1 ) and the formation of a mass which can no longer flow.
• the gel formed can be rapidly destructured if it is subjected to significant shearing: it is shear thinning. This property is an advantage in particular for cosmetic applications in which the aqueous thermogelling solution is diffused in the form of spray. operation, the polymer solution thermosensitive improved is strongly sheared and therefore very liquid, then in contact with the skin the solution gels.
• the various active principles and specific agents can be formulated with 3.5 to 5% of the heat-sensitive polymer, in aqueous solution, at room temperature. Liquid formulations below 25 ° C can then be applied as a spray on the skin, on the vaginal or nasal mucosa; the formulations will gel on contact. The creamy formulations can be spread over the skin and will thicken when the friction stops. In these two examples, the gelation of the formulation will allow a controlled and progressive release of the active ingredients.
• the increase in viscosity can also be used to stabilize the viscosity of sunscreens or paints.
• the presence of the thermosensitive polymer of the invention in the products makes it possible to compensate for the reduction in viscosity by its gelling (or here its viscosification).
• These polymers are formulated in aqueous solution to form pharmaceutical or non-pharmaceutical, in particular cosmetic, compositions which are capable, in particular, of being applied at low viscosity to the body and then of gelling thanks to the increase in temperature.
• a first example of application relates to pharmaceutical preparations comprising an improved thermosensitive polymer according to the invention in solution in water and an active principle.
• This type of preparation is applied in a substantially liquid form to the body and it then gels so that the active principle is distributed over the entire application surface and is maintained there by the gel.
• Eye drops for example, may be formulated as such.
• these preparations, containing an active principle are capable of being applied to the mucous membranes, in particular to the vaginal, nasal, those of the stomach or of the esophagus.
• a second example relates to the preparations intended to be applied subcutaneously to release an active principle slowly or to fill spaces or cavities, for example wrinkles.
• Breast prostheses are also capable of being constituted by a gel formulated with a heat-sensitive polymer in accordance with the invention. Thus, the prosthesis can be introduced in a liquid form which reduces the width of the necessary incision.
• Another application example concerns meatic plugs, intended to block the lacrimal duct.
• the stopper is produced by introducing into the bottom of the cavity a solution containing a polymer according to the invention in liquid form at ambient temperature in the region of 20 ° C and allowing it to warm up to body temperature in the region of 37 ° C so that it forms a plug in the bottom of the cavity.
• Yet another example of application relates to a garment or an undergarment comprising at least one part containing a thermoreversible gel obtained from an aqueous solution comprising an improved thermosensitive polymer according to the invention.
• isocyanate corresponding to the general formula: are added dropwise to the mixture over 10 minutes under a continuous flow of nitrogen.
• a tin-based catalyst is introduced (at a rate of 500 ppm) in the mixture which is maintained at reflux of the solvent for approximately 20 hours.
• FIG. 1 illustrates the viscosity curve of the thermoreversible gel obtained according to this first example, as a function of the temperature under a shear rate of 0.4 / s.
• an advantage of this first example of implementation of the invention lies in the increase in the viscosity of the gel by a value greater than 10 Pa.s in a temperature range between 29 and 34 ° C with a maximum viscosity value for about 32 ° C.
• thermosensitive polymer synthesis corresponding to the first type of polymer described above.
• the improved thermosensitive polymer includes polyacid blocks and amino tertiary blocks.
• the synthesis is carried out in two stages.
• a first step 3.8 ⁇ 10 ⁇ 3 moles of non-dried F127 Pluronic polymer containing 0.3% by mass of water are dissolved with 7.7 ⁇ 10 ⁇ 3 moles of N-methyl diethanolamine in 150 ml of 2-butanone.
• 2.3.10 "2 mole of 4.4 ' ⁇ methylene biscyclohexyl di-isocyanate are added dropwise for 10 minutes under a continuous flow of nitrogen.
• 1.2.10 " 2 mole of tartaric acid in solution in the 2-Butanone are added after six hours of reaction at 70 ° C.
• the polycondensation continues for 2 hours until the isocyanate functions have completely disappeared.
• the polymer is collected either directly in the aqueous phase, or after transfer of solvent or else by precipitation in ether or hexane.
• Figure 2 illustrates the variations in viscosity of the gel obtained with
• Figure 2 shows 3 curves corresponding to three different values of the pH of the solution forming the gel 3.7; 5.8; and 1, 8.
• the viscosity of the gel as a function of temperature behaves similarly to the gel obtained with the improved heat-sensitive polymer of the first example, except that the maximum viscosity is greater and that it reaches substantially 100
• thermosensitive polymer Thanks to the ionizable blocks of the improved thermosensitive polymer, it is possible to adjust the viscosity of the gel as a function of the acidity of the solution in which it is dissolved.
• thermosensitive polymer comprising ionizable polyacid blocks which confer a marked bioadhesive character to the gel.
• the synthesis is carried out in two stages. In a first step, 3.8 ⁇ 10 ⁇ 3 moles of non-dried F127 Pluronic polymer containing 0.3% by mass of water are dissolved in 150 ml of 2-butanone. Then 1, 5.10 ⁇ 2 moles of 4.4 ' -methylene biscyclohexyl di-isocyanate are added dropwise over 10 minutes under a continuous flow of nitrogen.
• FIG. 3 gives the variations in viscosity of the gel obtained with 5% by weight of the thermosensitive polymer synthesized in accordance with this example, as a function of the temperature under a shear rate of 0.3 / s.
• thermosensitive polymer having ramifications, which carry segments of polyethylene oxide of molar mass of 750 g.
• the synthesis is carried out in two stages; a first step consisting in producing a first polymer in accordance with the first step in Example 4 and a second step during which the polyethylene monohydroxylated oxide is introduced when only 26% of the initial isocyanate functions remain.
• the reaction continues for 24 hours.
• the gel formulated with 5% of this polymer has a maximum viscosity at 37 ° C and is very dense.
• FIG. 4 gives the viscosity curve of the thermoreversible gel obtained according to this example, as a function of the temperature under a shear rate of 0.3 / s.
• This synthesis example makes it possible to produce an improved thermosensitive polymer having branches carrying long chain aliphatic amines.
• the synthesis comprises a first step identical to the first step of the previous example and a second step in which octadecyl amine is introduced as soon as only 18% of the initial isocyanate functions remain.
• the gel formulated with 8% of said polymer has a maximum viscosity at 37 ° C and is very dense.
• the polymer is collected by precipitation in diethyl ether.
• This synthesis example makes it possible to produce an improved thermosensitive polymer having a higher proportion of urea groups as well as ramifications.
• the synthesis is carried out in two stages; a first step consisting in producing a first polymer by reaction of 3.8 ⁇ 10 ⁇ 3 mole of polymer F127 Pluronic not dried containing 0.3% by mass of water (7.6 ⁇ 10 ⁇ 3 mole) and 0.14 g of water added (7.6.10 "3 mole) with 4. 4.10" 2 mol of 4,4'-methylene biscyclohexyl diisocyanate added dropwise over 10 minutes under nitrogen stream.
• a tin-based catalyst is introduced 30 minutes after the end of the addition of the isocyanates, at a rate of 500 ppm in the mixture which is maintained at reflux of the solvent.
• 2.9 ⁇ 10 ⁇ 3 mole of 2,2- (bis hydroxymehtyl) butyric acid are added.
• the polycondensation continues for 24 hours at 70 ° C. until the complete disappearance of the initial isocyanate functions
• the polymer is collected by precipitation in diethyl ether
• the gel formulated with 5% of this polymer has in solution a dynamic viscosity of 3000 Pa.s under a shear rate of 0.003s -1 .

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