WO2005051428A2 - Method for obtaining a thermoreversible gel with a controlled three-dimensional structure, and gel obtained - Google Patents

Method for obtaining a thermoreversible gel with a controlled three-dimensional structure, and gel obtained Download PDF

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WO2005051428A2
WO2005051428A2 PCT/FR2004/050611 FR2004050611W WO2005051428A2 WO 2005051428 A2 WO2005051428 A2 WO 2005051428A2 FR 2004050611 W FR2004050611 W FR 2004050611W WO 2005051428 A2 WO2005051428 A2 WO 2005051428A2
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obtaining
gel
poloxamer
reagent
thermoreversible
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PCT/FR2004/050611
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WO2005051428A3 (en
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Bénédicte LANCON
Isabelle Coco
Eric Papon
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Rescoll
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/24—Crosslinking, e.g. vulcanising, of macromolecules
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • 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
    • 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
    • C08G18/4841—Polyethers containing oxyethylene units and other oxyalkylene units containing oxyethylene end groups
    • 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
    • C08G2220/00—Compositions for preparing gels other than hydrogels, aerogels and xerogels
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2371/00—Characterised by the use of polyethers obtained by reactions forming an ether link in the main chain; Derivatives of such polymers
    • C08J2371/02—Polyalkylene oxides

Definitions

  • the present invention relates to a process for obtaining a thermoreversible gel with controlled three-dimensional structure as well as the gel obtained by this process.
  • Thermoreversible gels are known and in particular the family of poloxamers which are terpolymers containing polyethylene glycol-polypropylene glycol-polyethylene glycol blocks.
  • thermoreversible gels are useful because they have thermoreversibility properties in the aqueous phase and they are liquid at room temperature for example while the viscosity increases appreciably when the temperature increases. This allows for example the introduction into the human body of these products by injection because this product is fluid at low temperature and then gels to the point of having the consistency of the dermis for example.
  • a thermoreversible gel can be used as a restructuring because it remains flexible but with a certain hardness.
  • One of the main disadvantages of these gels is their linear structure which makes them easily dilutable in water and which, in certain applications, leads to rapid absorption by the body. Improvements have been made to limit this rate of degradation and absorption by the body.
  • poloxa ers have also been modified in order to achieve a three-dimensional structure as indicated in the document of the prior art, patent application US 0 151 650.
  • the chain ends of these poloxamers carry acrylate functions which then ensure crosslinking under the action of ultraviolet radiation for example.
  • the gel obtained retains its thermoreversibility and its dissolution in water is limited by the presence of acrylic acid groups.
  • Crosslinking is a physical crosslinking between acrylic acid groups without covalent bonds, which tends to limit the cohesion of the gel over time.
  • the object of the present invention is to produce a gel which retains thermoreversibility properties while having a three-dimensional structure controlled by modification of a poloxamer.
  • the manufacturing process must be able to be carried out in a simple manner and without leaving traces of products incompatible with biomedical, cosmetic or pharmaceutical applications in particular.
  • the process according to the present invention can be industrialized and allows reproducibility.
  • the process according to the present invention is now described in detail according to a particular, nonlimiting embodiment, the single appended figure making it possible to observe the thermoreversibility and the different viscosity values reached as a function of the temperature. The method according to the present invention.
  • the reactive compound used in the context of the present invention is from the family of aromatic diisocyanates and more particularly toluene diisocyanate.
  • the diisocyanates have NCO functions which react with the alcohol functions of the poloxamer.
  • the process consists in reacting a diisocyanate, in excess, with a poloxamer having alcohol functions, this in a solvent medium, in this case acetone.
  • a solvent medium in this case acetone.
  • This solvent is important because it is tolerated biomedically in the form of traces.
  • this solvent is miscible in water and its evaporation temperature is low.
  • the two compounds, with excess diisocyanate are mixed with stirring in the solvent and an intermediate compound is obtained which comprises NCO isocyanate endings.
  • the diisocyanate is preferably added in excess in a stoichiometric ratio of NCO functions / OH functions of the poloxamer, of between 2 and 5.
  • This NCO / OH ratio must be limited to values less than 5 because beyond this, the viscosity increases to the point of disturbing the homogeneity of the mixture and therefore that of the reaction.
  • the intermediate product is then mixed in water.
  • the diisocyanate having been introduced in excess, all of the poloxamer has reacted and some diisocyanate remains.
  • the intermediate product it is a linear polymer.
  • a quantity of dry extract substantially identical to that of the starting poloxamer is determined, ie of the order of 20%.
  • two reactions occur: - the first concerns the reaction of the excess diisocyanate with water, which makes it possible to participate in the establishment of the three-dimensional network, - the second is the reaction of the isocyanate groups of the intermediate product together which allow the formation of the three-dimensional network.
  • the last step is the evaporation of the solvent, in this case acetone. It is appropriate to limit the temperature rise, preferably less than 40 ° C, if I 1 evaporation is carried out at atmospheric pressure. Another solution is also vacuum evaporation.
  • the gel obtained has a thermoreversibility character with dry extracts of less than 10%, more particularly 5 to 6%.
  • the fact of having a gel with a reduced amount of dry extract makes it possible, for example, to carry out injections into the human body with little material.
  • the advantage is the injection in the case of an anti-wrinkle action for example of a compound with a very low viscosity, therefore fluid and painless upon injection while its rheological properties vary after injection to become very viscous.
  • the three-dimensional structure then prohibits its absorption by the body.
  • Another advantage is the possibility of sterilizing the product for certain applications.
  • This sterilization can be carried out by irradiation, in particular by gamma rays.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Polymers & Plastics (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Inorganic Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Dermatology (AREA)
  • Neurosurgery (AREA)
  • Polyurethanes Or Polyureas (AREA)
  • Materials For Medical Uses (AREA)
  • Cosmetics (AREA)

Abstract

The invention relates to a method for obtaining a thermoreversible gel, said method being characterised by the following steps: a selected quantity of poloxamer is mixed with a water-miscible solvent and a reagent selected from the isocyanate family in order to obtain an intermediate product, the intermediate product is mixed with water, and the evaporation of the solvent is triggered.

Description

PROCEDE D'OBTENTION D'UN GEL THERMOREVERSIBLE A STRUCTURE TRIDIMENSIONNELLE CONTROLEE ET GEL OBTENU PROCESS FOR OBTAINING A THERMOREVERSIBLE GEL WITH CONTROLLED THREE-DIMENSIONAL STRUCTURE AND GEL OBTAINED
La présente invention concerne un procédé d'obtention d'un gel thermoréversible à structure tridimensionnelle contrôlée ainsi que le gel obtenu par ce procédé. On connaît des gels thermoréversibles et notamment la famille des poloxamers qui sont des terpolymeres à blocs polyéthylèneglycol-polypropylèneglycol- polyéthylèneglycol.The present invention relates to a process for obtaining a thermoreversible gel with controlled three-dimensional structure as well as the gel obtained by this process. Thermoreversible gels are known and in particular the family of poloxamers which are terpolymers containing polyethylene glycol-polypropylene glycol-polyethylene glycol blocks.
Les applications sont connues depuis longtemps dans le domaine biomédical, comme support de principe actif pour des applications topiques sur des muqueuses par exemple ou pour des injections dans le cas d'intervention en chirurgie esthétique.Applications have been known for a long time in the biomedical field, as an active ingredient support for topical applications on mucous membranes for example or for injections in the case of intervention in cosmetic surgery.
De tels gels sont utiles car ils ont des propriétés de thermoréversibilité en phase aqueuse et ils sont liquides à température ambiante par exemple tandis que la viscosité augmente sensiblement lorsque la température croît. Ceci permet par exemple l'introduction dans le corps humain de ces produits par injection car ce produit est fluide à faible température puis se gélifie au point d'avoir la consistance du derme par exemple. Ainsi, un gel thermoréversible peut-il être utilisé comme restructurant car il reste souple mais avec une certaine dureté. Un des principaux inconvénients de ces gels est leur structure linéaire qui les rend aisément diluable dans l'eau et qui, dans certaines applications, conduit à une rapide absorption par l'organisme. Des perfectionnements ont été conduits afin de limiter cette vitesse de dégradation et d'absorption par l'organisme.Such gels are useful because they have thermoreversibility properties in the aqueous phase and they are liquid at room temperature for example while the viscosity increases appreciably when the temperature increases. This allows for example the introduction into the human body of these products by injection because this product is fluid at low temperature and then gels to the point of having the consistency of the dermis for example. Thus, a thermoreversible gel can be used as a restructuring because it remains flexible but with a certain hardness. One of the main disadvantages of these gels is their linear structure which makes them easily dilutable in water and which, in certain applications, leads to rapid absorption by the body. Improvements have been made to limit this rate of degradation and absorption by the body.
Une solution consiste notamment à provoquer une réticulation, notamment en utilisant l'acide hyaluronique mois la gélification est dans ce cas non thermoréversible, si bien qu'un des avantages principaux de ces produits est perdu. On peut trouver la description de tels perfectionnements dans les brevetsOne solution consists in particular in causing crosslinking, in particular by using hyaluronic acid, the gelation is in this case not thermoreversible, so that one of the main advantages of these products is lost. The description of such improvements can be found in the patents
US 4 987744 et US 4957744.US 4 987744 and US 4957744.
Les poloxa ers ont aussi été modifiés afin d'atteindre une structure tridimensionnelle comme indiqué dans le document de l'art antérieur, demande de brevet US 0 151 650. Dans ce mode de traitement des poloxamers, les bouts de chaîne de ces poloxamers portent des fonctions acrylate qui assurent ensuite une réticulation sous l'action d'un rayonnement ultraviolet par exemple.The poloxa ers have also been modified in order to achieve a three-dimensional structure as indicated in the document of the prior art, patent application US 0 151 650. In this mode of treatment of poloxamers, the chain ends of these poloxamers carry acrylate functions which then ensure crosslinking under the action of ultraviolet radiation for example.
Le procédé de synthèse reste néanmoins long et comporte de nombreuses étapes de purification. Un autre brevet US 6 316 011 décrit un gel à base de poloxamer dont on provoque la copolymérisation par de l'acide polyacrylique.The synthesis process nevertheless remains long and includes numerous purification steps. Another patent US Pat. No. 6,316,011 describes a gel based on poloxamer, the copolymerization of which is caused by polyacrylic acid.
Le gel obtenu conserve sa thermoréversibilité et sa dissolution dans l'eau est limitée par la présence de groupements acide acrylique.The gel obtained retains its thermoreversibility and its dissolution in water is limited by the presence of acrylic acid groups.
La réticulation est une réticulation physique entre les groupements acide acrylique sans liaison covalentes, ce qui tend à limiter la cohésion du gel dans le temps.Crosslinking is a physical crosslinking between acrylic acid groups without covalent bonds, which tends to limit the cohesion of the gel over time.
Le but de la présente invention est de réaliser un gel qui conserve des propriétés de thermoréversibilité tout en ayant une structure tridimensionnelle contrôlée par modification d'un poloxamer. Le procédé de fabrication doit pouvoir être réalisé de façon simple et sans laisser de traces de produits incompatibles avec des applications biomédicales, cosmétiques ou pharmaceutiques notamment. Le procédé selon la présente invention peut être industrialisé et permet une reproductibilité. Lé procédé selon la présente invention est maintenant décrit en détail suivant un mode de réalisation particulier, non limitatif, la figure unique annexée permettant de constater la thermoréversibilité et les différentes valeurs de viscosité atteintes en fonction de la température. Le procédé selon la présente invention. Dans le cas de réactions de polycondensation entre un polyisocyanate et un polyol, dont les poloxamers, on peut utiliser des catalyseurs tels que des sels d'étain ou des aminés mais de tels composés sont incompatibles avec des applications biomédicales par exemple du fait que de très faibles quantités de catalyseurs n'ayant pas réagi peuvent subsister.The object of the present invention is to produce a gel which retains thermoreversibility properties while having a three-dimensional structure controlled by modification of a poloxamer. The manufacturing process must be able to be carried out in a simple manner and without leaving traces of products incompatible with biomedical, cosmetic or pharmaceutical applications in particular. The process according to the present invention can be industrialized and allows reproducibility. The process according to the present invention is now described in detail according to a particular, nonlimiting embodiment, the single appended figure making it possible to observe the thermoreversibility and the different viscosity values reached as a function of the temperature. The method according to the present invention. In the case of polycondensation reactions between a polyisocyanate and a polyol, including the poloxamers, it is possible to use catalysts such as tin salts or amines, but such compounds are incompatible with biomedical applications for example because very small amounts of unreacted catalysts may remain.
D'autre part, en l'absence de catalyseur, si l'on veut obtenir une f onctionnalisation du poloxamer, il faut associer un agent très réactif. Un autre paramètre à prendre en compte est la température puisque celle-ci au cours de la réaction doit être limitée. En effet, compte tenu que le gel initial est liquide, on peut assurer une homogénéité du mélange et une réaction complète alors que toute augmentation de la température provoque une gélification et donc une difficulté à homogénéiser le mélange du composé réactif avec le poloxamer.On the other hand, in the absence of a catalyst, if one wishes to obtain a functionalization of the poloxamer, a very reactive agent must be combined. Another parameter to take into account is the temperature since this during the reaction must be limited. In fact, given that the initial gel is liquid, it is possible to ensure homogeneity of the mixture and a complete reaction while any increase in temperature causes gelation and therefore a difficulty in homogenizing the mixture of the reactive compound with the poloxamer.
Le composé réactif retenu dans le cadre de la présente invention est de la famille des diisocyanates aromatiques et plus particulièrement le diisocyanate toluène.The reactive compound used in the context of the present invention is from the family of aromatic diisocyanates and more particularly toluene diisocyanate.
Les diisocyanates ont des fonctions NCO qui réagissent avec les fonctions alcools du poloxamer.The diisocyanates have NCO functions which react with the alcohol functions of the poloxamer.
Le procédé consiste à faire réagir un diisocyanate, en excès, avec un poloxamer ayant des fonctions alcool, ceci en milieu solvant en l'occurrence de l'acétone. Le choix de ce solvant est important car il est toléré biomédicalement sous forme de traces. De plus, ce solvant est miscible dans l'eau et sa température d' evaporation est basse. A température ambiante, les deux composés, avec du diisocyanate en excès, sont mélangés sous agitation dans le solvant et on obtient un composé intermédiaire qui comprend des terminaisons isocyanates NCO.The process consists in reacting a diisocyanate, in excess, with a poloxamer having alcohol functions, this in a solvent medium, in this case acetone. The choice of this solvent is important because it is tolerated biomedically in the form of traces. In addition, this solvent is miscible in water and its evaporation temperature is low. At room temperature, the two compounds, with excess diisocyanate, are mixed with stirring in the solvent and an intermediate compound is obtained which comprises NCO isocyanate endings.
Il est bien précisé que le diisocyanate est ajouté en excès de préférence dans un rapport stœchiométrique de fonctions NCO/ fonctions OH du poloxamer, compris entre 2 et 5.It is clearly specified that the diisocyanate is preferably added in excess in a stoichiometric ratio of NCO functions / OH functions of the poloxamer, of between 2 and 5.
Ce rapport NCO/OH doit être limité à des valeurs inférieures à 5 car au-delà la viscosité augmente au point de perturber l'homogénéité du mélange et donc celle de la réaction.This NCO / OH ratio must be limited to values less than 5 because beyond this, the viscosity increases to the point of disturbing the homogeneity of the mixture and therefore that of the reaction.
Le produit intermédiaire est ensuite mélangé dans l'eau. Le diisocyanate ayant été introduit en excès, la totalité du poloxamer a réagi et il subsiste du diisocyanate.The intermediate product is then mixed in water. The diisocyanate having been introduced in excess, all of the poloxamer has reacted and some diisocyanate remains.
Quant au produit intermédiaire, c'est un polymère linéaire.As for the intermediate product, it is a linear polymer.
Pour ce produit intermédiaire, on détermine une quantité d'extrait sec sensiblement identique à celle du poloxamer de départ soit de l'ordre de 20 %. De fait lors de l'introduction de l'eau, deux réactions se produisent : - la première concerne la réaction du diisocyanate en excès avec l'eau, ce qui permet de participer à l'établissement du réseau en trois dimensions, - la seconde est la réaction des groupes isocyanates du produit intermédiaire entre eux qui permettent la formation du réseau tridimensionnel.For this intermediate product, a quantity of dry extract substantially identical to that of the starting poloxamer is determined, ie of the order of 20%. In fact during the introduction of water, two reactions occur: - the first concerns the reaction of the excess diisocyanate with water, which makes it possible to participate in the establishment of the three-dimensional network, - the second is the reaction of the isocyanate groups of the intermediate product together which allow the formation of the three-dimensional network.
La dernière étape est l' evaporation du solvant, en l'occurrence l'acétone. Il convient de limiter la montée en température, de préférence inférieure à 40°C, si I1 evaporation est réalisée à pression atmosphérique. Une autre solution est également l' evaporation sous vide.The last step is the evaporation of the solvent, in this case acetone. It is appropriate to limit the temperature rise, preferably less than 40 ° C, if I 1 evaporation is carried out at atmospheric pressure. Another solution is also vacuum evaporation.
Le gel obtenu présente un caractère de thermoréversibilité avec des extraits secs inférieurs à 10%, plus particulièrement 5 à 6%. Dans le cas des applications médicales, le fait de disposer d'un gel avec une quantité d'extrait sec réduite, permet de réaliser par exemple des injections dans le corps humain avec peu de matière.The gel obtained has a thermoreversibility character with dry extracts of less than 10%, more particularly 5 to 6%. In the case of medical applications, the fact of having a gel with a reduced amount of dry extract makes it possible, for example, to carry out injections into the human body with little material.
L'intérêt est l'injection dans le cas d'une action anti-rides par exemple d'un composé avec une très faible viscosité, donc fluide et indolore à l'injection tandis que ses propriétés rhéologiques varient après injection pour devenir très visqueuses. La structure tridimensionnelle interdit ensuite son absorption par le corps.The advantage is the injection in the case of an anti-wrinkle action for example of a compound with a very low viscosity, therefore fluid and painless upon injection while its rheological properties vary after injection to become very viscous. The three-dimensional structure then prohibits its absorption by the body.
Un autre avantage est la possibilité de stérilisation du produit pour certaines applications.Another advantage is the possibility of sterilizing the product for certain applications.
Cette stérilisation peut être réalisée par irradiation, notamment par rayons gamma.This sterilization can be carried out by irradiation, in particular by gamma rays.
Il ne produit aucune modification du réseau et on constate l'absence de liaisons susceptibles de réagir sous l'apport d'énergie engendré par le rayonnement, telles que des doubles liaisons.It does not produce any modification of the network and there is the absence of bonds capable of reacting under the contribution of energy generated by the radiation, such as double bonds.
On note sur la courbe annexée en figure unique que la viscosité est variable en fonction de la dilution et qu'elle varie sur une plage importante ne serait-ce qu'entre 5 et 6%.It is noted on the curve appended in the single figure that the viscosity is variable as a function of the dilution and that it varies over a significant range if only between 5 and 6%.
Si l'on compare avec le poloxamer utilisé comme composé de départ et si l'on dilue ce poloxamer à 6%, on obtient un polymère qui est liquide quelle que soit la température. Le caractère viscosité variable avec réversibilité est perdu. On comprend aussi l'intérêt d'une telle dilution, car industriellement, la quantité de produit final par rapport au produit de départ est fortement augmentée.If we compare with the poloxamer used as starting material and if we dilute this poloxamer to 6%, we obtain a polymer which is liquid whatever the temperature. The variable viscosity with reversibility is lost. We also understand the advantage of such a dilution, because industrially, the amount of final product compared to the starting product is greatly increased.
Sur les courbes expérimentales présentées, on constate à dilution égale une variation de viscosité et plus exactement un décalage du pic de viscosité maximale. Ceci peut être engendré par une faible proportion de solvant subsistant et non évaporé.On the experimental curves presented, a variation in viscosity and more precisely a shift in the viscosity peak is observed at equal dilution. Max. This can be caused by a small proportion of solvent remaining and not evaporated.
On constate aussi à la lecture des courbes que lorsque le rapport NCO/OH augmente, la viscosité en fonction de la température augmente car le réseau tridimensionnel est plus dense. It can also be seen from the reading of the curves that when the NCO / OH ratio increases, the viscosity as a function of the temperature increases because the three-dimensional network is denser.

Claims

REVENDICATIONS
1. Procédé d'obtention d'un gel thermoréversible, caractérisé en ce qu'il consiste à réaliser la succession des étapes suivantes : - mélanger une quantité choisie de poloxamer avec un solvant miscible avec l'eau et un réactif choisi parmi la famille des isocyanates en sorte d'obtenir un produit intermédiaire, - mélanger le produit intermédiaire dans l'eau, et - provoquer I ' evaporation du solvant. 1. Method for obtaining a thermoreversible gel, characterized in that it consists in carrying out the succession of the following steps: - mixing a chosen quantity of poloxamer with a solvent miscible with water and a reagent chosen from the family of isocyanates so as to obtain an intermediate product, - mix the intermediate product in water, and - cause the solvent to evaporate.
2. Procédé d'obtention d'un gel réversible selon la revendication 1, caractérisé en ce que le réactif est ajouté en excès par rapport au poloxamer. 2. Method for obtaining a reversible gel according to claim 1, characterized in that the reagent is added in excess relative to the poloxamer.
3. Procédé d'obtention d'un gel réversible selon la revendication 1 ou 2, caractérisé en ce que le réactif est du diisocyanate. 3. Method for obtaining a reversible gel according to claim 1 or 2, characterized in that the reagent is diisocyanate.
4. Procédé d'obtention d'un gel réversible selon la revendication 3, caractérisé en ce que le réactif est du diisocyanate toluène. 4. Method for obtaining a reversible gel according to claim 3, characterized in that the reagent is toluene diisocyanate.
5. Procédé d'obtention d'un gel réversible selon l'une quelconque des revendications précédentes, caractérisé en ce que le rapport de fonctions NCO du réactif sur les fonctions OH du poloxamer est compris entre 2 et 5. 5. Method for obtaining a reversible gel according to any one of the preceding claims, characterized in that the ratio of NCO functions of the reagent to the OH functions of the poloxamer is between 2 and 5.
6. Procédé d'obtention d'un gel réversible selon l'une quelconque des revendications précédentes, caractérisé en ce que le solvant est de l'acétone. 6. Method for obtaining a reversible gel according to any one of the preceding claims, characterized in that the solvent is acetone.
7. Gel thermoréversible obtenu par le procédé selon l'une quelconque des revendications précédentes, caractérisé en ce qu'il comprend une quantité d'extrait sec inférieure à 107o. 7. thermoreversible gel obtained by the process according to any one of the preceding claims, characterized in that it comprises a quantity of dry extract less than 107 °.
8. Gel thermoréversible obtenu par le procédé selon l'une quelconque des revendications 1 à 6, caractérisé en ce qu'il comprend une quantité d'extrait comprise entre 4 et 6%. 8. thermoreversible gel obtained by the process according to any one of claims 1 to 6, characterized in that it comprises an amount of extract of between 4 and 6%.
PCT/FR2004/050611 2003-11-24 2004-11-23 Method for obtaining a thermoreversible gel with a controlled three-dimensional structure, and gel obtained WO2005051428A2 (en)

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FR0350890A FR2862652B1 (en) 2003-11-24 2003-11-24 PROCESS FOR OBTAINING THERMOREVERSIBLE GEL WITH THREE-DIMENSIONAL STRUCTURE CONTROLLED AND GEL OBTAINED
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WO2014095915A1 (en) * 2012-12-17 2014-06-26 Polymaterials Ag Chain-extending poloxamers, thermoreversible hydrogels formed by them which include biological materials, and medicinal applications of same
WO2016090361A1 (en) * 2014-12-05 2016-06-09 Akina, Inc. (An Indiana (Us) Corp) Polymers for inducing 3d spheroid formation of biological cells

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Publication number Priority date Publication date Assignee Title
FR3078965B1 (en) 2018-03-13 2021-07-30 Safran Ceram COMPOSITE WITH CERAMIC OXIDE / OXIDE MATRIX

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US6201065B1 (en) * 1995-07-28 2001-03-13 Focal, Inc. Multiblock biodegradable hydrogels for drug delivery and tissue treatment

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US6201065B1 (en) * 1995-07-28 2001-03-13 Focal, Inc. Multiblock biodegradable hydrogels for drug delivery and tissue treatment

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014095915A1 (en) * 2012-12-17 2014-06-26 Polymaterials Ag Chain-extending poloxamers, thermoreversible hydrogels formed by them which include biological materials, and medicinal applications of same
US10406231B2 (en) 2012-12-17 2019-09-10 Matthias Schieker Chain-extending poloxamers, thermoreversible hydrogels formed by them which include biological materials, and medicinal applications of same
WO2016090361A1 (en) * 2014-12-05 2016-06-09 Akina, Inc. (An Indiana (Us) Corp) Polymers for inducing 3d spheroid formation of biological cells

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WO2005051428A3 (en) 2005-07-28
FR2862652A1 (en) 2005-05-27

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