NL2001793C2 - Method for the preparation of a biocompatible hydrogel. - Google Patents

Method for the preparation of a biocompatible hydrogel. Download PDF

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Publication number
NL2001793C2
NL2001793C2 NL2001793A NL2001793A NL2001793C2 NL 2001793 C2 NL2001793 C2 NL 2001793C2 NL 2001793 A NL2001793 A NL 2001793A NL 2001793 A NL2001793 A NL 2001793A NL 2001793 C2 NL2001793 C2 NL 2001793C2
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hydrogel
water
resin
mercaptan
range
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NL2001793A
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Dutch (nl)
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Paul De Kleijn
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Parvus Beheer B V
Bolier Invest B V S
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Priority to NL2001793A priority Critical patent/NL2001793C2/en
Priority to PCT/NL2009/000147 priority patent/WO2010005290A1/en
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Publication of NL2001793C2 publication Critical patent/NL2001793C2/en

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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F290/00—Macromolecular compounds obtained by polymerising monomers on to polymers modified by introduction of aliphatic unsaturated end or side groups
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F283/00—Macromolecular compounds obtained by polymerising monomers on to polymers provided for in subclass C08G
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F283/00—Macromolecular compounds obtained by polymerising monomers on to polymers provided for in subclass C08G
    • C08F283/06—Macromolecular compounds obtained by polymerising monomers on to polymers provided for in subclass C08G on to polyethers, polyoxymethylenes or polyacetals
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F290/00—Macromolecular compounds obtained by polymerising monomers on to polymers modified by introduction of aliphatic unsaturated end or side groups
    • C08F290/02—Macromolecular compounds obtained by polymerising monomers on to polymers modified by introduction of aliphatic unsaturated end or side groups on to polymers modified by introduction of unsaturated end groups
    • C08F290/04—Polymers provided for in subclasses C08C or C08F
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F290/00—Macromolecular compounds obtained by polymerising monomers on to polymers modified by introduction of aliphatic unsaturated end or side groups
    • C08F290/02—Macromolecular compounds obtained by polymerising monomers on to polymers modified by introduction of aliphatic unsaturated end or side groups on to polymers modified by introduction of unsaturated end groups
    • C08F290/06—Polymers provided for in subclass C08G
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F290/00—Macromolecular compounds obtained by polymerising monomers on to polymers modified by introduction of aliphatic unsaturated end or side groups
    • C08F290/08—Macromolecular compounds obtained by polymerising monomers on to polymers modified by introduction of aliphatic unsaturated end or side groups on to polymers modified by introduction of unsaturated side groups
    • C08F290/14—Polymers provided for in subclass C08G
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L51/00—Compositions of graft polymers in which the grafted component is obtained by reactions only involving carbon-to-carbon unsaturated bonds; Compositions of derivatives of such polymers
    • C08L51/003—Compositions of graft polymers in which the grafted component is obtained by reactions only involving carbon-to-carbon unsaturated bonds; Compositions of derivatives of such polymers grafted on to macromolecular compounds obtained by reactions only involving unsaturated carbon-to-carbon bonds
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L51/00—Compositions of graft polymers in which the grafted component is obtained by reactions only involving carbon-to-carbon unsaturated bonds; Compositions of derivatives of such polymers
    • C08L51/08—Compositions of graft polymers in which the grafted component is obtained by reactions only involving carbon-to-carbon unsaturated bonds; Compositions of derivatives of such polymers grafted on to macromolecular compounds obtained otherwise than by reactions only involving unsaturated carbon-to-carbon bonds

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Organic Chemistry (AREA)
  • Materials For Medical Uses (AREA)

Description

P29445NLOO/MKO
Title: Method for the preparation of a biocompatible hydrogel
Technical Field
The invention relates to a method for the preparation of a biocompatible hydrogel. More in particular, the invention relates to a method for the preparation of a biocompatible hydrogel with a high refractive index. The invention further relates to implants for eye surgery made 5 with said hydrogels, as well as other medical applications.
Background Art A gel is an apparently solid, jelly-like material. A hydrogel is a network of polymer chains that are water-insoluble, in which water is the dispersion medium. A hydrogel is an aqueous solution of a hydrophilic polymer which is insoluble in water but swells to some equilibrium 10 state. Hydrogels differs in rheological properties from solutions. When a stirrer turns in a solution the stirrer forms a vortex below the surface. In a hydrogel the liquid creeps upwards the stirrer. Hydrogels possess also a degree of flexibility very similar to natural tissue, due to their significant water content.
Common uses for hydrogels are: 15 · currently used as scaffolds in tissue engineering. When used as scaffolds, hydrogels may contain human cells in order to repair tissue.
• environmentally sensitive hydrogels. These hydrogels have the ability to sense changes of pH, temperature, or the concentration of metabolite and release their load as result of such a change.
20 · as sustained-release delivery system * provide absorption, desloughing and debriding capacities of necrotics and fibrotic tissue.
• hydrogels that are responsive to specific molecules, such as glucose or antigens can be used as biosensors as well as in DDS (“drug delivery systems”).
25 * as dry powder in disposable diapers where they upon capturing urine form a hydrogel, or likewise in sanitary napkins • contact lenses (silicone hydrogels, polyacrylamides) - medical electrodes using hydrogels composed of cross linked polymers (polyethylene oxide, polyAMPS and polyvinylpyrrolidone) 30 · Water gel explosives
Other, less common uses include * breast implants * granules that can form a hydrogel by holding soil moisture in arid areas 2 • dressings for healing of bum or other hard-to-heal wounds. Wound GEL are excellent for helping to create or maintain environment.
• reservoirs in topical drug delivery; particularly ionic drugs, delivered by iontophoresis (see ion exchange resin) 5 Common ingredients are e.g. polyvinyl alcohol, sodium polyacrylate, acrylate polymers and copolymers with an abundance of hydrophilic groups.
For implants in eye surgery there is a demand for hydrogels with a high refraction index, high water content and good mechanical properties.
Disclosure of Invention 10 Accordingly, the invention provides for a method for the preparation of a biocompatible hydrogel by prepolymerizing a polyfunctional mercaptan, a vinylpyrrolidone and at least one water-soluble monomer or a mixture of water soluble monomers dissolved in an aqueous reaction medium into a resin, removing at least part of the aqueous reaction medium and/or treating the resin with steam, followed by photopolymerizing the resin into a hydrogel in the 15 presence of a photoinitiator, preferably one that is cleared for medical applications. Moreover, the invention provides a biocompatible hydrogel that is suitable for the uses mentioned above, in particular in medical applications, more in particular as implantation in and as application onto biomaterials.
Mode(s) for Carrying Out the Invention 20 For application were biocompatibility is necessary, the purity of the hydrogel is very important. However it has been found that by using the two-step process of the current invention, the amount of photoinitiator and impurities in the final hydrogel could remarkably be reduced, which makes the hydrogel suitable for implantation in and application onto biomaterials.
25 In the process of the current invention, it has been surprisingly found that polyfunctional mercaptans, although they are not water soluble, can form stable hydrogels when they are copolymerized with a vinylpyrrolidone such as n-vinyl-2-pyrrolidone and a water soluble monomer, preferably a polyfunctional monomer, such as PEGDA.
Polyfunctional mercaptans include difunctional-, trifunctional-, and multi-functional-thiols.
30 A preferred difunctional mercaptan is ethylene glycol dimercaptopropionate. Suitable difunctional mercaptans include, but are not limited to, diethylene glycol dimercaptopropionate, 4-t-butyl-1,2-benzenedithiol, bis-(2-mercaptoethyl)sulfide, 4,4'-thiodibenzenethiol, benzenedithiol, glycol dimercaptoacetate, glycol dimercaptopropionate ethylene bis(3-mercaptopropionate), polyethylene glycol dimercaptoacetates, polyethylene 35 glycol di(3-mercaptopropionates), 2,2-bis(mercaptomethyl)-1,3-propanedithiol, 2,5- dimercaptomethyl-1,4-dithiane, bisphenofluorene bis(ethoxy-3-mercaptopropionate), 4,8- 3 bis(mercaptomethyl)-3,6,9-trithia-1,11-undecanedithiol, 2-mercaptomethyl-2-methyl-1,3-propanedithiol, 1,8-dimercapto-3,6-dioxaoctane, and thioglycerol bismercapto-acetate.
A preferred trifunctional mercaptan is trimethylol propane (tris-mercaptopropionate) (TMPTMP). Suitable tri-functional mercaptans include, but are not limited to, 5 trimethylolpropane tris(3-mercaptopropionate), trimethylolpropane tris(3-mercaptoacetate), tris-(3-mercaptopropyl)isocyanurate, 1,2,3-trimercaptopropane, and tris(3-mercaptopropionate)triethyl-1,3,5-triazine-2,4,6-(1H,3H,5H)-trione.
A preferred multifunctional mercaptan is pentaerythrotol tetra-3-mercapto propionate (PETMP). Suitable polyfunctional mercaptans include, but are not limited to, poly 10 (mercaptopropyl methyl) siloxane (PMPMS); 4-mercaptomethyl-3,6-dithia-1,8- octanedithiolpentaerythritol tetrakis(3-mercaptoacetate), and pentaerythritol tetrakis (3-mercapto-propionate).
PETMP, available from e.g., Bruno Bock in Germany, is the preferred polyfunctional mercaptan.
15 Water-soluble monomers are known to the man skilled in the art. Preferred water-soluble monomers are carboxyl group-containing unsaturated monomers such as (meth)-acrylic acid and maleic acid anhydride; carboxyl acid salt group-containing monomers such as sodium (meth)acrylate, trimethylamine (meth)acrylate and triethanolamine (meth)acrylate, and quaternary ammonium salt group-containing monomers such as N,N,N-trimethyl-N-20 (meth)acryloyloxyethylammonium chloride. More preferred monomers in the present invention include, for example, acrylic acid, methacrylic acid, maleic acid, fumaric acid, crotonic acid, sorbic acid, itaconic acid, cinnamic acid, vinyl sulfonic acid, ally) sulfonic acid, vinyl toluene sulfonic acid, styrene sulfonic acid, sulfo(meth)acrylate, sulfopropyl(meth)acrylate, 2-acrylamid-2-methylpropane sulfonic acid, 2-25 hydroxyethyl(meth)acryloylphosphate, phenyl-2-acryloyloxyethylphosphate, the sodium, potassium and ammonium salts thereof, maleic anhydride and combinations thereof. Most preferred monomers in the current invention are diesters and polyesters of said carboxyl-group-containing monomers on the one hand, and a diol or a polyol on the other hand. Of particular preference are polyfunctional momomers, such as diacrylates and dimethacrylates 30 of polyethylene glycol.
Most preferably, the water soluble monomer is polyethylene glycol diacrylate (PEGDA), with a weight average molecular weight greater than 400, preferably greater than 500, more preferably 600 or greater. SR 610, available from Sartomer in Puteaux, France, is very suitable.
35 Commercial available water soluble monomers, such as acrylic and methacrylic monomers, are produced according a solventation process whereby an organic solvent is used, for instance, when the monomer is a (di)ester, to remove the water which is formed during the 4 condensation of the alcohol and the unsaturated acid. Therefore such monomers contain very often an aromatic solvent like toluene or xylene. Such monomers would therefore be not or less suitable for medical applications. However, as mentioned before, the process of the current invention overcomes this problem by forming a resin first and having the resin 5 solution treated by a steam distillation process (which includes removing part of the aqueous solvent by evaporation).
[0001] The preferred vinylpyrrolidone is n-vinyl-2-pyrrolidone. On the other hand, also isomers thereof may be used and/or substituted vinylpyrrolidones.
Preferably, the polyfunctional mercaptan, the vinylpyrrolidone and the water-soluble 10 monomer are used in a ratio resulting in a hydrogel with a refractive index corresponding to that of the refractive index of a human eye. The refractive index of the lens of a human eye is typically in the range of 1.3 to 1.5. The molar ratio of mercaptan to vinylpyrrolidone may vary from 3:1 to 1:30, preferably from 2:1 to 1:20, more preferably from 1:1 to 1:10, most preferably around 1:6. The molar ratio of mercaptan to water-soluble monomer or monomers 15 may vary from 3:1 to 1:20, preferably from 2:1 to 1:10, more preferably from 1:1 to 1:5.
The prepolymerization may be carried out with any kind of polymerization. Preferably, however, the polymerization is carried out with a photoinitiator. Preferably, the photoinitiator is of a kind that any initiator residues are removed when the resin is treated with steam and/or heated to the temperature that some of the water used as solvent evaporates. The 20 initiator is therefore of a kind that the residues have a boiling point below that of water, or that forms an azeotropic vapour with steam.
Suitable photoinitiators include 2-hydroxy-2-methyl-1-phenyl-propan-1-on (HMPP). HMPP is available as Darocur™ 1173 from Ciba in Basel, Switzerland. The initiator is used in amounts effective to cause the prepolymerization into a resin, e.g., in a molar ratio of 25 mercaptan to photoinitiator of from 10,000:1 to 1:1, more preferably of from 1,000:1 to 10:1. The method of the current invention involves mixing the vinylpyrrolidone in water, adding the water-soluble (multifunctional) monomer, the photoinitiator and the mercaptan. The order of addition is not relevant. Also the amount of water is not relevant; sufficient water should be available to dissolve all components. Then the prepolymer is made by photopolymerization. 30 This may be done with a UV lamp. Excellent results have been achieved with the stroboscopic UV flash lamp available from Parvus Fysica BV in Zeewolde, the Netherlands, which generates 100 flashes per second of 8 Joule each.
Next, the method of the current invention involves the treatment with steam and/or the removal of some of the water, leaving a low viscous resin. This resin is stable. Moreover, by 35 evaporation any impurity residues (including those resulting from the photoinitiator or present as impurity in the starting monomer) are removed.
5
Next, the resin is turned into a hydrogel by photopolymerization in the presence of a photoinitiator, preferably one that is cleared for medical applications. Again, the skilled person knows what photoinitiators may be used. Preferably, a photoinitiator is used that performs well when using an arctic source at a wavelength smaller than 390 nm. This has 5 the advantage that the resin/hydrogel can be used to treat e.g., an eye condition in-vivo, without causing damage to the vitreous humour: the cornea, the iris, the ciliary body, and/or the lens of the eye. Most preferably the photoinitiator used in this step is a hydroxyaryl ketone. For instance, excellent results have been achieved with Irgacure™ 2959 from Ciba. The monomers and/or the resin and/or the hydrogel may be mixed with other components. 10 For instance collagen, in particular collagen Type II is often used as component in hydrogels. Moreover, the hydrogel of the current invention may include bioactive material (stem cells, hormones, enzymes, growth regulators, [slow-release] drugs) and/or cosmetic material (colorants).
The hydrogels of the current invention may be used for the common uses mentioned in the 15 introduction of this patent application, in particular for use in the treatment of eye defects, and skin treatment.
The following example is provided to illustrate the current invention.
Example 1 333 gram (3 mole) of n-vinyl-2-pyrrolidone was dissolved in 500 gram of de-mineralized 20 water. 146 gram (0.5 mole) of SR 610, a polyethylene glycol diacrylate, was added, as well as 7 gram of HMPP. The components were mixed into a 2 litre Erlenmeyer. While the stirrer was turning, 244 gram (0.5 mole) of pentaerythrotol tetra-3-mercapto propionate (PETMP) was added. The clear liquid turned into a cloudy one, since the PETMP did not dissolved in the mixture.
25 The Parvus stroboscopic UV flash lamp was placed under the Erlenmeyer and switched on. Although the Erlenmeyer was made of borosilicate glass, enough UV light was transmitted into the liquid to start viscosity increase by formation of a water soluble resin. The liquid turned into a clear solution within three minutes. The irradiation was stopped when a viscosity of 300 mPa.s (room temperature) was reached.
30 The flash lamp was removed and replaced by a heating plate. The heating plate was turned on. When the water started boiling, the impurities including the photoinitiator residues were evaporated by steam distillation from the boiling water. Toluene and HMPP forms an azeotropic mixture with water and therefore separated from the liquid.
When 300 ml of water was removed the liquid was found to be liberated from monomer NVP 35 and low molecular polyethylene glycol diacrylate as well. The low viscous resin was stable, and did not increased in viscosity after three month storage at 7 degrees Celsius.
6
After addition of only 10 milligram of photoinitiator 4-(2-hydroxyethoxy)phenyl-(2-hydroxy-2-methylpropyl)ketone (Irgacure 2959) to 10 gram of the preparation, a photosensitive liquid was obtained which could be injected in a pig’s eye with a syringe. A drop of the photosensitive liquid was irradiation with an UV LED type NCCU033E from Nichia in Japan 5 and changed within 20 seconds into a hydrogel with the stiffness of a hard boiled egg.
It has been found that the hydrogels of the current invention show biocompatibility in the eye and on grazed skin. The hydrogel prepared above has a refractive index of about 1.5. In case water is added to this, the refractive will be around 1.4, which is therefore very close to that of a human eye.
10

Claims (23)

1. Werkwijze voor het bereiden van een biologisch verenigbaar hydrogel door het in 5 een hars prepolymeriseren van een polyfunctioneel mercaptaan, een vinylpyrrolidon en ten minste één in water oplosbaar monomeer, of een mengsel van in water oplosbare monomeren opgelost in een waterig reactiemedium, het verwijderen van ten minste een gedeelte van het waterige reactiemedium en/of het behandelen van de hars met stoom, gevolgd door het in aanwezigheid van een foto-initiator fotopolymeriseren van de hars tot 10 een hydrogel.Method for preparing a biocompatible hydrogel by prepolymerizing a polyfunctional mercaptan, a vinyl pyrrolidone and at least one water-soluble monomer in a resin, or a mixture of water-soluble monomers dissolved in an aqueous reaction medium, removing of at least a portion of the aqueous reaction medium and / or treating the resin with steam, followed by photopolymerizing the resin into a hydrogel in the presence of a photoinitiator. 2. Werkwijze volgens conclusie 1, waarbij het polyfunctionele mercaptaan een difunctioneel, een trifunctioneel of een multifunctioneel thiol of een combinatie daarvan omvat.The method of claim 1, wherein the polyfunctional mercaptan comprises a difunctional, a trifunctional or a multifunctional thiol or a combination thereof. 3. Werkwijze volgens conclusie 2, waarbij het polyfunctionele mercaptaan een multifunctioneel mercaptaan is, gekozen uit pentaerythrotol-tetra-3-mercaptopropionaat 15 (PETMP), poly(mercaptopropylmethyl)siloxaan (PMPMS); 4-mercaptomethyl-3,6-dithia-1,8-octaandithiolpentaerythritoltetrakis(3-mercaptoacetaat) en pentaerythritoltetrakis(3-mercaptopropionaat), waarbij het bij voorkeur PETMP is.The method of claim 2, wherein the polyfunctional mercaptan is a multifunctional mercaptan selected from pentaerythrotol tetra-3-mercaptopropionate (PETMP), poly (mercaptopropylmethyl) siloxane (PMPMS); 4-mercaptomethyl-3,6-dithia-1,8-octanedithiol pentaerythritol tetrakis (3-mercaptoacetate) and pentaerythritol tetrakis (3-mercapto propionate), preferably PETMP. 4. Werkwijze volgens een van de conclusies 1 tot 3, waarbij het in water oplosbare monomeer of de in water oplosbare monomeren onverzadigde carboxylgroep-bevattende 20 monomeren zijn.The process according to any of claims 1 to 3, wherein the water-soluble monomer or water-soluble monomers are unsaturated carboxyl group-containing monomers. 5. Werkwijze volgens conclusie 4, waarbij het in water oplosbare monomeer een polyfunctioneel monomeer is, bij voorkeur een diacrylaat of dimethacrylaat van polyethyleenglycol.The method of claim 4, wherein the water-soluble monomer is a polyfunctional monomer, preferably a diacrylate or dimethacrylate of polyethylene glycol. 6. Werkwijze volgens conclusie 5, waarbij het in water oplosbare monomeer 25 polyethyleenglycoldiacrylaat (PEGDA) is met een gewichtsgemiddeld molecuulgewicht van groter dan 400, bij voorkeur van groter dan 500, met meer voorkeur van 600 of groter.6. A method according to claim 5, wherein the water-soluble monomer is polyethylene glycol diacrylate (PEGDA) with a weight average molecular weight of greater than 400, preferably of greater than 500, more preferably of 600 or greater. 7. Werkwijze volgens een van de conclusies 1 tot 6, waarbij het vinylpyrrolidon n-vinyl-2-pyrrolidon is.The method of any one of claims 1 to 6, wherein the vinyl pyrrolidone is n-vinyl-2-pyrrolidone. 8. Werkwijze volgens een van de conclusies 1 tot 7, waarbij het polyfunctionele mercaptaan, 30 het vinylpyrrolidon en het in water oplosbare monomeer of monomeren worden gebruikt in een verhouding die een hydrogel geeft met een brekingsindex in het gebied van 1.3 tot 1.5 die overeenkomt met de brekingsindex van een menselijk oog.8. A method according to any of claims 1 to 7, wherein the polyfunctional mercaptan, the vinyl pyrrolidone and the water-soluble monomer or monomers are used in a ratio that gives a hydrogel with a refractive index in the range of 1.3 to 1.5 corresponding to the refractive index of a human eye. 9. Werkwijze volgens een van de conclusies 1 tot 7, waarbij de molaire verhouding van mercaptaan ten opzichte van vinylpyrrolidon zich bevindt in het gebied van 3:1 tot 1:30, bij 35 voorkeur in het gebied van 2:1 tot 1:20, met meer voorkeur in het gebied van 1:1 tot 1:10, waarbij deze met de meeste voorkeur ongeveer 1:6 bedraagt. δThe method according to any of claims 1 to 7, wherein the molar ratio of mercaptan to vinyl pyrrolidone is in the range of 3: 1 to 1:30, preferably in the range of 2: 1 to 1:20 , more preferably in the range of 1: 1 to 1:10, most preferably being about 1: 6. δ 10. Werkwijze volgens een van de conclusies 1 tot 7, waarbij de molaire verhouding van mercaptaan ten opzichte van in water oplosbaar monomeer of monomeren zich bevindt in het gebied van 3:1 tot 1:20, bij voorkeur in het gebied van 2:1 tot 1:10, met meer voorkeur in het gebied van 1:1 tot 1:5.The process according to any of claims 1 to 7, wherein the molar ratio of mercaptan to water-soluble monomer or monomers is in the range of 3: 1 to 1:20, preferably in the range of 2: 1 to 1:10, more preferably in the range of 1: 1 to 1: 5. 11. Werkwijze volgens een van de conclusies 1 tot 10, waarbij de prepolymerisatie wordt uitgevoerd met een foto-initiator, bij voorkeur met 2-hydroxy-2-methyl-1-fenyl-1-propanon (HMPP).The method according to any of claims 1 to 10, wherein the prepolymerization is carried out with a photoinitiator, preferably with 2-hydroxy-2-methyl-1-phenyl-1-propanone (HMPP). 12. Werkwijze volgens conclusie 11, waarbij HMPP wordt gebruikt in een molaire verhouding van mercaptaan ten opzichte van foto-initiator van 10.000:1 tot 1:1, met meer voorkeur van 10 1000:1 tot 10:1.The method of claim 11, wherein HMPP is used in a molar ratio of mercaptan to photoinitiator from 10,000: 1 to 1: 1, more preferably from 1000: 1 to 10: 1. 13. Werkwijze volgens een van de conclusies 1 tot 12, waarbij de hars door fotopolymerisatie in aanwezigheid van een foto-initiator, bij voorkeur van een hydroxyarylketon, wordt omgezet in een hydrogel.A method according to any of claims 1 to 12, wherein the resin is converted into a hydrogel by photopolymerization in the presence of a photoinitiator, preferably of a hydroxy aryl ketone. 14. Hydrogel dat verkregen is volgens de werkwijze volgens een van de conclusies 1 tot 13.A hydrogel obtained by the process according to any of claims 1 to 13. 15 15. Hydrogel volgens conclusie 14, omvattende een of meer van de volgende bestanddelen: collageen, in het bijzonder collageen type II; bioactief materiaal (stamcellen, hormonen, enzymen, groeiregelaars, geneesmiddelen [met een vertraagde afgifte]) en/of cosmetische stoffen (kleurstoffen).15. Hydrogel according to claim 14, comprising one or more of the following components: collagen, in particular collagen type II; bioactive material (stem cells, hormones, enzymes, growth regulators, medicines [with a delayed release]) and / or cosmetic substances (colorants). 16. Hydrogel volgens conclusie 14 of 15, waarbij de hars wordt gefotopolymeriseerd door 20 gebruik te maken van een stralingsbron met een golflengte van kleiner dan 390 nm.16. Hydrogel according to claim 14 or 15, wherein the resin is photopolymerized by using a radiation source with a wavelength of less than 390 nm. 17. Hydrogel volgens conclusie 16, waarbij de hars in vivo wordt gefotopolymeriseerd tot een hydrogel.The hydrogel of claim 16, wherein the resin is photopolymerized in vivo to form a hydrogel. 18. Hydrogel volgens conclusie 17, waarbij de hars in minder dan 5 minuten, bij voorkeur in minder dan 1 minuut, met meer voorkeur in minder dan 30 seconden, wordt 25 gefotopolymeriseerd.18. Hydrogel according to claim 17, wherein the resin is photopolymerized in less than 5 minutes, preferably in less than 1 minute, more preferably in less than 30 seconds. 19. Hydrogel volgens een van de conclusies 14 tot 18, voor gebruik als geneesmiddel.The hydrogel according to any of claims 14 to 18, for use as a medicine. 20. Hydrogel volgens een van de conclusies 14 tot 18, voor gebruik bij de behandeling van oogafwijkingen en/of voor het behandelen van de huid.A hydrogel according to any of claims 14 to 18, for use in the treatment of eye disorders and / or for treating the skin. 21. Hydrogel volgens een van de conclusies 14 tot 18, voor gebruik bij de behandeling van 30 oogafwijkingen, waarbij het gedurende een tijdsduur van minder dan 30 seconden bestralen met een golflengte van kleiner dan 390 is betrokken, waarbij het hydrogel een brekingsindex in het gebied van 1.3 tot 1.5 heeft.A hydrogel according to any of claims 14 to 18, for use in the treatment of eye disorders, wherein irradiation with a wavelength of less than 390 is involved for a period of less than 30 seconds, the hydrogel having a refractive index in the region from 1.3 to 1.5. 22. Oogimplantaten en/of-verbanden omvattende het hydrogel volgens een van de conclusies 14 tot 21.An eye implant and / or dressing comprising the hydrogel according to any of claims 14 to 21. 23. Medische implantaten bestaande uit of bekleed met het hydrogel volgens een van de conclusies 14 tot 21.Medical implants consisting of or coated with the hydrogel according to any of claims 14 to 21.
NL2001793A 2008-07-11 2008-07-11 Method for the preparation of a biocompatible hydrogel. NL2001793C2 (en)

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US9855359B2 (en) 2013-12-23 2018-01-02 Verily Life Sciences Llc Analyte sensors with ethylene oxide immunity
GB201519811D0 (en) * 2015-11-10 2015-12-23 Univ Belfast Ocular compositions

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