EP2490728A1

EP2490728A1 - Biodegradable hydrogel

Info

Publication number: EP2490728A1
Application number: EP10765758A
Authority: EP
Inventors: Heike Heckroth; Christoph Eggert; Harmut Nefzger; Jörg Hofmann; Edward Browne; Klaus Lorenz
Original assignee: Bayer MaterialScience AG
Current assignee: Covestro Deutschland AG
Priority date: 2009-10-21
Filing date: 2010-10-07
Publication date: 2012-08-29
Also published as: WO2011047789A9; CA2780919A1; AU2010310208A1; IN2012DN03446A; WO2011047789A1; US20120244107A1; KR20120098638A; JP2013508482A; BR112012009266A2; WO2011047789A8; CN102573947A

Abstract

The present invention relates to a hydrogel on the basis of polyurethane or polyurethane urea, said hydrogel comprising hydrolyzable functional groups in the polymer chain, to a method for producing the hydrogel and to the use of the hydrogel as adhesion barriers.

Description

Biodegradable hvdrogel

The present invention relates to a hydrogel based on polyurethane or polyurethaneurea, a process for the preparation of the hydrogel and the use of the hydrogel as an adhesion barrier. Adhesions are one of the most common complications after abdominal and pelvic surgery. Adhesions are fibrous bands that generally develop within the first seven days after surgery during the healing process. As a result, tissues and organs that are normally separated from each other grow together, resulting in a variety of complications such as hypertension. chronic pain, infertility or a life-threatening intestinal obstruction may occur. To avoid such complications, products have been developed in recent years that can reduce the formation of adhesions.

Among others, hydrogels have also been used as adhesion barriers. Hydrogels are hydrous polymers whose chains are covalently linked to a three-dimensional network. In water, these networks swell up to an equilibrium volume while maintaining their shape. The network formation occurs predominantly via chemical linkage of the individual polymer chains, but is also physically possible by electrostatic, hydrophobic or dipole / dipole interactions between individual segments of the polymer chains. The choice of the monomers used for the polymer synthesis, the type of crosslinking and the crosslinking density can be used to set desired properties of the hydrogels in a targeted manner. Usually, hydrogels are based on poly (meth) acrylic acids, poly (meth) acrylates, polyurethanes, polyvinylpyrrolidone or polyvinyl alcohol. They are generally well-tolerated by living tissues and are therefore often suggested for use as adhesion barriers.

Polyurethane hydrogels of hydrophilic NCO prepolymers are known per se. They are used for the medical treatment of wounds and are used e.g. used as wound dressings. They have the advantage of keeping especially dry wounds in a controlled manner moist, which has a favorable effect on wound healing.

DE 10 2006 050 793 describes polyurethane hydrogels based on aliphatic NCO polyether prepolymers. The hydrogels are also used as adhesion barriers. However, the described systems are not or at least very slowly biodegradable in the body. In general, mining takes longer than six months. An adhesion barrier, on the other hand, should be broken down within a few months as it is only intended to temporarily protect the organs from growing together during the wound healing process. , ,

The object underlying the invention was thus to produce a biocompatible adhesion barrier, which is biodegraded in a period of less than 6 months, the resulting degradation products must not have cell and tissue toxicity.

This object is achieved by a hydrogel based on polyurethane or polyurethane urea, which has hydrolyzable functional groups in the polymer chain, wherein the hydrogel by reaction of

A) Polyisocyanate prepolymers having the hydrolyzable groups in the polymer chain

B) water

C) optionally hydroxy-amino compounds having at least one tertiary amino group and at least three hydroxy groups

D) optionally catalysts and

E) optionally auxiliaries and additives, is obtainable and the Polyisocyanatprepolymere A) by reaction of

A I) polyisocyanates with

A2) Polyols which have the hydrolyzable groups in the polymer chain are obtainable, characterized in that the polyols A2) are polyesters and / or polyether esters which are liquid at room temperature and a shear viscosity of 200 to 8000 measured according to DIN 53019 at 23 ° C mPas, preferably from 400 to 4000 mPas.

For the purposes of the invention, a hydrolyzable group is understood to mean a group which, under physiological conditions, can be split into at least two separate subgroups in humans and mammals for an average period of less than 6 months.

The hydrogels of the invention are biocompatible, i. neither they themselves nor their degradation products show any cell or tissue toxicity. In addition, they are biodegraded in less than 6 months.

The specific polyether esters and / or polyesters used according to the invention are characterized in that they are easy to process. , ,

The polyetheresterpolyols and / or the polyesters may have a hydroxyl number of 20 to 140 mg OH / g, preferably of 20 to 100 mg OH / g and / or an acid number of 0.05 to 10 mg KOH / g, preferably of 0, 1 to 3 mg KOH / g and more preferably from 0.15 to 2.5 mg KOH / g. The polyols A2) may preferably have an average OH functionality of 2 to 4.

Preferably, the hydrolyzable functional groups are ester, acetal and / or carbonate groups.

The preparation of suitable polyester polyols is described, for example, in EP 2 095 832 A1. For polyether ester synthesis, mixtures of the higher molecular weight and the low molecular weight polyols can also be used.

Such molar excess low molecular weight polyols are polyols having molecular weights of 62 to 299 daltons, having 2 to 12 carbon atoms and hydroxyl functionalities of at least 2, which may further be branched or unbranched and whose hydroxyl groups are primary or secondary. These low molecular weight polyols may also have ether groups. Typical representatives are ethylene glycol, propanediol 1, 2, propanediol 1, 3, butanediol 1, 4, butanediol-2,3, 2-methyl-propanediol 1, 3, pentanediol 1, 5, hexanediol-1, 6 , 3-methyl-pentanediol-l, 5, 1, 8-octanediol, 1, 10-decanediol, 1, 12-dodecanediol, cyclohexanediol, diethylene glycol, triethylene glycol and higher homologs, dipropylene glycol, tripropylene glycol and higher homologues, glycerol, 1 , 1, 1-trimethylolpropane, and oligo-tetrahydrofurans with hydroxyl end groups. Of course, mixtures can be used within this group.

Molar excess high molecular weight polyols are polyols having molecular weights of 300 to 3000 daltons, which are obtained by ring-opening polymerization of epoxides, preferably ethylene-propylene oxide and / or butene oxide, as well as acid-catalyzed, ring-opening polymerization of tetrahydrofuran.

As polyols A2) it is also possible, for example, to use polyester ether polyols based on ester initiators. For their preparation, double metal cyanide compounds ("DMC catalysts") can be used for the alkylene oxide addition to ester-based starter compounds with Zerewitoff-active hydrogen atoms.The standard method of base-catalyzed addition of alkylene oxides can not be used in this case because it is too a hydrolysis of the starting compounds would lead. Hydrogen bonded to N, O or S is referred to as "Zerewitinoff-active" hydrogen (sometimes referred to as "active hydrogen") when it reacts with methyl magnesium iodide according to a method discovered by Zerewitinoff to provide methane Hydrogens are compounds containing carboxyl, hydroxyl, amino, imino or thiol groups as functional groups.

With the use of highly active DMC catalysts, e.g. in US Pat. No. 5,470,813, EP-A 700 949, EP-A 743 093, EP-A 761 708, WO 97/40086, WO 98/16310 and WO 00/47649, polyester-polyester production is at very low catalyst concentrations (25 ppm or less) possible, so that separation of the catalyst from the finished product is no longer required. In addition, polyester ether polyols based on propylene oxide or based on propylene oxide / ethylene oxide mixed block structures with very high molar masses can be prepared by DMC catalysis.

In general, the starter compounds initially introduced in an autoclave are reacted under an inert gas atmosphere at temperatures of 60-180 ° C., preferably at 100-170 ° C., in the presence of the alkylene oxide addition catalyst with alkylene oxides, the alkylene oxides being fed to the reactor in the usual manner be supplied in such a way that the safety pressure limits of the reactor system used are not exceeded. It is recommended that the alkylene oxide metering phase be preceded by an additional stripping step while passing in inert gases in order to remove any traces of water or other low molecular weight impurities which disturb the DMC catalysis from the starting medium.

Usually, the reactions are carried out in the pressure range from 10 mbar to 10 bar. After the end of the alkylene oxide metering phase, a post-reaction phase is followed, in which residual alkylene oxide reacts. The end of this post-reaction phase is reached when no further pressure drop can be detected in the reaction vessel. For complete removal of unreacted epoxides, the post-reaction phase can be followed by a vacuum or stripping step while passing in inert gases or steam.

Suitable alkylene oxides are, for example, ethylene oxide, propylene oxide, 1,2-butylene oxide or 2,3-butylene oxide, styrene oxide, 1,2-dodecene oxide and glycidyl ester or glycidyl ether derivatives. Preference is given to using propylene oxide, ethylene oxide and 1,2-butylene oxide. The various alkylene oxides can be metered in a mixture or in blocks. Products containing ethylene oxide endblocks are characterized, for example, by increased levels of primary end groups, which impart increased isocyanate reactivity to the systems. Preference is given to products in whose preparation ethylene oxide is used in amounts of> 50% by weight, more preferably> 60% by weight, based on the total amount of the metered epoxides. Suitable starter compounds containing Zerewitinoff-active hydrogen atoms have functionalities of 2 to 4. They are prepared analogously to the polyester polyols, as described in EP 2 095 832 A1), from hydroxy- or amino-functional low molecular weight compounds by esterification. Examples of hydroxy-functional starter compounds are propylene glycol, ethylene glycol, diethylene glycol, dipropylene glycol, 1, 2-butanediol, 1, 3-butanediol, 1, 4-butanediol, hexanediol, pentanediol, 3-methyl-l, 5-pentanediol, 1, 12 -Dodecanediol, glycerol, trimethylolpropane, triethanolamine, pentaerythritol, hydroquinone, catechol, resorcinol, bisphenol F, bisphenol A and 1, 3,5-tri-hydroxybenzene, examples of aminofunctional starter compounds are ammonia, ethanolamine, diethanolamine, isopropanolamine, diisopropanolamine, Ethylenediamine, hexamethylenediamine, aniline, the isomers of toluidine, the isomers of diaminotoluene and the isomers of diaminodiphenylmethane. In addition, ring-opening products of cyclic carboxylic acid anhydrides and polyols can be used as starter compounds. Examples are ring opening products of phthalic anhydride, succinic anhydride, maleic anhydride on the one hand and ethylene glycol, diethylene glycol, 1, 2-butanediol, 1, 3-butanediol, 1, 4-butanediol, hexanediol, pentanediol, 3-methyl-l, 5-pentanediol, 1 , 12-dodecanediol, glycerol, trimethylolpropane or pentaerythritol on the other hand. Of course, mixtures of different starter compounds can be used.

The starter compounds have OH numbers <400 mg KOH / g, preferably <300 mg KOH / g. Alternatively, polyetherester polyols can also be obtained directly by DMC catalysis by ring-opening copolymerization of alkylene oxides and lactones or cyclic dicarboxylic acid anhydrides (such as phthalic anhydride, succinic anhydride, etc.) to polyfunctional starter compounds. Suitable processes are similar to those described above for the DMC-catalyzed preparation of polyetherester polyols, and as additional monomers, suitable lactones and / or cyclic dicarboxylic anhydrides are simply metered in addition to the alkylene oxides. Reference may be made in this connection to DE 17 70 548 A, US 5, 145,883 and US 5,032,671.

Suitable polyester ether polyols have a hydroxyl number of from 5 to 140 mg KOH / g, preferably from 20 to 130 mg KOH / g. The polyether polyols optionally used as blending component in A2) have a molecular weight of 100 to 2000 g / mol, preferably 100 to 1000 g / mol, particularly preferably 100 to 400 g / mol. Their polyether chains consist partly or wholly of polyethylene oxide units. - -

If polyether polyols are used in addition to the polyesters or polyether esters in A2), their proportion is at most 70% by weight, preferably at most 50% by weight, based on the total component A2).

Preferably, the mass fraction attributable to ethylene oxide of the entire component A2) is preferably 40 to 95% by weight, particularly preferably 60 to 90% by weight.

The component A2) preferably also has an ester group concentration (in moles per kg) of from 0.5 to 5.5, particularly preferably from 1 to 3.5.

The component A2) can also have carbonate structural units. Depending on the type of polyols used for carbonate formation, different types of carbonate polyols result: For example, when oligoester polyols are carbonated, polyestercarbonate polyols are obtained. For example, the oligoesters contain ether groups, e.g. from oligoethylene glycols, e.g. Diethylene glycol, then polyetherestercarbonate polyols are obtained, etc.

The carbonation reaction per se is known to the person skilled in the art. As Carbonylquelle in particular diphenyl carbonate, dimethyl carbonate, but also phosgene or chloroformate in question. Preference is given to diphenyl carbonate (DPC) and dimethyl carbonate, most preferably diphenyl carbonate (DPC).

The polyisocyanates A I) may preferably have an average NCO functionality of from 2 to 2.6 and more preferably from 2 to 2.4.

The polyisocyanates AI) may be monomeric aliphatic and / or cycloaliphatic di- or triisocyanates, in particular 1,4-butylene diisocyanate (BDI), 1,6-hexamethylene diisocyanate (HDI), isophorone diisocyanate (IPDI), 2,2,4- and / or 2,4,4-trimethylhexa-methylene diisocyanate, the isomeric bis (4,4'-isocyanatocycIohexyi) -methanes and / or mixtures thereof any isomer content, 1, 4-cyclohexylene diisocyanate, 4-isocyanatomethyl-l, 8-octane diisocyanate (Nonane triisocyanate), and / or alkyl-2,6-diisocyanatohexanoate (lysine diisocyanate) with C 1 -C 8 -alkyl groups and / or mixtures of the above polyisocyanates.

Very particular preference is given to hexamethylene diisocyanate

The polyisocyanate prepolymers A) preferably contain less than 0.5% by weight, in particular less than 0.03% by weight, of monomeric di- and / or triisocyanate. This can be achieved, for example, by preparing the polyisocyanate prepolymers in the presence of an excess of di- and / or triisocyanate and then removing unreacted di- and / or triisocyanate by means of thin-layer distillation. It is further preferred if the polyisocyanate prepolymers A) have an NCO functionality of from 2 to 6 and preferably from 3 to 4.

In principle, the per se known catalysts such as amines or tin compounds and stabilizers such as benzoyl chloride, isophthaloyl chloride, di-butyl phosphate or methyl tosylate can be used in the preparation of prepolymer.

The polyisocyanate prepolymers A) preferably have a miscibility with water at 25 ° C. of at least 2% by weight, based on the resulting mixture. More preferably, they are miscible at 25 ° C in any ratio with water, whereby a homogeneous and clear mixture is obtained. Examples of hydroxy-amino compounds C) are amino alcohols such as triethanolamine or tripropanolamine or polyalkylene oxides started on ammonia, di- or polyamines or aminoalcohols, where, for example, ethylene oxide, propylene oxide but also butylene oxide or styrene oxide are used individually, mixed or block-wise structure can be used.

In the preparation of the hydrogels, water B) is used in amounts such that a gel formation is achieved, which is determined experimentally in preliminary experiments in preliminary cases. Based on the amount by weight of the compounds used in a) and b) (corresponding to one part by weight), 2 to 50 parts by weight, more preferably 4 to 19 parts by weight of water, are preferably used.

For hydrogel preparation, water B) is optionally mixed with hydroxy-amino compounds C), the hydroxy-amino compounds C) being used in amounts of 0.1 to 5% by weight, preferably 0.1 to 1%, of the total amount of A) and C) are used. The mixture is then added to the polyisocyanate prepolymers A) and stirred until a clear solution is formed. Usually, the stirring is carried out at room temperature, but can also be carried out at temperatures above room temperature at temperatures of 23 to 40 or at temperatures of 30 to 80 ° C. Furthermore, the temperature may be below room temperature, for example at 5 to 23 ° C or from -10 to + 10 ° C.

As agitator, a magnetic stirrer with Kreuzrührfisch has proven to be advantageous, but it can also be a Speedmixer or a laboratory standard Flügel- or Gitterrührer be used. The choice of mixing unit depends in each case, for example, on the amount to be mixed and their viscosity.

When stirring can also be carried out under a protective gas atmosphere, for example under nitrogen. Normally, work is not carried out under a protective gas atmosphere. Furthermore, under Normal pressure are mixed. But it can also be stirred under slightly elevated pressure, for example at 1013 to 1035 mbar or under reduced pressure, for example at 800 to 1013 mbar.

For better visibility of the gel formed on the tissue, the hydrogel can be stained. For this purpose, z. As methylene blue or the food color Brilliant Blue FCF. The dye is preferably added to the water B).

Of course, pharmacologically active agents such. B. antiphlogistics b) analgesics with and without anti-inflammatory action c) antimicrobial substances d) vasodilators e) growth factors.

The polyisocyanate prepolymers A) have a measured according to DIN EN ISO 1 1909 average NCO content of 2 to 10 wt .-%, preferably from 2.5 to 8 wt .-%.

Another object of the invention is a process for the preparation of a hydrogel, in which i) polyisocyanates are reacted with polyols having hydrolyzable groups in the polymer chain to Polyisocyanatprepolymeren and ii) water optionally with compounds containing at least one tertiary amino group and at least iii) the mixture of step ii) is added to the prepolymers of step i) and stirred.

A hydrogel obtainable by the process is also the subject of the invention.

The invention likewise relates to the use of the hydrogels as an adhesion barrier and to their use as coating compositions for sealing, bonding or covering cell tissues, where cell tissue can be both human tissue tissue and animal cell tissue. If the hydrogel is to be used as an adhesion barrier, it may be useful to color one or more of the components A) to C) used in order to make the barrier more easily visible.

In the in vivo application of a coating for producing a postoperative adhesion barrier, the necessary components are applied to the organ to be protected using a two-chamber dosing system with a suitable applicator. One chamber contains the Isocyanatprepolymer A, the second chamber water (B), optionally mixed with the hydroxy xyaminoverbindung C, and D and E. If pharmacologically active substances are used, they are formulated in the aqueous component. The hydrogel forms a protective polymer film on the organ. This adheres to the organ surface without penetrating the tissue. The film can be removed mechanically without damaging the tissue.

- -

Used devices and analysis methods:

Viscometer: MCR 51, Anton Paar, determination according to DIN EN ISO 3219 / A.3 Hydroxyl value: Determination according to DIN 53240

Acid value: Determination according to DIN 53402

Raw materials used: Polyether L5050: Bifunctionally started EO-PO polyether, Bayer MaterialScience

AG, with a hydroxyl number of about 57 mg OH / g.

Polyether L300: Bifunctionally started EO polyether, Bayer MaterialScience

AG, with a hydroxyl number of about 190 mg KOH / g.

Desmophen

VP.PU 41 WB01: Trifunctional started polyether, Bayer MaterialScience AG, with a hydroxyl number of approx. 37 mg KOH / g.

Polyether V657: Trifunctional started polyether, Bayer MaterialScience AG, with a hydroxyl number of approx. 255 mg KOH / g. ε-caprolactone: Perstorp HDI

(Hexamethylene diisocyanate): Bayer MaterialScience AG

Benzoyl chloride: Aldrich

Adipic acid: BASF

Pentaerythritol: Aldrich

Tin dichloride dihydrate: Aldrich

Ethylene oxide: Gerling, Wood & Co Butylene oxide: Aldrich Propylene oxide: Chemogas Trimethylolpropane: Aldrich Irganox 1076: Ciba Dibutyl phosphate: Aldrich diphenyl carbonate: Bayer MaterialScience AG DMC catalyst: double metal cyanide catalyst containing zinc hexacyanocobaltate, tert-butanol and polypropylene glycol having a number average molecular weight of 1000 g / mol; described in EP-A 700 949

Synthesis of Polvesteretherprepolvmere

example 1

In a 4-liter 4-necked flask equipped with a heater, mechanical stirrer, internal thermometer and reflux condenser, 762 g (5.6 mol) of pentaerythritol, 2554 g (22.4 mol) of ε-caprolactone and 66 mg (20 ppm) Zinndichlorid dihydrate under Stickstoffuberschleierung at 100 ° C presented. The temperature is raised to 200 ° C over 1 hour and the reaction is completed for an additional 20 hours under these conditions. The compound obtained has the following properties: hydroxyl number: 373 mg KOH g

Acid value: 0.5 mg KOH / g

Viscosity: 190 mPas (75 ° C)

Example 2 179.3 g of the compound from Example 1 and 0.52 g of DMC catalyst (prepared according to EP-A 700 949) under nitrogen are introduced into a 2 liter stainless steel pressure reactor and then taken up Heated to 130 ° C. After 1 h stripping with nitrogen at 0.1 bar is started at 130 ° C with the dosage of ethylene oxide and butylene oxide in a weight ratio of 75/25. After 618 g of ethylene oxide and 206 g of butylene have been metered within 2 h, the dosage is interrupted and 425.5 g of product removed from the reactor. Subsequently, at 130 ° C within 2 h further 694 g of ethylene oxide and 231 g of butylene oxide are metered. After a post-reaction time of 45 min at 130 ° C volatile components are distilled off at 130 ° C for 30 min in vacuo and the reaction mixture is then cooled to room temperature.

Product features:

OH number: 25.5 mg KOH / g Viscosity (25 ° C): 5780 mPas

Example 3, (Prepolvmer 3)

276 g of HDI and 1 g of benzoyl chloride are placed in a 1 liter four-necked flask. Within 2 h 724 g of the compound from Example 2 are added at 80 ° C. and stirred for 1 h. The excess HDI is then distilled off by thin-layer distillation at 130 ° C. and 0.13 mbar. The prepolymer 1 is obtained with an NCO content of 1.54% by weight. The residual monomer content determined according to DIN EN ISO 10283 was <0.03 wt .-% HDI. Viscosity: 15,600 mPas (23 ° C).

Example 4

In a 4-liter 4-neck flask equipped with a heater, mechanical stirrer, internal thermometer and reflux condenser 91 1 g (6.8 mol) of 1, 1, 1-trimethylolpropane, 2326 g (20.4 mol) of ε-caprolactone and 64 mg (20 ppm) of tin dichloride dihydrate under nitrogen blanketing at 100 ° C presented. The temperature is raised to 200 ° C. over the course of 1 hour and the reaction is completed for a further 20 hours under these conditions. The compound obtained has the following properties:

Hydroxyl number: 346 mg KOH / g

Acid number: 0.2 mg KOH g

Viscosity: 1510 mPas (25 ° C), 100 mPas (75 ° C) - -

Example 5

In a 2 liter stainless steel pressure reactor, 175.5 g of the compound from Example 4 and 0.48 g of DMC catalyst (prepared according to EP-A 700 949) are introduced under nitrogen and then heated to 130 ° C. After 1 h stripping with nitrogen at 0, 1 bar is started at 130 ° C with the dosage of ethylene oxide and butylene oxide in the weight ratio 75/25. After 618 g of ethylene oxide and 206 g of butylene have been metered within 2 h, the dosage is interrupted and 382.5 g of product removed from the reactor. Subsequently, at 130 ° C within 2 h further 662 g of ethylene oxide and 221 g of butylene oxide are metered. After a reaction time of 45 minutes at 130 ° C., volatile constituents are distilled off at 130 ° C. for 30 minutes in vacuo and the reaction mixture is then cooled to room temperature.

Product features:

Hydroxyl number: 25, 1 mg OH / g

Viscosity (25 ° C): 3170 mPas

Example 6, (prepolymer 6)

273 g of HDI and 1 g of benzoyl chloride are placed in a 1 liter four-necked flask. 727 g of the precursor from Example 5 are added at 80 ° C. within 2 h and stirring is continued for 1 h. Subsequently, the excess HDI is distilled off by thin-layer distillation at 130 ° C. and 0.13 mbar. The prepolymer 6 is obtained with an NCO content of 1.7% by weight. The residual monomer content (determined according to DIN EN ISO 10283) was <0.03 wt .-% HDI. Viscosity: 12,200 mPas (23 ° C)

Example 7

In a 2 liter stainless steel pressure reactor 198.2 g of a trifunctional starting polyether compound (composition: glycerol <r PO / EO (40/60), OH number = 260 mg KOH / g) and 0.12 g of DMC catalyst ( prepared according to EP-A 700 949) under nitrogen and then heated to 130 ° C. After 1 h stripping with nitrogen at 0, 1 bar is started at 130 ° C with the dosage of ethylene oxide, propylene oxide and caprolactone. After 561 g of ethylene oxide, 160 g of propylene oxide and 100 g of ε-caprolactone have been added within 2.5 h, the caprolactone metering is interrupted and then at 130 ° C within 0.5 h still further 140 g of ethylene oxide and 40 g of propylene oxide. The weight ratio of the dosed Mo monomer is thus: ethylene oxide / propylene oxide / ε-caprolactone = 70/20/10. After a reaction time of 2 h at 130 ° C volatile components are distilled off at 130 ° C for 30 min in vacuo and the reaction mixture is then cooled to room temperature.

Product properties: Hydroxyl value: 36.6 mg KOH / g

Viscosity (25 ° C): 1427 mPas

Example 8, (prepolymer 8)

732.4 g of HDI and 3.7 g of benzoyl chloride are placed in a 3 1 four-necked flask. Within 2 h 1532 g of the precursor from Example 7 are added at 80 ° C and stirred for 1 h. Subsequently, the excess HDI is distilled off by thin-layer distillation at 130 ° C. and 0.13 mbar. The prepolymer 8 is obtained with an NCO content of 2.47% by weight. The residual monomer content (GC) was 0.06% by weight HDI.

Example 9

In a 2-liter stainless steel pressure reactor, 201.4 g of a trifunctional starting polyether compound (composition: glycerol <r PO / EO (30/70), OH number = 37.0 mg OH / g) and 0.32 g of DMC catalyst ( prepared according to EP-A 700 949) under nitrogen and then heated to 130 ° C. After 1 h stripping with nitrogen at 0, 1 bar is started at 130 ° C with the dosage of ethylene oxide, propylene oxide, ε-caprolactone and glycerol. After first 768 g of ethylene oxide, 219 g of propylene oxide, 137 g of ε-caprolactone and 28 g of glycerol were added within 3 h, the ε-CaproIacton- and glycerol dosage is interrupted and then at 130 ° C within 0.5 h still a further 165 g of ethylene oxide and 33 g of propylene oxide are metered in. After a reaction time of 30 minutes at 130 ° C volatile constituents are distilled off at 130 ° C for 30 min in vacuo and the reaction mixture is then cooled to room temperature.

Product features:

Hydroxyl number: 34.5 mg KOH / g

Viscosity (25 ° C): 2513 mPas Example 10, (prepolymer 10)

85, 17 g of HD1 and 0.25 g of benzoyl chloride are placed in a 1 l four-necked flask. Within 2 h 164.58 g of the precursor from Example 9 are added at 80 ° C and stirred for 1 h. Subsequently, the excess HDI is distilled off by thin-layer distillation at 130 ° C. and 0.13 mbar. The prepolymer 10 is obtained with an NCO content of 1.89% by weight. The residual monomer content (GC) was <0.03 wt .-% HDI.

Example 11

In a 4-liter four-necked flask equipped with a heated mushroom, mechanical stirrer, internal thermometer and reflux condenser are 1650 g (2.5 mol) of polyether V657, 570 g (5 mol) of ε-caprolactone and 45 mg (20 ppm) of tin dichloride dihydrate under nitrogen blanketing at 100 ° C presented. The temperature is raised to 200 ° C over 1 hour and the reaction is completed for an additional 20 hours under these conditions. The compound obtained has the following properties: hydroxyl number: 191 mg OH / g

Acid value: 0.5 mg KOH / g

Viscosity: 430 mPas (25 ° C)

EXAMPLE 12 664 g (7 mol) of glycerol, 1596 g (14 mol) of ε-caprolactone and 45 mg (20 ppm) of tin dichloride dihydrate are placed in a 4 liter 4-necked flask equipped with a heated mushroom, mechanical stirrer, internal thermometer and reflux condenser Nitrogen over-veiling presented at 100 ° C. The temperature is raised to 200 ° C over 1 hour and the reaction is completed for an additional 20 hours under these conditions. The compound obtained has the following properties:

Hydroxyl number: 493 mg KOH / g

Acid value: 0.2 mg KOH / g

Viscosity: 240 mPas (50 ° C), 80 mPas (75 ° C) - -

Example 13

In a 20 liter stainless steel pressure reactor, 1800 g of the precursor from Example 11 and 0.9 g of DMC catalyst (prepared according to EP-A 700 949) are introduced under nitrogen and then heated to 130 ° C. After 1 h stripping with nitrogen at 0, 1 bar is started at 130 ° C with the dosage of ethylene oxide and propylene oxide in the weight ratio 69/31. After 5088 g of ethylene oxide and 2309 g of propylene oxide have been metered in within 3 hours, after a reaction time of 60 minutes at 130 ° C., volatile constituents are distilled off in vacuo for 30 minutes and the reaction mixture is then cooled to room temperature.

Product properties: Hydroxyl value: 37.4 mg KOH / g

Viscosity (25 ° C): 1275 mPas

Example 14

1566 g of the precursor from Example 12 and 1.0 g of DMC catalyst (prepared according to EP-A 700 949) are initially introduced under nitrogen and then heated to 130 ° C. in a 20 liter stainless steel pressure reactor. After 1 h stripping with nitrogen at 0, 1 bar is started at 130 ° C with the dosage of ethylene oxide and propylene oxide in the weight ratio 69/31. After 8484 g of ethylene oxide and 3748 g of propylene oxide have been metered in within 3 h, after a reaction time of 60 min at 130 ° C., volatile constituents are distilled off in vacuo for 30 min and then the reaction mixture is cooled to room temperature.

Product features:

Hydroxyl number: 55.2 mg KOH / g

Viscosity (25 ° C): 944 mPas

Example 15

In a 20-liter stainless steel pressure reactor 1403 g of the precursor of Example 1 and 4.8 g of DMC catalyst (prepared according to EP-A 700 949) are introduced under nitrogen and then heated to 130 ° C. After 1 h stripping with nitrogen at 0, 1 bar is at 130 ° C with the dosage started from ethylene oxide and propylene oxide. After 9124 g of ethylene oxide and 2603 g of propylene oxide have been metered in within 3 hours, the metering is interrupted and, after a reaction time of 60 minutes, 8436 g of product are removed from the reactor. Subsequently, at 130 ° C within 3 h further 1498 g of ethylene oxide and 642 g of propylene oxide are dosed (the dosage in 2 blocks has only procedural reasons: Due to the large OH number difference between the starter and the end product is to be used for a one-step dosing starter too small for the type of reactor used) After a reaction time of 60 minutes at 130 ° C., volatile constituents are distilled off in vacuo for 30 minutes and the reaction mixture is then cooled to room temperature. Product features:

Hydroxyl number: 24.7 mg KOH / g

Viscosity (25 ° C): 4403 mPas

Example 16 1436 g of the precursor from Example 4 and 4.8 g of DMC catalyst (prepared according to EP-A 700 949) under nitrogen are introduced into a 20 liter stainless steel pressure reactor and then heated to 130 ° C. After 1 h stripping with nitrogen at 0.1 bar is started at 130 ° C with the dosage of ethylene oxide and propylene oxide. After 9310 g of ethylene oxide and 2553 g of propylene oxide have been metered in within 3 hours, the metering is interrupted and, after a reaction time of 60 minutes, 9506 g of product are removed from the reactor. Subsequently, at 130 ° C within 3 h further 1338 g of ethylene oxide and 577 g of propylene oxide are metered (the dosage in 2 blocks has only procedural reasons: Due to the large OH number difference between starter and end product is to be used for Einschrittdosierung starter too small for the type of reactor used) After a reaction time of 60 minutes at 130 ° C., volatile constituents are distilled off in vacuo for 30 minutes and the reaction mixture is then cooled to room temperature.

Product features:

Hydroxyl number: 24.5 mg KOH / g

Viscosity (25 ° C): 3806 mPas Example 17, prepolymer 17

359 g of HDI and 1 g of benzoyl chloride are placed in a 2 1 four-necked flask. Within 2 h .641 g of the precursor from Example 13 are added at 80 ° C. and stirred for 1 h. The excess HDI is then distilled off by thin-layer distillation at 130 ° C. and 0.13 mbar. The prepolymer 17 is obtained with an NCO content of 2.27% by weight and a viscosity of 4570 mPas (23 ° C.). The residual monomer content was <0.03 wt .-% HDI.

Example 18, prepolymer 18

453 g of HDI and 1 g of benzoyl chloride are placed in a 2 1 four-necked flask. 547 g of the precursor from Example 14 are added at 80 ° C. within 2 h and stirring is continued for 1 h. Subsequently, the excess HDI is distilled off by thin-layer distillation at 130 ° C. and 0.13 mbar. The prepolymer 18 is obtained with an NCO content of 3.32% by weight and a viscosity of 3430 mPas (23 ° C.). The residual monomer content was <0.03 wt .-% HDI.

Example 19, prepolymer 19

270 g of HDI and 1 g of benzoyl chloride are placed in a 2 1 four-necked flask. Within 2 h, 730 g of the precursor from Example 15 are added at 80 ° C. and stirred for 1 h. Subsequently, the excess HDI is distilled off by thin-layer distillation at 130 ° C. and 0.13 mbar. The prepolymer 19 is obtained with an NCO content of 1.66% by weight and a viscosity of 20,200 mPas (23 ° C.). The residual monomer content was <0.03 wt .-% HDI.

Example 20, prepolymer 20

360 g of HDI and 1 g of benzoyl chloride are placed in a 2 1 four-necked flask. Within 2 h 640 g of the precursor from Example 16 are added at 80 ° C and lh stirred. Subsequently, the excess HDI is distilled off by thin-layer distillation at 130 ° C. and 0.1 torr. The prepolymer 20 is obtained with an NCO content of 2.3% by weight and a viscosity of 5960 mPas (23 ° C.). The residual monomer content was <0.03 wt .-% HDI. - 1 -

Example 21

In a 4-liter four-necked flask equipped with a heated mushroom, mechanical stirrer, internal thermometer, 40 cm packed column, column head, descending intensive condenser and membrane vacuum pump are 1 152 g (1, 95 mol) of polyether L300, 1535 g (0.34 mol ) Desmophen VP.PU 41 WB01, 98 g (0.73 mol) of 1, 1, 1-trimethylolpropane and 285 g (1, 95 mol) of adipic acid weighed under nitrogen overweight and heated at 200 ° C under atmospheric pressure, distilling off water. After 4 hours, 60 mg (equivalent to 20 ppm) of tin dichloride dihydrate are added under nitrogen blanketing. The pressure is reduced in the course of 1 hour to 15 mbar and completes the reaction for a further 48 hours under these conditions. The product has the following properties:

Hydroxyl number: 57 mg KOH / g

Acid value: 1, 1 mg KOH / g

Viscosity: 4580 mPas (25 ° C), 1310 mPas (50 ° C), 570 mPas (75 ° C)

Example 22, Prepolmer 22

101, 43 g of HDI and 0.28 g of benzoyl chloride are placed in a 1 1 four-necked flask. Within 2 hours 148.29 g of the precursor from Example 21 are added at 80 ° C and stirred for 1 h. Subsequently, the excess HDI is distilled off by thin-layer distillation at 130 ° C. and 0.13 mbar. The prepolymer 22 is obtained with an NCO content of 3.37% by weight. The residual monomer content was <0.03 wt .-% HDI.

Example 23

In a 4-liter four-necked flask equipped with a heated mushroom, mechanical stirrer, internal thermometer, 40 cm packed column, column head, descending intensive condenser, and membrane vacuum pump, 1078 g (1.82 mol) of polyether L300, 1533 g (0.34 Mol) Desmophen VP.PU 41 WB01, 146 g (1, 09 mol) of 1, 1, 1-trimethylolpropane, 155 g (1, 06 mol) of adipic acid and 155 g (0.77 mol) of sebacic acid weighed under nitrogen and at atmospheric pressure heated to 200 ° C, with water distilled off. After 4 hours, 60 mg (20 ppm) of stannous chloride dihydrate are added under nitrogen blanketing. The pressure is reduced in the course of 1 hour to 15 mbar last and completes the reaction for a further 48 hours _2Q these conditions. It is cooled to 80 ° C and stirred 300 mg (100 ppm) of dibutyl phosphate. The product has the following properties:

Hydroxyl number: 76 mg KOH / g

Acid value: 0.9 mg KOH / g Viscosity: 2710 mPas (25 ° C.), 790 mPas (50 ° C.), 350 mPas (75 ° C.)

Example 24, Prepolvmer 24

132.96 g of HDI and 0.25 g of benzoyl chloride are placed in a 1 1 four-necked flask. Within 1 h, 1.77 g of the precursor from Example 23 are added at 80 ° C. and stirring is continued for 1 h. Subsequently, the excess HDI is distilled off by thin-layer distillation at 130 ° C. and 0.13 mbar. The prepolymer 24 is obtained with an NCO content of 4.27%. The residual monomer content was <0.03% HDI.

Example 25 In a 4-liter four-necked flask equipped with a heated mushroom, mechanical stirrer, internal thermometer, 40 cm packed column, column head, descending intensive condenser and membrane vacuum pump, 1894 g (0.95 mol) of polyether L5050, 341 g (0.58 Mol) polyether L300, 248 g (1.24 mol) of polyethylene glycol 300, 213 g (2.32 mol) of glycerol, 403 g (2.76 mol) of adipic acid and 883 g (7.75 mol) of ε-caprolactone were weighed under nitrogen blanketing and heated at normal pressure to 200 ° C, with distilling off water. After 4 hours, 60 mg (20 ppm) of stannous chloride dihydrate are added under nitrogen blanketing. The pressure is reduced in the course of 1 hour to 15 mbar last and completes the reaction for another 48 hours under these conditions. It is cooled to 80 ° C and stirred 300 mg (100 ppm) of dibutyl phosphate. The product has the following properties: Hydroxyl value: 92 mg KOH / g

Acid value: 0.3 mg KOH / g

Viscosity: 2470 mPas (25 ° C), 640 mPas (50 ° C), 260 mPas (75 ° C) Example 26, prepolymer 26

173.46 g of HDI and 0.3 g of benzoyl chloride are placed in a 1 liter four-necked flask. Within 2 hours 126.24 g of the precursor from Example 25 are added at 80 ° C and stirred for 1 h. Subsequently, the excess HDI is distilled off by thin-layer distillation at 130 ° C. and 0.13 mbar. The prepolymer 26 is obtained with an NCO content of 4.71% by weight. The residual monomer content was <0.03 wt .-% HDI.

Example 27

In a 10-liter four-necked flask equipped with a heated mushroom, mechanical stirrer, internal thermometer, 40 cm packed column, heatable distillation bridge, heatable descending intensive cooler, and membrane vacuum pump and oil pump are 375 g (2.50 mol) of triethylene glycol, 4663 g (1, 03 mol) of polyether VP.PU 41 WB01, 385 g (3.38 mol) of ε-caprolactone and 75 mg of dibutyltin oxide weighed and stirred for 20 hrs. Under nitrogen at 200 ° C. The mixture is cooled to 150 ° C. and gives 530 g (2.65 mol) of polyethylene glycol 200, 355 g (2.65 mol) of 1,1,1-trimethylolpropane, 103 g (5, 15 mol) of diphenyl carbonate and 75 mg of dibutyltin oxide to. The mixture is stirred under nitrogen at atmospheric pressure for one hour at 180 ° C, cooled to 120 ° C, reduces the pressure to 15 mbar and heated bridge and condenser with 45 ° C warm water, with phenol distilled off. In the course of 10 hours, the temperature is raised to 200 ° C, distilling off 871 g of phenol. By means of an oil pump, the pressure is reduced to 1 mbar and the reaction is completed in the course of 2 hours, with a further 107 g of phenol distilling off. It is cooled to 80 ° C and stirred 640 mg (100 ppm) of dibutyl phosphate. The product has the following properties:

Hydroxyl number: 89 mg KOH / g

Acid value: 0.2 mg KOH / g

Viscosity: 2690 mPas (25 ° C), 740 mPas (50 ° C), 310 mPas (75 ° C)

Free phenol: 0.02 wt% (GC) Example 28, prepolymer 28

142.58 g of HDI and 0.25 g of benzoyl chloride are placed in a 1 liter four-necked flask. 107 g, 16 g of the precursor from Example 27 are added at 80 ° C. within 2 h and stirred for one hour. Subsequently, the excess HDI is distilled off by thin-layer distillation at 130 ° C and 0, 1 Torr. The prepolymer 28 is obtained with an NCO content of 4.92% by weight. The residual monomer content was <0.03 wt .-% HDI.

Example 29

In a 2-liter four-necked flask equipped with heated mushroom, mechanical stirrer, internal thermometer, 40 cm packed column, column head, descending intensive condenser and membrane vacuum pump, 141.7 g (1.2 mol) succinic acid, 720 g (1, Weighed 2 mol) of polyethylene glycol 600 and 25.4 g (0.27 mol) of glycerol under nitrogen blanketing and heated at normal pressure to 200 ° C, distilling off water. After 4 hours, 89 mg (100 ppm) of stannous chloride dihydrate are added under nitrogen blanketing. The pressure is reduced in the course of 1 hour to 15 mbar last and completes the reaction for another 48 hours under these conditions. It is cooled to 80 ° C and stirred 300 mg (100 ppm) of dibutyl phosphate. The product has the following properties:

Hydroxyl number: 46 mg KOH / g

Acid value: 0.6 mg KOH / g

Example 30, prepolymer 30

252 g of HDI and 0.62 g of benzoyl chloride are placed in a 2 1 four-necked flask. 365.2 g of the precursor from Example 29 are added at 80 ° C. within 2 h and stirring is continued for 1 h. Subsequently, the excess HDI is distilled off by thin-layer distillation at 130 ° C. and 0.13 mbar. This gives the prepolymer 30 with an NCO content of 3, 1 wt .-%. The residual monomer content was 0.09% by weight HDI, the viscosity 22,400 mPas (25 ° C.). Example 31

In a 2-liter V-ierhalskolben equipped with a heater, mechanical stirrer, internal thermometer, 40 cm packed column, column head, descending intensive condenser, and membrane vacuum pump 1 75.4 g (1, 4 mol) of adipic acid, 720 g (0 , 6 mol) of polyethylene glycol 600 and 34.8 g (0.12 mol) of trimethylolpropane under nitrogen blanketing and heated at atmospheric pressure to 200 ° C, distilling off water. After 4 hours, 90 mg (100 ppm) of stannous chloride dihydrate are added under nitrogen blanketing. The pressure is reduced in the course of 1 hour to 15 mbar last and completes the reaction for another 48 hours under these conditions. It is cooled to 80 ° C and stirred 300 mg (100 ppm) of dibutyl phosphate. The product has the following properties:

Hydroxyl number: 43 mg KOH / g

Acid value: 0.2 mg KOH / g

Example 32, prepolymer 32 400 g of HDI and 1, 02 g of benzoyl chloride are placed in a 2 l four-necked flask. 621.3 g of the precursor from Example 31 are added at 80 ° C. within 2 h and the mixture is stirred for 1 h. Subsequently, the excess HDI is distilled off by thin-layer distillation at 130 ° C. and 0.13 mbar. The prepolymer 32 is obtained with an NCO content of 2.99% by weight. The residual monomer content was <0.03 wt .-% HDI, the viscosity 28,000 mPas (25 ° C).

Preparation of hydrogels

For the preparation of the hydrogels, in each case 1 g of the corresponding prepolymer was stirred with a mixture of 8 g of water and 0.06 g of triethanolamine with a magnetic stirrer with cross-stirring fish for 1 min. The time (processing time) after which a solid gel was formed was measured. Prepolymer processing time [min]

3 4

6 9

8 4

10 6

17 4

18 8

19 3

20 10

22 5

24 5

26 7

28 3

30 4

32 9

Example 33, biodegradation of the hydrogels

The corresponding hydrogels were cured in a tube (diameter 0.5 cm, length 2 cm). The resulting 2.7 g test specimens were in each case 10 ml buffer solution (pH 7.4, Aldrich P-5368) for 48 h at 60 ° C in a shaking incubator with 150 U / min swelled. The samples were then rinsed with deionized water and blotted dry. The weight of the samples was registered as start weight. The samples were further equalized in 10 ml of buffer solution (pH 7.4, Aldrich P-5368) at 60 ° C and 37 ° C in a shaking incubator, respectively , -

Conditions shaken. The weight of the samples was determined weekly. The hydrogel was considered degraded if it had dissolved completely without sediment.

The samples were completely degraded after the following periods: gel from 30: 7 days (60 ° C), 14 days (37 ° C) gel from 20:35 days (60 ° C) gel from 18: 42 days (60 ° C ) Gel from 32: 7 days (60 ° C), 14 days (37 ° C)

Claims

claims

1. Hydrogel based on polyurethane or polyurethane urea, which has hydrolyzable functional groups in the polymer chain, wherein the hydrogel by reaction of

B) water

D) optionally catalysts and

E) optionally auxiliaries and additives, is obtainable and the Polyisocyanatprepolymere A) by reacting A 1) polyisocyanates with

A2) Polyols which have the hydrolyzable groups in the polymer chain are obtainable, characterized in that the polyols A2) are polyesters and / or polyether esters which are liquid at room temperature and a shear viscosity of 200 according to DIN 53019 at 23 ° C. to 8000 mPas, preferably from 400 to 4000 mPas.

2. Hydrogel according to claim 1, characterized in that the hydrolyzable functional groups are ester, acetal and / or carbonate groups.

3. Hydrogel according to one of claims 1 or 2, characterized in that the polyetherester and / or the polyesters have a hydroxyl number of 20 to 140 mg KOH / g, preferably from 20 to 100 mg KOH g and / or an acid number of 0 , 05 to 10 mg KOH g, preferably from 0.1 to 3 mg KOH g and particularly preferably from 0, 15 to 2.5 mg KOH / g.

4. Hydrogel according to one of claims 1 to 3, characterized in that the polyisocyanates AI) monomeric aliphatic and / or cycloaliphatic di- or Triisocya- nate, in particular 1, 4-butylene diisocyanate (BDI), 1, 6-hexamethylene diisocyanate (HDI), isophorone diisocyanate (IPDI), 2,2,4- and / or 2,4,4-trimethylhexamethylene diisocyanate, the isomeric bis ( 4,4'-isocyanatocyclohexyl) methanes and / or mixtures thereof any isomer content, 1, 4-cyclohexylene diisocyanate, 4-Isocyanatomethyl- l, 8-octane diisocyanate (nonane triisocyanate), and / or alkyl-2,6-diisocyanatohexanoate (lysine diisocyanate ) with Cl-C8-alkyl groups and / or mixtures of the above polyisocyanates.

5. Hydrogel according to one of claims 1 to 4, characterized in that the polyisocyanate cyanatprepolymere A) less than 0.5 wt .-%, preferably less than 0.03 wt .-% monomeric di- and / or triisocyanate.

6. Hydrogel according to one of claims 1 to 5, characterized in that the polyisocyanate prepolymers A) have an NCO functionality of 2 to 6, preferably from 3 to 4.

7. Hydrogel according to one of claims 1 to 6, characterized in that the hydroxy-amino compounds C) are tri-functional amino alcohols started Polyalky- lenoxide.

8. Hydrogel according to one of claims 1 to 7 for use as an adhesion barrier.

9. A process for preparing a hydrogel according to any one of claims 1 to 8, wherein i) polyisocyanates with polyols having hydrolyzable groups in the polymer chain are reacted to form Polyisocyanatprepolymeren and ii) water optionally with compounds containing at least one tertiary amino group and at least three hydroxyl groups are mixed iii) the mixture of step ii) is added to the prepolymers of step i) and stirred.