WO2012123425A1

WO2012123425A1 - Tissue adhesive based on prepolymers containing ester groups

Info

Publication number: WO2012123425A1
Application number: PCT/EP2012/054297
Authority: WO
Inventors: Heike Heckroth; Christoph Eggert
Original assignee: Bayer Materialscience Ag
Priority date: 2011-03-16
Filing date: 2012-03-12
Publication date: 2012-09-20

Abstract

The present invention relates to an isocyanate-functioning prepolymer A), which can be obtained by reacting an isocyanate A1) of general formula (I), in which X is a propyl, butyl, or pentyl group and Y is a linear or branched aliphatic C2 to C10 group, with a polyol A2) of an average OH functionality of 2 to 6, for producing a biodegradable polyurea system, a biodegradable polyurea system that can be obtained using the prepolymer according to the invention, and a metering system for applying the polyurea system.

Description

Tissue adhesive based on ester group-containing prepolymers

The present invention relates to an isocyanate-functional prepolymer for the production of a biodegradable polyurea system, a biodegradable polyurea system obtainable using the prepolymer according to the invention and a dosing system for the application of the polyurea system.

Various materials used as tissue adhesives are commercially available. These include cyanoacrylates Dermabond® ^® (octyl-2-cyanoacrylate) and histoacryl Blue ^® (butyl cyanoacrylate). The prerequisite for efficient bonding of cyanoacrylates, however, are dry substrates. With heavy bleeding such adhesives fail. As an alternative to cyanoacrylates, biological adhesives such as BioGlue ^® , a mixture of glutaraldehyde and bovine serum albumin, various collagen and gelatine-based systems (FloSeal ^® ) and fibrin glue (Tissucol) are available. These systems are primarily used for hemostasis (haemostasis). In addition to the high costs, fibrin sealants are characterized by a relatively low adhesive strength and rapid degradation, so that they can only be used for smaller injuries on untended tissue. Collagen and gelatin based systems such as FloSeal ^® are for hemostasis only. In addition, since fibrin and thrombin are derived from human, collagen and gelatin from animal material, there is always a risk of infection in biological systems. Biological materials must also be stored refrigerated, so that use in emergency care such. B. in disaster areas, military insertion, etc. is not possible. For the treatment of traumatic wounds, QuikClot ^® or QuikClot ACS + ™ is available, which is a mineral granulate that is brought into the wound in an emergency and leads to coagulation there by removing water. In the case of QuikClot® this is a strongly exothermic reaction leading to burns. QuikClot ACS + ™ is a gauze in which the salt is embedded. The system must be firmly pressed onto the wound for hemostasis.

WO 2009/106245 A2 discloses the production and use of polyurea systems as tissue adhesives. The systems disclosed herein comprise at least two components. This is an amino-functional aspartic acid ester and an isocyanate-functional prepolymer obtained by reacting aliphatic polyisocyanates with polyester polyols. The two-component polyurea systems described can be used as tissue adhesives for the closure of wounds in human and animal cell aggregates. In this case, a very good adhesive result can be achieved. The polyurea systems are designed to biodegrade within a period of up to 6 months. In the systems known from WO 2009/106245 A2, the ester group cleaved primarily during biodegradation is present in the polyol component of the prepolymer used. The production of a corresponding component is associated with a relatively large effort. It has therefore been desired to provide a novel prepolymer which is more readily available on the one hand and has, on the other hand, an additional or alternative physiologically cleavable functional group.

The object of the invention was therefore to provide such a prepolymer.

This object is achieved by an isocyanate-functional prepolymer A) by reaction

an isocyanate AI) of the general formula (I)

O

(I)

in the

X is a propyl, a butyl or a pentyl radical and

Y is a linear or branched aliphatic C 2 to C 10 radical

a polyol A2) having an average OH functionality of 2 to 6

solved.

It has been found that such a prepolymer, when reacted with an amino functional compound, reacts to a polyurea degradable under physiological conditions.

In the present invention, a polyurea system is considered degradable under physiological conditions when it dissolves in an isotonic NaCl solution (containing 0.9 weight percent NaCl dissolved in water) at 37 ° C.

Suitable isocyanates AI) are obtainable, for example, in the following way: By acidic cleavage of ε-caprolactam, the corresponding hydrochloride can be prepared with elimination of water and simultaneous introduction of HCl gas, which is further reacted in situ with the desired alcohol hydrochloride hydrochloride. The resulting dihydrochloride is purified by crystallization and then phosgenated in a suitable solvent. According to a preferred embodiment, it is provided that Y is a linear, aliphatic C 2 to C 8, preferably C 2 to C 6 radical and particularly preferably an ethyl, a propyl or a butyl radical.

Examples of particularly preferred isocyanates AI) are 2-isocyanatoethyl-6-isocyanatohexanoate, 3-isocyanatopropyl-6-isocyanatohexanoate, 3-isocyanatobutyl-6-isocyanatohexanoate,

It is likewise preferred if the polyol A2) has a number-average molecular weight of> 400 g / mol, preferably> 4000 and <8500 g / mol.

The polyol A2) may in particular comprise or consist of a polyester polyol and / or a polyester-polyether polyol and / or a polyether polyol. Particularly preferably, the polyol A2) may comprise or consist of a polyester polyol and / or a polyester-polyether polyol. With such a prepolymer, a polyurea system can be obtained which is particularly rapidly degradable due to the increased number of functional ester groups which can be cleaved under physiological conditions.

More preferably, the polyester-polyether polyol and / or the polyether polyol may have an ethylene oxide content of> 60 and <90 wt .-%.

Suitable polyetheresterpolyols can according to the prior art by polycondensation of polycarboxylic acids, anhydrides of polycarboxylic acids, and esters of polycarboxylic acids with volatile alcohols, preferably Cl to C6 monools, such as methanol, ethanol, propanol or butanol, with molar excess, low molecular weight and / or be produced higher molecular weight polyol. In this case, polyols containing ether groups may optionally be used in mixtures with other polyols which are free of ether groups. Of course, mixtures of the higher molecular weight and the low molecular weight polyols can be used for the synthesis of polyethers. Suitable 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 their hydroxyl groups may be primary or secondary. Such low molecular weight polyols may also have ether groups. Typical representatives are ethylene glycol, 1,2-propanediol, 1,3-propanediol, 1,4-butanediol, 2,3-butanediol, 2-methylpropanediol-1,3, 1,5-pentanediol, 1,6-hexanediol , 3-methylpentanediol-l, 5, 1,8-octanediol, 1, 10-decanediol, 1,12-dodecanediol, cyclohexanediol, diethylene glycol, triethylene glycol and higher homologues, dipropylene glycol, tripropylene glycol and higher homologues, glycerol, 1, 1 , 1-trimethylolpropane, as well as Oligo-tetrahydrofane with hydroxyl end groups. Molar excess high molecular weight polyols are polyols having molecular weights of 300 to 3000 dalton, which can be obtained by ring-opening polymerization of epoxides, preferably ethylene and / or propylene oxide, as well as by acid-catalyzed, ring-opening polymerization of tetrahydrofuran. For ring-opening polymerization of epoxides, either alkali metal hydroxides or double metal cyanide catalysts can be used.

As starters for ring-opening Epoxidpolymerisationen all at least bifunctional molecules from the group of amines and o.g. low molecular weight polyols can be used. Typical representatives are 1, 1, 1-trimethylolpropane, glycerol, o-TDA, ethylenediamine, propylene glycol-1,2, etc., and water, including mixtures thereof. The structure of the higher molecular weight polyols, as far as hydroxyl-terminated polyalkylene oxides of ethylene oxide and / or propylene oxide are concerned, may be random or blockwise, although mixed blocks may also be present.

Polycarboxylic acids are both aliphatic and aromatic carboxylic acids, which may be both cyclic, linear, branched or unbranched and which may have between 4 and 24 carbon atoms.

Examples are succinic, glutaric, adipic, azelaic, sebacic, 1, 10-decanedicarboxylic, 1, 12-dodecanedicarboxylic, phthalic, terephthalic, isophthalic, trimellitic, pyromellitic. Succinic acid, glutaric acid, adipic acid, sebacic acid, lactic acid, phthalic acid, terephthalic acid, isophthalic acid, trimellitic acid, pyromellitic acid are preferred. Particularly preferred are succinic acid, glutaric acid and adipic acid.

Furthermore, the group of polycarboxylic acids also hydroxycarboxylic acids, or their internal anhydrides, such. Caprolactone, lactic acid, hydroxybutyric acid, ricinoleic acid, etc. Also included are monocarboxylic acids, in particular those which have more than 10 carbon atoms, such as soybean oil fatty acid, palm oil fatty acid and peanut oil fatty acid, wherein their share of the total, the polyetheresterpolyol constituent reaction mixture 10 wt. -% should not exceed and, in addition, the concomitant minor functionality is compensated by the concomitant use of at least trifunctional polyols, be it on the side of the low molecular weight or the high molecular weight polyols.

The preparation of the polyetherester polyol is carried out according to the prior art, preferably at elevated temperature in the range from 120 to 250 ° C., preferably initially under atmospheric pressure, later in particular under application of a vacuum of 1 to 100 mbar, preferably but not necessarily using an esterification - or transesterification catalyst, wherein the Reaction is completed so far that the acid number to values of 0.05 to 10 mg KOH / g, preferably from 0, 1 to 3 mg KOH / g and more preferably from 0, 15 to 2.5 mg KOH / g decreases.

Furthermore, in the context of the normal pressure phase before the application of vacuum, an inert gas can be used. Of course, alternatively or for individual phases of the esterification, liquid or gaseous entrainers may also be used. For example, the reaction water can be discharged by using nitrogen as a carrier gas as well as by using an azeotrope-dragging agent such as e.g. Benzene, toluene, xylene, dioxane, etc.

Of course, blends of polyether polyols with polyester polyols in any ratios can be used. Polyether polyols are preferably polyalkylene oxide polyethers based on ethylene oxide and optionally propylene oxide.

These polyether polyols are preferably based on di- or higher-functional starter molecules such as dihydric or higher-functional alcohols or amines.

Examples of such initiators are water (considered as a diol), ethylene glycol, propylene glycol, butylene glycol, glycerol, TMP, sorbitol, pentaerythritol, triethanolamine, ammonia or ethylenediamine.

It is likewise possible to use hydroxyl-containing polycarbonates, preferably polycarbonatediols, having number-average molecular weights M _{n of} from 400 to 8000 g / mol, preferably from 600 to 3000 g / mol. These are obtainable by reaction of carbonic acid derivatives such as diphenyl carbonate, dimethyl carbonate or phosgene with polyols, preferably diols. Examples of suitable diols are ethylene glycol, 1,2- and 1,3-propanediol, 1,3- and 1,4-butanediol, 1,6-hexanediol, 1,8-octanediol, neopentyl glycol, 1,4-bishydroxymethylcyclohexane, 2- Methyl-l, 3-propanediol, 2,2,4-Trimethylpentandiol-l, 3, dipropylene glycol, polypropylene glycols, dibutylene glycol, polybutylene glycols, bisphenol A and lactone-modified diols of the aforementioned kind.

For the preparation of the prepolymer A), the isocyanate AI) with the polyol A2) at an NCO / OH ratio of preferably 4: 1 to 12: 1, more preferably 8: 1 reacted and then the proportion of unreacted isocyanate by means of suitable methods be separated. Usually, the thin film distillation is used for this purpose, a prepolymer having a residual monomer content of less than 1 wt .-%, preferably less than 0, 1 wt .-%, most preferably less than 0.03 wt .-% is obtained. Optionally, stabilizers such as benzoyl chloride, isophthaloyl chloride, dibutyl phosphate, 3-chloropropionic acid or methyl tosylate may be added during the preparation of the prepolymer A).

The reaction temperature in the preparation of the prepolymer A) is preferably 20 to 120 ° C and more preferably 60 to 100 ° C.

The prepolymer A) preferably has an average NCO content of from 2 to 10% by weight, preferably from 2.5 to 8% by weight, measured according to DIN EN ISO 1 1909.

The average NCO functionality of the prepolymer A) is preferably 1.5 to 2.5, more preferably 1.6 to 2.4, even more preferably 1.7 to 2.3, very particularly preferably 1.8 to 2.2 and in particular 2.

Another object of the invention is a polyurea system comprising

an inventive isocyanate-functional prepolymer A) and

an amino-functional compound B) of the general formula (II)

in the Ri is an organic radical which has no Zerewitinoff-active hydrogen, R _{2 is} a linear or branched C 1 to C 4 alkyl, a cyclopentyl, a cyclohexyl radical, H or a CH 2 COOR 3 radical, wherein R3 is an organic radical that does not have Zerewitinoff active hydrogen,

a linear or branched, unsubstituted or heteroatom-substituted in the chain organic radical and

> 1 and <6

is.

For the definition of Zerewitinoff-active hydrogen, reference is made to Römpp Chemie Lexikon, Georg Thieme Verlag Stuttgart. Preferably, groups having Zerewitinoff-active hydrogen are OH, NH or SH. The polyurea system according to the invention is particularly suitable for sealing, bonding, gluing or covering cell tissue, in particular for arresting the escape of blood or tissue fluids, or for closing leaks in cell tissue. So it can be produced with a fast-curing, elastic and durable bond. This is also degradable under physiological conditions.

According to a first preferred embodiment of the polyurea system according to the invention Ri and optionally R3 are each independently or simultaneously a C l to CIO, preferably a C l to C8, more preferably a C2 to C6 alkyl radical and most preferably a methyl and / or an ethyl radical.

It is also preferred if Q is a linear or branched, unsubstituted or substituted with hetero atoms also in the chain C 1 to C 10, preferably C 2 to C 8, particularly preferably C 3 to C 6 radical.

According to another preferred embodiment, it is provided that Q is a (CEb p-O group with p> 2 <4 or comprises a CEb group.

Particularly preferred is k> 1 and <4 and more preferably> 2 and <3.

It is also possible that Q has an acetal group, especially in the chain. This leads to the fact that the resulting polyurea system is even faster degradable.

Particular preference is therefore given to an amino-functional compound B) of the formula (III)

solved, in the

R _{3 is} a C 1 to C 6 alkyl radical or H,

R 4 is an organic radical containing a secondary amino function,

R5, R5 are each independently an organic radical which does not have Zerewitinoff active hydrogen,

R7, R 'are each independently a CEb-COORsi residue, where R9 is an organic

Is a radical which has no Zerewitinoff-active hydrogen, a linear or branched C 1 - to C 4 -alkyl radical, a cyclopentyl radical, a cyclohexyl radical or H, Each of Zi, Z ₂ independently represents a (CH ₂ ) _p -O radical, where p> 2 <4, or a

CH 2 -rest are,

n, m are each independently> 1 and <6 and

o> 1 and <10.

Very particularly preferred here is when R5 is a radical of the formula (IV)

in which each independently is an organic radical which has no Zerewitinoff active hydrogen.

Rio can be a linear or branched, saturated organic radical optionally substituted by heteroatoms in the chain, in particular a linear or branched, saturated, aliphatic C 1 to C 10, preferably C 2 to C 8 and particularly preferably C 2 to C 6 hydrocarbon radical.

RH can preferably be a radical of the formula (V)

be in the

R 12, R 13 are each, independently of one another or simultaneously a C 1 to C 10, preferably a C 1 to C 8, particularly preferably a C 2 to C 6 alkyl radical and very particularly preferably a methyl and / or an ethyl radical.

Such compounds react particularly quickly with the prepolymer to form a three-dimensional polyurea system.

It is also preferred if in the formula (IV) R 1, R 9 are each a CF b COOR 4 radical in which R 7 is an organic radical which has no Zerewitinoff-active hydrogen. Re, R7 and optionally R9 can each independently or simultaneously a Cl- to CIO, preferably a Cl to C8, more preferably a C2 to C6 alkyl radical and most preferably a methyl and / or an ethyl radical.

It is also preferred if Zi and Z2 are each simultaneously an Orb radical.

The indices n and m can each independently or simultaneously be> 1 and <6, preferably> 1 and <4 and particularly preferably 1 or 2.

It is also advantageous if o> 1 and <10, preferably> 1 and <4 and particularly preferably 1 or 2.

It is also advantageous if Q has a secondary amino function, in particular in the chain. As a result, the system cures very quickly.

An aminofunctional compound of the formula (VI) is therefore particularly advantageous.

O O

/ \

14 <15

(VI) in the

R14, R15 are each independently identical or different organic radicals which have no Zerewitinoff-active hydrogen and each independently saturated, linear or branched, optionally also heteroatom-substituted in the chain, organic Res te, which have no Zerewitinoff-active hydrogen are.

In the formula (I), the radicals Rie, R17, Ris can each independently be linear or branched, in particular saturated, aliphatic Cl to C12, preferably C2 to CIO, especially preferably C3 to C8 and very particularly preferably C3 to C6 hydrocarbon radicals , Such Aminofunctional compounds are characterized by the fact that they cure very rapidly with the prepolymer to form a strongly adhesive, elastic and solid polyurea network.

The radicals Ru, R15 can each independently be linear or branched organic C 1 to C 10, preferably C 1 to C 8, particularly preferably C 2 to C 6, very particularly preferably C 2 to C 4 radicals and in particular aliphatic hydrocarbon radicals. This compound is characterized by a fast network formation in a reaction with the prepolymer.

It is also preferred if in each case the radicals R ^ and R15 are the same and / or in each case the radicals Rie, R17, Ri8 are identical.

Very particular preference is given to a compound of the formula (VI) in which Ru and R15 are each simultaneously methyl or ethyl and Rie, R17, Ris are each simultaneously ethyl, propyl or butyl.

Also preferred is an amino-functional compound B) of the general formula (VII)

in the

Z3 is an organic radical, preferably containing a secondary amino function,

R 19, R 20 are identical or different organic radicals which have no Zerewitinoff active hydrogen and

s is an integer of at least 2,

Particularly preferably, s in the formula (VII) is an integer> 2 <4 and most preferably equal to 2.

Z3 may in particular be a radical of the formula (VIII)

be in the

each independently of one another are an organic radical which has no Zereptinoff-active hydrogen. Particularly preferred here is when R21, R22 each independently or simultaneously a linear or branched, optionally substituted in the chain with heteroatoms saturated saturated organic radical, in particular a linear or branched, saturated, aliphatic C 1 to CIO, preferably C2 to C8 and most preferably C2 to C6 are hydrocarbon radical. Such polyurea systems cure very quickly.

Also advantageous is a compound of the formula (VII) in which the radicals R 19, R 20 are each independently linear or branched C 1 to C 10, preferably C 1 to C 8, particularly preferably C 2 to C 6, very particularly preferably C 2 to C 4 organic radicals and in particular aliphatic radicals Hydrocarbon radicals are. Examples of particularly suitable radicals are methyl, ethyl, propyl and butyl. It is furthermore preferred if the polyurea system according to the invention comprises an organic filler C).

The organic fillers C) may preferably be hydroxy-functional compounds, in particular polyether polyols having repeating ethylene oxide units.

It is also advantageous if the fillers C) have an average OH functionality of from 1.5 to 3, preferably from 1.8 to 2.2 and particularly preferably from 2.

For example, as organic fillers at 23 ° C liquid polyethylene glycols such as PEG 200 to PEG 600, their mono- or dialkyl ethers such as PEG 500 dimethyl ether, liquid polyether and polyester polyols, liquid polyesters such. Ultramoll (Lanxess AG, Leverkusen, DE) and glycerine and its liquid derivatives, such as Triacetin (Lanxess AG, Leverkusen, DE) are used.

In a further preferred embodiment of the polyurea system according to the invention, polyethylene glycols which have a number-average molecular weight of from 100 to 1000 g / mol, particularly preferably from 200 to 400 g / mol, are used as organic fillers.

The viscosity of the organic fillers measured according to DIN 53019 at 23 ° C. is preferably from 10 to 20,000 mPas, more preferably from 50 to 4000 mPas and particularly preferably from 50 to 2000 mPas.

In order to increase the rate of cure, the polyurea system may additionally comprise water and / or a tertiary amine D).

According to a further preferred embodiment of the polyurea system according to the invention, it is therefore provided that component D) is a tertiary amine of the general formula (IX) ^R 23

N

^R 25 ^R 24

(IX), in the

Pv23, Pv24, Pv25 independently of one another can be alkyl or heteroalkyl radicals having heteroatoms in the alkyl chain or at the end thereof, or R7 and R 'together with the nitrogen atom carrying them can form an aliphatic, unsaturated or aromatic heterocycle which optionally contains further heteroatoms may contain.

The tertiary amine may in particular be a compound selected from the group triethanolamine, tetrakis (2-hydroxyethyl) ethylenediamine, N, N-dimethyl-2- (4-methylpiperazin-1-yl) ethanamine, 2 - {[2- (Dimethylamino) ethyl] (methyl) amino} ethanol, 3,3 ', 3 "- (l, 3,5-triazinane-l, 3,5-triyl) tris (N, N-dimethyl-propane-1-amine ) act.

Particularly high curing rates can also be achieved if component D) contains 0.2 to 2.0% by weight of water and / or 0.1 to 1.0% by weight of the tertiary amine.

The polyurea system may also comprise a pharmacologically active compound E), in particular an analgesic with or without antiinflammatory activity, an antiinflammatory drug, an antimicrobial active substance or an antimycotic.

The polyurea system according to the invention can also very particularly preferably be used for the production of a means for closing, joining, gluing or covering human or animal cell tissue. It can be used to produce fast-curing, highly adherent, transparent, flexible and biocompatible adhesive bonds that degrade under physiological conditions.

Yet another object of the invention is metering system with two chambers for a polyurea system according to the invention, wherein in one chamber the prepolymer A) and in the other chamber, the amino-functional compound B) and optionally the filler C), the water and / or the amine D) and the active compound E) are contained. Such a metering system is particularly suitable for applying the polyurea system as an adhesive to tissue. Examples:

The invention will be explained in more detail below with reference to examples.

methods:

Molecular weight: The molecular weights were determined by gel permeation chromatography (GPC) as follows: The calibration was carried out with polystyrene standards having molecular weights of Mp 1,000,000 to 162. The eluent was tetrahydrofuran p.A. used. The following parameters were observed during the double measurement: Degassing: Online - Degasser; Flow: 1 ml / min; Analysis time: 45 minutes; Detectors: refractometer and UV detector; Injection volume: 100 μΐ - 200 μΐ. The calculation of the molecular weight averages Mw; Mn and Mp and the polydispersity Mw / Mn were software-based. Baseline points and evaluation limits were determined in accordance with DIN 55672 Part 1.

NCO content: Unless expressly stated otherwise, the NCO content was determined volumetrically in accordance with DIN-EN ISO 1 1909.

Viscosity: The viscosity was determined according to ISO 3219 at 23 ° C.

Residual monomer content: The residual monomer content was determined according to DIN ISO 17025.

Melting point: The melting point was determined according to EN ISO 1 1357-1.

substances:

HDI: Hexamethylene diisocyanate (Bayer MaterialScience AG)

All other chemicals and solvents used are from Aldrich and Fluka. 2-isocyanatoethyl-6-isocyanatohexanoat

2-aminoethyl-6-aminocaproate dihydrochloride

339 g (3 mol) of ε-caprolactam were heated to 80 ° C. with 72 g (4 mol) of water, during which HCl gas was introduced until no more was taken up. After addition of 250 ml of toluene, excess water was distilled off on a water separator. 293 g (3 mol) of ethanolamine hydrochloride were added dropwise to the resulting emulsion. With further introduction of HCl gas, water was distilled off until the reaction was complete.

After recrystallization from isopropanol, the dihydrochloride was obtained in a yield of 85% (697 g). (Mp .: 183-189 ° C)

2-isocyanatoethyl-6-isocyanatocaproat

The dihydrochloride was slurried in chlorobenzene to a 10-15% suspension and phosgenated at 100-125 ° C until a clear solution had formed. The solvent was distilled off and the diisocyanate was purified by thin film distillation.

65% of the product was obtained. Boiling point: 140-142 ° C (0, 1 mbar).

Prepolymer 1

56.5 g of 2-isocyanatoethyl-6-isocyanatocaproate was placed in a 1 liter four-necked flask. Within 2 h, 84.03 g of a polyether having an ethylene oxide content of 71% and a propylene oxide content of 29% (in each case based on the total alkylene oxide content) started at 80 ° C. were added to TMP (3-functional) and stirred for 1 h. Subsequently, the excess monomer was distilled off by thin-layer distillation at 150 ° C and 0, 13 mbar. The resulting prepolymer has an NCO content of 2.7%. The residual monomer content was 0.05%

Viscosity: 7000 mPas / 23 ° C

Aspartate A 2 mol of diethyl maleate was slowly added dropwise under nitrogen to 1 mol of 2-methyl-1,5-diaminopentane so that the reaction temperature did not exceed 60.degree. The mixture was then heated to 60 ° C until no diethyl maleate was detectable in the reaction mixture. There was a quantitative implementation.

in vitro adhesion of muscle tissue

4 g of the prepolymer 1 were stirred well with 0.6 g of aspartate A in a beaker and applied thinly to the muscle tissue to be bonded. There has been a strong bond after 2 minutes. By pulling the fabric pieces could not be separated without fiber damage. When applied to the surface of the fabric, complete cure occurred to form a clear film within 5 minutes.

Tissue adhesive from prepolymer 1 and aspartate B, biodegradation study

0.54 g aspartate A was well mixed with 4 g of prepolymer 1 and cured in a tube (diameter 0.5 cm, length 2 cm). The resulting test specimen was 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 sample was then rinsed with deionized water and blotted dry. The weight of the sample was determined as takeoff weight. The sample was further shaken in 10 ml of buffer solution (pH 7.4, Aldrich P-5368) at 60 ° C in a shaking incubator under the same conditions. The weight of the sample was determined weekly.

After 32 weeks at 60 ° C, the specimen was completely degraded.

Claims

claims:

1. Isocyanate-functional prepolymer A) obtainable by reaction

an isocyanate AI) of the general formula (I)

O

(I)

in the

X is a propyl, a butyl or a pentyl radical and

Y is a linear or branched aliphatic C 2 to C 10 radical

a polyol A2) having an average OH functionality of 2 to 6.

2. Prepolymer according to claim 1, characterized in that Y is a linear, aliphatic C 2 to C 8, preferably C 2 to C 6 radical and particularly preferably an ethyl, a propyl or a butyl radical.

3. Prepolymer according to one of claims 1 or 2, characterized in that the polyol A2) has a number average molecular weight of> 400 g / mol, preferably> 4000 and <8500 g / mol.

4. Prepolymer according to one of claims 1 to 3, characterized in that the polyol A2) comprises or consists of a polyester polyol and / or a polyester-polyether polyol and / or a polyether polyol.

5. Prepolymer according to claim 4, characterized in that the polyester-polyether polyol and / or the polyether polyol has an ethylene oxide content of> 60 and <90 wt .-%.

6. comprising polyurea system

in inventive isocyanate-functional prepolymer A) and

an amino-functional compound B) of the general formula (II)

in the

an organic radical which has no Zerewitinoff-active hydrogen, a linear or branched C 1 - to C 4 -alkyl radical, a cyclopentyl radical, a cyclohexyl radical, H or a CH 2 -COOR 3 radical, where R 3 is an organic radical

Remainder that does not have Zerewitinoff active hydrogen,

Q is a linear or branched, unsubstituted or heteroatom-substituted in the chain organic radical and

k> 1 and <6

is.

7. polyurea system according to claim 6, characterized in that Ri and optionally R3 each independently or simultaneously a Cl to CIO, preferably a Cl to C8, more preferably a C2 to C6 alkyl radical and most preferably a methyl and or an ethyl radical.

8. polyurea system according to any one of claims 6 or 7, characterized in that Q is a linear or branched, unsubstituted or substituted with hetero atoms also in the chain C1 to CIO, preferably C2 to C8, particularly preferably C3 to C6 radical.

9. polyurea system according to one of claims 6 to 8, characterized in that Q in particular in the chain has an acetal group and / or a secondary amino function.

10. A polyurea system according to any one of claims 6 to 9, characterized in that Q is a (CH 2) _p -O group with p> 2 <4 or comprises an Orb group.

11. polyurea system according to one of claims 6 to 10, characterized in that it comprises an organic filler C), which in particular has a viscosity measured according to DIN 53019 at 23 ° C in the range of 10 to 20,000 mPas.

12. polyurea system according to one of claims 6 to 11, characterized in that it comprises water and / or a tertiary amine D), wherein the tertiary amine in particular from the group triethanolamine, tetrakis (2-hydroxyethyl) ethylenediamine, N, N -Dimethyl-2- (4-methylpiperazin-1-yl) ethanamine, 2- {[2- (dimethylamino) ethyl] (methyl) amino} ethanol, 3, 3 ', 3 "- (1,3,5-triazinane - 1,3,5-triyl) tris (N, N-dimethyl-propane-1-amine) is selected.

13. polyurea system according to one of claims 6 to 12, characterized in that it comprises a pharmacologically active compound E), in particular an analgesic with or without anti-inflammatory action, an antiphlogistic, an antimicrobial active substance or an antimycotic.

14. polyurea system according to one of claims 6 to 13 for closing, connecting, bonding or covering of cell tissue, in particular for stopping the escape of blood or tissue fluids or the closure of leaks in cell tissue.

15. dosing system with two chambers for a Polyhamstoff system according to one of claims 6 to 14, characterized in that in one chamber, the prepolymer A) and in the other chamber, the amino-functional compound B) and optionally the filler C), the water and / or the amine D) and the active compound E) are contained.