HK1201546B - Modified beta-amino acid ester (aspartate) curing agents and the use thereof in polyurea tissue adhesives - Google Patents

Description

β-Amino acid ester-modified (aspartic acid ester) hardener and its use in polyurea tissue adhesives

The present invention relates to a β-amino acid ester, in particular a β-amino acid ester-modified aspartic acid ester, a method for preparing the same and use of the compound as a hardener for preparing polyurethane urea or polyurea, in particular for tissue adhesives.

Tissue adhesives are commercially available in various forms. These include the cyanoacrylates ^Dermabond® (octyl-2-cyanoacrylate) and Histoacryl ^Blue® (butyl cyanoacrylate). However, cyanoacrylates require a dry subsurface for effective adhesion. These types of adhesives can fail in cases of severe bleeding.

Bioadhesives such as ^BioGlue® , mixtures of glutaraldehyde and bovine serum albumin, various collagen- and gelatin-based systems ( ^FloSeal® ), and fibrin adhesives (Tissucol) are all alternatives to cyanoacrylates. The primary function of these systems is to stop bleeding (hemostasis). Besides their high cost, fibrin adhesives also have relatively weak adhesive strength and rapid decomposition, limiting their use to less severe injuries on non-extensible tissues. Collagen- and gelatin-based systems such as ^FloSeal® are only used to achieve hemostasis. Furthermore, since fibrin and thrombin are derived from human materials, and collagen and gelatin are derived from animal materials, there is a constant risk of infection with biological systems. Furthermore, biomaterials must be stored refrigerated, making them unsuitable for emergency care, such as in disaster areas or the military. In these cases, traumatic injuries can be treated with ^QuikClot® or QuikClot ACS+™, which are mineral granules that are applied to the wound during emergency treatment and induce blood clotting by removing water. QuikClot® produces a highly exothermic reaction, which can cause burns. QuikClot ACS+™ is a gauze pad with saline embedded in it. The system must be pressed firmly against the wound to stop the bleeding.

WO 2009/106245 A2 discloses the preparation and use of polyurea systems as tissue adhesives. The disclosed system comprises at least two components: an amino-functional aspartic acid ester and an isocyanate-functional prepolymer, which can be obtained by reacting an aliphatic polyisocyanate with a polyester polyol. The described two-component polyurea system can be used as a tissue adhesive for sealing wounds in human and animal tissue structures. This achieves a very positive adhesive effect.

To ensure good mixing of the two components of the polyurea system, their viscosity at 23°C should, if possible, be less than 10,000 mPas. Prepolymers with an NCO functionality of less than 3 have correspondingly low viscosities. If such prepolymers are used, an aspartic acid ester with an amino functionality greater than 2 must be used as the second component, as otherwise no polymer network can be formed. However, this is essential for the polyurea system or the adhesive bond composed thereof to possess the required mechanical properties, such as elasticity and strength. Furthermore, the use of difunctional aspartic acid esters has the disadvantage that curing can take up to 24 hours, after which the polyurea system often remains tacky—that is, it is not "tack-free." Furthermore, the resulting adhesives are primarily designed for surface application and are not biodegradable in vivo within a short period of time, for example, six months or less. However, for in vivo use, adhesive systems must meet this requirement.

WO 2010/066356 discloses an adhesive system for medical applications in which an isocyanate-terminated prepolymer is reacted or hardened with a secondary diamine. In this case, the disadvantages already mentioned with respect to WO 2009/106245 A2 also occur.

Therefore, except actual bonding strength, the hardening time of tissue adhesive is also an important parameter.If described adhesive hardens too fast, then leave the user and be applied to the available time of wound area to be bonded and may be too little.On the contrary, the hardening time of extension is undesirable, because produces long waiting time like this and within this time, wound must be fixed so that wound area to be bonded does not separate again.The hardening time of suggestion can be specified as, for example 1-5 minute, and wherein optimal hardening time is finally consistent with corresponding application purpose.Yet during described hardening time, adhesive should keep and can be used for as long as possible.

Obviously, adjusting the desired curing time is a challenge, as the hardener must be coordinated with the prepolymer or prepolymer composition to be cured. In the described method, the use of a diamine may result in too rapid a curing for the particular prepolymer to be cured; on the other hand, the aforementioned aspartic acid ester hardener may be too slow.

The object of the present invention is to provide a novel compound as a hardener, wherein the compound should be able to achieve the desired hardening time for various polyurethaneurea systems. Thus, the effect of the compound on the hardening rate should be adjustable within a certain range. Furthermore, it is desirable to ensure sufficient biodegradability after application in animals or humans.

This object is achieved by compounds of the formula (I)

in

R ₁ , R ₂ , and R ₃ are each independently the same or different organic residues that do not contain Zerevitinoff-active hydrogen atoms,

R ₄ is independently hydrogen, the same or different organic residues containing no Zerevitinoff-active hydrogen, or together form an unsaturated or aromatic ring, which may optionally contain heteroatoms, wherein R ₄ contains no Zerevitinoff-active hydrogen,

X is a linear or branched organic radical, optionally even containing heteroatoms in the chain, said radical containing no Zerevitinoff-active hydrogens,

n 0 < n ≤ 2 and

m 0 ≤ m < 2,

where n + m = 2.

In other words, the above compounds have different proportions of β-amino acid ester groups and optional aspartic acid ester groups. This means that n and m are not necessarily integers, but the desired composition can represent a mixture of differently substituted compounds falling within the above formula (I). In this respect, the mixture can naturally also contain a certain proportion of diaspartic acid ester according to different preparations, wherein this proportion is preferably less than 90 mol %, in particular less than 75 mol %, based on the total molar amount of the compounds.

Surprisingly, it has been demonstrated that these compounds exhibit high curing rates when used as hardeners in polyurethaneurea systems. Thus, the curing rate can be adjusted to the desired level by varying n or m within a specific range. Tissue adhesives, such as those based on polyurethaneurea, that cure in this manner detackify within a short time, which greatly simplifies their use.

In one embodiment of the compounds according to the invention, the residues R ₁ , R ₂ , R ₃ are each independently a linear or branched, in particular saturated, aliphatic C1-C10 hydrocarbon residue, preferably C2-C18, particularly preferably C2-C6 and very particularly preferably C2-C4.

Furthermore, the residue X can be a linear, branched, or cyclic organic C2-C16 residue, preferably a C3-C14 residue, and particularly preferably a C4-C12 residue. In this context, the residue X particularly denotes an aliphatic hydrocarbon residue. Particularly preferred residues are 2-methylpentamethylene residues, hexamethylene residues, or isophorone residues, to name a few. In principle, mixtures of compounds having different X residues can also be used.

In order to achieve the most uniform possible curing behavior, the residues R ₁ and R ₂ can each be identical in the compounds according to the invention, wherein in particular the residues R ₁ , R ₂ and R ₃ can be identical.

According to a preferred embodiment of the compounds according to the present invention, 0 < n < 2 and 0 < m < 2, where n is in particular 0.5-1.5, preferably 0.6-1.4, more preferably 0.7-1.3, particularly preferably 0.8-1.2, and very particularly preferably 0.9-1.1. In other words, this configuration of the present invention relates to a mixture of compounds of formula (I), wherein statistically at least some of the compounds have both β-amino acid groups and aspartate ester groups. Within the aforementioned numerical range of n and m approximately equal to 1, such a mixture statistically comprises almost exclusively β-amino acid ester-modified aspartate esters. This is particularly advantageous because the reactivity of the hardener can be varied by adjusting n and m. Thus, in the case of compounds according to formula (I), a statistical increase in the proportion of β-amino acid groups, i.e., the variable n, increases the curing rate of, for example, a polyurethaneurea system. Conversely, in the case of excessively high curing rates, the proportion of aspartate ester groups, i.e., the variable m, can be increased.

The adjustment of the ratio of the β-amino acid groups and the aspartic acid ester groups described above can be achieved in various ways. Thus, by selecting the appropriate mixture ratio of the reactants used to produce the corresponding functional groups, the ratio of these groups can be adjusted during the preparation process. This point will be further explained below. In addition, it is possible to mix a pure di-β-amino acid ester compound of formula (I) (i.e., n=2, m=0) or a pure di-aspartic acid ester compound of formula (I) (i.e., n=0, m=2) with a pure β-amino acid ester-modified aspartic acid ester compound of formula (I) (i.e., n, m=1) in a suitable ratio. As described above, the mixture can also contain a certain ratio of di-aspartic acid ester and di-β-amino acid ester, wherein in this case, this ratio is preferably less than 90 mol %, particularly less than 75 mol %, based on the total molar amount of the compounds.

Another object of the present invention relates to a method for preparing a compound according to any one of claims 1 to 5, wherein the diamine compound of general formula (II)

With acrylate of general formula (III)

and, if desired, reacted with a diester of an unsaturated dicarboxylic acid of the general formula (IV),

wherein n moles of acrylate and m moles of diester are used per mole of diamine compound,

And among them

R ₁ , R ₂ , and R ₃ are each independently the same or different organic residues that do not contain Zerevitinoff-active hydrogen atoms,

R ₄ is independently hydrogen, the same or different organic residues containing no Zerevitinoff-active hydrogen, or forms an unsaturated or aromatic ring, which may optionally contain heteroatoms, wherein R ₄ contains no Zerevitinoff-active hydrogen,

X is a linear or branched organic radical, optionally even containing heteroatoms in the chain, said radical containing no Zerevitinoff-active hydrogens,

n 0 < n ≤ 2,

m 0 ≤ m < 2,

where n + m = 2.

In principle, all types of diamines can be used in the process according to the invention. Apart from the two primary amino groups, they do not contain any Zerewitinoff-active hydrogen atoms.

In the context of the present invention, the term "Zerevich-active H atoms" refers to acidic or "active" H atoms. They can be determined in a conventional manner by their reactivity with the corresponding Grignard reagent. The amount of Zerevitch-active H atoms is generally measured by the release of methane, which is carried out in the reaction of the substance to be tested with methylmagnesium bromide (CH ₃ -MgBr) according to the following reaction equation (Formula 1):

Zerev active H atoms generally come from CH acidic organic groups, -OH, -SH, _-NH2 , or -NHR and -COOH with R as an organic residue.

As acrylates, for example, those of the (meth)acrylate type can be used. In this respect, for example, C1-C12 acrylates, particularly C1-C10 acrylates, preferably C1-C8 acrylates, more preferably C2-C6 acrylates can be used.

For example, maleic acid esters or esters of tetrahydrophthalic acid (especially 3,4,5,6-tetrahydrophthalic acid) and combinations thereof can be used as diesters of unsaturated dicarboxylic acids. In this context, the two residues R ₄ in the case of maleic acid esters each correspond to a hydrogen atom, while in the case of tetrahydrophthalic acid the two residues R ₄ together form an unsaturated 6-membered ring.

Nevertheless, it is also possible to select the diesters from the C1-C12 esters of the corresponding diacids, in particular from the C1-C8 esters, preferably from the C2-C4 esters.

In the process according to the invention, n moles of acrylate and m moles of diester are used per mole of diamine compound. This allows the aforementioned mixture of compounds of formula (I) to be prepared directly. The aforementioned adjustment of the curing rate can thus be achieved by appropriately controlling the preparation process.

The present invention also relates to compounds of formula (I), which can be prepared according to the process of the present invention.

A further object of the present invention relates to a polyurea system comprising:

as component A) an isocyanate-functional prepolymer obtainable by reacting an aliphatic polyisocyanate A1) with a polyol A2), which polyol may have, in particular, a number-average molecular weight of ≥400 g/mol and an average OH functionality of 2 to 6,

As component B) a compound of the present invention of the general formula (I),

Preference is given as component C) to organic fillers, which may in particular have a viscosity of 10 to 6000 mPas, measured at 23° C. in accordance with DIN 53019,

Preferred as component D) are reaction products of isocyanate-functional prepolymers according to component A) with compounds according to component B) and/or organic fillers according to component C), and

Preference is given as component E) to water and/or tertiary amines.

The polyurea system according to the invention is obtained by mixing a prepolymer A) with a compound B) according to the invention of the general formula (I) and optionally components C), D) and/or E). In this regard, the ratio of free or blocked amino groups to free NCO groups is preferably 1:1.5, particularly preferably 1:1. In this process, water and/or an amine is added to component B) or C).

Isocyanate-functional prepolymers A) are obtainable by reacting polyisocyanates A1) with polyols A2), optionally using catalysts and auxiliaries and additives.

As polyisocyanates A1), it is possible to use, for example, monomeric aliphatic or cycloaliphatic diisocyanates or triisocyanates, such as 1,4-butylene diisocyanate (BDI), 1,6-hexamethylene diisocyanate (HDI), isophorone diisocyanate (IPDI), 2,2,4- and/or 2,4,4-trimethylhexamethylene diisocyanate, bis(4,4′-isocyanatocyclohexyl)methane isomers or mixtures thereof with any isomer content, 1,4-cyclohexylene diisocyanate, 4-isocyanatomethyl-1,8-octane diisocyanate (nonane triisocyanate), and 2,6-diisocyanatohexanoic acid alkyl esters having a C1-C8 alkyl group (lysine diisocyanate).

In addition to the above-mentioned monomeric polyisocyanates A1), it is also possible to use their higher molecular weight derivatives having a uretdione, isocyanurate, urethane, allophanate, biuret, iminooxadiazinedione or oxadiazinetrione structure, and mixtures thereof.

Preference is given to using polyisocyanates A1) of the aforementioned type which have exclusively aliphatically or cycloaliphatically bonded isocyanate groups or mixtures thereof.

Preference is likewise given to using polyisocyanates A1) of the aforementioned type having an average NCO functionality of 1.5 to 2.5, preferably 1.6 to 2.4, particularly preferably 1.7 to 2.3 and very particularly preferably 1.8 to 2.2 and in particular 2.

Hexamethylene diisocyanate is very particularly preferably used as polyisocyanate A1).

A preferred embodiment of the polyurea system according to the invention provides that the polyol A2) is a polyester polyol and/or a polyester-polyether polyol and/or a polyether polyol. In this regard, polyester-polyether polyols and/or polyether polyols having an ethylene oxide content of 60 to 90% by weight are particularly preferred.

It is also preferred that the polyol A2) has a number-average molecular weight of from 4000 to 8500 g/mol.

Suitable polyetheresterpolyols are preferably prepared according to the prior art by polycondensation of polycarboxylic acids, anhydrides of polycarboxylic acids and esters of polycarboxylic acids with volatile alcohols, preferably C1-C6 monohydric alcohols such as methanol, ethanol, propanol or butanol, with a molar excess of low-molecular and/or high-molecular polyols; polyols containing ether groups are optionally used as polyols in a mixture with other polyols without ether groups.

Naturally, mixtures of high-molecular-weight and low-molecular-weight polyols can also be used in the polyetherester synthesis.

This molar excess of low-molecular-weight polyols is a polyol having a molar mass of 62 to 299 Dalton, 2 to 12 carbon atoms, and a hydroxyl functionality of at least 2. It may also be branched or unbranched, and its hydroxyl groups may be primary or secondary. These low-molecular-weight polyols may also have ether groups. Typical representatives are ethylene glycol, 1,2-propylene glycol, 1,3-propylene glycol, 1,4-butanediol, 2,3-butanediol, 2-methyl-1,3-propanediol, 1,5-pentanediol, 1,6-hexanediol, 3-methyl-1,5-pentanediol, 1,8-octanediol, 1,10-decanediol, 1,12-dodecanediol, cyclohexanediol, diethylene glycol, triethylene glycol and higher homologs, dipropylene glycol, tripropylene glycol and higher homologs, glycerol, 1,1,1-trimethylolpropane, and oligo-tetrahydrofuran with hydroxyl end groups. Naturally, mixtures of these groups can also be used.

The molar excess of high molecular weight polyols is a polyol with a molar mass of 300-3000 Dalton, which can be obtained by ring-opening polymerization of epoxides, especially ethylene oxide and/or propylene oxide, and by acid-catalyzed ring-opening polymerization of tetrahydrofuran. Alkali metal hydroxides or double metal cyanide catalysts are used for the ring-opening polymerization of epoxides.

As initiators for the ring-opening polymerization of epoxides, all at least difunctional molecules from the group consisting of amines and the aforementioned low-molecular-weight polyols can be used. Typical examples include 1,1,1-trimethylolpropane, glycerol, o-TDA, ethylenediamine, 1,2-propylene glycol, and water, including mixtures thereof. Naturally, mixtures of this group of high-molecular-weight polyols in excess can also be used.

In the case of hydroxyl-terminated polyalkylene oxides derived from ethylene oxide and/or propylene oxide, the structure of the high molecular weight polyols can occur randomly or in blocks, which can also contain mixed blocks.

The polycarboxylic acids are aliphatic or aromatic carboxylic acids which may be cyclic, linear, branched or unbranched and may contain 4 to 24 carbon atoms.

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

In addition, this group of polycarboxylic acids also includes hydroxycarboxylic acids or their internal anhydrides, such as caprolactone, lactic acid, hydroxybutyric acid, ricinoleic acid, etc. Also included are monocarboxylic acids, in particular those containing more than 10 C atoms, such as soybean oil fatty acid, palm oil fatty acid and peanut oil fatty acid, where their proportion in the total reaction mixture to form the polyetherester polyols does not exceed 10% by weight and, in addition, the resulting reduced functionality is compensated by using at least trifunctional polyols, both for the low-molecular and the high-molecular polyol fractions.

According to the prior art, polyetherester polyols are prepared initially at atmospheric pressure and subsequently by applying a vacuum of 1 to 100 mbar at elevated temperatures of 120 to 250° C., preferably, although not necessarily, by using an esterification or transesterification catalyst, the reaction being complete to the extent that the acid number has fallen to 0.05 to 10 mg KOH/g, preferably 0.1 to 3 mg KOH/g and particularly preferably 0.15 to 2.5 mg KOH/g.

Furthermore, an inert gas can be used within the atmospheric pressure phase before the vacuum is applied. Alternatively, liquid or gaseous entrainers can be used or used in separate esterification phases. For example, the removal of the reaction water can be carried out using nitrogen as a carrier gas, as can the use of azeotropic entrainers such as benzene, toluene, xylene, dioxane, etc.

Naturally, mixtures of polyether polyols and polyester polyols can be used in any ratio.

The polyether polyols are preferably polyalkylene oxide polyethers based on ethylene oxide and optionally propylene oxide.

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

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

It is also possible to use polycarbonates containing hydroxyl groups, preferably polycarbonate diols, having a number-average molecular weight Mn of 400-8000 g/mol, preferably 600-3000 g/mol. These can be obtained by reacting carbonic acid derivatives, such as diphenyl carbonate, dimethyl carbonate or phosgene, with polyols, preferably diols.

Examples of such diols are ethylene glycol, 1,2- and 1,3-propylene glycol, 1,3- and 1,4-butanediol, 1,6-hexanediol, 1,8-octanediol, neopentyl glycol, 1,4-dihydroxymethylcyclohexane, 2-methyl-1,3-propanediol, 2,2,4-trimethylpentane-1,3-diol, dipropylene glycol, polypropylene glycol, dibutylene glycol, polybutylene glycol, bisphenol A and lactone-modified diols of the aforementioned types.

The polyisocyanates A1) can be reacted with the polyols A2) in an NCO/OH ratio of preferably 4:1 to 12:1, particularly preferably 8:1, to prepare the prepolymers A), after which the unreacted polyisocyanate fractions can be separated off by suitable methods. Thin-film evaporation is generally used in this case, and prepolymers having a residual monomer content of less than 1% by weight, preferably less than 0.1% by weight, and particularly preferably less than 0.03% by weight, can be obtained.

During the preparation process, stabilizers such as benzoyl chloride, isophthaloyl chloride, dibutyl phosphate, 3-chloropropionic acid or methyl toluenesulfonate may optionally be added.

The reaction temperature when preparing the prepolymer A) is preferably from 20 to 120°C and more preferably from 60 to 100°C.

The prepolymers produced have an average NCO content, measured to DIN EN ISO 11909, of from 2 to 10% by weight, preferably from 2.5 to 8% by weight.

According to a further embodiment of the polyurea system of the invention, the prepolymer A) can have an average NCO functionality of 2 to 6, preferably 2.3 to 4.5, more preferably 2.5 to 4, most particularly preferably 2.7 to 3.5 and in particular 3.

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

Advantageously, the fillers of component C) have an average OH functionality of from 1.5 to 3, preferably from 1.8 to 2.2 and particularly preferably of 2.

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

The viscosity of the organic filler, measured at 23° C. in accordance with DIN 53019, is preferably from 50 to 4000 mPas, particularly preferably from 50 to 2000 mPas.

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

In order to further reduce the average equivalent weight of the compounds used for prepolymer crosslinking overall, based on NCO-reactive groups, it is also possible to prepare reaction products of the prepolymer A) with the compounds B) according to the invention of the general formula (I) and/or the organic fillers C) (if they are amino- or hydroxy-functional) in a separate preliminary reaction and then use them as the higher molecular weight hardener component.

Preferably, a ratio of isocyanate-reactive groups to isocyanate groups of 50:1 to 1.5:1, particularly preferably 15:1 to 4:1, is set in the pre-extension.

The advantage of such modification by pre-growth is that the equivalent weight and equivalent volume of the hardening component can be modified to a greater extent. Thus, in application, commercially available two-chamber metering systems can be used to obtain a binder system that can be set with the desired ratio of NCO-reactive groups to NCO groups at the given chamber volume ratios.

A further preferred embodiment of the polyurea system according to the invention provides that component E) contains a tertiary amine of the general formula (V),

in

_R5 , _R6 and _R7 may independently be alkyl or heteroalkyl residues having heteroatoms in the alkyl chain or at their ends, or _R5 and _R6 may form together with their heteroatoms an aliphatic, unsaturated or aromatic heterocycle which may optionally contain further heteroatoms.

These polyurea systems are characterized by particularly rapid hardening.

The compounds used in component E) may particularly preferably be tertiary amines selected from the group consisting of triethanolamine, tetrakis(2-hydroxyethyl)ethylenediamine, N,N-dimethyl-2-(4-methylpiperazin-1-yl)ethylamine, 2-{[2-(dimethylamino)ethyl](methyl)amino}-ethanol, 3,3',3"-(1,3,5-triazine-1,3,5-triyl)tris(N,N-dimethyl-propan-1-amine).

Very particularly high hardening speeds can also be achieved if component E) contains 0.2 to 2.0% by weight of water and/or 0.1 to 1.0% by weight of a tertiary amine.

Naturally, pharmaceutical active substances, such as analgesics with or without anti-inflammatory action, anti-inflammatory drugs, antibacterial active substances, antifungal active substances and antiparasitic active substances or combinations thereof can also be incorporated into the polyurea system.

The active substance may be a pure active substance or in encapsulated form, for example to achieve delayed release. Within the scope of the present invention, many types and kinds of active substances can be used as pharmaceutical active substances.

A kind of pharmaceutical active substance of this type can comprise, for example, a component that releases nitric oxide under in vivo conditions, preferably L-arginine or a component containing or releasing L-arginine, particularly preferably L-arginine hydrochloride. Proline, ornithine and/or other biogenic intermediates can also be used, such as biogenic polyamines (spermine, spermidine, putrescine or biologically active artificial polyamines). As is known, these types of components promote wound healing, wherein their continuous release of almost equal amounts is particularly beneficial for healing wounds.

Additional active substances that can be used according to the present invention include at least one substance selected from the following group: vitamins or provitamins, carotenoids, analgesics, antibacterial agents, hemostatics, antihistamines, antibacterial metals or their salts, plant-based wound healing promoting substances or substance mixtures, plant extracts, enzymes, growth factors, enzyme inhibitors and combinations thereof.

Suitable analgesics are, in particular, non-steroidal analgesics, especially salicylic acid, acetylsalicylic acid and derivatives thereof, such as Aspirin®, aniline and derivatives thereof, paracetamol, for example Paracetamol®, anthranilic acid and derivatives thereof, such as mefenamic acid, pyrazoles or derivatives thereof, such as methamidazole, Novalgin®, phenazone, Antipyrin®, isopropyl antipyrine and very particularly preferably arylacetic acid and derivatives thereof, heteroarylacetic acid and derivatives thereof, arylpropionic acid and derivatives thereof and heteroarylpropionic acid and derivatives thereof, such as Indometacin®, Diclophenac®, Ibuprofen®, Naxoprophen®, Indomethacin®, Ketoprofen®, Piroxicam®.

As growth factors, the following should especially be mentioned: aFGF (acidic fibroblast growth factor), EGF ((epidermal) growth factor), PDGF (platelet-derived growth factor), rhPDGF-BB (becaplermin), PDECGF (platelet-derived dermal cell growth factor), bFGF (basic fibroblast growth factor), TGF alpha (transforming growth factor alpha), TGF beta (transforming growth factor beta), KGF (keratinocyte growth factor), IGF1/IGF2 (insulin-like growth factor) and TNF (tumor necrosis factor).

Suitable vitamins or provitamins include, in particular, fat-soluble or water-soluble vitamins, vitamin A, retinoids, provitamin A, carotenoids, in particular beta-carotene, vitamin E, tocopherols, in particular alpha-tocopherol, beta-tocopherol, gamma-tocopherol, delta-tocopherol and alpha-tocotrienol, beta-tocotrienol, gamma-tocotrienol and delta-tocotrienol, vitamin K, phylloquinone, in particular phytomenaquinone or plant-based vitamin K, vitamin C, L-ascorbic acid, vitamin B1, thiamine, vitamin B2, riboflavin, vitamin G, vitamin B3, niacin, nicotinic acid and niacinamide, vitamin B5, pantothenic acid, provitamin B5, panthenol or dexpanthenol, vitamin B6, vitamin B7, vitamin H, biotin, vitamin B9, folic acid and combinations thereof.

As antimicrobial agents, it is desirable to use agents which act as bactericides, sterilizers, bacteriostatics, fungicides, virucides, virucidals and/or general microbicides.

Particularly suitable are substances selected from the group consisting of resorcinol, iodine, iodine-povidone, chlorhexidine, benzalkonium chloride, benzoic acid, benzoyl peroxide, or cetylpyridinium chloride. Furthermore, antimicrobial metals can be used as antimicrobial agents. In particular, silver, copper, or zinc, as well as their salts, oxides, or complexes, can be used together or independently as antimicrobial metals.

In the context of the present invention, particular mention may be made of chamomile extract, witch hazel extract, such as Hamamelis Virginiana, calendula extract, aloe vera extract, such as Aloe vera, Aloe barbadensis, Aloe feroxoder or Aloe vulgaris, green tea extract, seaweed extract, such as red algae or green algae extract, avocado extract, myrrh extract, such as Commophora molmol, bamboo extract and combinations thereof as active ingredients that promote wound healing.

The content of active substance is essentially consistent with the medically required dosage and the tolerability with the remaining components of the composition according to the invention.

The polyurea systems according to the present invention are particularly suitable for sealing, bonding, adhering, or covering tissue, and in particular for stopping the loss of blood or tissue fluid or for sealing leaks in tissue. The systems are particularly suitable for applying or producing preparations for sealing, bonding, adhering, or covering human or animal tissue. The systems can facilitate the production of adhesive bonds that harden quickly, strongly adhere to tissue, are transparent, flexible, and biocompatible.

Another object of the present invention is a metering system for the polyurea system according to the invention having two chambers, one chamber containing component A) of the polyurea system and the other chamber containing component B) and optionally components C), D) and E). Such a metering system is particularly suitable for applying the polyurea system as an adhesive to tissue.

Example:

The present invention will be further explained in detail below using application examples.

method:

Molecular weight:

Molecular weight was determined using gel permeation chromatography (GPC) as follows: calibration was performed using polystyrene standards with molecular weights ranging from Mp 1,000,000 to 162. Analytical-grade tetrahydrofuran was used as the eluent. The following parameters were maintained during both measurements: degassing: online degasser; flow rate: 1 ml/min; analysis time: 45 minutes; detection: refractometer and UV detector; injection volume: 100 µl to 200 µl. The molar mass averages Mw, Mn, and Mp, as well as the polydispersity Mw/Mn, were calculated using software. The baseline point and evaluation limits were determined according to DIN 55672 Part 1.

NCO content:

If not expressly stated otherwise, the NCO content is determined volumetrically in accordance with DIN-EN ISO 11909.

Viscosity:

Viscosity is measured according to ISO 3219 at 23°C.

Residual monomer content:

The residual monomer content is determined according to DIN ISO 17025.

A Bruker DRX 700 apparatus was used for NMR.

Synthesis of NCO-terminated prepolymer A

465 g of HDI and 2.35 g of benzoyl chloride were placed in a 1-liter four-necked flask. 931.8 g of a trifunctional polyether (product of Bayer MaterialScience AG) were added over 2 hours at 80°C and subsequently stirred for 1 hour. The ethylene oxide content was 71% and the propylene oxide content was 29%, respectively, based on the total alkylene oxide content. The excess HDI was then distilled off by thin-film evaporation at 130°C and 0.13 mbar. This yielded 980 g (71%) of a prepolymer (equivalent weight: 1660 g/mol) with an NCO content of 2.53% and a viscosity of 4500 mPas/23°C. The residual monomer content was <0.03% HDI.

Polyol B and lactide are used to synthesize prepolymer C

98.1 g of glycerol, a starting poly(oxypropylene)triol with an OH number of 400 mg KOH/g, 48.4 g of lactide (Dilactid), and 0.107 g of DMC catalyst (prepared according to EP-A 700 949) were added to a 2-liter stainless steel pressure reactor under a nitrogen atmosphere and subsequently heated to 100°C. After stripping with nitrogen at 0.1 bar for 30 minutes, the temperature was raised to 130°C, and at this temperature, a mixture of 701.8 g of ethylene oxide and 217.8 g of propylene oxide was metered in over 130 minutes. After a subsequent reaction time of 45 minutes at 130°C, the volatile components were distilled off under vacuum at 90°C for 30 minutes, and the reaction mixture was then cooled to room temperature.

Product performance:

OH value: 33.7 mg KOH/g

Viscosity (25°C): 1370 mPas

Polydispersity (Mw/Mn): 1.13.

Synthesis of NCO-terminated prepolymer C

293 g of HDI and 1.5 g of benzoyl chloride were placed in a 1-liter four-necked flask. 665.9 g of Polyol B were added over 2 hours at 80°C and stirred for 1 hour. Excess HDI was then distilled off by thin-film evaporation at 130°C and 0.13 mbar. This gave a prepolymer with an NCO content of 2.37% (equivalent weight: 1772 g/mol). The residual monomer content was < 0.03% HDI. Viscosity: 5740 mPas at 23°C.

Synthesis of the hardener according to the invention:

The hardeners according to the present invention are each synthesized based on a diamine compound. In the method, the following compounds are prepared:

Hardener Diamine/acrylate X Equivalent weight Use prepolymer A until hardening time Time until hardening of prepolymer C HA1 Dytek A/Ethyl Acrylate 0.5 200.72 g/mol 4 minutes 5 minutes HA2 Dytek A/Ethyl Acrylate 0.25 215.38 g/mol 6 minutes 8 minutes HA3 Dytek A/Ethyl Acrylate 0.125 226.72 g/mol 6.5 minutes 8.5 minutes HB1 Hexamethylenediamine/ethyl acrylate 0.5 208.95 g/mol 3 minutes 3 minutes HB2 Hexamethylenediamine/ethyl acrylate 0.25 217.05 g/mol 5 minutes 5 minutes HB3 Hexamethylenediamine/ethyl acrylate 0.125 221.34 g/mol 5.5 minutes 5.5 minutes HC1 Isophorone diamine/ethyl acrylate 0.5 220.47 g/mol 20 minutes > 5 hours HC2 Isophorone diamine/ethyl acrylate 0.25 239.32 g/mol > 5 hours > 5 hours HC3 Isophorone diamine/ethyl acrylate 0.125 247.79 g/mol > 5 hours > 5 hours HD Dytek A/Butyl Acrylate 0.375 216.21 g/mol 6 minutes 7 minutes HE Hexamethylenediamine/Butyl acrylate 0.375 215.38 g/mol 5 minutes 5 minutes HF Isophorone diamine/butyl acrylate 0.375 239.32 g/mol > 5 hours > 5 hours

The following methods were used to prepare the aforementioned compounds:

At room temperature, 0.5 mol of the corresponding diamine (solid amine is added as a melt) is added, and (1-x) mol of diethyl maleate (0 ≤ x ≤ 1) is added dropwise over 1 hour, the temperature of the reaction mixture not exceeding 60° C. After stirring at room temperature for 12 hours, x mol of acrylate is added dropwise over 1 hour, the temperature of the reaction mixture not exceeding 60° C. After a moderate exothermic reaction, the reaction mixture is stirred at 60° C. for 24 hours.

After cooling to room temperature, the reaction mixture was added to three volumes of water for purification and concentrated hydrochloric acid was added until a clear solution (pH = 1) was formed. The resulting solution was extracted three times with the same volume of ethyl acetate or dichloromethane and the phases were separated (the organic phase was removed). The aqueous phase was made alkaline (pH = 10) with concentrated caustic soda and extracted three more times with the same volume of ethyl acetate or dichloromethane and the phases were separated. The organic phase was dried over sodium sulfate and the solvent was removed in vacuo. A yellow oil was obtained in a quantitative yield.

Hardening test:

1 equivalent of prepolymer A or C and 1 equivalent of hardener (HA1-3, HB1-3, HC1-3, HD, HE, HF) were added to a plastic cup and mixed thoroughly for 30 seconds. The time until the mixture lost its viscosity was measured.

In vitro tissue adhesion test

One equivalent of each hardener (HA1-3, HB1-3, HC1-3, HD, HE, HF) was added to one equivalent of prepolymer A and carefully stirred in a cup for 20 seconds. A thin layer of the polyurea system was then applied directly to the muscle tissue to be bonded. The processing time was determined as the time during which the adhesive system maintained a low viscosity, allowing it to be applied to the tissue without difficulty.

The time after which the polyurea system ceases to be tacky (tack-free time) is measured by an adhesion test using a glass rod. To this end, the glass rod is brought into contact with the polyurea system layer. If the layer no longer remains tacky, the system is considered to be tack-free. In addition, the adhesive strength is determined by coating two pieces of muscle tissue (length = 4 cm, height = 0.3 cm, width = 1 cm) with the polyurea system at a distance of 1 cm from each other at the ends and adhering them in an overlapping manner. The adhesive strength of the polyurea system is tested in each case by tensile testing.

The results of tissue adhesion tests using prepolymer A are summarized in the following table:

hardener Processing time Tack-free time Adhesive strength HA1 0:30 minutes 2:15 minutes + HA2 3:00 minutes 3:10 minutes ++ HA3 3:30 minutes 4:00 minutes ++ HB1 0:33 minutes 1:50 minutes + HB2 2:00 minutes 2:50 minutes ++ HB3 3:45 minutes 3:15 minutes ++

The results demonstrate that hardeners HA2, HA3, HB2, and HB3 offer a particularly good combination of long processing time and short tack-free time with good bond strength. In contrast, hardeners HA1 and HB1 tack-free particularly quickly and can be processed in relatively short times. Furthermore, these hardeners are characterized by a significantly lower bond strength compared to other hardeners.

Claims (15)

1. Compounds of formula (I) in R ₁ , R ₂ , and R ₃ are each independently the same or different organic residues that do not contain Zerevitinoff-active hydrogen atoms, R ₄ is independently hydrogen, the same or different organic residues containing no Zerevitinoff-active hydrogen, or together form an unsaturated or aromatic ring, the ring optionally containing heteroatoms, wherein R ₄ contains no Zerevitinoff-active hydrogen, X is a linear or branched organic radical, optionally even substituted by heteroatoms in the chain, which radical contains no Zerevitinoff-active hydrogens, n 0 < n < 2 and m 0 < m < 2, where n + m = 2. 2 . The compound according to claim 1 , wherein the radicals R ₁ , R ₂ and R ₃ are each independently a linear or branched hydrocarbon residue. 3. Compounds of formula (I) in R ₁ , R ₂ , and R ₃ are each independently the same or different organic residues that do not contain Zerevitinoff-active hydrogen atoms, R ₄ is independently hydrogen, the same or different organic residues containing no Zerevitinoff-active hydrogen, or together form an unsaturated or aromatic ring, the ring optionally containing heteroatoms, wherein R ₄ contains no Zerevitinoff-active hydrogen, X is a linear or branched organic C2-C16 residue, n 0 < n < 2 and m 0 < m < 2, where n + m = 2. The compound according to claim 3 , wherein the radicals R ₁ , R ₂ and R ₃ are each independently a linear or branched hydrocarbon residue. 5 . The compound according to claim 1 , wherein the residues R ₁ and R ₂ are respectively identical. 6. A process for preparing a compound according to claim 1, wherein the diamine compound of general formula (II) With acrylate of general formula (III) and reacting with a diester of an unsaturated dicarboxylic acid of formula (IV), wherein n moles of acrylate and m moles of diester are used per mole of diamine compound, And among them R ₁ , R ₂ , and R ₃ are each independently the same or different organic residues that do not contain Zerevitinoff-active hydrogen atoms, R ₄ is independently hydrogen, the same or different organic residues containing no Zerevitinoff-active hydrogen, or forms an unsaturated or aromatic ring, said ring optionally containing heteroatoms, wherein R ₄ contains no Zerevitinoff-active hydrogen, X is a linear or branched organic radical, optionally even substituted by heteroatoms in the chain, which radical contains no Zerevitinoff-active hydrogens, n 0 < n < 2, m 0 < m < 2, where n + m = 2. 7. Polyurea system, including as component A) an isocyanate-functional prepolymer obtainable by reaction of an aliphatic polyisocyanate A1) with a polyol A2), As component B), a compound according to one of claims 1 to 5, optionally as component C) an organic filler, optionally as component D) reaction products of isocyanate-functional prepolymers according to component A) with compounds according to component B) and/or organic fillers according to component C), and Optionally as component E) water and/or tertiary amines. 8. The polyurea system according to claim 7, characterized in that the polyol A2) comprises a polyester polyol and/or a polyester-polyether polyol and/or a polyether polyol. 9. The polyurea system according to claim 7, wherein the organic filler of component C) is a hydroxy-functional compound. 10. The polyurea system according to claim 7, wherein component E) contains a tertiary amine of the general formula (V), in _R5 , _R6 and _R7 are independently alkyl or heteroalkyl radicals having heteroatoms in the alkyl chain or at its end, or _R5 and _R6 together with the nitrogen atom carrying them form an aliphatic, unsaturated or aromatic heterocycle which optionally contains further heteroatoms. 11. The polyurea system according to claim 7 , wherein the tertiary amine is selected from the group consisting of triethanolamine, tetrakis(2-hydroxyethyl)ethylenediamine, N,N-dimethyl-2-(4-methylpiperazin-1-yl)ethylamine, 2-{[2-(dimethylamino)ethyl](methyl)amino}-ethanol, and 3,3′,3″-(1,3,5-triazine-1,3,5-triyl)tris(N,N-dimethyl-propan-1-amine). 12 . The polyurea system according to claim 7 , wherein component E) contains 0.2 to 2.0% by weight of water and/or 0.1 to 1.0% by weight of a tertiary amine. 13. The polyurea system according to claim 7, for sealing, bonding, adhering or covering cell tissue. 14. The polyurea system according to claim 13, for sealing, bonding, adhering or covering human or animal tissue. 15. A two-chamber metering system for a polyurea system according to claim 7, wherein component A) of the polyurea system is contained in one chamber and component B) and optionally components C), D) and E) are contained in the other chamber.