DE102021106358A1 - Tissue adhesive in the form of a two-component adhesive for use in pancreatic anastomosis as part of pancreatic resection - Google Patents

Abstract

The present invention relates to a tissue adhesive in the form of a two-component adhesive with at least one amino-functional aspartic acid ester as a hardener as the first component and an isocyanate-functional prepolymer as the second component for use in pancreatic anastomosis during pancreatic resection. The invention also relates to a kit made from this tissue adhesive and a surgical suture material.

Description

The present invention relates to a tissue adhesive in the form of a two-component adhesive with at least one amino-functional aspartic acid ester as a hardener as the first component and an isocyanate-functional prepolymer as the second component for use in pancreatic anastomosis during pancreatic resection. The invention also relates to a kit made from this tissue adhesive and a surgical suture material.

State of the art:

Despite advances in surgical techniques used during hepatobiliary and pancreatic (HPB) surgery, bleeding, bile leakage, and the development of pancreatic fistulas are still major contributors to postoperative mortality and morbidity (Kollär D, Huszär T, Pohärnok Z , Cselovszky E, Oláh A (2016) A review of techniques for closure of the pancreatic remnant following distal pancreatectomy.Dig Surg 33:320-328). Efforts have been made to reduce these undesirable effects through the use of topical hemostatic agents and medical adhesives. To this end, fibrin glue, absorbable gelatin sponges, oxidized regenerated cellulose, collagen and thrombin combinations and the like have been proposed. However, the disadvantage of fibrin glue and other protein-based products in particular is that they are quickly digested by pancreatic enzymes, often before adequate wound healing is even possible. However, the use of these agents is known to improve the quality of surgical tissue management and reduce the incidence of biliary, pancreatic, and enteric anastomotic leaks. In addition, the hospital stay time is reduced and the patient's recovery and quality of life is improved after such a surgical procedure.

With continued improvement in suture reinforcement and/or sealing using tissue adhesives in visceral surgical practice, the need for better next-generation medical adhesive materials is being addressed. The development of customized biodegradable products with good biocompatibility, such as the fully synthetic polyurethane-based test compounds, is one approach.

There is therefore still a need for an improved approach to closing sections in pancreatic operations, with good biodegradability of the materials used and at the same time good resistance to typical pancreatic fluids being ensured. In addition, the occurrence of postoperative problems, such as the occurrence of pancreatic fistulas in particular, should be avoided as far as possible.

Task:

The object of the present invention was therefore to provide an improved tissue adhesive for use in pancreatic anastomosis in the context of pancreatic resection, which on the one hand has high resistance to typical pancreatic fluids and at the same time has good biodegradability in the human or animal body. In addition, the tissue adhesive should allow a reliable and fast pancreatic anastomosis.

Solution:

The object is achieved by a tissue adhesive in the form of a two-component adhesive with at least one amino-functional aspartic acid ester as a hardener as the first component and an isocyanate-functional prepolymer as the second component for use in pancreatic anastomosis as part of pancreatic resection.

The invention is based on the finding that when the tissue adhesive according to the invention is used in the form of a two-component adhesive ("adhesive system") in a pancreatic anastomosis, on the one hand a very rapid closure of the surgical opening can be achieved and, for example, the operated area can be closed within 2 to 3 minutes is locked. Laboratory tests have also shown that the two-component adhesive according to the invention shows a significantly improved resistance to typical pancreatic fluids, which contain amylase and lipase, for example, compared to a fibrin adhesive. Accordingly, the incisions made in the pancreatic anastomosis heal sufficiently quickly before the adhesive breaks down.

A further advantage of the solution according to the invention is that the two-component adhesive according to the invention is also compatible with surgical suture material, ie the adhesive system according to the invention can be used together with conventional surgical methods.

In addition, the two-component adhesives according to the invention are characterized by good biodegradability, which, depending on the amount the lactide groups or the comonomer content according to the EP 2 794 710 B1 can be, for example, 4 weeks to 12 months.

A further advantage of the two-component adhesive according to the invention is that the cured tissue adhesive according to ISO 10993-5:2009 has no cytotoxicity.

Adhesives preferred according to the invention are, for example, those as described in EP 2 145 634 B1 and EP 2 794 710 B1 are revealed. Particularly preferably those of Examples 1 and 2 of EP 2 145 634 B1 and the example of polyol 1 and prepolymer 2 of EP 2 794 710 B1 and a hardener of Aspartate A/Aspartate B/PEG 200 in the ratio of 0.369/0.098/0.53. The Revelation of EP 2 145 634 B1 and EP 2 794 710 B1 is hereby incorporated by reference into the present disclosure.

• ein isocyanatfunktionelles Präpolymer als Komponente A), erhältlich durch
  1. a) Umsetzung einer wenigstens ein Zerewitinoff-aktives H-Atom aufweisenden H-funktionellen Starterverbindung mit einer Alkylenoxidverbindung und einem Co-Monomer zu einer Hydroxylgruppen tragenden Vorstufe, wobei das Co-Monomer ausgewählt ist aus der Gruppe umfassend Lactide, Glycolide, sowie Kombinationen hiervon und Kombinationen von Lactiden und / oder Glycoliden mit cyclischen Dicarbonsäureanhydriden und wobei das Co-Monomer durch eine statistische Copolymerisation in die Polymerkette(n) der Hydroxylgruppen tragenden Vorstufe eingebaut ist, sowie
  2. b) Umsetzung der Hydroxylgruppen tragenden Vorstufe aus Schritt a) mit einem polyfunktionellen Isocyanat zu dem isocyanatfunktionellen Präpolymer,
• ein aminofunktioneller Asparaginsäureester als Komponente B) der allgemeinen Formel (I)
  
  ist, wobei X ein n-wertiger organischer Rest ist, R1, R2 gleiche oder verschiedene organische Reste sind, die keine Zerewitinoff-aktiven H-Atome aufweisen, n eine ganze Zahl ≥ 2 ist, sowie optional ein Umsetzungsprodukt des isocyanatfunktionellen Präpolymers A) mit dem aminofunktionellen Asparaginsäureester B) als Komponente C).

According to a preferred embodiment of the system according to the invention, the tissue adhesive comprises or consists of the following components:

• an isocyanate-functional prepolymer as component A), obtainable from
  1. a) Reaction of an H-functional starter compound having at least one Zerewitinoff-active H atom with an alkylene oxide compound and a comonomer to give a hydroxyl-bearing precursor, the comonomer being selected from the group comprising lactides, glycolides and combinations thereof and Combinations of lactides and/or glycolides with cyclic dicarboxylic acid anhydrides and where the co-monomer is incorporated into the polymer chain(s) of the hydroxyl-bearing precursor by a statistical copolymerization, as well as
  2. b) reaction of the hydroxyl-bearing precursor from step a) with a polyfunctional isocyanate to form the isocyanate-functional prepolymer,
• an amino-functional aspartic acid ester as component B) of the general formula (I)
  
  is, where X is an n-valent organic radical, R1, R2 are identical or different organic radicals that have no Zerewitinoff-active H atoms, n is an integer ≥ 2, and optionally a reaction product of the isocyanate-functional prepolymer A) with the amino-functional aspartic acid ester B) as component C).

In other words, the isocyanate-functional prepolymer according to the invention contains ester groups in the polymer chains, which are produced by random copolymerization of alkylene oxide compounds and lactides, glycolides and/or cyclic dicarboxylic acid anhydrides onto starter compounds containing Zerewitinoff-active H atoms. In particular, the ester groups are not incorporated in blocks. The indefinite article "a", "an" etc. is to be understood as meaning that several of these components can also be implemented with one another. The components mentioned, in particular the comonomer, can also be used in dimer, trimer, etc., for example as dilactide.

Such isocyanate-functional prepolymers are biodegradable in a patient's body. The degradation time is longer than the healing time for the wound to be closed, for example 4 weeks. The statistical distribution of the comonomer units in the polymer chain(s) in particular seems to have an advantageous effect on the rate of degradation, since these function as "predetermined breaking points" in the cured adhesive. When the comonomer building blocks are attacked and broken down during biological degradation, the polymer chain length shortens particularly quickly.

At the same time, the isocyanate-functional prepolymers according to the invention are distinguished by high adhesion, in particular to human or animal tissue, and a high rate of curing. In addition, tissue adhesives with an isocyanate-functional prepolymer according to the invention meet the requirements with regard to histotoxicity and thrombogenicity.

The present invention provides for the H-functional starter compound to carry at least one Zerewitinoff-active H atom. In the context of the present invention, a Zerewitinoff-active H atom is understood as meaning an acidic H atom or “active” H atom. Such can be determined in a manner known per se by a reaction with a corresponding Grignard reagent. The amount of Zerewitinoff-active H atoms is typically measured via the methane released when the substance to be tested reacts with methylmagnesium bromide (CH3-MgBr) according to the following reaction equation: CH ₃ -MgBr + ROH → CH ₄ + Mg(OR)Br

Zerewitinoff-active H atoms are typically derived from C-H acidic organic groups, -OH, -SH, -NH2 or -NHR with R as an organic radical, and -COOH.

Particularly suitable H-functional starter compounds have an H functionality of 1 to 35, in particular 1 to 16, preferably 1 to 8, where the H functionality relates to the aforementioned Zerewitinoff-active H atoms.

Polyhydroxy-functional polymers are particularly suitable as H-functional starter compounds, which are selected in particular from straight-chain and/or branched polyethers, polyesters, polyether polyesters, polycarbonates, polyether polycarbonates, and combinations thereof.

If the polymer containing hydroxyl groups used as the H-functional starter compound is a polyether or has polyether groups, these more preferably contain ethylene oxide units, the proportion by weight of the ethylene oxide units in such a prefabricated alkylene oxide addition product being in particular at least 40% by weight, preferably at least 50% by weight. For example, the proportion by weight of ethylene oxide units is 40 to 90% by weight, preferably 50 to 80% by weight, based in each case on the mass of the polymer bearing hydroxyl groups. The remainder of the polyether skeleton or the polyether building blocks can in each case be built up by other alkylene oxide units such as, in particular, (poly)propylene oxide, (poly)butylene oxide or other (poly)alkylene oxide groups and mixtures thereof. The molecular weights of the H-functional starter compound can vary over a wide range. For example, the mean molecular weight can be from 17 to 10000 g/mol, in particular from more than 200 to 9000 g/mol. In the case of polymeric compounds, the average molecular weight denotes their number average, which can be determined using methods known per se, for example using gel permeation chromatography or determining the OH number. In other words, a monomeric starter compound, such as ammonia or ethylene glycol, can be selected as the H-functional starter compound for the prepolymer according to the invention. Oligomeric starter compounds are also included, for example polyethers with an average molecular weight of 200 to 600 g/mol and polymeric starter compounds with higher molecular weights, for example more than 600 to 10000 g/mol or 800 to 9000 g/mol.

In addition to the hydroxy-functional starters which are to be used with preference, amino-functional starters can also be used. Examples of hydroxy-functional starter compounds are methanol, ethanol, 1-propanol, 2-propanol and higher aliphatic monols, in particular fatty alcohols, phenol, alkyl-substituted phenols, propylene glycol, ethylene glycol, diethylene glycol, dipropylene glycol, 1,2-butanediol, 1,3-butanediol, 1 ,4-butanediol, hexanediol, pentanediol, 3-methyl-1,5-pentanediol, 1,12-dodecanediol, glycerol, trimethylolpropane, pentaerythritol, sorbitol, sucrose, hydroquinone, catechol, resorcinol, bisphenol F, bisphenol A, 1,3 ,5-Trihydroxybenzene, and methylol-containing condensates of formaldehyde and phenol or urea. Highly functional starter compounds based on hydrogenated starch hydrolysis products can also be used. Such are, for example, in EP 1525244 A1 described.

Examples of H-functional starter compounds containing amino groups are ammonia, ethanolamine, diethanolamine, triethanolamine, isopropanolamine, diisopropanolamine, ethylenediamine, hexamethylenediamine, aniline, the isomers of toluidine, the isomers of diaminotoluene, the isomers of diaminodiphenylmethane and in the condensation of aniline with formaldehyde to form diaminodiphenylmethane resulting higher-nuclear products, also methylol-containing condensates from formaldehyde and melamine and Mannich bases. In addition, ring-opening products from cyclic carboxylic acid anhydrides and polyols can also be used as starter compounds. Examples are ring opening products from phthalic anhydride or succinic anhydride on the one hand and ethylene glycol, diethylene glycol, 1,2-butanediol, 1,3-butanediol, 1,4-butanediol, hexanediol, pentanediol, 3-methyl-1,5-pentanediol, 1,12-dodecanediol , glycerin, trimethylolpropane, pentaerythritol or sorbitol on the other hand. In addition, it is also possible to use monofunctional or polyfunctional carboxylic acids directly as starter compounds.

Furthermore, prefabricated alkylene oxide addition products of the starter compounds mentioned, i.e. polyether polyols preferably with OH numbers of 5 to 1000 mg KOH/g, preferably 10 to 1000 mg KOH/g, can also be used as starter compounds in the process or added to the reaction mixture. It is also possible to use polyester polyols, preferably with OH numbers in the range from 6 to 800 mg KOH/g, as starters or co-starters in the process according to the invention. Polyester polyols suitable for this purpose can be prepared by known processes, for example, from organic dicarboxylic acids having 2 to 12 carbon atoms and polyhydric alcohols, preferably diols, having 2 to 12 carbon atoms, preferably 2 to 6 carbon atoms.

Furthermore, polycarbonate polyols, polyester carbonate polyols or polyether carbonate polyols, preferably polycarbonate diols, polyester carbonate diols or polyether carbonate diols, preferably each with OH numbers in the range from 6 to 800 mg KOH/g, can be used as starters or co-starters as H-functional starter substances. These are prepared, for example, by reacting phosgene, dimethyl carbonate, diethyl carbonate or diphenyl carbonate with difunctional or higher alcohols or polyester polyols or polyether polyols.

It is also possible to use polyether carbonate polyols, such as are obtainable, for example, by the catalytic reaction of alkylene oxides (epoxides) and carbon dioxide in the presence of H-functional starter substances (see, for example, EP-A 2046861 ). These polyether carbonate polyols preferably have an OH number of ≧5 mg KOH/g to ≦240 mg KOH/g, particularly preferably ≧9 to ≦200 mg KOH/g.

In step a) of the preparation of the prepolymer according to the invention, amino-free, H-functional starter compounds with hydroxyl groups are preferably used as carriers for the active hydrogens, such as methanol, ethanol, 1-propanol, 2-propanol and higher aliphatic monols, in particular fatty alcohols, phenol, alkyl-substituted phenols, propylene glycol , Ethylene Glycol, Diethylene Glycol, Dipropylene Glycol, 1,2-Butanediol, 1,3-Butanediol, 1,4-Butanediol, Hexanediol, Pentanediol, 3-Methyl-1,5-pentanediol, 1,12-Dodecanediol, Glycerin, Trimethylolpropane, Pentaerythritol , sorbitol, sucrose, hydroquinone, catechol, resorcinol, bisphenol F, bisphenol A, 1,3,5-trihydroxybenzene, methylol-containing condensates of formaldehyde and phenol and hydrogenated starch hydrolysis products. Mixtures of different H-functional starter compounds can also be used.

Alkylene oxide compounds which can be used according to the invention can be those representatives which have 2 to 24 carbon atoms, in particular 2 to 12 carbon atoms, more preferably 2 to 6 carbon atoms, and the combination of different alkylene oxide compounds of the aforementioned type. The epoxides having 2 to 24 carbon atoms are for example one or more compounds selected from the group consisting of ethylene oxide, propylene oxide, 1-butene oxide, 2,3-butene oxide, 2-methyl-1,2-propene oxide (isobutene oxide), 1-pentene oxide, 2,3-pentene oxide, 2 -Methyl-1,2-butene oxide, 3-methyl-1,2-butene oxide, 1-hexene oxide, 2,3-hexene oxide, 3,4-hexene oxide, 2-methyl-1,2-pentene oxide, 4-methyl-1 ,2-pentene oxide, 2-ethyl-1,2-butene oxide, 1-heptene oxide, 1-octene oxide, 1-nonene oxide, 1-decene oxide, 1-undecene oxide, 1-dodecene oxide, 4-methyl-1,2-pentene oxide, butadiene monoxide , isoprene monoxide, cyclopentene oxide, cyclohexene oxide, cycloheptene oxide, cyclooctene oxide, styrene oxide, methyl styrene oxide, pinene oxide - or polyepoxidized fats as mono-, di- and triglycerides, epoxidized fatty acids, C1-C24 esters of epoxidized fatty acids, epichlorohydrin, glycidol, and derivatives of glycidol such as methyl glycidyl ether, ethyl glycidyl ether, 2-ethylhexyl glycidyl ether, allyl glycidyl ether, glycidyl methacrylate and epoxy-functional alkyloxysilanes such as 3-glycidyloxypropyltrimethoxysilane, 3-glycidyloxypropyltriethoxysilane, 3-glycidyloxypropyltripropoxysilane, 3-glycidyloxypropylmethyldimethoxysilane, 3-glycidyloxypropylethyldiethoxysilane and 3-glycidyloxypropyltriisopropoxysilane. Ethylene oxide and/or propylene oxide are preferably used. In particular, the proportion by weight of ethylene oxide, based on the total mass of the metered alkylene oxide compounds, can be at least 40% by weight, preferably at least 50% by weight. For example, the proportion by weight of ethylene oxide is 40-90%, preferably 50-80%, based in each case on the total mass of the metered alkylene oxide compounds.

According to the invention, the isocyanate-functional prepolymer contains building blocks originating from lactides, glycolides and/or cyclic dicarboxylic acid anhydrides, which are built into the polymer chain of the hydroxyl-bearing precursor by statistical copolymerization. The molar ratio of the alkylene oxide compound to this comonomer in the hydroxyl-bearing precursor is preferably 200:1 to 1:1, in particular 10:1 to 5:1. These molar ratios are particularly preferred because a tissue adhesive containing such a prepolymer precursor has good adhesion with a short curing time and also degrades quickly under physiological conditions.

In principle, it is also possible to incorporate other co-monomers, such as e.g. cyclic anhydrides or carbon dioxide, into the polymer chain of the hydroxyl-bearing prepolymer by statistical copolymerization.

The preparation of component A) can be carried out without catalysis, but the use of a catalyst is preferred. In particular, step a) can be catalyzed via a double metal cyanide catalyst (DMC catalyst) which contains in particular zinc hexacyanocobaltate (III), zinc hexacyanoiridate (III), zinc hexacyanoferrate (III) or cobalt(II) hexacyanocobaltate (III). A particular advantage of this embodiment is that the hydroxyl-bearing precursor obtained as an intermediate of step a) has a comparably narrow molecular chain ten-length distribution. One of the reasons can be seen in the use of DMC catalysis, because such catalysts show so-called "catch-up" kinetics. This means that as the chain length increases, the catalytic activity for the attachment of the next monomer building block gradually decreases, and with it the reaction rate.

wobei R1, R2, R3 gleiche oder verschiedene organische Reste sind, die keine Zerewitinoff-aktiven H-Atome aufweisen.As explained above, the preferred amino-functional aspartic acid ester used is one of the general formula (I). More preferred is an amino-functional aspartic acid ester of the general formula (II)

where R1, R2, R3 are identical or different organic radicals which do not have any Zerewitinoff-active H atoms.

To improve the biological compatibility, the polyfunctional isocyanate is preferably selected from aliphatic isocyanates, in particular from hexamethylene diisocyanate (HDI), isophorone diisocyanate (IPDI), butylene diisocyanate (BDI), bisisocyanatocyclohexylmethane (HMDI), 2,2,4-trimethylhexamethylene diisocyanate, bisisocyanatomethylcyclohexane, bisisocyanatomethyltricyclodecane, xylene diisocyanate , tetramethylxylylene diisocyanate, norbornane diisocyanate, cyclohexane diisocyanate, diisocyanatododecane, or combinations thereof. Here, hexamethylene diisocyanate (HDI), isophorone diisocyanate (IPDI), butylene diisocyanate (BDI) and bis(isocyanatocyclohexyl)methane (HMDI) are preferred. Hexamethylene diisocyanate, isophorone diisocyanate, butylene diisocyanate are particularly preferred, and hexamethylene diisocyanate and isophorone diisocyanate are very particularly preferred.

In principle, however, the invention is not limited to the use of aliphatic isocyanates, so conventional aromatic isocyanates can also be used, such as toluene diisocyanate (TDI) or diphenylmethane diisocyanate (MDI).

The reaction of the hydroxyl-bearing prepolymer obtained after step a) with the polyfunctional isocyanate in step b) can be carried out at an NCO/OH ratio of 4:1 to 12:1, preferably 8:1, and then the proportion of unreacted Isocyanate are separated by suitable methods. Thin-film distillation is usually used for this, giving a prepolymer having a residual monomer content of less than 1% by weight, preferably less than 0.1% by weight, very particularly preferably less than 0.03% by weight.

Optionally, stabilizers such as benzoyl chloride, isophthaloyl chloride, dibutyl phosphate, 3-chloropropionic acid, or methyl tosylate may be added during preparation of the isocyanate-functional prepolymer.

The reaction temperature in the reaction in step b) is preferably from 20 to 120.degree. C. and more preferably from 60 to 100.degree.

The isocyanate-functional prepolymer preferably has an average NCO content, measured according to DIN EN ISO 11909, of 2 to 10% by weight, preferably 2.5 to 8% by weight.

The average NCO functionality of the isocyanate-functional prepolymer is preferably from 1.5 to 6, more preferably from 1.6 to 5, even more preferably from 1.7 to 4, very particularly preferably from 1.8 to 3.5 and in particular 3.

According to the invention, the adhesive used is characterized by an aspartate hardener. However, the tissue adhesive can preferably comprise at least one further hardener. According to a particularly preferred embodiment, the tissue adhesive according to the invention also comprises a further hardener, which is selected in particular from polyols with a number-average molar mass of 1000 Da or less, in particular 600 Da or less, more preferably 400 Da or less or even 300 Da or fewer. PEG or PPG, for example, are suitable as polyols. By adding these additional hardeners, the curing speed of the tissue adhesive according to the invention can be influenced, that is to say it can generally be shortened, so that the tissue adhesive can be manufactured as required. For example, a polyethylene glycol 200 is preferably used.

Of course, pharmacologically active ingredients such as analgesics with and without anti-inflammatory effects, antiphlogistics, antimicrobial substances, antimycotics, antiparasitic substances can also be incorporated into the tissue adhesive.

The active ingredients can be present as a pure active ingredient or in encapsulated form, for example in order to achieve a time-delayed release. Within the scope of the present invention, a large number of types and classes of active substances can be used as medicinal active substances.

Such a medicinal active substance can, for example, comprise a component which releases nitrogen monoxide under in vivo conditions, preferably L-arginine or an L-arginine-containing component or an L-arginine-releasing component, particularly preferably L-arginine hydrochloride. Proline, ornithine and/or other biogenic intermediates such as biogenic polyamines (spermine, spermite, putrescine or bioactive artificial polyamines) can also be used. It is known that components of this type support wound healing, and their continuous, almost uniform release in terms of quantity is particularly beneficial for wound healing.

Other active ingredients that can be used according to the invention include at least one substance selected from the group of vitamins or provitamins, carotenoids, analgesics, antiseptics, haemostatics, antihistamines, antimicrobial metals or their salts, herbal substances or mixtures of substances that promote wound healing, plant extracts, enzymes, growth factors, enzyme inhibitors and combinations thereof.

Analgesics include, in particular, non-steroidal analgesics, in particular salicylic acid, acetylsalicylic acid and their derivatives, e.g. Aspirin®, aniline and its derivatives, acetaminophen, e.g. Paracetamol®, antranilic acid and its derivatives, e.g. mefenamic acid, pyrazole or its derivatives, e.g. methamizole, Novalgin®, phenazone, Antipyrin® , Isopropyl-iphenazone and very particularly preferably arylacetic acids and derivatives thereof, heteroarylacetic acids and derivatives thereof, arylpropionic acids and derivatives thereof and heteroarylpropionic acids and derivatives thereof, e.g. Indomethacin®, Diclophenac®, Ibuprofen®, Naxoprophen®, Indomethacin®, Ketoprofen®, Piroxicam®.

The following growth factors should be mentioned in particular: aFGF (Acidic Fibroplast Growth Factor), EGF (Epidermal) Growth Factor), PDGF (Platelet Derived Growth Factor), rhPDGF-BB (Becaplermin), PDECGF (Platelet Derived Endothelial Cell Growth Factor), bFGF ( basic fibroblast growth factor), TGFα; (Transforming Growth Factor alpha), TGF β (Transforming Growth Factor beta), KGF (Keratinocyte Growth Factor), IGF1/IGF2 (Insulin-Like Growth Factor) and TNF (Tumor Necrosis Factor).

Vitamins or provitamins are in particular the fat-soluble or water-soluble vitamins vitamin A, group of retinoids, provitamin A, group of carotenoids, in particular β-carotene, vitamin E, group of tocopherols, in particular α-tocopherol, β-tocopherol, γ-tocopherol, δ -Tocopherol and α-tocotrienol, β-tocotrienol, γ-tocotrienol and δ-tocotrienol, vitamin K, phylloquinone in particular phytomenadione or vegetable vitamin K, vitamin C, L-ascorbic acid, vitamin B1, thiamin, vitamin B2, riboflavin, vitamin G, Vitamin B3, niacin, nicotinic acid and nicotinamide, vitamin B5, pantothenic acid, provitamin B5, panthenol or dexpanthenol, vitamin B6, vitamin B7, vitamin H, biotin, vitamin B9, folic acid and combinations thereof.

An antiseptic should be used that has a gemicidal, bactericidal, bacteriostatic, fungicidal, virucidal, virustatic and/or generally microbiocidal effect.

Substances that are particularly suitable are those selected from the group consisting of resorcinol, iodine, iodine-povidone, chlorhexidine, benzalkonium chloride, benzoic acid, benzoyl peroxide or cethylpyridinium chloride. In addition, antimicrobial metals in particular can also be used as antiseptics. In particular, silver, copper or zinc and their salts, oxides or complexes can be used in combination or alone as antimicrobial metals.

In connection with the present invention, extracts of chamomile, hamamelis extracts such as Hamamelis virgina, calendula extract, aloe extract, e.g. aloe vera, aloe barbadensis, aloe feroxoder or aloe vulgaris, green tea extracts, seaweed Extract, for example red algae or green algae extract, avocado extract, myrrh extract, for example Commophora molmol, bamboo extracts and combinations thereof.

The content of the active substances depends primarily on the medically required dose and also on the compatibility with the other components of the tissue adhesive according to the invention.

The system according to the invention can also comprise surgical suture material. In principle, all surgical suture materials known to the person skilled in the art can be used for this purpose. With this material, the severed and rejoined tissue parts can be stabilized in addition to the adhesive. For this purpose, for example, a support seam is produced from the surgical suture material. This measure is expediently carried out before the adhesive is applied.

1. a) Durchtrennen des Pankreas und Entfernen von Pankreasgewebe, gegebenenfalls bis zum Dünndarm und/ oder Magen;
2. b) Zusammenführen der beiden Enden des Gewebes des Pankreas, gegebenenfalls mit denen des Dünndarms und/ oder des Magens so dass die Kanten des Gewebes noch voneinander beabstandet sind oder auf Stoß zusammenliegen;
3. c) optionales Erzeugen einer Stütznaht aus chirurgischem Nahtmaterial, mit der die Enden des durchtrennten Pankreasgewebes, Dünndarmgewebes und/ oder Magengewebes miteinander verbunden werden;
4. d) Vermischen der ersten und zweiten Komponente des Zweikomponenten-Klebstoffs und Auftragen des Klebstoffs zumindest auf die Öffnungsstelle der den Bereich der zusammengefügten Enden des durchtrennten Pankreasgewebes;
5. e) Aushärtenlassen des Gewebeklebers.

The invention further relates to a method for pancreatic anastomosis in the context of pancreatic resection using a tissue adhesive according to the invention, the method comprising the following steps:

1. a) Transection of the pancreas and removal of pancreatic tissue, optionally up to the small intestine and/or stomach;
2. b) Bringing together the two ends of the tissue of the pancreas, optionally with those of the small intestine and/or the stomach, so that the edges of the tissue are still spaced apart or are butt together;
3. c) optionally creating a support seam from surgical suture material, with which the ends of the severed pancreatic tissue, small intestine tissue and/or stomach tissue are connected to one another;
4. d) mixing the first and second components of the two-component adhesive and applying the adhesive at least to the opening site of the region of the joined ends of the severed pancreatic tissue;
5. e) allowing the tissue adhesive to set.

The invention also relates to a kit comprising or consisting of a tissue adhesive according to the invention and surgical suture material and optionally instructions for the pancreas anastomosis in the context of pancreas resection, which describes the above-mentioned method according to the invention.

• Nach einer ersten Ausführungsform betrifft die Erfindung einen Gewebekleber in Form eines Zweikomponenten-Klebstoffs mit wenigstens einem aminofunktionellen Asparaginsäureester als Härter als erste Komponente und einem isocyanatfunktionellen Präpolymer als zweite Komponente zur Verwendung bei der Pankreasanastomose im Rahmen der Pankreasresektion.

The invention relates in particular to the following embodiments:

• According to a first embodiment, the invention relates to a tissue adhesive in the form of a two-component adhesive with at least one amino-functional aspartic acid ester as a hardener as the first component and an isocyanate-functional prepolymer as the second component for use in pancreatic anastomosis during pancreatic resection.

• ein isocyanatfunktionelles Präpolymer als Komponente A), erhältlich durch
  1. a) Umsetzung einer wenigstens ein Zerewitinoff-aktives H-Atom aufweisenden H-funktionellen Starterverbindung mit einer Alkylenoxidverbindung und einem Co-Monomer zu einer Hydroxylgruppen tragenden Vorstufe, wobei das Co-Monomer ausgewählt ist aus der Gruppe umfassend Lactide, Glycolide, sowie Kombinationen hiervon und Kombinationen von Lactiden und / oder Glycoliden mit cyclischen Dicarbonsäureanhydriden und wobei das Co-Monomer durch eine statistische Copolymerisation in die Polymerkette(n) der Hydroxylgruppen tragenden Vorstufe eingebaut ist, sowie
  2. b) Umsetzung der Hydroxylgruppen tragenden Vorstufe aus Schritt a) mit einem polyfunktionellen Isocyanat zu dem isocyanatfunktionellen Präpolymer,
• ein aminofunktioneller Asparaginsäureester als Komponente B) der allgemeinen Formel (I)
  
  ist, wobei X ein n-wertiger organischer Rest ist, R1, R2 gleiche oder verschiedene organische Reste sind, die keine Zerewitinoff-aktiven H-Atome aufweisen, n eine ganze Zahl ≥ 2 ist, sowie optional ein Umsetzungsprodukt des isocyanatfunktionellen Präpolymers A) mit dem aminofunktionellen Asparaginsäureester B) als Komponente C).

According to a second embodiment, the invention relates to a system according to embodiment 1, characterized in that the tissue adhesive comprises or consists of the following components:

• an isocyanate-functional prepolymer as component A), obtainable from
  1. a) Reaction of an H-functional starter compound having at least one Zerewitinoff-active H atom with an alkylene oxide compound and a comonomer to give a hydroxyl-bearing precursor, the comonomer being selected from the group comprising lactides, glycolides and combinations thereof and Combinations of lactides and/or glycolides with cyclic dicarboxylic acid anhydrides and where the co-monomer is incorporated into the polymer chain(s) of the hydroxyl-bearing precursor by a statistical copolymerization, as well as
  2. b) reaction of the hydroxyl-bearing precursor from step a) with a polyfunctional isocyanate to form the isocyanate-functional prepolymer,
• an amino-functional aspartic acid ester as component B) of the general formula (I)
  
  is, where X is an n-valent organic radical, R1, R2 are identical or different organic radicals that have no Zerewitinoff-active H atoms, n is an integer ≥ 2, and optionally a reaction product of the isocyanate-functional prepolymer A) with the amino-functional aspartic acid ester B) as component C).

ist,
wobei R1, R2, R3 gleiche oder verschiedene organische Reste sind, die keine Zerewitinoff-aktiven H-Atome aufweisen.According to a third embodiment, the invention relates to a system according to embodiment 2, characterized in that the amino-functional aspartic acid ester is one of the general formula (II)

is,
where R1, R2, R3 are identical or different organic radicals which do not have any Zerewitinoff-active H atoms.

According to a fourth embodiment, the invention relates to a system according to embodiment 2 or 3, characterized in that the alkylene oxide compound is selected from ethylene oxide and/or propylene oxide, the proportion of ethylene oxide units in the polymer chain of the hydroxyl-bearing precursor being at least 40% by weight.

According to a fifth embodiment, the invention relates to a system according to one of embodiments 2 to 4, characterized in that the polyfunctional isocyanate is chosen from aliphatic isocyanates.

According to a sixth embodiment, the invention relates to a system according to one of the preceding embodiments, characterized in that the tissue adhesive has at least one comprises a further hardener which is selected in particular from polyols having a number-average molar mass of 1000 Da or less, in particular 600 Da or less.

According to a seventh embodiment, the invention relates to a system according to one of the above embodiments, characterized in that the tissue adhesive contains at least one pharmacologically active ingredient selected from the group consisting of analgesics with and without anti-inflammatory effects, anti-inflammatory drugs, antimicrobial substances, antimycotics, antiparasitic agents Substances or mixtures of these, the active ingredients being present in particular as a pure active ingredient or in encapsulated form.

According to an eighth embodiment, the invention relates to a system according to embodiment 7, characterized in that the active substance is selected from components which release nitrogen monoxide under in vivo conditions, preferably L-arginine or an L-arginine-containing component or an L-arginine-releasing component , particularly preferably L-arginine hydrochloride,
proline, ornithine and/or biogenic polyamines, in particular spermine, spermite, putrescine or bioactive artificial polyamines,
Vitamins or provitamins, carotenoids, analgesics, antiseptics, haemostatics, antihistamines, antimicrobial metals or their salts, herbal substances or substance mixtures that promote wound healing, plant extracts, enzymes, growth factors, enzyme inhibitors and combinations thereof.

According to a ninth embodiment, the invention relates to a system according to one of the above embodiments, characterized in that the system comprises surgical suture material

1. a) Durchtrennen des Pankreas und Entfernen von Pankreasgewebe, gegebenenfalls bis zum Dünndarm und/ oder Magen;
2. b) Zusammenführen der beiden Enden des Gewebes des Pankreas, gegebenenfalls mit denen des Dünndarms und/ oder des Magens so dass die Kanten des Gewebes noch voneinander beabstandet sind oder auf Stoß zusammenliegen;
3. c) optionales Erzeugen einer Stütznaht aus chirurgischem Nahtmaterial, mit der die Enden des durchtrennten Pankreasgewebes, Dünndarmgewebes und/ oder Magengewebes miteinander verbunden werden;
4. d) Vermischen der ersten und zweiten Komponente des Zweikomponenten-Klebstoffs und Auftragen des Klebstoffs zumindest auf die Öffnungsstelle der den Bereich der zusammengefügten Enden des durchtrennten Pankreasgewebes;
5. e) Aushärtenlassen des Gewebeklebers.

According to a tenth embodiment, the invention relates to a method for pancreatic anastomosis in the context of pancreatic resection using a tissue adhesive according to one of embodiments 1 to 9, the method comprising the following steps:

1. a) Transection of the pancreas and removal of pancreatic tissue, optionally up to the small intestine and/or stomach;
2. b) Bringing together the two ends of the tissue of the pancreas, optionally with those of the small intestine and/or the stomach, so that the edges of the tissue are still spaced apart or are butt together;
3. c) optionally creating a support seam from surgical suture material, with which the ends of the severed pancreatic tissue, small intestine tissue and/or stomach tissue are connected to one another;
4. d) mixing the first and second components of the two-component adhesive and applying the adhesive at least to the opening site of the region of the joined ends of the severed pancreatic tissue;
5. e) allowing the tissue adhesive to set.

According to an eleventh embodiment, the invention relates to a kit containing or consisting of a tissue adhesive according to one of embodiments 1 to 6 and surgical suture material and optionally a method manual for pancreas resection, which describes the method according to embodiment 10.

According to a twelfth embodiment, the invention relates to a kit according to embodiment 11, characterized in that the two components of the tissue adhesive are present in separate chambers of a two-chamber syringe, the two-chamber syringe being provided with a static mixer on the outlet side and optionally with an application nozzle.

According to a thirteenth embodiment, the invention relates to a kit according to embodiment 12, characterized in that the application nozzle is a slot nozzle.

Example:

The present invention is explained in more detail below using exemplary embodiments.

Materials used:

Tissue Adhesive (According to the Invention): Two-component tissue adhesive based on the polyol 1 of EP 2 794 710 B1 , which is converted into prepolymer 2 and then formulated with aspartates A and B and PEG 200 in the following mixing ratio (aspartate A/aspartate B/PEG 200; 0.369/0.098/0.53). Both tissue adhesives according to the invention were used with a two-chamber syringe with a static mixer attached.
Tachosil® (comparison): collagen fleece with human fibrinogen and thrombin (Takeda Pharma Vertrieb GmbH & Co. KG, Berlin, Germany)
Surgical suture material (comparison): Ethilon 6/0 (Ethicon®, Hamburg, Germany)

Measurement methods:

The OH numbers were determined in accordance with the provisions of DIN 53240.

The viscosities of the polyols were determined using a rotational viscometer (Physica MCR 51, manufacturer: Anton Paar) in accordance with the specifications of DIN 53019 (2008).

The number average M _n and the weight average M _w of the molecular weight and the polydispersity (M _w /M _n ) were determined by means of gel permeation chromatography (GPC). The procedure was according to DIN 55672-1: "Gel permeation chromatography, part 1 - tetrahydrofuran as eluent" (SECurity GPC system from PSS Polymer Service, flow rate 1.0 ml/min; columns: 2xPSS SDV linear M, 8x300 mm, 5 µm; RID Detector). Polystyrene samples of known molar mass were used for calibration.

Unless expressly stated otherwise, NCO contents were determined volumetrically in accordance with DIN-EN ISO 11909.

The residual monomer content was determined according to DIN ISO 17025:2018-03.

1 In vitro experiments

Incubation experiments with pancreatic juice

Further in vitro incubation tests were carried out to characterize the tissue adhesive according to the invention and its resistance to the enzymatically active pancreatic juice. For this purpose, pellets of the cured tissue adhesive according to the invention of a defined mass were incubated in highly active pancreatic juice (very high enzyme concentrations; amylase: 102,800 U/L; lipase 151,800 U/L) at 36.7° C. and the weight of the sample was measured every 24 hours for 10 days determined again with the tissue adhesive according to the invention and renewed the incubation solution. A fibrin sealant (Tachosil) was used as a control article and treated in the same way. Test and control articles were also incubated with physiological electrolyte solution as a control. Based on the weight development over a period of 10 days, a clear difference between the tissue adhesive according to the invention and Tachosil was recognizable: while Tachosil strongly absorbed the control solution over 10 days (relative increase in weight up to 850%), the pancreatic juice was also absorbed on day 1 (relative increase in weight up to 350%), but led to a degradation of the fibrin sealant so that it was already completely lysed on day 5. In contrast, the tissue adhesive of the present invention showed constant absorption of the control solution and pancreatic juice of approximately 200% over the 10-day test period. The tissue glue of the present invention was not lysed by the pancreatic enzymes and there was no difference between the control solution and the pancreatic juice. It can be concluded from these results that the tissue adhesive according to the invention has a significantly higher resistance to the pancreatic enzymes amylase and lipase compared to Tachosil.

2 In vivo experiments

In order to investigate the efficiency and safety of the tissue adhesive according to the invention in the sealing of a pancreatic anastomosis, tests were carried out in the model organisms rat and pig. While a resection of the distal pancreas was performed in the rat, both the distal resection (simultaneously to the rat) and a simplified pancreatogastrostomy (vPG) were performed in the pig, in which the head of the pancreas was resected and the pancreas stump was attached to the stomach. The experiments are described in detail below.

2.1 Distal resection (rat)

The distal portion (about 1/3 of the entire organ) was resected and ligated with suture. Then the test article, the tissue adhesive according to the invention, the control article Tisseel (fibrin) or, in the case of rats of the control group, exclusively physiological saline solution was applied to the resection surface. Test and control articles were allowed a time of 5 minutes for the adhesives to fully polymerize. After different test periods (14, 21 or 90 days), the rats were euthanized and dissected in accordance with animal welfare. The following parameters were used to assess the efficiency and safety of the tissue adhesive according to the invention: Clinical observations, clinical-chemical and hematological blood values, macroscopic observations during the dissection (adhesions within the abdomen, detachment of the adhesive from the resection area, degradation of the adhesive), pancreatic fistulas, histopathological evaluation.

All animals treated with the tissue adhesive of the present invention recovered very well from the surgery and were maximally exposed to moderate stress during the acute recovery period (14 days). The stress corresponded to that of the control animals (physiological saline solution) and is therefore attributable to the surgical procedure and not to the use of the tissue adhesive according to the invention. The hematological parameters of the small blood count did not deviate at any time significantly from the values before the operation or the values of the control animals, so that no influence of the tissue adhesive according to the invention was detected. The pancreatic enzymes amylase and lipase in the blood of the animals showed a significant increase 90 days after the operation in a group of animals treated with the tissue adhesive according to the invention. However, since no signs of a pancreatic fistula were found during the autopsy, the increase in concentration is classified as irrelevant. The rats treated with the tissue adhesive according to the invention showed significantly milder adhesion within the construction space compared to rats treated with Tisseel or physiological saline solution. Furthermore, the tissue adhesive according to the invention showed a very low rate of detachment (in one out of 10 animals at the point in time 21 days), which suggests very good adhesion to the pancreatic tissue. The histopathological evaluation showed the formation of a connective tissue capsule surrounding the tissue adhesive, a mild inflammation which was detected locally around the tissue adhesive and was not active, and progressive degradation of the tissue adhesive according to the invention with increasing test duration. This local tissue reaction corresponded to the expectations when the adhesive was introduced into a tissue and did not show any toxicological or adverse effects at any time.

In summary, it can be stated that the tissue adhesive according to the invention was not only very efficient in the model of distal pancreatic resection in rats (prevention of pancreatic fistula, very low detachment rate, resistant to pancreatic fluid), but also did not induce any adverse effects. No changes in the blood count or signs of local or systemic toxicity were detected, which is why the tissue adhesive according to the invention can be assessed as safe over the test period of 90 days.

2.2 Distal resection (pig)

The positive results of the tissue adhesive according to the invention in the pancreas resection in rats were then examined in a model organism which is very well comparable to humans in terms of anatomy, way of life and function. For this purpose, the pig was selected as a model organism and a distal pancreas resection was performed in 36 pigs simultaneously with the rat experiment. The study periods of the animals were 21, 90 and 180 days and Tisseel® was used as a comparison product.

The formation of a pancreatic fistula or resulting peritonitis was not detected in any of the animals. The adhesive remained at the site of application (pancreas stump) and no detachments were found. The haematological examinations did not show any pathological values, the CRP values of all animals as an indicator for active inflammation were without any special findings and there were no indications of liver toxicity (AST and ALT values without any special findings). The histopathological evaluation confirmed the results from the rat study: formation of a connective tissue capsule, a mild inflammatory reaction surrounding the tissue adhesive according to the invention and progressive degradation of the adhesive with increasing test duration. After 180 days, the tissue adhesive according to the invention was almost completely degraded. This local tissue reaction corresponded to the expectations when the adhesive was introduced into a tissue and did not show any toxicological or adverse effects at any time.

In summary, it can be stated that the tissue adhesive according to the invention was not only very efficient in the model of distal pancreatic resection in pigs (prevention of pancreatic fistula, very low detachment rate), but also did not induce any adverse effects. No changes in the blood count or signs of local or systemic toxicity were detected, which is why the tissue adhesive according to the invention can be assessed as safe over the test period of 180 days. Furthermore, it could be confirmed that the tissue adhesive according to the invention was almost completely degraded within 180 days when pancreas resection was used in pigs.

2.3 Simplified Pancreatogastrostomy (vPG)

A simplified pancreatogastrostomy (vPG) was performed in the model organism pig in order to simulate a surgical method that is frequently used in the clinic, the pancreatogastrostomy (PG). In vPG, the tail of the pancreas was resected, the end of the pancreas guided into the stomach and sutured to the gastric mucosa. This anastomosis was sealed either intraluminally (inside the stomach) or extraluminally (outside the stomach) with the tissue adhesive according to the invention. Blockage of the pancreatic ducts was also examined. For this purpose, a vPG was first performed, the pancreas-stomach anastomosis was sealed intraluminally using the tissue adhesive according to the invention, and the main pancreatic duct and the large side pancreatic ducts were also blocked using the tissue adhesive. The aim of this was to locally prevent the secretion of pancreatic juice and thus prevent the development of postoperative pancreatic fistulas. After a survival time of 14 days, the pigs were humanely euthanized and dissected. Animals were closely monitored after surgery and clinical observation was documented. Haematological examinations and enzyme determinations (amylase and lipase) in the blood and in the abdominal drainage fluid were carried out in all animals on postoperative days (POD) 1, 3, 5, 10 and 14.

All test animals showed a good state of health after the operation and there were no complications in the recovery phase associated with the tissue adhesive according to the invention. Overall, the hematological findings were unremarkable and non-pathological fluctuations were attributable to the surgical intervention per se. The examination of amylase and lipase in the drainage fluid showed a significant increase in POD1, which, however, normalized completely up to POD5 and there was no evidence of a pancreatic fistula in any animal (definition of pancreatic fistula: 3-fold amylase value in abdominal drainage compared to the serum amylase concentration beyond POD7 or for 3 consecutive days). Drainage fluid was no longer collected after POD5, indicating good healing of the pancreatic stump. Macroscopic observations during the dissection at POD14 showed minor adhesive residue at the anastomosis, very mild adhesions within the abdomen, and almost complete digestion of the pancreatic stump at the anastomosis. These results indicate very good wound healing within 14 days. No relevant differences were found between animals from different test groups (intraluminal, extraluminal, blocking).

In summary, it can be stated that the tissue adhesive according to the invention is suitable for the intraluminal and extraluminal sealing of a pancreatic-stomach anastomosis and for blocking the pancreatic ducts and completely prevents the formation of pancreatic fistulas. With regard to the good state of health of the animals after the operation, unremarkable haematological, amylase and lipase values in the blood and drainage fluid and the absence of macroscopic findings during the dissection, the use of the tissue adhesive according to the invention in the vPG over a period of 14 days can be assessed as safe .

QUOTES INCLUDED IN DESCRIPTION

This list of documents cited by the applicant was generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Patent Literature Cited

• EP 2794710 B1 [0009, 0011, 0068]
• EP 2145634 B1 [0011]
• EP 1525244 A1 [0021]
• EP 2046861 A [0025]

Claims (10)

Tissue adhesive in the form of a two-component adhesive with at least one amino-functional aspartic acid ester as a hardener as the first component and an isocyanate-functional prepolymer as the second component for use in pancreatic anastomosis as part of pancreatic resection. tissue glue claim 1 , characterized in that the tissue adhesive comprises or consists of the following components: an isocyanate-functional prepolymer as component A), obtainable by a) reacting an H-functional starter compound having at least one Zerewitinoff-active H atom with an alkylene oxide compound and a comonomer a hydroxyl-bearing precursor, wherein the comonomer is selected from the group consisting of lactides, glycolides, and combinations thereof and combinations of lactides and / or glycolides with cyclic dicarboxylic acid anhydrides and wherein the comonomer by a statistical copolymerization in the polymer chain (s) the hydroxyl-functional precursor is incorporated, and b) reaction of the hydroxyl-functional precursor from step a) with a polyfunctional isocyanate to form the isocyanate-functional prepolymer, an amino-functional aspartic acid ester as component B) of the general formula (I)

is, where X is an n-valent organic radical, R _1, R ₂ are identical or different organic radicals that have no Zerewitinoff-active H atoms, n is an integer ≥ 2, and optionally a reaction product of the isocyanate-functional prepolymer A ) with the amino-functional aspartic acid ester B) as component C). tissue glue claim 2 , characterized in that the amino-functional aspartic acid ester is one of the general formula (II)

is, where R1, R2, R3 are identical or different organic radicals that have no Zerewitinoff-active H atoms. tissue glue claim 2 or 3 , characterized in that the alkylene oxide compound is selected from ethylene oxide and/or propylene oxide, the proportion of ethylene oxide units in the polymer chain of the hydroxyl-bearing precursor being at least 40% by weight. Tissue adhesive according to one of claims 2 until 4 , characterized in that the polyfunctional isocyanate is selected from aliphatic isocyanates. Tissue adhesive according to one of the preceding claims, characterized in that the tissue adhesive comprises at least one further hardener which is selected in particular from polyols with a number-average molar mass of 1000 Da or less, in particular 600 Da or less. Method for pancreatic anastomosis in the context of pancreatic resection using a tissue adhesive according to one of Claims 1 until 6 , wherein the method comprises the following steps: f) severing the pancreas and removing pancreatic tissue, optionally down to the small intestine and/or stomach; g) Bringing together the two ends of the tissue of the pancreas, optionally with those of the small intestine and/or the stomach, so that the edges of the tissue are still spaced apart or are butt together; h) optionally creating a support seam from surgical suture material, with which the ends of the severed pancreatic tissue, small intestine tissue and/or stomach tissue are connected to one another; i) mixing the first and second components of the two-component adhesive and applying the adhesive at least to the opening site of the region of the joined ends of the severed pancreatic tissue; j) allowing the tissue adhesive to set. Kit containing or consisting of a tissue adhesive according to one of Claims 1 until 6 and surgical sutures and, optionally, a pancreatic resection procedural manual that describes the procedure according to claim 7 describes. kit after claim 8 , characterized in that the two components of the tissue adhesive are present in separate chambers of a two-chamber syringe, the two-chamber syringe being provided on the outlet side with a static mixer and optionally with an application nozzle. kit after claim 9 , characterized in that the application nozzle is a slot nozzle.