WO2012175563A1

WO2012175563A1 - Biocompatible adhesive and method for the production thereof

Info

Publication number: WO2012175563A1
Application number: PCT/EP2012/061856
Authority: WO
Inventors: Michael Sittinger; Jochen Ringe; Tilo Dehne; Boris Habermann; Rafael Valbuena; Günter Westphal
Original assignee: Charité - Universitätsmedizin Berlin
Priority date: 2011-06-20
Filing date: 2012-06-20
Publication date: 2012-12-27
Also published as: DE102011077809A1

Abstract

The present invention relates to an adhesive, containing or consisting of 1 to 20% by weight of collagen, 0.5 to 15% by weight of hyaluronic acid or hyaluronate and 65 to 98.5% by weight of water, the percentages by weight relating to the total weight of the adhesive; and to a method for producing such an adhesive.

Description

Biocompatible adhesive and process for its preparation

Biocompatible adhesives or adhesives are used in many areas of medicine. It is not only important that the adhesive has a high adhesive effect, but it is also important that the adhesive is well-tolerated and thus biocompatible. For this reason, efforts are made to provide adhesives, which preferably consist of well-tolerated components. For example, from US 5,209,776, US 2005/02081 14A1 or US 4,280,954 adhesives are known which may contain the components collagen and hyaluronic acid.

A problem with these adhesives is e.g. in that these adhesives either contain denatured collagen, a covalent bond between collagen and hyaluronic acid is produced and / or catalysts or other constituents are used which bring about an increased allergy potential.

The object of the present invention is to provide improved adhesives and processes for their preparation. In particular, it is an object of the present invention to provide adhesives and processes for their preparation which combine a sufficient adhesive effect with a high biocompatibility and a low allergy potential.

The object is achieved by providing a method for producing an adhesive, characterized in that an aqueous collagen solution having a dissolved collagen concentration of 0.01 to 5% (w / v) and a pH of 2 to 5 with an aqueous hyaluronate solution having a hyaluronate or hyaluronic acid concentration of 0.02 to 5% (w / v) and a pH of 5 to 7, preferably 6 to 7, mixed and the resulting precipitate is separated from the liquid phase , Preferably, the mixture of the aqueous collagen solution and the aqueous hyaluronate solution is stirred until the precipitate has formed.

The inventive method is characterized in particular by the fact that the preparation of the adhesive requires no addition of a catalyst.

The resulting precipitate is a biocompatible adhesive with good adhesion, high biocompatibility and low allergy potential. The adhesive according to the invention contains or consists of 1 to 20% by weight of collagen, 0.5 to 15% by weight of hyaluronic acid or hyaluronate and 65 to 98.5% by weight of water; the data in% by weight relate to the total weight of the adhesive.

After thorough mixing of the two components, aqueous collagen solution and aqueous hyaluronate solution, the starting polymers are structured as a polyionic complex (PIK) of positively charged collagen and negatively charged hyaluronic acid. Between the polymers arise ionic interactions and no covalent bonds. By means of a polyion complex, an improved sustainability of the adhesive properties is achieved via the interaction mechanism. The functional groups of the polymers are reversibly associated with each other via ionic interactions and are therefore fully reactive again after a temporary separation. The interaction of the two polymers results in a liquid phase and a gelatinous, sticky solid phase as a precipitate (also referred to herein as a coprecipitate or adhesive). The biocompatible adhesive, that is the solid, sticky phase, precipitate or coprecipitate, is recovered by separation from the liquid phase. To separate the two phases, various methods such as centrifugation, filtration or simple decanting can be used. The formed PIKs of the precipitate further possess functional, in particular nucleophilic groups, which can ensure a continuous interaction with surrounding cellular systems or tissues. The free functional groups of the polymers in the precipitate (adhesive) can thus bonds with the environment, eg. B. in the form of tissues or frameworks, received. The adhesive is particularly suitable for use in the medical field.

In the method according to the invention, an aqueous collagen solution is used which has a concentration of dissolved collagen of 0.01% to 5% (w / v), based on the total volume of the aqueous collagen solution. The aqueous collagen solution preferably has a concentration of dissolved collagen of from 0.1% to 1% (w / v), in each case based on the total volume of the aqueous collagen solution.

The aqueous collagen solution has a pH in the acidic range of from pH 2 to pH 5, preferably a pH of from 2.3 to pH 4.5. For the purposes of the present invention, dissolved collagen is understood as meaning collagen which is present dissolved in the aqueous collagen solution and is substantially non-hydrolyzed and / or non-denatured. The collagen can be used as a natural collagen or renatured. Preferably, the dissolved collagen is present in the aqueous collagen solution in native triple helical structure. The recovery of such collagen is known to those skilled in principle. Preferably, the collagen can be obtained from the skin, especially from the skin of animals such as pigs.

The collagen used according to the invention contains or consists preferably of type I collagen or of a mixture of different types of collagen, with type I collagen in the mixture preferably making up the largest proportion by mass in comparison to every other type of collagen. Other collagen types may be, for example, Type II, III, V collagen. However, other types of collagen may also be present in the mixture. The collagen according to the invention is preferably collagen type I in substantially pure form or a mixture of different types of collagen, type I collagen making up at least 30%, particularly preferably at least 50%, of the total collagen mass. The collagen may contain or consist of atelocollagen and / or tropocollagen. Atelocollagen is characterized by the fact that it is dissolved collagen without telopeptides.

The aqueous collagen solution is mixed in the process according to the invention with an aqueous hyaluronate solution. Hyaluronic acid or hyaluronate is preferably used here, which has an average molecular weight of from 1, 400 to 2,400 kDa. The aqueous hyaluronate solution has a hyaluronic acid concentration or a hyaluronate concentration of from 0.02% to 5% (w / v), preferably from 0.2% to 1% (w / v), in each case based on the total volume of the aqueous hyaluronate solution. The hyaluronate used is a salt of hyaluronic acid with various cations, preferably the sodium salt of hyaluronic acid.

Before being mixed with the aqueous collagen solution, the aqueous hyaluronate solution has a pH of from pH 5 to 7 or pH 6 to pH 7, preferably from pH 5.5 to 6.5, more preferably from pH 6.3 to pH 6.5.

The concentration data for collagen and hyaluronic acid or hyaluronate and the pH ranges for the aqueous collagen solution and the aqueous hyaluronate solution before the mixture of the two aqueous solutions are essential components for the fact that the precipitate and thus the desired adhesive can form without the use of a catalyst. This ensures that the adhesive on the one hand contains collagen in native or renatured form and thus the formation of a polyion complex with the Hyaluronic acid, on the other hand, allows the use of catalysts which possibly have allergenic potential or are only slightly biocompatible, can be avoided.

The allergy potential of the resulting adhesive can be further reduced if, for example, hyaluronate or hyaluronic acid of non-animal origin, preferably of bacterial origin, is used. This can be obtained, for example, biotechnologically. It has proven particularly favorable when the hyaluronate or hyaluronic acid is peptide-free. In the method of the present invention, the aqueous collagen solution and the hyaluronate aqueous solution are mixed together to produce a precipitate which, separated from the aqueous phase, is an adhesive of the present invention. Particularly favorable results are achieved when the aqueous collagen solution and the aqueous hyaluronate solution are mixed with each other in a fixed mass ratio. Preferably, the aqueous collagen solution and the aqueous hyaluronate solution are mixed together in a mass ratio of 1: 0.5 to 1: 1, 5, more preferably in a mass ratio of 1: 0.7 to 1: 1.2.

The efficiency of the preparation of the adhesive with the method according to the invention can be further increased by stirring the mixture until a precipitate is formed.

After formation of the precipitate, the precipitate is separated from the aqueous phase and can be used as the adhesive of the present invention. The separation of the precipitate from the aqueous phase of the mixture can be achieved by conventional methods, for example by centrifugation, filtration and / or decantation.

Due to the choice of collagen in a native or renatured state and hyaluronic acid or hyaluronate as components of the adhesive, the resulting adhesive is characterized by a high biocompatibility. In principle, aqueous collagen solution and / or aqueous hyaluronate solution and thus, if appropriate, also the resulting adhesive may additionally comprise further constituents, in which case preferably biocompatible constituents are used. For example, biocompatible ions, salts, organic or inorganic acids and / or bases, sugars, proteins, amino acids, oligopeptides, telopeptides and / or gelatin and mixtures thereof can be used. In order to provide a particularly homogeneous adhesive which is uniform in its adhesive action, it may be provided in the process according to the invention to homogenize the precipitate obtained. This homogenization can be carried out, for example, by treating the precipitate with shearing forces. The optimum range for the peripheral speed of a rotor-stator arrangement for generating the shear forces is in the range of 2 to 25 m / s. The resulting precipitate can be homogenized before, during or after separation from the liquid phase. Homogenization is preferably carried out after separation of the precipitate from the liquid phase. With the method according to the invention, an adhesive can be produced, which is characterized by a particularly favorable stability in higher pH ranges. In particular, it has been shown that in a pH range of 5.0 to 7.5, a particularly favorable stability is achieved. This is achieved, for example, by adding arginine and calcium hydroxide in the process so that the resulting precipitate contains from 1 to 6% by weight of arginine and from 1 to 6% by weight of calcium hydroxide, the data in% by weight being based on the Total weight of the precipitate refer. In this case, the arginine and / or calcium hydroxide may be added to the aqueous collagen solution and / or to the aqueous hyaluronate solutions prior to their mixing and / or to the separated precipitate. In the process of the invention, the aqueous collagen solution is preferably arginine and the aqueous

Hyaluronate solution Calcium hydroxide added before mixing the aqueous collagen solution and the aqueous Hyaluronatlösung.

In the process according to the invention, the arginine is preferably added in such a way that a concentration of from 1 to 6% by weight of arginine is achieved in the adhesive, the details in% by weight being based on the total weight of the adhesive.

The calcium hydroxide can be added in such a way that a concentration of 1 to 6 wt .-% calcium hydroxide is achieved in the adhesive, wherein the data in wt .-% based on the total weight of the adhesive.

Preferably, the calcium hydroxide is added as an aqueous solution.

In a particular embodiment of the method according to the invention, the addition of arginine and / or calcium hydroxide takes place during the homogenization of the precipitate.

The present invention also relates to an adhesive comprising or consisting of: 1 to 20% by weight of collagen,

0.5 to 15% by weight of hyaluronic acid or hyaluronate and

65 to 98.5% by weight of water;

the data in% by weight relate to the total weight of the adhesive.

In a preferred embodiment, the adhesive according to the invention contains or consists of:

5 to 15% by weight of collagen,

3 to 10 wt .-% hyaluronic acid or hyaluronate and

75 to 92% by weight of water;

the data in% by weight relate to the total weight of the adhesive.

A particular embodiment of the adhesive according to the invention, which has improved stability at higher pH ranges, contains arginine and calcium hydroxide. In a preferred embodiment, the adhesive according to the invention contains or consists of: 1 to 15% by weight of collagen,

0.5 to 10% by weight of hyaluronic acid or hyaluronate

1 to 6 wt .-% arginine

1 to 5 wt .-% Caiciumhydroxid and

75 to 95% by weight of water;

the data in% by weight relate to the total weight of the adhesive.

The adhesive according to the invention can be distinguished, in particular, in that it contains no other sticking or adhesion-promoting substances ("tackifying agent") Such other tacky or adhesion-promoting substances can be understood to mean, for example, dextran, polyglucosides, polyvinylpyrrolidone, bioresorbable starch or derivatives thereof and / or bioresorbable cellulose or derivatives thereof, such as, for example, cellulose ethers and salts thereof For the preparation of the adhesive according to the invention, the arginine and / or the calcium hydroxide can be added to the corresponding aqueous collagen or hyaluronic acid or hyaluronate solutions prior to their mixing and / or directly to the separated one The calcium hydroxide is preferably metered in as an aqueous solution, and the precipitate is homogenized in order to obtain a homogeneous product and to further improve the adhesive properties of the precipitate (polyionic complex) For example, by using preselected shear forces. The homogenization can already take place during the addition of the arginine and / or the calcium hydroxide. The adhesive according to the invention is distinguished by a particularly favorable adhesive effect if collagen and hyaluronic acid or hyaluronate are present in a weight ratio of 0.5: 1 to 5: 1 in the adhesive.

The adhesive of the present invention may be prepared by the above-described process of the present invention for producing an adhesive.

The present invention also relates to the use of the adhesive of the invention in the medical field. In particular, the adhesive according to the invention can be used as a surgical adhesive, for the local introduction of cells with or without cell carriers, for the local introduction of active ingredients and / or excipients, for the treatment of wounds (externally and / or in the body) and in the implantation of medical devices ,

The invention will be explained in more detail with reference to subsequent embodiments.

Characters:

Figure 1: shows results from the SDS-PAGE study of native collagen extracted with acid solutions, where in lane 1 a molecular weight standard (band at 64, 98, 148 and 250 kDa), in lane 2 a collagen standard

(Mixture of collagen type I and collagen type II) and shown in lanes 3 to 7 are native collagens extracted with acid solutions. It means: Col I = collagen type I (with a1 / a2 chains at about 100 kDa, ß1 1 / ß 12 chains at about 200 kDa and γ chains at about 300 kDa); Col III = collagen type III; Col V = collagen type V. FIG. 2: shows the IR spectrum of a coprecipitate of atelocollagen

Hyaluronate of biotechnological origin.

Figure 3: shows the results of a determination of adhesiveness in vital cartilage (A) and

Bone tissue (B). Shown are the average values from 5 measurements with the standard deviation as error bars. Examples:

First, the preparation of pig skin for collagen production is described in detail: Raw, depilated and mechanically largely defatted pig skin (1, 5 to 2.5 mm thick), which was optionally stored in a NaCl solution for preservation, is in pieces (about 2 to 4 mm ² surface) cut. Then proceed in the following steps.

- Pre-cleaning: Separation of dirt and blood residues and, where appropriate, NaCI removal; for hydration and loosening of the tissue, the cut skin is washed with 5 times the amount of water three times with stirring (each 2 hours treatment time).

- Skin degreasing: the washed skin is extracted three times with pure acetone (each 2 hours treatment time, skin-acetone ratio 1: 5 w / v) with stirring.

- Swelling of the skin: for the renewed hydration of the skin, it is again extracted three times with pure water (in each case 2 hours treatment time, skin-water ratio 1: 5 w / v) with stirring, after acetone extraction.

- Protein separation: non-collagenous proteins are to be separated from the skin. For this purpose, a solution containing 6% NaCl (w / v) and 1% formic acid (w / v) is prepared. The swollen skin is extracted with this solution twice with stirring (each 24 hours treatment time, skin-to-solution ratio 1: 5 w / v).

- re-swelling of the skin - this step is analogous. As with all o. G.

Treatments, after the lapse of time, the skin is separated from the extractant. After pretreatment, collagen extraction from the pigskin can be done in different ways.

Example 1: Recovery of tropocollagen

In the extraction by means of acetic acid, 20 g of the treated skin are mixed with 125 ml of acetic acid (0.1M to 1.0M, preferably 0.5M) and extracted with stirring for 48 hours at 25 ° C. Subsequently, the liquid phase (collagen solution) is separated from the solid phase (skin residue). The collagen solution is then purified by ultrafiltration (cross-flow filtration on a UF membrane of polyethersulfone, MWCO 50 kDa) and concentrated. The amount of collagen can be determined by an amino acid analysis or a hydroxyproline determination according to the method of Stegemann and Stalder. The determination of the proportion of native collagen can be determined by means of CD spectroscopy and SDS-PAGE Electrophoresis done. The collagen extracted in this way is present as tropocollagen (see Table 1 and Figure 1).

In the extraction by means of urea, 20 g of the treated skin are mixed with 125 ml of urea-based substance solution (4 M to 8 M, preferably 6 M) and extracted with stirring for 48 hours at 25 ° C. Subsequently, the collagen solution is separated from the skin residue and purified by dialysis (dialysis tube of regenerated cellulose, pore size 8 - 15 kDa) against 0.1 M acetic acid. The collagen is also present as tropocollagen, here renatured before (see Table 1).

Example 2: Preparation of Atelocollagen from Porcine Skin

20 g of the treated skin are mixed with 125 ml of a 0.5 M acetic acid solution containing 5% pepsin (w / v) and extracted with stirring for 48 hours at 5 'C. Subsequently, 1 l of a 0.1 M acetic acid solution is added and the mixture for further enzyme action for three weeks at 25 ° C left. After addition of 0.1 M acetic acid to a total volume of 3 l and adjusting the pH to 8 to 9 by means of 10 M NaOH, the pepsin is precipitated and separated from the supernatant (collagen solution) by centrifugation. To purify the collagen solution obtained, the pH is adjusted to 3 to 4 with acetic acid and the collagen is precipitated with NaCl (2.5 M NaCl in the total mixture) and then centrifuged off. There are two further cleaning steps. In each of these steps, the collagen is redissolved in 0.1 M acetic acid, reprecipitated with NaCl (1.8 M NaCl in the total mixture) and then removed by centrifugation. Finally, to remove NaCI, the purified collagen is finally dialyzed against 0.1 M acetic acid (dialysis tube made of regenerated cellulose, pore size 8 - 15 kDa). The collagen is present as atelocollagen (see Table 1).

Table 1: Amino acid composition of tropocollagen (Example 1) and atelocollagen

(Example 2)

Pro [number per 1000 amino acids] 134.90 135.32 130.94

Gly [number per 1000 amino acids] 331, 87 336.85 337.22

Ala [number per 1000 amino acids] 1 1 1, 29 109.37 108.23

Val [number per 1000 amino acids] 25,89 22,97 23,55

Met [number per 1000 amino acids] 4.23 3.03 4.86

[number per 1000 amino acids] 10,30 9,69 10,34

Leu [number per 1000 amino acids] 25.47 24.52 22.32

Tyr [number per 1000 amino acids] 1, 69 3, 12 1, 45

Phe [number per 1000 amino acids] 13.54 13.67 12.44

His [number per 1000 amino acids] 5.92 5.46 7.57

Hyl [number per 1000 amino acids] 5.77 6.30 6.1 1

Lys [number per 1000 amino acids] 28.74 25.99 27.33

Arg [number per 1000 amino acids] 52.04 50.76 46.08

Hyp / Pro 0.59 0.62 0.68

Hyp / (Hyp + Pro) 0.37 0.38 0.40

Hyl / Lys 0.20 0.24 0.22

Hyl / (Hyl + Lys) 0, 17 0.20 0.18

Hyl / Hyp 0.07 0.07 0.07

μg of protein inj 3, 17 10, 18 2.78

μg protein / sample 3959.32 2544.37 2782.96

μg collagen 3251, 17 2216.06 2550.18

% Collagen 82, 10 87, 10 91, 60

Example 3: Preparation of an adhesive of collagen based on tropocollagen

A collagen solution obtained as in Example 1, which mainly contains tropocollagen molecules (collagen concentration 0.1 to 1.0% w / v) and has a pH of 2.3 to 4.5, is mixed with an already prepared solution from Na-hyaluronate of biotechnological origin (pH 6.3 to 6.5, concentration 0.2 to 1, 0% w / v, MG of hyaluronate 1 .400 to 2,400 kDa) in a mass ratio of 1: 1 (collagen solution to hyaluronate solution) mixed , The mixture is then stirred until a coprecipitate is formed. This is separated from the liquid phase by centrifuging or decanting. The coprecipitate is highly adhesive and constitutes the adhesive. The coprecipitate contains 5.0 to 15.0% (w / w) collagen, 3.0 to 10.0% (w / w) hyaluronic acid and 75.0 to 92.0 % Water.

Example 4: Preparation of an adhesive of collagen and hyaluronic acid using atelocollagen Example 4 describes the preparation of an adhesive based on atelocollagen. A collagen solution obtained as in Example 2, mainly

Atelokollagenmoleküle contains (concentration of collagen 0.1 to 1, 0% w / v) and has a pH of 2.3 to 4.5, with an already prepared solution of Na-hyaluronate of biotechnological origin (pH 6.3 to 6.5, concentration 0.2 to 1, 0% w / v, mg of the

Hyaluronate 1 .400 to 2400 kDa) in a mass ratio of 1: 1 (collagen solution to hyaluronate solution) mixed. The mixture is then stirred until a coprecipitate is formed. This is separated from the liquid phase by centrifuging or decanting. The

Coprecipitate is highly adhesive and constitutes the adhesive. The coprecipitate contains 5.0 to 15.0% (w / w) collagen, 3.0 to 10.0% (w / w) hyaluronic acid and 75.0 to 92.0%. Water. Figure 2 shows the IR spectrum of a coprecipitate of atelocollagen and Na-hyaluronate of biotechnological origin.

Example 5: Preparation of an adhesive of collagen and hyaluronic acid using arginine, calcium hydroxide and shear forces

To optimize the polyion complex stability with arginine and calcium hydroxide, the arginine was dissolved in the collagen solution (0.9 g of arginine per 100 g of 0.8% strength

Atelocollagen). Then, with respect to the collagen solution, twice the amount of a 0.2% Na-hyaluronate solution was added with stirring. The polyion complex formed was then separated by centrifugation and added dropwise with the aid of shearing forces (homogenization) with a 1.6 M calcium hydroxide solution to the desired pH. The optimum range for the peripheral speed of the rotor-stator arrangement for generating the shear forces is 2 to 25 m / s.

For the measurement of the adhesiveness of the adhesives prepared according to Examples 3 to 5 in the biological tissue, vital bone and cartilage tissue from the pig was used. The reference adhesive used was fibrin glue from Baxter (TISSUCOL Duo S).

In preparation for the measurement were using a round punch cylinder of 10 mm

Diameter and 20 mm length from the medial and lateral condyle of a

Femur bone made of pig. This raw punch contains both bone and cartilage tissue. To prepare a cartilage punch used for the measurement, the surface was cut flat using a microtome. For a bone punch used in the measurements, the cartilage layer was completely removed. For the measurement of adhesiveness, two cylinders (cartilage or bone) were vertically opposed, centered and placed at a distance of 5 mm in a Zwick force measuring stand (Z005) by means of a round sample holder. The course of the measurement was as follows.

40 μΙ of the adhesive to be tested were first distributed on the surface of the lower tissue cylinder. At a speed of 10 mm per minute, the opposing tissue surfaces were then moved against each other until a force of 1 Newton [N] acted on the measuring surface (A = 0.875 cm 2). This position was for 30 seconds

held before the two measuring surfaces were pulled apart again at a speed of 10 mm per minute. The course of the occurring force over time was recorded, which counteracts the vertical movement. The maximum value was corrected by the force that occurs with the same procedure without the use of an adhesive. The force thus determined is a measure of the adhesiveness.

In the measuring arrangement described, an adhesion of on average 15.2 kN / m ² with a standard deviation of 1.0 kN / m ² could be measured for the adhesive produced according to the invention in comparison to cartilage tissue. For fibrin glue, this value in the same tissue was only 5.2 kN / m ² , with a standard deviation of 2.5 kN / m ² (Figure 3A). In the bone tissue an adhesion of 1 1, 8 kN / m ² , with a standard deviation of 1, 9 kN / m ^{2 was} determined for the collagen hyaluronic acid adhesive. For fibrin glue it was significantly lower at 2.6 kN / m ² and the standard deviation was 1.9 kN / m ² (Fig. 3B). The adhesive effect of the adhesives prepared according to Examples 3 and 4 does not differ, but the adhesive prepared on the basis of atelocollagen has a reduced allergy potential.

Claims

claims:

A method for producing an adhesive, characterized in that an aqueous collagen solution having a concentration of dissolved collagen of 0.01 to 5% (w / v) and a pH of 2 to 5 with an aqueous hyaluronate solution having a hyaluronate or hyaluronic acid concentration from 0.02 to 5% (w / v) and a pH of from 5 to 7, preferably from 6 to 7, and the resulting

Precipitate is separated from the liquid phase.

The method of claim 1, wherein the obtained precipitate is homogenized.

The method of claim 1 or 2, wherein the aqueous collagen solution is a

Concentration of dissolved collagen is from 0.1 to 1% (w / v).

Method according to one of the preceding claims, wherein the aqueous

Collagen solution has a pH of 2.3 to 4.5.

Method according to one of the preceding claims, wherein the aqueous

Hyaluronate solution has a hyaluronate or hyaluronic acid concentration of 0.2 to 1% (w / v).

Method according to one of the preceding claims, wherein the aqueous

Hyaluronatlösung has a pH of 5.5 to 6.5, preferably from 6.3 to 6.5.

Method according to one of the preceding claims, wherein the aqueous collagen solution and the aqueous hyaluronate solution in a mass ratio of 1: 0.5 to 1: 1, 5 are mixed, preferably from 1: 0.7 to 1: 1, 2.

Method according to one of the preceding claims, wherein the aqueous collagen solution and / or the aqueous hyaluronate solution may contain further constituents, for example ions, salts, organic acids, sugars, proteins, amino acids, oligopeptides, telopeptides and / or gelatin.

A process according to any one of the preceding claims, wherein the aqueous

Collagen solution and / or the aqueous Hyaluronatlösungen before mixing and / or the separated precipitate arginine and / or Caiciumhydroxid be added.

10. The method of claim 9, wherein the arginine is added so that a concentration of 1 to 6 wt .-% arginine is achieved in the adhesive, and / or wherein the Caiciumhydroxid is added so that the adhesive has a concentration of 1 to 6 % By weight is achieved

the data in% by weight relate to the total weight of the adhesive.

1 1. Adhesive containing or consisting of:

1 to 20% by weight of collagen,

0.5 to 15% by weight of hyaluronic acid or hyaluronate and

65 to 98.5% by weight of water;

the data in% by weight relate to the total weight of the adhesive.

12. An adhesive according to claim 1 1, containing or consisting of:

5 to 15% by weight of collagen,

3 to 10 wt .-% hyaluronic acid or hyaluronate and

75 to 92% by weight of water;

the data in% by weight relate to the total weight of the adhesive.

13. An adhesive according to claim 1 1, containing or consisting of:

1 to 15% by weight collagen,

0.5 to 10% by weight of hyaluronic acid or hyaluronate,

From 1 to 6% by weight of arginine,

1 to 5 wt .-% Caiciumhydroxid and

75 to 96.5% by weight of water;

the data in% by weight relate to the total weight of the adhesive.

14. An adhesive according to any one of claims 1 1, 12 or 13, wherein in the adhesive collagen and hyaluronic acid or hyaluronate in a weight ratio of 0.5: 1 to 8: 1, preferably from 0.5: 1 to 5: 1.

5. An adhesive according to any one of claims 1 1 to 14, wherein the adhesive is prepared by a method according to any one of claims 1 to 10.