AU754458B2 - Fibrin-based glue granulate and corresponding production method - Google Patents

Abstract

The invention relates to a flowable fibrin glue granulate containing thrombin, factor XIII, fibrinogen and a calcium salt in the form of granules with a particle size of more than 50 mu m to 1000 mu m. Said granulate is useful for the healing of wounds in surgery, tissue therapy and/or as supporting material for biological factors. The invention also relates to an effervescent granulate and an effervescent powder for producing a foam that is suitable for hemostasis. The invention further relates to preparations to arrest bleeding containing an nonwoven fabric for wounds consisting of a biodegradable supporting material that is coated with a fibrin glue granulate mixture or mixed granulate.

Description

WO 00/38752 2 PCT/EP99/06898 TRANSLATED FROM THE GERMAN Fibrin adhesive granulate and method for its preparation The object of the invention is a flowable fibrin adhesive granulate that contains all substances required for the formation of a stable fibrin gel and can be used directly for wound adhesion. It is generated by spray drying in a fluidized bed by means of a fluidization gas.

It is known that after the creation of a wound, wound healing is initiated through an activation cascade of several subsequent coagulation factors. This finally leads to the reaction between the activated thrombin and fibrinogen in the presence of calcium ions to form a fibrin matrix that covers the wound and thus leads to hemostasis. Said fibrin matrix is further strengthened by the activated Factor XIII (F XIIIa) through additional covalent bonds, which increases the mechanical stability of said fibrin matrix and makes it resistant to premature proteolytical degradation.

In modern surgery, hemostasis continues to gain in significance because of fibrin adhesion and because so-called fibrin adhesives are a well tolerated biomaterial that promotes wound healing. The method is excellently suited for the hemostasis of strongly bleeding wounds during surgery on parenchymatous inner organs, skin transplants, in emergency surgery for internal and external injuries, but primarily also as a supporting seal for sutures to avoid postoperative bleeding. In ear, nose and throat surgery and facial surgery, fibrin adhesive is preferred to sutures for cosmetic reasons for the healing of external wounds.

Fibrin adhesive is also used increasingly in endoscopic surgery, for example to arrest bleeding in stomach ulcers.

In addition to inorganic salts and amino acids, the currently available commercial fibrin adhesives such as Beriplast® also contain the coagulation factors fibrinogen, thrombin and Factor XIII, which are obtained from human plasma, as well as albumin WO 00/38752 PCT/99/06898 and fibronectin to promote wound healing. Although the preparation exhibits good biochemical and haemostatic properties, it requires extensive preparations prior to use. The separate fibrinogen- and thrombin lyophilisates are dissolved separately, drawn into two separate syringes, and clamped into a special holding device. This process is time-consuming and requires specially trained personnel. A variant of the fibrin adhesive is already commercially available in dissolved form in the syringes under the name Tissucol®, but it can be stored only at low temperatures of -20 oCelsius and requires defrosting in a water bath prior to use. Thus, both variants of the fibrin adhesive cannot be used in situations that call for a ready-touse fibrin adhesive that does not require advance preparation.

Furthermore, a ready-to-use and easily dosable fibrin adhesive would be more economical simply because it would avoid needless preparations or the discarding of excess material.

A possible improvement in the handling of the fibrin adhesive could be a one-component-adhesive that contains all components necessary for the formation of the fibrin in one compartment.

However, the development of a one-component adhesive in an aqueous solution is extremely difficult to realize in practice.

The only possibility may be to mix the components of the fibrin glue in dry condition so they would dissolve in the blood fluid or the wound exudate after being applied to the wound and then form a fibrin matrix in situ, which would lead to hemostasis.

This would also require transforming the fibrinogen, which by nature does not dissolve easily, into a dry form from which it would dissolve quickly while at the same time immediately reacting with the thrombin.

There have also been attempts to use a specific lyophilisation process to develop particles containing fibrinogen and thrombin, which are mixed after preparation and activated in the wound.

Thus, international patent application WO 97/44015 describes the preparation of so-called micro particles on which fibrinogen and V 0 WO0/38752 PT9/69 PCT/99/06898 thrombin are spray-dried individually. Over 90 of said particles have a grain size of up to 20 pm. They should dissolve well and can be mixed and used for wound healing. However, a disadvantage of said micro particles is that they form a very dusty powder, which makes a direct application to the wound impossible. Thus, a powder of this type requires a special application system, which drastically reduces its handling and clinical indications.

The problem was therefore to develop a fibrin adhesive granulate that dissolves well, is flowable, is not dusty, and can therefore be applied directly to the wound, for example, in the principle of a salt shaker.

The problem is solved in accordance with the invention by a flowable fibrin adhesive granulate containing thrombin, Factor XIII, fibrinogen and a calcium salt in pellets with a particle size of more than 50 to approximately 1000 jm, preferably with a particle size of 100 to 200 jm. Because of the particle size, the fibrin adhesive in accordance with the invention is not dusty, dissolves well, is flowable, and is excellently suited for application to a wound surface or moist tissue, where it immediately forms a fibrin matrix.

Albumin, fibronectin, amino acids and physiologically safe inorganic salts can be added to a fibrin adhesive granulate of this type. Furthermore, it can also be used as a release system for biological, vegetable and/or synthetic factors. These factors can support wound healing or act as antifibrinolytic, antibiotic, chemotherapeutic, or immune modulators. They are added to the fibrin adhesive granulate during the spray drying process.

An appropriate principal method for the preparation of the fibrin adhesive granulate in accordance with the invention is already known from the international patent application WO WO 00/38752 PCT/99/06898 96/15849, which describes a method for the drying of blood plasma, blood plasma fractions, or blood plasma products obtained therefrom, where the treatment product is sprayed in liquid or dissolved condition into an evacuatable container which performs the drying up to granulate form by means of a fluidization gas in a fluidized bed. However, this method cannot be readily applied to fibrinogen and thrombin because it is known that these substances react to fibrin after coming into contact with aqueous solutions. Therefore, the use of aqueous solutions is not an option for the spray drying of these components. To obtain both components in one particle nevertheless, the components in accordance with the invention are suspended together in one single organic solvent and spray dried from it. Fibrinogen, thrombin and Factor XIII can also be more or less homogeneously suspended in organic solvents such as the lower alcohols, preferably isopropanol or ethanol, acetone, nitrilene, liquid carboxylic acid esters, ethers, chloroform, dimethyl formamide and dimethyl sulfoxide, also in the presence of CaCl2, without exhibiting a reaction to fibrin. After the organic solvent is removed, they are again capable of fibrin formation in the aqueous phase.

In accordance with the invention, spray drying is performed either with a top-spray-process, where the liquid is supplied to the fluidization gas in the counter current, or in co-current flow (bottom-spray-process). A fine distribution is achieved by spraying the liquid treatment product into the evacuatable container through an appropriate nozzle. In this way, the fluidization gas swirls the product to be treated and also transfers heat. For this reason, a heated gas is used as fluidization gas. Gentle drying can be maintained by measuring the product temperature during the fluidization bed process controlling the process on the basis of said measurements.

Either air or an inert gas such as nitrogen can be used as a fluidization gas. The drying is continued until the treatment product is available in finely dispersed granulate form with a WO0/38752 PCT/99/06898 particle size of 50 to approximately 1000 pm, preferably 100 to 200 pm.

The fibrin granulate adhesive in accordance with the invention can be produced in the evacuatable container with or without a support medium as a receiver. Appropriate support media are primarily sugar and sugar alcohols such as saccharose, lactose or mannitol, which have a good bio-tolerance. However, it is also possible to use proteins such as serum albumin as a support medium. It is especially preferred to use the fibrin adhesive component itself, fibrinogen, Factor XIII, thrombin, CaCl2 or their mixtures, in powder condition as a support medium. The aqueous solution or suspension of the fibrin adhesive component in organic solvent is then sprayed onto said support medium to form a granulate. This makes obsolete the addition of a further support medium such as a sugar, mannitol or albumin.

An especially preferred method is two-phase spray drying where a fibrinogen granulate is prepared first. In addition to fibrinogen, said granulate can also contain other proteins, carbohydrates, amino acids and physiologically safe inorganic salts, and also calcium salt as well. The particle size of said granulate is more than 50 and up to approximately 1000 pm, with the preferred particle size being between 100 and 200 pm. A fine thrombin suspension in an organic solvent is sprayed onto said fibrinogen granulate. Said thrombin suspension can comprise dissolved calcium ions unless they were added already to the fibrinogen granulate. The concentration of the calcium ions is 1 to 100 mM, preferably 10 to 50 mM. This yields a fibrin adhesive granulate with a particle size that is preferably between 100 and 200 pm and has a grainy structure that dissolves very well.

This does not yield any compact particles such as small pellets, but rather a granulate with many tiny channels. In this way, it is possible to obtain a relatively large particle size, which renders the product simultaneously free of dust and is very soluble, similar to the.known instant coffee. This granulate is WO 00/38752 PCT/99/06898 also excellently suited to be applied to a wound surface and immediately forms a solid and elastic fibrin gel after it comes into contact with an aqueous medium.

The fibrin adhesive granulate in accordance with the invention can also be obtained by spray-drying fibrinogen concentrate from an aqueous solution on a receiver, such as mannitol.

To that end, a fibrinogen/mannitol-granulate is obtained first, and then thrombin/calcium salt, for example from an isopropanolic suspension, is sprayed onto said granulate. The organic solvent prevents the formation of fibrin following the contact between fibrinogen and the thrombin.

Finally, it is also possible to prepare separate fibrinogen- and thrombin granulates with the aforementioned particle size in separate processes, whereby both substances can be spray-dried from aqueous solutions. However, for the preparation of the thrombin granulate, this would require a sufficient portion of a support medium because the quantity of thrombin in the fibrin adhesive is smaller by a factor of 102 to 10 than the quantity of fibrinogen. The two granulates are then mixed and can be used appropriately for hemostasis and wound healing.

The fibrinogen adhesive granulates prepared in accordance with the aforementioned method were then tested as to their biomechanical properties and the following results were obtained: Tear strength following in vitro tissue gluing (adhesion surface: 2.25 cm 2 Results of a comparative study based on a randomization list on the tear strength of the uniform granulate (thrombin, fibrinogen and Factor XIII in one particle), the granulate mixture WO 00/38752 8 PCT/99/06898 (fibrinogen granulate thrombin granulate) and the fluid fibrin adhesive (Beriplast®): Test substance Tear Strength Uniform granulate (mixed 3.3 N granulate) Granulate mixture 1.8 N Beriplast® 1.5 N The measured values clearly show the advantage of the uniform granulate (mixed granulate) compared to the granulate mixture with respect to the biomechanical properties. The quantity of active components was nearly identical in all three testing substances.

Additionally, the fibrin adhesive granulate in accordance with the invention can be stored at room temperature as well as at temperatures of 2 8 oCelsius for at least 6 to 8 months without any noticeable loss of activity in the individual components.

The flowable fibrin adhesive granulate in accordance with the invention distinguishes itself from the previously known fibrin adhesives in that it is easier to handle, does not require any preparatory measures and is always in a ready-to-use condition.

It is therefore particularly suitable for emergency surgery. It also has the advantage of an extraordinarily simple use in that it can be applied to wound surfaces in the same way as using a saltshaker. It is excellently suited for surgical applications where the objective is to achieve a quick hemostasis by soaking up blood with simultaneous fibrin adhesion.

Although the aforementioned granulates simplify the use of the fibrin adhesive significantly and reduce high-effort surgery preparations that require specially trained personnel and PCT/99/06898 WO 00/38752 appropriate devices, there is a continued demand for simple fibrin adhesive preparations that should be in every physician's emergency bag and can be used immediately at the site of an accident without lengthy preparations.

It was possible to find a solution for this problem by developing an effervescent granulate or an effervescent powder to generate a foam that is suitable for hemostasis and contains the substances required for the formation of CO 2 in addition to the granulate mixture or mixed granulate according to the invention containing fibrinogen, Factor XIII, thrombin and a soluble calcium salt.

In addition to many other advantages, the effervescent granulate or effervescent powder in accordance with the invention also has the advantage of loosening up the granulate mass through the foaming, which allows the liquid easier access into the interior of the granulate pellets. This leads quite quickly to the creation of stable fibrin foam that covers the bleeding wound and quickly arrests the bleeding. The formation of the foam can take place directly on the wound, with the wound secretions providing the moisture needed to create the foam. It is also possible, though, to create the foam in a dish or on a plate by adding liquid, and then placing the finished foam on the bleeding wound. Because of its tremendous flexibility, the foam created in this way cannot only be used for the external covering of wounds, but also for bleeding wounds during surgery, where the foam is packed into the bleeding surgery wound and places itself on the bleeding tissue to quickly arrest the bleeding.

There is room for further improvement in the therapeutic value of the effervescent granulate or effervescent powder in accordance with the invention if biological, vegetable or synthetic active substances that promote wound healing, such as immunoglobulins, chemotherapeutics or antibiotics, are added to WO 00/38752 PCT/99/06898 said effervescent granulate or powder. These substances are sprayed on the flowable, dry fibrin adhesive granulate during the production of the granulate or the effervescent powder or are mixed therewith. It is also possible to make an effervescent tablet from said mixture, which contains the ingredients for the preparation of a foam that is suitable for hemostasis in a form that is in a precise dosage and easy to handle.

It is generally sufficient to apply the effervescent granulate or effervescent powder in accordance with the invention in a quantity that contains, depending of the size of the bleeding wound, fibrinogen in a quantity of 0.1 to 2.5 grams and thrombin in a quantity of less than 10 I.E. If an effervescent tablet is used, said tablets can also have imprinted breaking grooves that allow breaking off part of a tablet to arrest bleeding in smaller wounds if the quantity of foam generated with part of the tablet is already sufficient to arrest the bleeding.

In addition, the granulate mixtures or mixed granulates in accordance with the invention can also be used to produce galenic preparations that are excellently suited for hemostasis, can be used in a very simple manner, and are available immediately at the site of an accident without requiring lengthy preparations.

This objective is achieved with a biodegradable wound fleece that is able to arrest bleeding even on larger wound surfaces.

To that end, a fibrin adhesive granulate is applied, either directly or in combination with a biocompatible auxiliary, to a support medium that is comprised of a biodegradable polymer in which the fibrin adhesive is embedded. A suitable support medium for this purpose is primarily natural or chemically modified collagen, keratin, gelatin, carbohydrates or cellulose derivatives. The support medium can also be comprised of a synthetic, biodegradable polymer. Suitable polymers include polyhydroxy carboxylic acids, polyesters, polycyanoacrylate, t Q WO 00/39752 PCT/99/06898 polyaminoacids, polyalcohols as well as silicon. A preparation is applied to said support medium which preferably contains fibrinogen in a quantity of 0.05 to 50 mg/cm 2 preferably 1 to mg/cm 2 as well as thrombin in a quantity of 1 pg to mg/cm preferably 0.05 to 2 mg/cm 2 To improve adhesion, polyethylene glycol (PEG) with a suitable molecule size or a mixture of several polyethylene glycols of various molecule sizes can be added to the fibrin adhesive preparation as auxiliaries.

A further improvement in hemostasis can be achieved by applying the aforementioned wound care fleece to a bandage or plaster bandage. Said bandage should be coated with a wound care fleece in accordance with the invention on the side that will be applied to the bleeding wound. Polyethylene glycol 4000 or polyethylene glycol 6000 or mixtures thereof are preferably used for the preparation of the bandages in accordance with the invention. To prepare the coating, the polyethylene glycol is dissolved in an organic solvent, preferably isopropanol, which is used in a concentration of 0.5 to 70 preferably in a concentration of 5 to 30 The fibrin adhesive granulate is spread on the bandage and then wetted with the isopropanolpolyethylene glycol 6000-solution. After the organic solvent has evaporated, the resulting biodegradable wound care fleece has a fibrin adhesive coating with good adhesion. The organic solvent is excellently suited for the coating because it evaporates easily, prevents a reaction with fibrin and ensures that the activity of the individual components is maintained.

Furthermore, the granulate form is maintained after treatment in the organic solvent, preferably isopropanol.

The aforementioned, haemostatic, salve- or gel-type preparation is generally applied only to one side of the wound care fleece in accordance with the invention. However, there are application cases where it is preferable to coat both sides of the wound care fleece. If the wound is covered with this type of bandage, WO 00/38752 PCT/99/06898 the haemostatic effect of the fibrin adhesive will unfold directly on the wound as soon as the fibrin is formed from the action of the wound secretion and the components in the bandage.

In many cases, the application can be simplified further by applying the wound care fleece in accordance with the invention to a waterproof or water-permeable surface material suitable for plaster preparation, whereby room is left on the side for adhesive strips that are coated with a physiologically safe adhesive. This type of plaster can be used quickly and permanently to cover the bleeding wound in a simple way und leads to a quick hemostasis.

Hemostasis can also be achieved in a simple way by embedding the particles of a fibrin adhesive into a salve- or gel-type preparation comprised of a hydrophilic, non-aqueous salve base.

Especially suitable for a hydrophilic, non-aqueous salve base are polyols, for example polyethylene glycols, polypropylene glycols or ethylene propylene copolymers in which the particles of the fibrin adhesive are evenly distributed and which take up the moisture contained in the wound secretions. Once moisture enters, the components of the fibrin adhesive immediately form a fibrin mesh that quickly and effectively covers the wound and arrests the bleeding. It is obvious that salve bases that contain fats or are water-repellent are not suitable for this use.

The fibrin adhesive contained in the preparations in accordance with the invention contains a dry mixture of fibrinogen, Factor XIII, thrombin and a soluble calcium salt. The preparation can be also appropriately filled into a salve tube and can then be stored over a long period of time and readily used in this form.

It goes without saying that the effectiveness of the aforementioned preparations to achieve hemostasis is guaranteed only if any addition of aqueous fluids and thus a premature formation of fibrin is avoided prior to their use. This must i 0 WOO00/38752 PCT/99/06898 also be taken into account during the production of the preparations, when the granulate mixtures or the mixed granulates in accordance with the invention are impasted with the hydrophilic, but non-aqueous salve-base in the known manner.

The salve- or gel-type preparation obtained in this way can then be applied to the biodegradable support medium to prepare a wound care fleece, or it can be used directly.

A further improvement of the preparations in accordance with the invention can be achieved if other biological, vegetable or synthetic active substances such as immunoglobulin, chemotherapeutics, or antibiotics are added in addition to the fibrin adhesive.

The wound care fleece in accordance with the invention, the bandage or plaster, or the salve- or gel-type preparation can be used in a simple and effective manner for the hemostasis of interior and exterior wounds.

The invention is explained by the following examples.

Example 1 Preparation of fibrinogen granulate without support medium as receiver A 10 protein solution of Beriplast®-fibrinogen concentrate (also contains F XIII) was spray dried according to the topspray-method in a fluidized bed. Said process was performed in a GPCG 1-facility by Glatt GmbH and is claimed and described in detail in International Patent Application WO 96/15849. The conditions were: Input temperature: 37 oCelsius Output temperature: 30 'Celsius Spraying pressure: 3.0 bar '7WOO00/38752 PT9/69 PCT/99/06898 Spraying rate: 3.2 g/min The fibrinogen granulate prepared in this way had a mean particle size of 100 pm and dissolved very well. Analytical measurements of the activity showed that the activity of fibrinogen and F XIII was not negatively affected by the spray drying process under the aforementioned conditions.

Example 2 Preparation of fibrinogen granulates with support medium as receiver 200 grams of mannitol or albumin was placed in the spray-drying chamber. 100 grams of fibrinogen concentrate was sprayed on the receiver in the fluidized bed under the following conditions: Input temperature: 30 oCelsius Output temperature: 24 "Celsius Spraying pressure: 2.5 bar Spraying rate: 3.0 to 8.0 g/min The resulting granulate was flowable, dissolved very well, and had a mean particle size of 100 pm, with full recovery of the fibrinogen- and F XIII activity.

Example 3 Preparation of fibrin adhesive granulate An isopropanolic thrombin/CaCl 2 -suspension was sprayed on the fibrinogen granulate prepared in Examples 1 or 2. The process conditions were as follows: Input temperature: 30 'Celsius Output temperature: 25 'Celsius WOO00/38752 PCT/99/06898 Spraying pressure: 2.5 bar Spraying rate: 3.0 to 8.0 g/min The fibrin adhesive granulate prepared in this manner had a mean particle size of 100 pm; it was flowable, did not give off dust, immediately formed a stable fibrin coagulum after coming into contact with an aqueous solution, and was rendered covalent by F

XIII.

Example 4 Preparation of thrombin granulate An aqueous 0.3 thrombin solution was sprayed on a mannitol or human serum albumin receiver. The conditions were as follows: Input temperature: 30 'Celsius Output temperature: 23 'Celsius Spraying pressure: 2.5 bar Spraying rate: 4.2 g/min The resulting granulate had a mean particle size of approximately 65 pm; it was flowable and did not give off dust.

It mixed well with the fibrinogen granulate and was also suitable for use as fibrin adhesive.

Example Preparation of a fibrin adhesive granulate from an isopropanolic suspension containing all fibrin adhesive components An isopropanolic suspension containing all fibrin adhesive components, fibrinogen, Factor XIII, thrombin, CaCl2 or mixtures thereof, was sprayed into a spray-drying chamber according to Examples 1 and 2, which contained either no support medium at all or a support medium such as mannitol, albumin or WO 00/38752 PCT/99/06898 one or more powdered fibrin adhesive components, and then spraydried in the fluidized bed. The process was performed under the following conditions: Input temperature: 30 oCelsius Output temperature:, 25 oCelsius Spraying pressure: 2.5 bar Spraying rate: 3.0 to 8.0 g/min The fibrin adhesive granulate prepared in this manner had a mean particle size of approximately 100 pm; it was flowable, did not give off dust, and immediately formed a stable, cross-linked fibrin coagulum after coming into contact with an aqueous solution.

Example 6 Preparation of a biodegradable bandage coated with fibrin adhesive 250 mg fibrin adhesive powder or granulate was placed on a 50 x mm 2 Type 6 Ethisorb® patch (Ethicon GmbH) and distributed evenly 10 mg fibrin adhesive powder or granulate per cm2).

Then a total of 2.5 ml of a solution of isopropanol/20 PEG 6000 was sprayed evenly on the coating. The biodegradable bandage obtained after the evaporation of the isopropanol was comprised of a support medium and fibrin adhesive coating with good adhesion and did not crumble after bending.

Example 7 Preparation of a biodegradable bandage coated with fibrin adhesive mg fibrin adhesive powder or granulate was applied to a 20 x mm 2 Type 6 Vicryl-fleece (Ethicon GmbH) and spread evenly mg powder per cm 2 Then a total of 0.6 ml of a solution of isopropanol 20 PEG 6000 was sprayed evenly on the coating. After the isopropanol had evaporated, a flexible, biodegradable bandage with a fibrin adhesive coating and good adhesion was obtained.

Example 8 Collagen fleece coated with fibrin adhesive The Interceed collagen fleece (Johnson Johnson), size 50 x 50 mm 2 was mixed evenly with 250 mg fibrin adhesive powder or granulate. Then a total of 0.6 ml of a solution of isopropanol 10 PEG 6000 was sprayed evenly on the coating. After the isopropanol had evaporated, a combined fibrin adhesive collagen fleece was obtained.

"Comprises/comprising" when used in this specification is taken to specify the presence of stated features, integers, steps or components but does not preclude the presence or addition of one or more other features, integers, steps, components or groups thereof.

o*oo

Claims (24)

1. Flowable fibrin adhesive granulate, comprising granulate pellets with a particle size of from 50 to approximately 1000 im which contain thrombin, Factor XIII, fibrinogen and a calcium salt.

2. The fibrin adhesive granulate as claimed in claim 1, characterized in that the granulate pellets have a particle size of 100 to 200 Vm.

3. The fibrin adhesive granulate as claimed in claim 1 or 2, characterized in that it also contains albumin, fibronectin, and/or other substances that promote wound healing.

4. Effervescent granulate or effervescent powder to generate a foam suitable for hemostasis, characterized in that in addition to the flowable fibrin adhesive granulate as claimed in any one of claims 1 to 3, it also contains the substances required for the formation of CO2.

5. The effervescent granulate or effervescent powder as claimed in claim 4, **characterized in that it contains a mixture of a carbonate and a physiologically 0 .0 safe organic acid for the formation of CO2.

6. A preparation to arrest bleeding, characterized in that it contains a wound care fleece comprising a biodegradable support medium coated with a flowable fibrin adhesive granulate as claimed in any one of claims 1 to 3.

7. The preparation as claimed in claim 6, comprising a wound care fleece coated with a hydrophilic, non-aqueous salve base, and the fibrin adhesive as claimed in any one of claims 1 to 3 embedded in said salve base.

8. The wound care fleece as claimed in claim 6 or 7, characterized in that the biodegradable support medium comprises a natural or chemically modified Scollagen, keratin, gelatin, carbohydrates or cellulose derivatives. 19

9. The wound care fleece as claimed in claim 6 or 7, characterized in that the biodegradable support medium comprise a polymer selected from the group consisting of polyhydroxy carboxylic acids, polyesters, polycyano acrylates, polyamino acids, polyalcohols or silicones. The wound care fleece as claimed in any one of claims 6 to 9, comprising fibrinogen in a quantity of from 0.05 to 50 mg/cm 2 and thrombin in a quantity of from 1 p~g to 20 mg/cm 2

11. The wound care fleece as claimed in any one of claims 6 to characterized in that the preparation containing the fibrin adhesive is applied to one or both sides of the support medium.

12. Bandage, characterized in that it is coated with a wound care fleece as claimed in any one of claims 6 to 11 at the location that will be applied to the bleeding wound. Plaster, comprising a water-proof or water-permeable surface material ."0 coated with a wound care fleece as claimed in any one of claims 6 to 11 at the location that will be applied to the bleeding wound and has adhesive surfaces at the edges.

14. Preparation to arrest bleeding, comprising a hydrophilic, non-aqueous salve base into which the particles of a fibrin adhesive as claimed in any one of claims 1 to 3 are embedded. Method for the preparation of the fibrin adhesive granulate as claimed in one of claims 1 to 3, characterized in that all components of the fibrin adhesive are suspended in an organic solvent and are spray-dried in an evacuatable container by means of a fluidization gas in the fluidized bed with a particle size of from 50 to 1000 tm.

16. The method as claimed in claim 15 wherein the fluidization gas in the ,-pA uidization bed has a particle size of from 100 to 200 pm.

17. The method as claimed in claim 15 or 16, characterized in that it is prepared with or without a support medium placed into the container as receiver.

18. Method for the preparation of a fibrin adhesive as claimed in any one of claims 1 to 3, characterized in that a fibrinogen granulate is prepared first, and that a suspension of an organic solvent containing thrombin is sprayed onto said fibrinogen granulate, whereby a calcium salt is added either to the fibrinogen granulate or to the thrombin solution.

19. Method for the preparation of a fibrin adhesive granulate as claimed in any one claims of 1 to 3, characterized in that the separately prepared fibrinogen- and thrombin granulate pellets, each of which have a particle size of from 50 im to approximately 1000 ptm, are mixed with one another. A method for preparing a preparation as claimed in any one of claims 6 to 14, characterized in that the fibrin adhesive, which is available as a granulate ~mixture or as mixed granulate, is layered on a biodegradable support medium. o•

21. A method for preparing the preparation as claimed in claim 14, characterized in that a fibrin adhesive that is available as a granulate mixture or as mixed granulate is impasted with the hydrophilic, non-aqueous salve base.

22. A method for preparing a preparation as claimed in any one of claims 6 to S. 14, characterized in that other biological, vegetable or synthetic active substances, which promote wound healing, are added to the fibrin adhesive 9 9granulate. *23. The method as claimed in claim 22, wherein the biological, vegetable or S* synthetic active substances comprises immunoglobulins, chemotherapeutics or antibiotics.

24. The use of a fibrin adhesive granulate as claimed in any one of claims 1 to for wound healing in surgery, tissue therapy, and/or as support medium for biological factors. The use of a preparation as claimed in any one of claims 6 to 14, for wound healing in surgery, tissue therapy and/or as a support medium for biological factors.

26. Use of the wound care fleece, the bandage, the plaster or the salve or a gel-type preparation as claimed in any one of claims 6 to 14 for the hemostasis of interior or exterior wounds.

27. Use of an effervescent granulate or an effervescent powder as claimed in claim 4 or 5 for the preparation of an effervescent pressed tablet.

28. A method of healing surgical wounds, and/or tissue therapy comprising administering to a person in need of such treatment a fibrin adhesive granulate as claimed in any one of claims 1 to

29. A method of healing surgical wounds, and/or tissue therapy comprising administering to a person in need of such treatment a preparation as claimed in 99 one of claims 6 to 14. A hemostatic treatment of interior or exterior wounds comprising administering to a person in need of such treatment a wound care fleece, the bandage, the plaster or the salve or a gel-type preparation as claimed in any one of claims 6 to 14.

31. An effervescent pressed tablet comprising an effervescent granulate or an 9999 effervescent powder as claimed in claim 4 or DATED this 16th day of August 2002 ~AVENTIS BEHRING GMBH WATERMARK PATENT TRADE MARK ATTORNEYS 290 BURWOOD ROAD HAWTHORN VICTORIA 3122 AUSTRALIA