DE2319852A1 - Process for the production of an absorbent fiber mass from protein, especially from collagen, suitable for the absorption of medicinal products - Google Patents

Description

GÜNTER LGEISS

PATENT ENGINEER

7760 RADQLFZELL / BODENSEE

MARKETPLATZ 9 - FERN CALL 07732-37 82 MY CHARACTER: B 401 - RADOLFZELL / ON April 17, 1973

Biological Concept Inc., 342 Madison Avenue, New York, ».Υ .. 10017, USA ...... ..

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Process for the production of an absorbent fiber mass suitable for the absorption of medicaments from protein, especially from collagen.

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309843/1105

COPY

The invention relates to a method for producing an absorbent which is suitable for absorbing medicaments Fiber mass made from collagen. " "·

Absorbent sponges of this type made from collagen, in particular Gelatine, are already in use in surgery. Your advantage over e.g. absorbent mass made of cellulose or Cotton consists in the fact that it is absorbable and has a light antigenic effect, which is why it - if necessary · »in the body can be left.

The previously known processes for the production of collagen sponge are described in U.S. Patents 3,157,524 and 3,368,911, after which swollen collagen is acidified, frozen out and then with an organic solvent dehydrates ^ · a known from GB »patent specification 1.056.007 Process provides for freeze drying and in the US patent 2.166.074 is the production of absorbent gelatin sponges described.

Furthermore, the production of medicaments is described in US Pat. No. 3,435,110, which are intended for oral use " ¹ and are incorporated in collagen fiber mass. The use of stable, homogeneous oil-in-water suspensions or emulsions is described in US Pat Patent 3,435,117.

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As is well known, collagen is the fiber-like protein connective tissue and makes up almost 3o% of body protein. Besides its main physical function in the body As a support, it also serves as an ion exchanger and binds electrolytes. Drugs and Metabolites. It binds many substances in the tissue such as tetracycline, anti-inflammatory drugs as well as metals such as copper, silver, iron and mercury. The interaction between collagen and heparin or glyco « proteins is also known as bonds of an ionic nature.

Collagen reacts with a number of water-soluble drugs to form complexes. Such are in some Cases desirable because they give the drug »e.g. a vitamin or an immunologically active substance ·· only

slowly and thus enable a dosage form that can be used parenterally. In such an application, the pharmacological one The effect of the drug is delayed compared to the same drug without a complex.

Water-soluble drugs can be bound to collagen by spreading the solution on a collagen matrix will. Subsequent tanning causes slow release of the drug, as in the US patents 3.435.110 and 3.435.117 is described. In GB patent 1,056,007 there is the incorporation of hemostatic substances

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such as fibrin or thrombin, or antibiotics such as Chlortetracycline in amounts below 10% by weight dry matter described. The collagen mass containing these substances must are then frozen at -20 to -70 C and a foam is obtained by freeze-drying. ,

All of the above-described previously known methods are very time-consuming and - especially with the necessary freeze-drying - also very expensive. Also limiting the Pharmaceutical proportions to 10% by weight, dry substance can be a considerable disadvantage in many cases.

The invention is based on the object of creating a method which, with the greatest possible reduction to complete Avoidance of freeze-out and freeze-drying processes the production of an absorbent, sponge-like collagen fiber mass in which higher amounts of medication than before can be incorporated ..

According to the invention, this object is cost in that first a dispersion of swollen protein fibers in an aqueous solution or suspension of natural or synthetic Resin produced and this is then added a tanning or crosslinking agent, after which the fiber mass at a temperature above the freezing point of the solution or

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Suspension hardened and then the excess Water is removed from the mixture.

This process is very simple and cheap to carry out and the fiber mass obtained in this way can be pressed Bring the above deformations into any desired Foom and dimension. Endless fabrics as well as plates in any desired thickness as well as spheres, cylinders and other bodies can be produced will. If collagen is used as the basic material for the process here as well as below, possibly also in the form of gelatin is mentioned as preferred, this does not exclude other proteinaceous fiber masses which are suitable for the inventive Methods are also suitable.

The preferred protein collagen used here has a molecular weight of about 300,000; Gelatin is a through Heat denatured collagen. Preferred for the invention a collagen fiber material swollen by acid treatment with a fiber diameter between 5,000 to 90,000 Angstrom units approximately used. The extraction of Such acid-swollen collagen from animal tissue such as fish skins, from bones, etc. is known per se. In the method according to the invention, it can take place in that a collagen-carrying tissue such as calf skin with an aqueous extractant - e.g. 0.1% vinegar

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acid - treated for about 24 hours and then cleaned. Using a suitable cleaning method for collagen dialysis or salt extraction is on page 210 of the book "Chemistry of Collagen" (edited by G.N. Ramachandran Academic Press, New York, 1967).

The method according to the invention now provides for the collagen to disperse in an aqueous solution or suspension of natural or synthetic resin. The collagen concentration is advantageously between 0.1 to 3.0% based on the dry weight. Among the natural resins you can Gum arabic, karaya, tragacanth, agar or, for example, guar can be used; suitable semi-synthetic dispersants are e.g. Methyl cellulose, carboxymethyl cellulose, etc .; synthetic resins like polymer 1212A, polymer 705-D-B are also here applicable.

These resins are used in varying amounts depending on the type. When using swollen collagen, the amount is expediently to be set in such a way that in the collagen-resin mixture a concentration between 0.01 and 5 wt.% - preferably between 0.05 and 0.5 wt.% results. An alternative The possibility is that the collagen - or other proteins - is dispersed in water and this dispersion then to a separate solution or dispersion of the resin

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is mixed. However, adding collagen directly to the solution or dispersion of the resin is more advantageous. the The presence of the resin itself plays an important role in improving the physical properties, especially

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particular of the coherence, of the spongy product. the

Experience has shown that without the addition of resin, none

Sponge formation is possible, but the Fajermasse simply disintegrates.

The following operation of the method according to the invention consists in adding a hardener in the form of a tanning agent or crosslinking agent. As such, fabrics are special suitable that have an aldehyde group, such as acyclic aldehydes such as formaldehyde, acetaldehyde, glutaraldehyde, methylglyoxal, Glyoxal and others, but also e.g. trimethylolamine or maleic anhydride. Also a combination of several hardeners can be beneficial; Experience has shown, for example, that a mixture of formaldehyde and maleic anhydride is special effective. The crosslinking agents are added in such amounts that they correspond to the addition of the resins and be approximately between 0.02 and 5 wt.%.

In some cases it can be advantageous to improve the strength and texture of the product by adding To improve fillers. These can, for example, come from natural

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products such as cellulose, chemically treated cellulose, cotton, Silk and the like, including those made from synthetic fibers made of linear polyamides and polyester fibers. Furthermore, plasticizers such as glycerine, propylene, glycol or the like can also be used, if necessary. can also be used. The amount of this Additives depend on the desired properties of the end product. Of the ^ fillers, for example, amounts of up to 30% by weight and even more can be added, without adversely changing the structure of the collagen sponge.

It is particularly advantageous in the preliminary procedural sections, when an aqueous suspension of the acid-swollen collagen in the aqueous solution of a resin dispersed in the desired concentration and then the appropriate Amount of a hardener, crosslinking or tanning agent is added.

The pH of the resulting suspension is adjusted according to the desired properties of the end product. in the it is generally between 5 and 8. The end product will turn out to be felt-like density when the suspension has a pH value at about 5-6.5. If, on the other hand, it has a pH of 6.5 to 7.5, the end product becomes spongy and particularly absorbent. One lying in the alkaline range

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The pH value of the suspension gives the end product an extremely absorbent, pulpy consistency. When the aforementioned fillers are to be incorporated, it must be ensured that the mass is stirred particularly vigorously until it foams becomes, for which suitable stirring devices are already known are.

In the next step of the method according to the invention the fiber mass at a temperature above the freezing point of the solution or suspension, so generally at about 0 C - preferably at 0 to +7 C - cured. The time required for this depends on the respective amount of the crosslinking agent o, like. and is usually between 1 and 7 days. Experience has shown that the properties of the end product sometimes can be improved if the fiber mass for some time · - a few hours or even several days is kept below freezing point. The curing can take place, for example, so that the start time is above of the freezing point a time of 6 hours to three days follows, during which the fiber mass is kept at a temperature of 0 to -8 C. It should be emphasized, however, that this measure is not absolutely necessary.

After the above-described 'curing, the excess Water mechanically - depending on the consistency of the fiber mass

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Filtering or pressing - removes what the product is in Water washed and dried if necessary.

These products obtained by the process according to the invention are particularly suitable for taking drugs. In contrast to the known freeze-drying process The products produced according to the invention have the ability to produce fiber masses which are water-soluble Medicines, haemostatically active substances and the like in quantities to bind well over 10% by weight. They are even suitable To bind drugs and substances that are insoluble or sparingly soluble in water such as steroid hormones, prostaglandins, fat-soluble vitamins, antimicrobial substances, vaccines etc.

The complex of fiber mass and medicaments obtained in this way can be introduced into body cavities or implanted in other regions of the body and in this way pharmacologically gisch cause a long-term effect, whereby the daily Administration of tablets or injections replaces or can be saved.

Products made from swollen collagen are particularly suitable because of the interaction between it and drugs favors better access to its reactive groups

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because the swollen collagen is preserved by the swelling process a high degree of water solubility or dispersibility. This is where the collagen structure becomes the ones Removed groups that block the appropriate reactive groups.

A release of the reactive groups in the collagen can, among other things, by an enzymatic treatment, by lyotropic Agents such as concentrated sodium perchlorate or sodium iodide solution can be achieved or roughly by separating the collagen from the other proteins by removing the latter be dissolved in concentrated saline solution e.g. 10 M. In the latter case, collagen and the other proteins are precipitated can be extracted, thereby obtaining pure collagen. In the method according to the invention, this can Form of collagen production using the acid swelling process be combined.

In order to achieve the collagen-drug complex aimed at by the invention which has a slow release property, the collagen - e.g. gelatin - will accordingly prepared, especially if the medicinal product, such as vitamins and others, is essentially insoluble in water is. Of course, these measures can also be used in the same way for water-soluble drugs.

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For the production of this collagen-drug complex
He sees the method according to the foundling style as two basic ones
Steps before: once the collagen becomes a treatment
subjected, so that it swells profusely, a fibrous
Mass forms and so distributed in an aqueous medium
is that its reactive groups are accessible to the drug, and on the other hand then becomes the drug
brought into contact with the swollen collagen with the help of a water-soluble solvent which has the ability to dissolve the drug, but on the other hand
neither reacts with the collagen nor dissolves it itself.
In this way, the drug dissolved in an organic solvent is brought into the collagen phase and thereby forms the desired complex. The swelling of the collagen takes place here preferably under acidic conditions. The organic solvent is said to be inert to the collagen
be. It can be based on the following interaction:

Experience has shown that the mixing of swollen collagen with the organic solution of the drug ceases slowly
Balance between water, swollen collagen and
organic solvent phase. The drug is then located in the network of the swollen collagen and is bound there as a result of the differences between its binding capacity and its solubility in the through

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Water diluted organic solvent phase. As an organic, The solvent miscible with water must of course be chosen which is inert to collagen and this does not solve either. This applies to aliphatic alcohols such as methyl, ethyl, propyl and isopropyl alcohol to and / i to water-soluble glycols such as ethylene glycol, propylene glycol and water-soluble ethers such as dioxane, and low molecular weight ketones such as acetone or methyl ethyl ketone. Of these, preference is given in particular to ethyl alcohol or isopropyl alcohol because of their low toxicity and others advantageous properties used.

The concentration of the drug in the organic solvent used varies widely depending on the Structure of the drug and the choice of solvent. The ratio of drug-solvent phase to aqueous collagen phase, in turn, depends on the distribution coefficient of the drug in the two Phases and is important to the release of the drug ensure from the organic solvent into the collagen phase. The concentration is adjusted so that the final concentration of the organic solvent in the total mixture is 5-25, preferably 10-15% by weight.

It 'is not in the case of the complex prepared according to the invention

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absolutely necessary to dissolve the medicine - it can also in the form of an aqueous suspension of the collagen phase to be added. In this case, however, it is desirable for the drug to bind optimally to the collagen to be achieved before tanning or crosslinking occurs. You should therefore wait a few hours here before a tanning or crosslinking agent is added to the mixture.

This is a particular advantage of the method according to the invention The new option is collagen-drug complexes to produce atie more than 10 wt.% Medicinal product, it is particularly important where it is necessary appears to enable a long-term effect, as in the case of antibiotics.

The method according to the invention is also suitable for making combinations of collagen and trace elements such as cobalt or copper, which are implanted in pets achieve a long-term effect and deficiency symptoms by means of fix these trace elements. For implantations of this type, the above-mentioned products are particularly suitable, the obtained a felt-like structure as a result of the pH adjustment to about 5-6.5 cfier suspension. By the way, you can particularly competitive complexes also through the binding of

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collagen obtained from vaccines. This makes it possible to produce a vaccine-collagen complex against foot-and-mouth disease and in the animals treated with it one Achieve immunity that lasts twice as long as it does with the conventionally administered agents known up to now was possible.

A number of proteins can also be used with collagen in accordance with the invention or polypeptides exhibiting chemotherapeutic activity are combined. For example the trophic hormone the pituitary gland, the hormones of the hypothalamus and the prostaglandins, water-soluble esters of steroid hormones such as the Ostradiol-3 sulfate sodium salt.

A particular advantage of the invention is that it is possible to use complexes and such combinations of collagen and to produce drugs that are hardly or not soluble in water such as testosterone, estradiol, estriol, Progesterone or cortisol, as well as synthetic pregnancy hormones such as norethindrone, norgestrel, athynodiol, diacetate or megestrol acetate.

Steroid hormones bound to Kallagen have a valuable long-term effect. For example, a progesterone-collagen complex implanted subcutaneously or in the uterus

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brought in a / ^ ntifertilitätseffekt cause. A complex from collagen with estradiol or estriol in the form of a tampon can be used to treat age vaginitis in the vagina introduced, eliminating the undesirable systemic Effects of estrogen, can be prevented.

The invention also offers the advantageous possibility also bind several drugs to one collagen. For example, it is possible without difficulty., A valuable Medicines by 'creating that on collagen once a drug against trichomads and one against fungi binds, possibly also an antibacterial one Agents such as a sulfonamide. The collagen multi-drug complex obtained in this way - applied in the form of a tampon - can be used for the infectious treatment of the vagina used.

The invention basically offers the advantages that the Production of an absorbent fiber mass from collagen is essentially simplified and cheaper in itself, without the very cumbersome and expensive treatment below freezing point is absolutely necessary. Will she mind carried out in a modified form, the hardener, Tanning and crosslinking agents are dispensed with. The production of drug complexes is of particular advantage .

Application examples:

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The following is based on practical examples, which, however, should not be regarded as exclusive and limiting are, the method according to the invention is shown:

Production of the collagen sponge Example 1:

2 liters of a slurry of acid-swollen collagen 1.5% based on dry matter are cooled to 5 ° C. 0.25% by weight of gum arabic is added. The suspension is brought to p "7.0 with 2N sodium hydroxide solution. After adding 15 ml of a k0 ^c /> strength formaldehyde solution, the mixture is stirred vigorously for 10 seconds. The foamy product is poured into stainless dishes and left to react for 7 days at 2 ° C. The water is removed mechanically, the spongy product is washed with water and dried. The sponge has great absorbency. Example 2:

Example 1 is repeated. The ρ value brought to 8.5. This process becomes a fluffy Get a soft product, which has about twice the absorbency of commercial paper pulp. Example 4:

100 ml of acid-swollen collagen slurry are mixed with enough of a 3 ^c / o ± gen aqueous solution of gum arabic that a final concentration of $ 0.01 is achieved. The ρ value is increased with caustic soda

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5fO set. The mixture is mixed well into one Poured the bowl so that a layer thickness of about 1 cm is created and cooled in a refrigerator for 8 hours » Then the dish is kept at +5 C for 3 days. The excess water is removed and the product is washed and dried. The result is a parchment-like membrane that can be used as an artificial skin substitute or for Seems suitable for dialysis purposes. Example 5 s

100 ml of acid-swollen collagen slurry, which contain 3 % dry matter, are mixed with 100 ml of a 0.1% aqueous solution of gum arabic, the p _TT value is brought to 8 with 2N sodium hydroxide solution; Cresol red serves as an indicator. It is intensively mixed until the mixture is frothy. Another sample was made in the same way, except that tap water was used instead of the gum arabic solution. " Both experimental set-ups were poured into trays / stainless / and cooled in the refrigerator. They are then kept at +4 in the refrigerator for 2 days. When using gum arabic, a sponge was obtained which absorbed 26 times its weight in water. In the experiment without gum arabic, no sponge was obtained.
Example 6:

There are k experimental arrangements of collagen slurry with 0.05 / ό gum arabic and h experimental arrangements only

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with tap water, as already described in Example 5, with the difference that the PjT value is set to 7.0. All samples are kept at -8 C for 24 hours. It is then held at + 5 ° C for 2, 3 and 7 days as indicated in the table below. The water is then removed and the material is dried. The following tests were carried out t

Porosity: It has a circular disc punched out and the average thickness _t determined and determines the weight. The porosity index (PI) results as follows:

Thickness in mm X 100

Dry weight in mg

Absorbency: A specimen — collagen sponge of certain The weight is immersed in water for one minute. The excess water is allowed to drip off and determined the weight. The absorbency is expressed as follows:

Weight of the damp sponge _t mg

Weight of dry Sponge s, mg Result: Length of stay
i. days PI. Aptitude i Gum arabic.
Control verse CM CM 2.9
0.8 18.5
2.5 Gum arabic.
Control vers. cn cn 3.0
0.7 14.0
3.8 Gum arabic.
Control _{verse or similar} 7th
7th 7.3
0.9 28.0
4.0

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It appears from these requests that the addition of gum arabic results in a more porous and absorbent sponge.
Example 7 s

Example 6 was repeated with the exception that both the gum arabic experiment and the control experiment were held at -10 ° C for 5 days. The experiment with gum arabic resulted in: PI 7.7 »absorbency: 71 · ^ he control experiment yielded: P ₀ I · 3.5» absorbency: 26, example 8:

A series of experiments with varying amounts of gum arabic or methyl cellulose added in aqueous solutions, carried out »The experiments were carried out for

k / je

Frozen for 7 days and then tested / in experiment 6. the results are:

Resin, concentration in the solution

P ₀ I.

absorbency

Gum arabic 1

0.5 0.05 0.025

Methyl cellulose 0.5 0.25 0.05

15th
11
10

3.4

7.7 10.0

-43

40

18 40
43

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Example 9 ί

Example 1 was repeated, only methylcellulose $ 0.01 based on the finished solution was used. The sponge obtained was very absorbent. The absorbency index was 22 »

Preparation of Collagen Drug Complexes Example 10;

50 ml of a collagen suspension (2 ^c / i> ± g based on dry substance) are cooled to +5 C and 25 ml of a solution of 10 mg progesterone (C marked) are dissolved in 1 ml propylene glycol and diluted with 24 ml water while stirring. The mixture is kept at +5 ° C. for 6 hours. Then the p “value is 2N

ri

Caustic soda set to 6.5 »0.5ml formaldehyde $ 40 is added, the mixture is mixed intensively for 15 seconds, the foamy product is poured into a bowl and held at 2 ° C for 5 days. After 5 days, a certain part of the excess water was removed, to determine the radioactivity. The activity present was insignificant, from which it can be seen that the all of the progesterone was bound to collagen. The excess alkali was removed by dialysis. The obtained felt-like product was cut into 10 narrow strips of the same size. This collagen pro ge st er on-Matrix was implanted subcutaneously in 6 rats, one strip in each animal. The animals were after

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6 punch killed. The decrease in the collagen-progesterone matrix, determined by the weight loss, averaged $ 15. This shows that such a collagen-progesterone matrix could produce a biological effect of 35-40 weeks o
Example 11: ^

100ml of a collagen suspension (2fo ± g) was mixed with 100ml of a suspension of testosterone in water (2mg / ml). It was, with dilute sodium hydroxide solution on p _TT _

brought and held at 5 G for 2k hours. Then 0.4 ml of formaldehyde kOfo was added, mixed well and left to harden for 7 days at 1 ° C. The excess fluid was checked for testosterone spectrophotometrically. The result was negative, indicating that all of the testosterone has been bound to collagen,

Example 12: -

The above experiment was repeated, but a ^ ö of tetracycline hydrochloride (6 mg / ml) was used. Examination of the excess solution showed binding of 85% of the tetracycline to collagen. This means that 2g "collagen binds 500mg tetracycline. Example 13 *

An absorbent collagen swarf was made according to Example 10 except that the following drugs were used on 1 gram of collagen; Metronidazole, 250mg; Nystatin, 100,000 units; and

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a mixture of 3 sulfonamides (sulfothiazole $ 34.2; sulfamide 28 , kfo and N-benzoylsulfamide $ 37.4), 200mg. ^ he mixture was poured into cylindrical molds after adding formaldehyde. After curing, cylinders resulted which were suitable for the treatment of vaginal infections.
Example 14:

100ml of acid-swollen collagen (2%) was added with 400mg Tetracycline hydrochloride in 100ml water containing 50mg Contained gum arabic, added. After adding 0.33 ml of formaldehyde and 0.7 ml of a 2N sodium hydroxide solution, was The mixture was kept at +3 C for 24 hours, then whipped into a foam and kept at -8 C for 3 days. The sponge obtained was absorbent and suitable for treating infections in body cavities. Example 15s

An absorbent collagen sponge was produced according to Example 13 with the exception that 40 mg prostaglandin E was used on 1 g collagen. The obtained sponge caused a dilatation of the cervix after insertion into the vagina.
Example 16:

Absorbent collagen sponge produced according to Example 13 with the exception that 400 mg of diphenylthiocarbazone was used on 1 g of collagen. The received sponge prevented fertilization in animals after introduction into the uterus.

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Example 17:

Example 4 was repeated with the exception that as much silver nitrate solution was added by one Total concentration of $ 0.5 silver based on collagen— to achieve dry weight «The product obtained was valuable in treating skin burns,

Example 3: (addendum to page I)

Example 1 is repeated , but instead of formaldehyde, 20 ml of a 25% glutaraldehyde solution are used. The sponge obtained has the same absorbent properties as that obtained from Example 1. Example 18: '

Example 13 was repeated, but here a sufficient one Amount of fluocinolone acetonide (6 ", 9 * i-dif luro-11/3, 16 ^, 17 ^, 21-Tetrahydroxy-1,4-Pregnadiene-3.20 ~ Dione-16, 17-Äcetonjiid) added to a final concentration of 0.025 wt.% dry substance to obtain. The pH of the solution was adjusted to about 6.5. The one resulting from this, similar to ülz Sponge works well for treating skin inflammation.

Patent claims:

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Claims (19)

B 401-73 - ** --- Biological Concept Inc., 342 Madison Avenue, New York, USA. Patent claims: (T \ / Process for the production of an absorbent fiber mass suitable for the absorption of drugs from protein, in particular from collagen, characterized in that
first a dispersion of swollen protein fibers in an aqueous solution or suspension of natural
or synthetic resin and this is then added a tanning or crosslinking agent, after which the fiber mass is cured at a temperature above the freezing point of the solution or suspension and then the excess water is removed from the mixture. 2. / The method according to claim 1, characterized in that
collagen is used as the fiber mass. 3. / The method according to claim 2, characterized in that the collagen previously by treatment with an acid for Swelling is brought about. 309843/1105 4. / Method n-ach claim 1, characterized in that the Concentration of the fiber mass in the dispersion is approximately between 0.1 and 3% by weight of dry substance. 5. / The method according to claim 1, characterized in that-as natural resin of such a vegetable origin is used. 6. / The method according to claim 5, characterized in that as vegetable resin gum arabic is used. 7. / The method according to claim 1, characterized in that the concentration of the resin in the dispersion to approximately between o, oil and 5 wt.% Is set. 8. / The method according to claim 1, characterized in that the fiber mass is first dispersed in water and then this Dispersion of that of the resin is added. 9. / The method according to claim 1, characterized in that as Tanning or crosslinking agents an aldehyde is chosen. 10./ The method according to claim 1, characterized in that a further curing period from six hours to three Days at temperatures below 0 C. 309843/1105 11./ The method according to claim 10, characterized. That no tanning or crosslinking agents are used. 12./ A method for producing a complex of one or more medicaments and an absorbent fiber mass which is produced according to claim 1 from swollen protein fibers, characterized in that the swollen protein fibers are distributed in an aqueous medium and contain the medicament in a water-soluble solvent which has the ability to dissolve the drug, but neither reacts nor dissolves the YLjiXX) igf £ fi protein fibers for at least the time required for the drug to bind into the protein fibers. 13./ The method according to claim 1 ^., Characterized in that as Protein fiber collagen is used. 14./ The method according to claim IJ ,, characterized in that as Solvent aliphatic alcohol is used. 15./ The method according to claim 12, characterized in that in the mixture of the aqueous suspension of the fiber mass with of the drug solution, the amount of the latter is adjusted to about 5-25% by weight. 3-098 ^ 3/1105 16./ The method according to claim 12, characterized. ,, that the Mixing the drug solution with the Fasei-mass en-Suspens ion is taken before you use the tanning or crosslinking agents be admitted. 17./ The method according to claim 12, characterized in that the Medicinal product is water soluble and will be in the pulp incorporated proportion greater than 10% by weight of the entire complex Τ> Π? Χ is measured. 18./ The method according to claim 12, characterized in that as Medicinal a steroid hormone is used. 19./ The method according to claim 12, characterized in that as Fibrous collagen and a pregnancy hormone is used as a medicinal product. The representative: // '- r Ij GÜNTER L. GEiSS PATENT lNQENiEUR 776Ο RADOLF CELL MARKETPLACE θ 309843/1105