DD295994A5 - METHOD FOR PRODUCING A COLLAGEN TABLE WITH RESORBIBLE CARRIER MATERIALS - Google Patents

Abstract

The invention relates to a method for producing a collagen fleece with resorbable traeger substances. The non-woven material consists of organically rapidly absorbed inorganic and organic components. As inorganic constituents one, but preferably several materials with different fast resorbability can be used. Optionally, it is also possible to use up to 40 * of an untreated or a surface-treated tricalcium phosphate. As organic components, collagens have been used. To the inorganic traegerstoff prostaglandins of the E-series are coupled. The new collagen fleece can be used as an absorbable implant for the filling of cavities and for the bridging of bone defects in human medicine. {Material, osteoinductive; Bone graft; re-ossification; absorbability; prostaglandins; Material, glassy; Material, glassy-crystalline; Drug coupling; collagen}

Description

Field of application of the invention

The invention relates to a method for producing a collagen fleece with resorbable carriers and products resulting therefrom.

The aterial combination can be used for filling cavities, but in particular for bridging bone defects in human medicine.

Characteristic of the known state of the art

The effect of prostaglandin is widely described in the patent literature.

For the local application of PG, combinations with "pharmaceutically accepted carriers (EP 249194) are proposed. In this sense, adsorbates of PG are mentioned, which are bound to pregelatinized starch (DE 304880 AD, crospovidone (DE 3304867 A1) and dextrans (DE 3304864 A1).

On the other hand, z. For example, tricalcium phosphate (TCP) has been used as a pharmaceutical storage carrier for gentamycin, etc. (see EP 34004). For the o.g. Applications, d. H. In connection with PG, probably TCP is not suitable as a carrier material, since it is z. B. administered subcutaneously may cause irritation.

In bone tissue, however, the TCP or suitable modifications have been used successfully for bone defect repair and it is possible to refer to the limited absorbability of this bone replacement material (EP-A 237043). However, it has often been pointed out in the scientific literature on the too long absorption times, d. H. a delayed reossification.

In the scientific literature on the use of PG, inter alia, on a bone formation-influencing effect of prostaglandin E _{2 was} pointed out (Jee, WSS, et al .: The effects of PG E ₂ in growing rats: increased metaphyseal hard tissue and cortico-endosteal bone Formation; Calcif. Tissue Int. Vol. 37 [1985] pp. 148-157). In this work areas of restricted and enhanced bone growth were detected.

In US-P 4621100 a treatment of osteoporosis disease with PG of the Ε series or with their derivatives is also proposed for the field of human medicine. The drug delivery takes place orally according to the claim of the invention. The described effect of the PG-substances according to the examples is more or less represented as systemic concerning the entire bone structure.

In contrast, it has recently become known that PG has been chemically coupled to surface-modified bioactive calcium phosphate-containing bone substitute materials, including not only long-term stable implant materials but also resorbable tricalcium phosphate (TCP).

This represents a significant advance, but the resorption times of the TCP appear to be too long, even when filling large bone cavities or bridging large bone defects, even with this surface modified material. This does not change the local administration of PG, although bone formation seems to be induced faster and more sustainably compared to systemic administration.

Object of the invention

It is the object of the invention to overcome the described disadvantages of the prior art, the too slow absorption of the inorganic support of the PG and the hitherto exclusively in granular form application

Essence of the invention

The invention has the object of providing a first material which is rapidly soluble in vivo, good to melt, shedding and handling let

Erfmdungsgemaß a manufacturing method and a material having these features has been developed, which consists of a hereinafter described closer inorganic carrier material with defined rate of dissolution, which carries certain active ingredients and which is evenly distributed in a collagen nonwoven to the inorganic carrier material is obtained in the following manner

Melted mixture of the composition of (in parts by mass in%)

0-14 K ₂ O preferably 0.1-14,

0-15 MgO, preferably 0.1-15, 30-55 P ₂ O ₆

0-15 SiO ₂ , preferably 0.1-15,

0-40 Na ₂ SO ₄ and / or K ₂ SO ₄ , preferably 0.1-35

a, sheds or frits them, one obtains spontaneously crystallized glass-ceramics, which surprisingly contain a previously not in the ASTM file and in the relevant literature not designated crystalline phase, which is referred to in the context of this description, "X", or one obtains mixed crystals In this phase "X" X-ray diffractometry, this phase is characterized by "X" and mixed crystals of this phase are approximately characterized by the following d-values and intensities

Composition example с

d-value 3,945 3,650 3,384 3,199 2,885 2,717 2,552 2,351 2,239 2,164 1,980 1,827 1,597 1,569 1,517

Intensities 20 20 2 8 90 100 10 10 20 8 40 8 10 10 10

Composition Example

d-value 3.904 3.618 3.347 3.189 2.851 2.679 2.529 2.321 2.209 2.141 1.953 1.808 1.578 1.547 1.498

Intensities 20 20 2 8 90 100 10 10 20 8 40 8 10 10 10

Composition example d

d value 3,892 3,611 3,338 3.15 2,844 2,667 2,523 2,310 2,199 2,135 1,945 1,804 1,571 1,539 1.495

Intensities 15 20 2 8 90 100 10 10 20 8 40 8 10 10 10

Composition Example b

d-value 3,875 3,600 3,325 3,12 2,835 2,663 2,514 2,303 2,195 2,131 1,941 1,800 1,569 1,537 1,491

Intensities 20 20 2 8 90 100 10 10 20 8 40 8 10 8 8

This crystalline phase is therefore similar to the phase referred to in the literature as "A" phase (see this Ando, J, Matsuno S Ca ₃ (PO ₄ ) J-CaNaPO ₄ system, Bulletin Chem Soc Japan 41 [1968] 342-347) but differs from it by significant line shifts and intensity changes as well as the absence of strong diffraction at the network plane (421). Phase "A" has been described by Ando as a superstructure of hexagonal calcium sodium orthophosphate, including both the high and low molecular weight The low-temperature form of CaNaPO _{4 is} referred to as alpha or beta-rhenate and the simple formulation rhenanit therefore includes both forms. This usage of language or this definition of rhenanite we will follow in the present description

The structure type of "A" is also the phase "X" assigned, although apparently over half of the sodium can be replaced by potassium and calcium can be partially substituted by magnesium in this structure These substitutions are in general, so also here, referred to as mixed crystal formation The materials containing this phase now show the desired properties in terms of a defined rapid solubility, in particular with regard to the bone substitution, it was surprisingly found that a certain part of these substances without combination with PG of the Ε-series or derivative of which or a stabilized form of the der-series PG or mixtures thereof (merely) induces connective tissue formation These claims are not modified by the presence of collagen

The new rapidly absorbable materials are in the cooled state at room temperature as a glass or glass crystalline material, but can in principle be converted into the glass crystalline state and have essentially physiological constituents. The dissolution rate of the materials will vary widely according to the application, as will be the case detailed below, so adjusted that no toxic reactions or overconcentrations of any components are implied

An expansion of the melting range leads beyond the "X" phase to further crystalline phases known per se. In addition, the phase "A" or its mixed crystals, rhenanite or its mixed crystals can be present in the material produced according to the invention in addition to or in each case These composition variations are also suitable for application in the applications mentioned in terms of the objective, as well as the inclusion of the known isomorphism of the sulfates of potassium and sodium

This extended composition area thus extends to the already mentioned components in their mass fractions in%:

0.01-15K ₂ O

0-40 Na ₂ SO ₄ and / or K ₂ SO ₄

However, a further increase in the Calciumorthophosphatanteils leads to increasingly heavier or non-meltable and non-pourable materials, thus approaching the known materials both from their production process and in their properties (solubilities) or depart from the objectives of the present invention. Particularly advantageous embodiments are therefore in the concentration ranges (mass fractions in%)

21-50 CaO, especially 23-50

5-20 Na ₂ O, especially 6-20

0.1-14 K ₂ O, especially 2-14

0.1-12 MgO, especially 0.5-10

32-48 P ₂ O ₅ , especially 35-48

0.1-15 SiO ₂ , in particular 1-10

0.1-35 Na ₂ SO ₄ and / or K ₂ SO ₄ , in particular 0.1-10

Another preferred embodiment of the material according to the invention consists of

22-55 CaO, 6-12 Na ₂ O, 3-14 K ₂ O, 2-8 MgO, 37-43 P ₂ O ₅ , 0.5-10 SiO ₂ , 0.5-20 Na ₂ SO ₄ and / or K ₂ SO ₄ .

The material of the invention is further characterized in that it can be converted at a temperature in the range of 1 200 to 1 550 ⁰ C in a pourable melt. Further characteristics of the material are that the melt can be converted to the glassy state at room temperature at a cooling rate of greater than about 150 ° C per minute and that the melt, when cooled below normal cooling rate or at a cooling rate slower than about 35 ° C per minute, spontaneously crystallized. This forms a fine crystalline structure.

It has furthermore been found that spontaneously crystallized material of the same chemical composition as the corresponding glass (obtained under extreme cooling conditions) or the crystalline material produced from the glass by tempering each have different solubilities.

It has furthermore been found that the spontaneously crystallized glass-ceramic as crystalline main constituents at least one of the phases of Rhenanits, mixed crystals of Rhenanits, the phase "A", mixed crystals of the phase "A", the above-mentioned new phase "X" and / or mixed crystals contains the phase "X". The material may additionally contain glaserite and / or crystalline potassium sulfate.

These sulfates surprisingly need not be extracted in the present application prior to combination with the E series PG or a derivative thereof or a stabilized form of the der series PG or mixtures thereof, although when removed, it may be z. slightly higher binding levels were measured.

If the main crystalline constituents of the material are rhenanite or mixed rhenanite crystals, the composition of the material in the mixture is as follows (in% by mass and calculated on an oxide basis):

30-40CaO; 15-20 Na ₂ O, 0-1 K ₂ O, preferably 0.01-0.1 K ₂ O; 0-5 MgO, preferably 0.1-5 MgO; 40-55 P ₂ O ₆ , 0-15 SiO ₂ , preferably 0.1-8 SiO ₂ ; 0-30 Na ₂ SO ₄ and / or K ₂ SO ₄ , preferably 0.1-25 Na ₂ SO ₄ and / or K ₂ SO ₄ .

By "crystalline main ingredient" is meant that the percentage of the component is higher than the proportion of other components present in the material.

If the material contains the phase "A" as main crystalline constituents, the composition of the material in the mixture is as follows (in parts by mass in% and calculated on an oxide basis):

40-50 CaO; 8-20 Na ₂ O; 0-1 K ₂ O, preferably 0.1-1 K ₂ O; 0-5 MgO, preferably 0.1-5 MgO; 40-50 P ₂ O ₆ ; 3-20 SiO ₂ ; 0-30 Na ₂ SO ₄ and / or K ₂ SO ₄ , preferably 0.1-25 Na ₂ SO ₄ and / or K ₂ SO ₄ .

If the material contains the phase "X" or mixed crystals of the phase "X" as main crystalline constituents, the composition of the material in the mixture is as follows (in parts by mass in% and calculated on an oxide basis):

22-45 CaO; 8-20 Na ₂ O; 0-14 K ₂ O, preferably 0.1-14 K ₂ O; 0-15 MgO, preferably 0.1-15 MgO; 30-55 P ₂ O ₅ ; 0-15 SiO ₂ , preferably 0.1-15 SiO ₂ ; 0-40 Na ₂ SO ₄ and / or K ₂ SO ₄ , preferably 0.1-35 Na ₂ SO ₄ and / or K ₂ SO ₄ .

A particular advantage of the invention is that the material is biocompatible, sometimes even bioactive in the sense of a direct bone attachment or under constant release allows the formation of new bone tissue. In combination with the der-series PG or a derivative thereof or a stabilized form of the der-series PG or mixtures thereof, all o. G. Materials osteoinductive, even those without these PG-donations - in the absence or in the presence of collagen - only lead to connective tissue formation.

The rapidly absorbable material is first prepared as granules with a grain size in the range of 63-800 μιη, preferably 200-500 цт.

It is also possible to mix rapidly resorbable materials of the present invention having a different absorption capacity before the combination with PG of the Ε-series or a derivative thereof or a stabilized form of the PG of the Ε-series or mixtures thereof. Alternatively, it is also possible in this sense additionally to use TCP (as the slowest absorbable material), but the proportion should not be greater than 40 wt .-%. In the case of the treatment of smaller bone defects (<approximately 5 ... 8cm ³ ), this proportion of TCP should be considerably lower, ie approximately less than or equal to 20% by mass. The further combination according to the invention with collagen and the nonwoven form made therefrom are in no way influenced by the mixture of various inorganic materials provided with PG-gifts.

The nonwoven material is such that the material contains at least two substances of different absorbability and a suitable stag-series prostaglandin (PG) or derivatives thereof or stabilized forms of the der-series PG or mixtures thereof. The PG component is bound to the inorganic rapidly absorbable component by simple impregnation or chemical coupling. The preferred variants include several graded resorbable substances. This achieves dynamic tissue or bone repair of the defect, and there is no undesirable separation of the replacement material from the bone.

The areas of application in the medical field primarily concern the surgical disciplines of orthopedics, maxillofacial surgery, otolaryngology and traumatology.

For a number of applications, it would be beneficial if materials in granular form were not exclusively available for the application. Especially with severely bleeding wounds, it is difficult to fix the granules locally, so that an application of the granules in nonwoven form is desirable. The matrix material that makes the nonwoven form, of course, is in turn biocompatible and absorbable.

The object of the invention was further achieved in that, in addition to rapidly absorbable inorganic materials, collagen preparations have also been developed whose absorption behavior can be regulated over a wide range and whose absorption times are to a certain extent consistent with those of the rapidly absorbable inorganic materials.

The coincidence of the resorption times of the collagens and the inorganic materials prevents the structural and inertness of the inorganic portion of collagen-ceramic combinations resulting from premature resorption of collagen in older specimens and the related collapse of the inorganic material during the advance of the newly formed endogenous cell tissue.

Even if the residue-free absorption behavior of the collagen fraction in the gradually absorbable phosphate-containing moldings, which can be regulated in wide ranges, is an essential criterion for its suitability as a material mix component, the problem-free application of the moldings is bound to further quality features of the collagen.

For the ability to combine materials of distinctly different chemical structures and physical properties, which also do not enter into chemical bonds, but are to form a stable, malleable, dimensionally stable composite, the components of which are homogeneously distributed in one another until residue-free absorption is based on the preservation of the highest degree of nativity of the skieroprotein collagen with its adhesion and scaffolding favoring micro- and macrofibrillar structure attach great importance.

Elution of the albumins and globulins, elimination of lipoproteins and other non-collagenous components of the animal starting materials must be carried out very intensively according to the invention, but the necessary chemical process steps for isolation of desired collagen types must only take place under conditions which ensure the greatest possible nativity, but also desantigenization and haemostasis. It has been ensured according to the invention that the uniqueness of the collagen fiber braiding is maintained, which alone ensures optimum combinability with bioceramics. While in every other weaving a certain regularity of interweaving is recognizable, free fiber ends can be detected and individual fibers isolated, collagen fibers are three-dimensionally intertwined and intergrown so that never a beginning or end of fibers can be detected and only fragments of fibers can be isolated. The collagen fibers are made up of fiber bundles and these in turn are made of the finest collagen fibrils, in which the parallel ordered fibrils can again meet in sub-bundles, in order to separate soon afterwards in new sub-bundles and reunite. A continuous single fibril can thus soon belong to the one bundle of fibrils, that is to say one fiber and soon the other.

This network of fibers is further completed and solidified by transverse collagen fibrils which irregularly and randomly connect the individual fiber bundles.

The structure of the collagen fiber bundles from normalmicroscopic visible individual fibers, the fibers of ultramicroscopically visible subfibrils or filaments, the filaments of molecular size protofibrils results for skin collagen a very large reactive fiber surface in the order of 500m ² to 2500m ² per kg of collagen.

According to the invention care has been taken that this order of magnitude of the surface in the nonwovens made of collagen, the inorganic portion of the shaped body for physical bonding is available.

It is also important that protofibrils consist of three helical twisted polypeptide chains and that polypeptide chains also self-assemble helically, with an average of 3.6 amino acids accounted for by a helix interconnected by peptide bonds and by other amino acids in preceding and following hydrogen bonds between NH groups and the oxygen atoms of the СО groups

The side chains of the amino acids are located on the outside of the screw radially to the axis. The carriers of the reactivity of the proteins are the side-valently acting peptide groups characterized by their polar character and the terminal or side chain amino and carboxyl groups.

According to the invention, the reactivity of the collagen is reduced by blocking its reactive groups. In the clear case, irreversible solidifications of the molecular lattice between peptide groups of parallel-stored polypeptide chains can be achieved by incorporation of methylene bridges. After many studies, the finding is confirmed that z. B. aldehyde crosslinks of the collagen take place both with the amino groups of the side chains and with the peptide groups.

With the degree of blocking of reactive groups in the collagen, it is now possible to reach areas of absorbability of collagen, which correspond to the absorption times of the particularly rapidly absorbable inorganic phosphate-containing portions in the inventive shaped body. Overall, therefore, the goal of the graded absorbability of the shaped body reached

Almost comparable resorption times of the organic macrostructured and the inorganic microstructured portions cause dimensional stability during the entire exposure time of the ceramic-collagen combinations and thus a favorable course of osteogenesis

The combination of the and / or the resorbable materials and optionally further up to a maximum of 40% by mass of admissible amounts of a TCP granulate with PG of the Ε-series or a derivative thereof or a stabilized form of the PG of the Ε-series or mixtures thereof can take place

(a) by simple adsorption (impregnation) of the surface or

(b) by chemical coupling according to a method previously described and used in the patent only for TCP TCP The coupling of drugs can therefore be carried out according to the method described in DD-WP A61 F / 320174/1 The coupling of drugs to the For comparison purposes, completely untreated, to the OH ~ -ion bearing bases, which are free of toxic Begeltkomponenten, pretreated or pre-treated with bases and subsequently silanized with an organosilane, erfmdungsgemaße carrier material is carried out at temperatures between 0 and 100 ⁰ C, wherein The incubation times are between 5 and 300 minutes. Times of around 120 minutes have proven to be particularly favorable incubation times. Used amounts of active ingredient depend on the intended use and are, for example, between 0.01 in the case of the antibiotics and 5 mg / ml granules For special purposes however, the amount is also much higher for this group of drugs

However, it has surprisingly been found that the rapidly absorbable materials have a priori sufficient OH ~ ions on the surface, so that the intermediate step of the treatment by an OH ~ -ion bearing base may possibly even be omitted

The content of the prostaglandin component will be in the range of about 2 to 6, preferably 3 to 4 milligrams PG of the Ε series or its derivatives or converted stabilized forms of PG of the Ε series per patient, with a spontaneous release always below about 3 milligrams should

Having already been pointed to the method for combining the inorganic component or components with PG of the E series or a derivative thereof or a stabilized form of the PG of the Ε-series or mixtures thereof (impregnation or partial application of DD-WP A 61 F 320174 / 1), the process for the preparation of the novel rapidly resorbable materials will be described, which consists in that a mixture consisting of (in mass proportions in% and calculated on oxide basis)

20-55 CaO, 5-25 Na ₂ O, 0-15 K ₂ 0.0-15 MgO, 30-55 P ₂ O ₅ , 0-15 SiO ₂ , 0-40 Na ₂ SO ₄ and / or K ₂ SO ₄ melts for at least 10 minutes at a temperature of about 1200 to 1 580 ^° C. and the melt is cooled. The preferred compositions already mentioned above are preferably usable

As already shown above, the cooling can be carried out with a very high Aokuhlgeschwindigkeit of at least 150, but better 5 χ 10 ^2o C per minute while a glassy material can be obtained. However, the main way of producing erfmdungsgemaßen rapidly soluble materials in the melting with subsequent spontaneous crystallization Therefore, in the following all embodiments should preferably be aligned with this process route. The melt is cooled at a rate of less than about 35 ° C. per minute, the spontaneous crystallization occurring. The spontaneously crystallized material is advantageously subjected to a customary tempering process Temperature range of about 600 to 1 200 ⁰ C, depending on the chemical composition and the crystal phase to be grown to the crystalline portion - usually this is the crystalline main phase-still further increase the relationship of chem As a result of the treatment according to the invention, the crystal phases of rhenanite, phase "A", mixed crystals of phase "A", phase "X", mixed crystals of phase "X", glaserite and / or crystalline potassium sulfate

It is advantageous for the process according to the invention to use P ₂ O ₅ in the form of phosphoric acid. An advantageous material form of the rapidly resorbable substance, also for the subsequent nonwoven production, is the granulate form, so that the material cooled and optionally tempered from the melt is comminuted by conventional methods and classified

If the sulfate content is to be removed or partially reduced, the granules are subjected to a treatment with distilled water over a period of 0.1 to 10 hours at elevated temperature, preferably at about 80 to 100 ^° C. This results in an increase in the internal surface of the material which manifests itself in an increase in solubility, and the sulfate content is forcibly reduced. In addition, the sulfate recovered in this way can be recycled to the processing process

As already stated, the new rapidly dissolving material can be used as a resorbable bone substitute material, acting in combination with der-series PG or a derivative thereof or a stabilized form of the PG-series PG or mixtures thereof osteoinductive Not affected by collagen production In order to arrive at a nonwoven which is easy to process during the surgical procedure, 5 to 60% by mass of the nonwoven is made by collagen, consequently 40 to 95% by mass of the inorganic granules, of which up to 40 Ma fractions can consist of pure or surface-modified TCP (for example according to DD 258713) (ie, 16 to 38% by mass with respect to the nonwoven). Furthermore, the experiments have shown that, in particular, a collagen content of 10 to 40 % by mass erfmdungsgemaßen goals is fair

In order to compare the in vitro solubility of different substances, two different approaches were chosen, one being the determination of solubility in a differential cell and the other a rapid method to be noted here

The material to be examined is comminuted and the selected for the determination of grain fraction of 315-400цт is removed The sample material is washed with ethanol and then dried at 110 ⁰ C are 10 samples and each about 2 g of the test substance weighed on the analytical balance Bidistilled water heated to 37 ° C and 200ml each in the beaker are mixed with the weighed about 2g This sample is 24h in the incubator at 37 ° C, covered with a watch glass, stand After this time, the samples are quantitatively transferred into previously balanced frits then the filters dried with the sample substance at 110 ⁰ C after cooling in a desiccator re reweighing to determine the weight loss takes place after

(Weight in mg - weight in mg) χ 1 000 / weight in mg = result in mg loss of substance / g weight Then the standard deviation is calculated

Material or material Code * mg Substance lost / g Weighing

Ca ₃ (PO ₄ J ₂ charge 1 3.1 ± 0.39

4CaOxP ₂ Os Batch 1 1.8 + 0.72

а Batch 1 5.9 ± 0.27 Batch 2 6.6 ± 0.55 CHARGE3 6.2 ± 0.28 b 5.7 ± 0.84 с 14.7 ± 0.77 d Batch 1, untreated 93.6 ± 3.57 Batch 2, untreated 87.6 ± 1.22 Lot 1, treated 23.1 ± 1.23 e untreated 36.6 ± 1.68 treated 3.8 ± 0.77 f (glassy, quenched) 54.9 ± 7.12 G 9.8 ± 1.98 O Lot 10, untreated 188.0 ± 0.99 (л = 5) P Lot 10, untreated 244.9 ± 0.5 (n = 6)

* Compositions see Table 1

According to the results of the rapid method for determining the solubility, it is apparent that a coarse division of the materials after the main crystal phases can be carried out

Rhenanitbzw mixed crystals of Rhenanit ca 3 .10mg / g

Phase "A" or mixed crystals of phase "A" approx. 1 4 mg / g

Phase "X" or mixed crystals of phase "X" approx. 7 15 mg / g

Of course, with the addition of the sulphate components or after carrying out a corresponding treatment (leaching) of materials with high sulphate contents, this classification no longer has any validity, these values are then, as desired, considerably exceeded

However, it remains to be said in general that especially materials containing the (new) phase "X" or mixed crystals of phase "X" are particularly suitable for the production of the pure and sulphated mixed melts and products derived from them in the good pourability of the melts, the homogeneity of the materials, the Auslaugfahigkeit in the presence of sulfates etc from

In general, for the preparation of the graded absorbable materials according to the invention, it can be stated that the solubility is in the period of about 15 days to about 20 months, can be extended by addition of TCP according to the proportion and within the period of time in the order crystal phase " X "-» Rhenanit -> crystal phase "A" decreases the solubility (see table above and inferences therefrom) This means that a high proportion of crystal phase "X" ensures a faster solubility than a high rhenanite content, with corresponding sulfate levels further increasing the solubility and TCP levels can extend them. Within these rules, the skilled person can adjust for him favorable opportunities depending on the application

The invention also relates to the process for producing nonwovens based on collagen from animal tendons, hollow organs and skins and their combination with the inorganic resorbable biocompatible material prepared according to the invention

The essence of the method of Vhesherstellung consists on the one hand of the unique macro-and microstructure of collagen with its extremely large internal surface of 500m ² to 2000m ² per kg of collagen, the polar nature of the peptide formation and the reactive ammo and carboxyl groups in the side chains in To obtain the highest possible Nativitat, on the other hand by mechanical crushing of the compact collagenous material to the order of the microscopically visible individual fibers and their joining to fleece space for the inorganic, rapidly absorbable biocompatible materials to make difficult to itself absorbability of the collagen, that the Resorption times of the collagen correspond to those of the particularly rapidly absorbable, biocompatible material and, finally, by desantigenization to avoid incompleteness, for example antibody formation in the human body after implantation iden

According to the invention, the object is achieved in that after mechanical removal of mchtkollagener components initially by mild alkali and acid treatment Interfibrillarsubstanz is removed from the collagen of animal origin, followed by the desantigenization with oxygen-evolving substances, preferably hydrogen peroxide, followed It has been experimentally proven that the on the Collagen, which has been treated as described above, shows a very high level of responsiveness, which, in addition to the ability to quench bleeding, is also documented in the extremely important property for the intended use of adhasively binding the inorganic, rapidly resorbable, biocompatible material with surprisingly high strength As a disadvantage of the high responsiveness of collagen, the relatively short absorption time has the

The osteogenic and formative efficacy of the generally less absorbable inorganic biocompatible materials was greatly reduced in this case due to the too quickly occurred structural and untension of the implant granules The chemist has it, however in hand, by crosslinking the collagen with, for example, aldehydes, phenol condensation products and / or other substances to drastically prolong the absorption times of the webs made from cross-linked collagens after implantation into the human body. However, the theoretically derivable prognosis was confirmed by experiment, according to which 100% Cross-linked collagen is strongly reduced in its ability to bind adhesively to inorganic, rapidly absorbable, biocompatible material. Nonwovens of fully cross-linked collagen cause the inorganic, rapidly absorbed, biocompatible Mat to trickle down erial almost quantitatively out under the premise of broad consensus, the resorption of inorganic and organic compounds or the graded absorbability of the inventive moldings, it is now possible to create optimally effective combinations Extremely fast resorbable, inorganic, biocompatible material is so conveniently with webs of non-crosslinked collagens while slowly resorbable, inorganic, biocompatible material should be combined with webs of proportionately cross-linked collagen. It also behaves similarly when combining inorganic biocompatible materials with graded absorbability. The drawback of the reduced adherent binding of more absorbable, inorganic, biocompatible material in a combination containing greater proportions of cross-linked collagen is compensated by the fact that the cross-linked collagen partial functions of the inorganic en material takes over

The crosslinking of the collagen is conveniently still in its compact state. The desired degree of crosslinking can be achieved both by the fact that only the stoichiometrically necessary amount of crosslinking agent is offered to the collagen to be crosslinked, as well as the fact that collagen crosslinks all binding possibilities until complete saturation and is combined in subsequent steps with uncrosslinked collagen in the desired ratio

Consequently, compact uncrosslinked or cross-linked collagen is to be comminuted into fiber suspensions, conveniently firstly coarsely ground, then flossed several times (up to five times) in Kolloridmuhlen. The suspensions of cross-linked and uncrosslinked collagen are stirred into each other homogeneously in the desired ratio. It is possible to isolate individual types of the collagen, their separate grinding with addition of water to fiber suspensions and their homogeneous mixing in the suspensions prepared in the described manner, the granular, inorganic, rapidly absorbable, provided with PG, biocompatible material evenly in the ratio of 40Ma - to 95 Ma%, ie 5Ma -% to 60 Ma -% collagen, based on the total dry mass of the shaped body to be distributed If necessary, the granulated, inorganic, rapidly absorbable, biocompatible material by pure od before mixing with the fiber suspension and PG treatment It then replaces surface-modified alpha-tricalcium phosphate in an amount of up to 40% by mass, based on the total inorganic content. The respective mixtures of differently soluble, inorganic materials to which the PG are bound are homogeneously distributed in the protein fiber suspension vorgefuhlten forms of physiologically harmless material to überfuhren, gefnerzutrocknen and m known manner to double weld in Poiyethenfolie and sterilize

Exemplary embodiments

The preceding statements, which only reveal the full scope of the invention, are explained in more detail below by a few examples. The mixtures listed in Table 1 were melted and comminuted according to the following application tests. The crystalline phases were determined, the solubility according to the rapid method described and tested in the differential circuit cell Some of these results have already been presented in the preceding section. Here are some examples of some examinations with regard to the application

Examples 1-19 (a-s)

Table 1 - List of Composition Examples

Code- Oxide composition in MgO Ma -% K ₂ O P ₂ O ₆ SiO ₂ additions designation CaO 5.4 Na ₂ O 13.3 40.1 8.9 _ a 24.0 5.52 8.3 6.94 41,18 7.38 - b 25.11 _ 13.70 13.3 40.1 8.9 - с 31.5 5.4 8.3 13.3 40.1 8.9 10Na ₂ SO ₄ d 24.0 5.52 8.3 6.94 41,18 7.38 10Na ₂ SO ₄ e 25.11 6.04 13.70 14.12 34.05 9.05 - f 26.63 6.73 9.27 15.64 38.63 10.00 - G 18.68 4.64 10.32 17.48 40.85 - - H 25.76 4.64 11.27 17.48 40.85 _ 8Na ₂ SO ₄ I 25.76 - 11.27 6.94 41.48 7.38 - J 32.75 _ 13.7 6.94 41.48 7.38 4Na ₂ SO ₄ к 32.75 5.52 13.7 13.54 40.54 7.21 - I 24.35 8.84

Table 1 (continued)

Code- Oxide composition in Ma -% MgO Na ₂ O K ₂ O P ₂ O ₆ SiO ₂ additions designation CaO 5.52 8.84 13.54 40.54 7.21 4K ₂ SO ₄ m 24.35 5.52 8.84 13.54 40.54 7.21 10K ₂ SO ₄ η 24.35 5.52 8.84 13.54 40.54 7.21 30 Na ₂ SO ₄ 0 24.35 5.4 8.3 13.3 40.1 8.9 20Na ₂ SO ₄ P 24.0 5.4 8.3 13.3 40.1 8.9 10 Na ₂ SO ₄ and q 24.0 10K ₂ SO ₄ 5.52 8.84 13.54 40.54 7.21 4.5 Na ₂ SO ₄ and r 24.35 4.5 K ₂ SO ₄ 4.64 11.27 17.48 40.85 - 3Na ₂ SO ₄ and S 25.76 18K ₂ SO ₄

Example 20

The silanization was carried out by known methods (according to DD-WP A 61 F320174 / 1), as follows

I) The rapidly absorbable carrier material is incubated with a 1% solution of gamma-aminopropyltriethoxysilane in ethanol / water solvent (1 1) at 50 ⁰ C for 4 hours after washing three times with 20ml 0.1 M phosphate buffer solution pH = 7.2, the carrier material was mixed with a 2% glutaraldehyde solution in phosphate buffer solution, incubated for 2 more hours at 37 ° C and washed again three times in phosphate buffer solution

II) The rapidly absorbable carrier material is incubated with a 1% solution of glycidoxypropyltriethoxysilane in the ethanol / water solvent (11) at 50 ° C. for 4 hours after washing three times with 20 ml each of a 0.1 M phosphate buffer solution, pH = 7.2, the PG coupling reaction can take place

Example 21

Portions of 2 grams each of composition a material and composition d of grain size between 200-500 micrometers, silaminated according to Examples I and II, were mixed with a PG ethanol PG solution containing a total of 10 milligrams of PGI egg, incubated for about 60 minutes and then dried at 37 ° C in a vacuum

A nonwoven fabric prepared by 40% by mass of collagen was prepared as described above. As a test model, rabbit defects were set in the tibial metaphysis, each filled with 1.0 g of nonwoven containing the treated material. As a control group, animals were selected Fleece was implanted containing only untreated (PG-free) material For the determination of osteogenesis and osteomedication the animals were killed and various histological examinations were carried out after 3 months. It was shown that the bone regeneration and, surprisingly, the absorption in this group was the furthest The unprocessed (PG-free) nonwoven material of composition d only led to the formation of bmde tissue in the bone. No groups could be found between the groups whose materials were silaminated after I or II and subsequently provided with PG secured differences be determined

Example 22

Portions of 2 grams of a composition of composition a of grain size between 100 and 300 microns with an ethanolic PG E ₂ solution (50% ethanol / water solution) containing a total of 10 milligrams of PG E ₂ were added for approximately 60 minutes incubated at 37 ° C and then dried at 37 ⁰ C in a vacuum Then, a nonwoven with 50 Ma -% collagen was prepared from it The animal experiments were carried out analogously to Example 21 Again, as expected, a similar experimental result was achieved as in Example 21 It was confirmed Impression that the formation of bone was increased and the absorption by the PG-administration was further accelerated. The control group used was that from Example 21

Claims (12)

1. A process for producing a collagen nonwoven fabric with resorbable carriers, characterized in that a mixture consisting of {% by mass and calculated on an oxide basis) 20-55% CaO; 5-25% Na ₂ O; 0-15% K ₂ O; 0-15% MgO; 30-50% P ₂ O ₅ ; 0-15% SiO ₂ ; 0-40% Na ₂ O ₄ and / or K ₂ SO ₄ melts for at least 10 minutes at a temperature of 1 200 to 1 580 ^c C, the melt at a cooling rate of greater than 150 ^c C / min. or less than 35 ° C / min. and the resulting glassy or glassy crystalline material, which may optionally be comminuted and leached, with the liquid phase prostaglandin (PG) E series or its derivatives or a stabilized form of the PG series or mixtures thereof over incubated for a period of at least 5 minutes and then 40 to 95 parts by mass in% of the active ingredient-carrying inorganic material in finely divided form with 5 to 60 parts by mass in% purified and finely divided collagen, which is present as a protein fiber suspension in an aqueous medium, homogeneously mixed and dried as a nonwoven , 2. The method according to claim 1, characterized in that the coupling of the prostaglandin after treatment of the material with a 0H-ion-bearing base, which is free of toxic accompanying components, and / or an organosilane. 3. The method according to claim 1, characterized in that after the silane treatment, however, an activation of the material with glutaraldehyde takes place before the coupling of the prostaglandin. 4. The method according to claim 1, characterized in that the prostaglandin E is selected from the group consisting of prostaglandin E ₁ (PGE ₁ ), prostaglandin E ₂ (PGE ₂ ) and derivatives of PGE ₁ or PGE ₂ and stabilized forms of PGE ₁ or PGE ₂ exists. 5. The method according to claim 1, characterized in that the incubation (coupling) in a period of 5 minutes to 300 minutes, preferably up to 120 minutes, at a temperature of 0 to 100 ^c C, preferably at room temperature and the pH of the prostaglandin solution not above pH 9. 6. The method according to claim 1, characterized in that the mixture consists of 20-55% CaO, preferably 21-50, especially 23-50 5-25% Na ₂ O, preferably 5-20, especially 6-20 0.1-15% K ₂ O, preferably 0.1-14, especially 2-14 0.1-15% MgO, preferably 0.1-12, in particular 0.5-10 30-50% P ₂ O ₅ , preferably 32-48, in particular 35-48 0.1-15% SiO ₂ , preferably 2-15, in particular 3-15 0.1-35% Na ₂ SO ₄ and / or K ₂ SO ₄ , preferably 0.1-20, in particular 0.1-15. 7. The method according to claim 1, characterized in that the mixture consists of 22-50 CaO; 6-12 Na ₂ O; 3-14 K ₂ O; 2-8 MgO; 37-43 P ₂ O ₅ ; 0.5-10 SiO ₂ ; 0.5-20 Na ₂ SO ₄ and / or K ₂ SO ₄ 8. The method according to claim 6 or 7, characterized in that the spontaneously crystallized material is subjected to a conventional annealing process in the temperature range of about 600 to 1 200 ⁰ C, depending on the chemical composition to further increase the crystalline content, wherein the Rhenanite crystal phases, rhenanite mixed crystals, phase "A", phase "A" mixed crystals, "X" phase, "X" phase mixed crystals, glaserite and / or crystalline potassium sulfate, but usually the proportion of Main crystal phases is further increased. 9. The method according to claim 1, characterized in that the crushed material is subjected to a treatment with distilled water over a period of 0.1 to 10 hours at elevated temperature, preferably at 80 to 100 ⁰ C, when the content of sodium or potassium sulfate is about equal to or greater than 3 parts by weight in% in the initial mixture. 10. The method according to claim 1 to 9, characterized in that the proportion of Proaglandintragenden inorganic material can be replaced by active ingredient-carrying pure tricalcium phosphate or by active ingredient-carrying and according to DD 258713 surface-modified tricalcium phosphate up to 40%. 11. The method according to claim 1, characterized in that the protein fiber suspension contains crosslinked and uncrosslinked collagen types I, II and / or III and contains prostaglandin-carrying glassy or glassy-crystalline material of grain sizes up to 1 000 microns and in precooled forms of physiologically harmless Material is shaped and then freeze-dried. 12. collagen fleece with resorbable carriers, characterized in that the mixture of the carrier prior to firing of the material has the following chemical composition (in% by weight and calculated on an oxide basis) 20 to 55% CaO 5 to 25% Na ₂ O 0.01 to 15% K ₂ O 0 to 15% MgO 30 to 50% P ₂ O ₅ 0 to 15% SiO ₂ 0 to 40% Na ₂ SO ₄ and / or K ₂ SO ₄ and the glassy or glassy-crystalline material having fast solubility is uniformly distributed in an amount of 40 to 95 mass% in the collagen nonwoven fabric, wherein the carrier as the coupled active ingredient is a Pro-series prostaglandin (PG) or its derivatives or a stabilized form of the der-series PG or mixtures thereof.