DD295981A5 - METHOD FOR PRODUCING A MATERIAL WITH COUPLED ACTIVE SUBSTANCES AND THE MATERIAL PRODUCED THEREWITH - Google Patents

Abstract

Process for the preparation of a material with coupled active ingredients and the material produced therewith. The invention relates to a process for the preparation of an inorganic glassy or glassy-crystalline material consisting of (statements in * 20-55 CaO; 5-25 Na2O; 0-15 K2O; 0-15 MgO; 30-50 P2O5; 0-15 SiO2; 0-40 Na 2 SO 4 and / or K 2 SO 4, to which, after cooling, an active substance selected from the group consisting of: antibiotic drugs, proteins, antibodies, antigens, nucleic acids, cells, viruses is also covered by the invention has a rapid solubility and can be used as an absorbable implant for filling cavities and bridging bone defects in human medicine {material, osteoinductive; bone graft; reossification; absorbability; antibiotics; proteins; antibodies; antigens; nucleic acid; cells; viruses; material , glassy; material, glassy-crystalline; drug coupling}

Description

Field of application of the invention

The invention relates to methods of preparation of materials which are defined to be rapidly soluble and release no toxic substances with respect to their use. They can be used wherever defined solution rates are required in a wide range, such as the application of active ingredients in bone and soft tissue as well as in selected areas of biotechnology.

Characteristic of the known state of the art

Materials having extremely fast solubility are known in the art by considering naturally occurring or synthetically produced salts. However, the extremely rapid release of all components often creates an unphysiological, even partially toxic, concentration of inherently physiological components. Another disadvantage is that consequently any active substances coupled thereto would be released spontaneously. In the bone or connective tissue substitution such simple salts have also not been successful. To remedy this disadvantage, so-called resorbable bone substitutes based on tricalcium phosphate (TCP) or hydroxyapatite have been introduced, whose absorption time is again too long in many applications. This statement is independent of possibly coupled to these substances active substances.

In the field of bioactive bone replacement materials, as already mentioned, resorbable materials are used only in the field of calcium orthophosphates, whereby their originally low solubility can be varied within certain limits by various chemical and mechanical processes. (See also: Bauer, G, Hohenberger, G .: Causes of different behavior of bioactive calcium phosphate ceramics in the organism, cfi / Ber. DKG 66 [1989] [1/2], 23-27.)

EP0237043 describes the preparation of calcium phosphate-containing biocompatible laminates, wherein the main body has a layer which allows a higher calcium release than the main body itself. Other solutions expressly refer to the ion donor effect of both calcium ions and magnesium, sodium and potassium ions. In DE2346739 a sintered product of apatite, glass / vitreous and permutite for use as implant material is described from this point of view.

The bioactive materials of CaO-P ₂ O ₆ -SiO ₂ -TyP described in DD 248351 and DE-053306648 show in granulated form a stronger release of calcium, sodium, potassium and magnesium ions, but at the same time also larger proportions released on silicon, so that use of these materials is possible only in a compact form. Furthermore, the use of TCP as a carrier material for active ingredients is known. For example, according to EP-A-87662, TCP is compressed with the active ingredient (eg an antibiotic which may be gentamicin) alone or with a binding agent (eg CaSO ₄ ). Also, "introduction", for example by impregnation of a body provided with an open (residual) porosity, seems to be previously known (cf., for this purpose, Randzio, J. et al .: Gentamycin-containing β-TCP ceramics as "drug depot"; Z. Zahnärztl. Implantologie II, [1986] 254-261).

However, to ensure too fast flushing, not too fast drug release, the pores were closed.

Thus, for example, a porous TCP is described whose pores are closed with a mixture of an antibiotic and another filler, in particular an amino acid (EP-A-242672).

To become a more effective, d. H. Chemical coupling is described in DD-WPA61F / 320172/5, a method on which the present description is based in the further.

So far, a material with a defined fast solubility has not been developed, which covers just the area that helps to overcome the (still) too low resorption capacity of bone replacement materials, especially of TCP.

Object of the invention

It is the object of the invention to overcome the described disadvantages of the prior art, that is to develop materials with freely adjustable absorbability, thereby enabling a chemical coupling of active ingredients.

Essence of the invention

The invention has for its object to provide a material which is rapidly soluble both defined in and ex vivo and can be melted well, shed and produced in granular form and can be chemically coupled to the active substances.

According to the invention, a material and a production method for this material has been developed, which consists of an inorganic carrier described in more detail below with a defined dissolution rate and other active ingredients. Active substances in the context of the invention are antibiotic drugs (1), such as oxytetracycline, sulfonamides, gentamycin or quinolone derivatives, proteins or protein mixtures (2), such as enzymes, albumin or antibodies (3), or antigens or nucleic acids (4) or cells ( 5) or viruses (6) understood. The inorganic carrier material is obtained in the following way:

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

0-14K ₂ O, preferably 0.1-14;

0-15 MgO, preferably 0.1-15; 30-55 P ₂ O ₅

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 so far in the ASTM file and in the relevant literature not designated crystalline phase, which is referred to in the context of this description with "X", or obtained Mixed crystals of this phase "X".

By X-ray diffractometry this phase becomes "X" or mixed crystals of this phase are roughly characterized by the following d-values and intensities:

Composition example с

d-value: 3,945 3,650 3,904 3,618 3,892 3,611 3.875 3,600 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 20 20 15 20 20 20 2 8th 90 100 10 10 20 8th 40 8th 10 10 10 Composition Example Composition example d Composition Example b d-value: d-value: d-value: 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: intensities: intensities: 2 8th 90 100 10 10 20 8th 40 8th 10 10 10 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 2 8th 90 100 10 10 20 8th 40 8th 10 10 10 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 2 8th 90 100 10 10 20 8th 40 8th 10 8th 8th

This crystalline phase is thus similar to the phase referred to in the literature as phase "A" (see also: Ando, J. Matsuno, S .: Ca ₃ (PO ₄ I ₂ -CaNaPO ₄ System, Bulletin Chem.Soc 41 [1968] 342-347), but differs from them by significant line shifts and intensity changes as well as the absence of a strong diffraction line at the mesh plane 421. Phase A has been described by Ando as a superstructure of hexagonal calcium sodium orthophosphate. where he designates both the high and the low temperature form of CaNaPO ₄ as alpha- and beta-rhenanite, respectively, and the mere formulation rhenanit thus includes both forms, and this usage of this definition of rhenanite follows 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 also calcium can be partially substituted by magnesium in this structure. These substitutions are generally referred to herein as mixed crystal formation.

The materials containing this phase now also show the desired properties with regard to a defined rapid solubility, in particular with regard to the bone substitution. In animal studies, it has also surprisingly been found that a certain part of these substances in turn induces connective tissue formation. Thus, these materials can be applied in combination with drugs in both bone and soft tissue. The new materials are in the cooled state at room temperature as glass or glassy crystalline material and have essentially physiological constituents. The rate of dissolution of the materials, according to the application, is adjusted within wide limits, as described in more detail below, so that no toxic reactions or overconcentrations of any components are implied.

A widening of the melting range leads beyond the "X" phase to further crystalline phases known per se.Also, the phase "A" or its mixed crystals, rhenanite or its mixed crystals can additionally or individually be present in the material produced according to the invention his. These compositional variations are also suitable for application in the mentioned fields of application 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, in particular 23-50 5-20 Na ₂ O, in particular 6-20 0.1-14 K ₂ O, in particular 2-14 0.1-12 MgO, in particular 0.5-10 32-48 P ₂ O ₅ , in particular 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 0.1-20

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

22-55 CaO, 6-12 Na ₂ 0.3-14 K ₂ 0.2-8 MgO, 37-43 P ₂ O ₆ , 0.5-10 SiO ₂ , 0.5-20 Na ₂ SO ₄ and / or K ₂ SO ₄ .

The material according to the invention is further characterized in that it can be converted at a temperature in the range of 1200 ° C to 1 550 ° C in a pourable melt. Further characteristics of the material are that the melt can be converted into the glassy state at room temperature at a cooling rate greater than about 150 ^° C. per minute, and that the melt, when cooled below a 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.

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; 0-5MgO, preferably 0.1-5MgO; 40-55P ₂ O ₅ ; 0-15SiO 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 as main crystalline constituents of phase "A", the composition of the material in the batch is as follows (in% by weight 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 ₅ ; 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 ₆ ; 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.

The coupling of active ingredients, such as antibiotics, etc., this will not affect the general behavior, provided that these materials are not drugs, from which osteoinductive properties emanate.

The material can be used, for example, as granules with a grain size in the range of 63-1500 цт, preferably 200-500 or 500-1000 цт.

The invention furthermore relates to a process for producing a resorbable material which, according to the invention, can be glassy or glassy-crystalline and has a rapid solubility. The method consists of obtaining a mixture consisting of (in parts by mass in% and on oxide basis):

20-55 CaO; 5-25 Na ₂ O; 0-15 K ₂ O; 0-15 MgO; 30-55 P ₂ O ₆ ; 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 1 200 ° C to 1 580 ⁰ C and the melt cools. Preferably used are the preferred compositions already mentioned above.

As already shown above, the cooling can be carried out with a very high cooling rate of at least 150 ° C, but better 5 χ 10 ^2o C per minute while a glassy material can be obtained.

However, the main route to the production of rapidly soluble materials according to the invention consists in melting with subsequent spontaneous crystallization. Therefore, in the further all embodiments should preferably be aligned with this procedure. In this case, the melt is cooled at a rate of less than about 35 ° C per minute, wherein the spontaneous crystallization occurs. Advantageously, the spontaneously crystallized material is subjected to a conventional tempering process. This takes place in the temperature range of about 600 ⁰ C to 1200 ⁰ C, depending on the chemical composition and the crystal phase to be generated in order to increase the crystalline portion - usually this is the crystalline main phase - even further. The relationship between chemical composition and crystal phase has already been generally described above. It occur through the treatment according to the invention, the crystal phases of rhenanite, the phase "A", mixed crystals of the phase "A", the phase "X", mixed crystals of the phase "X", glaserite and / or crystalline potassium sulfate in appearance.

It is advantageous for the process according to the invention to use P ₂ O ₆ in the form of phosphoric acid.

An advantageous material form is the granular form, so that the cooled and optionally tempered material is comminuted and classified by conventional methods.

One can reduce the sulfate fractions of the granulate in that exposing the granules to a treatment with distilled water over a period of 0.1 to 10 hours at elevated temperature, preferably at about 80 ⁰ C to 100 ° C. As a result, an increase in the inner surface of the material is achieved, which is expressed in an increase in the solubility.

As already stated, the new rapidly dissolving material can be used as a resorbable bone substitute material to which additional active ingredients, such as antibiotics, etc., are coupled or as a pure active substance carrier in the soft tissue.

In these cases, it is expedient granules in the desired particle size in the corresponding body regions, eg. As postoperative cavities in the human body to bring, and this can also be done in admixture with other substances, e.g. with less rapidly soluble biocompatible materials acc. DD 258713.

When used for the induction of connective tissue, the specific composition selected first determines the success of the treatment; however, mixtures with other substances known to result in no bone attachment may also be used in this case.

The coupling of active ingredients can be carried out according to the method described in DD-WP A61F / 320172/5. The coupling of active substances to the - for comparison purposes - completely untreated, to the OH ~ -ionic bases, which are free of toxic Begeltkomponenten, pretreated or pretreated with bases and subsequently silanized with an organosilane, inventive carrier material is carried out at temperatures between 0 ⁰ C and 100 ⁰ C, which is preferably carried out at 10 ⁰ C to 50 ° C, in particular at room temperatures. The incubation times are between 5 and 300 minutes. Times of 120 minutes have proven to be particularly favorable incubation times.

Used amounts of active ingredient depend on the intended use and are for example in the case of antibiotics between 0.01 and 5 mg / ml granules. However, for special purposes, the amount may well be much higher for this group of drugs.

Active substances in the context of the invention are antibiotic drugs (1), such as oxytetracycline, sulfonamides, gentamycin or quinolone derivatives, proteins or protein mixtures (2), such as enzymes, albumin or antibodies (3), or antigens or nucleic acids (4) or cells ( 5) or viruses (6) understood.

Since the rapidly absorbable material is also suitable as a resorbable bone substitute material, for. As for the filling of bone defects, it should also be used in the control of osteomyelithic processes application, if it succeeds at the same time to bring in this way an antibiotic in the defect, which is released delayed. As promising antibiotics, the following substances were successfully included in the studies: oxytetracycline (OTC), sulfonamides, gentamycin and quinolone derivatives.

As active ingredients in the context of the present invention are also understood div. Proteins. For example, for various other processes both in medicine and biotechnology, it is necessary to couple substances such as human serum albumin (HSA), bovine serum albumin (RSA), haptoglobins etc. and of course various enzymes to the carrier material.

These proteins can act as well as by further binding another drug

enable.

For the purposes of the present invention, it is almost immaterial whether the base treatment takes place before the silanization. It has surprisingly been found that the materials can both be silanized without this base pretreatment and it has been found that a remarkable silanunspezifische coupling can take place (see.

Embodiments). The latter statement applies preferably to materials which originally contained considerable proportions of sulfate, but which were again largely removed by boiling.

In order to draw a comparison to the in vitro solubility of the novel materials, two different approaches have been followed, first the solubility determination in a differential cell and secondly a rapid method, which should be noted here:

The material to be examined is comminuted and the selected for the determination of grain fraction of 315-400pm is removed. The sample material is washed with ethanol and then dried at 110 ⁰ C. 10 samples of approximately 2 g each of the test substance are weighed on the analytical balance. Bidistilled water is heated to 37 ° C and 200ml each in the beaker are mixed with the weighed about 2g. This sample remains in the incubator for 24 hours at 37 ° C, covered with a watch glass, stand. After this time, the samples are quantitatively transferred to pre-weighed fries.

Thereafter, the filters are dried with the sample substance at 11O ⁰ C. After cooling in the desiccator, the new weighing is carried out to determine the weight loss after:

(Weighed in mg-weighted in mg) * 1000 / Weighed in mg = Result in mg Substance lost / g Weighing Then the standard deviation is calculated.

The following values result from this method:

Material or material code *)

mg loss of substance / g weight

Ca ₃ (PO ₄ I ₂ Batch 1 3.1 ± 0.39 Batch 2 3.0 ± 0.63 Batch 3 2.9 ± 0.60 Batch 4 2.2 ± 0.16 4CaOxP ₂ O ₅ Batch 1 1.8 ± 0.72 a Batch 1 5.9 ± 0.27 Batch 2 6.6 ± 0.55 Batch 3 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

Batch 10, untreated 188.0 ± 0.99 (n = 5) Batch 10, untreated 244.9 ± 0.5 (n = 6)

*) Compositions see table.

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

Rhenanite or mixed crystals of Rhenantis approx. 3 ... 10mg / g

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

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

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 will then be as desired

still considerably exceeded.

It should be noted, however, in general that particularly materials containing the (new) phase "X" or mixed crystals of the phase "X" are particularly well suited for the production of the pure and the sulfonated mixed melts and products derived therefrom. This expresses u. a. in the good pourability of the melts, the homogeneity of the materials, the leaching ability in the presence of sulfates, etc. from.

In general, for the preparation of the graded resorbable materials of 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 adding TCP in proportion to the proportion, and within the above mentioned. Period in the order Crystal Phase "X" - »Rhenanite -> Crystal Phase" A "

solubility decreases (see table above and conclusions). This means that a high proportion of crystal phase "X" ensures faster solubility than a high rhenanite content, with corresponding sulfate levels further increasing solubility and TCP levels can extend them Within these rules, one skilled in the art can set favorable solubilities for the application ,

embodiment

The preceding embodiments, which show only the full scope of the invention are explained in more detail below by a few examples. The mixtures mentioned in Table 1 were melted and comminuted according to the following application tests. The crystalline phases were determined, the solubility tested by the described rapid method and in the differential cycle cell. Some of these results have already been presented in the preceding section

 In the following, examples will be given of some examinations with regard to the application.

Examples 1-19 (a to s)

Table 1 - List of composition examples:

Code- Oxide composition in% by mass MgO Na ₂ O K ₂ O P ₂ O ₅ SiO ₂ additions designation CaO 5.4 8.3 13.3 40.1 8.9 - a 24.0 5.52 13.70 6.94 41.48 7.38 - b 25.11 - 8.3 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 13.70 6.94 41.48 7.38 10Na ₂ SO ₄ e 25.11 6.04 9.27 14.12 34.05 9.05 - f 26.63 6.73 10.32 15.64 38.63 10.00 - G 18.68 4.64 11.27 17.48 40.85 - - H 25.76 4.64 11.27 17.48 40.85 - 8Na ₂ SO ₄ i 25.76 - 13.7 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 8.84 13.54 40.54 7.21 - I 24.35 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 ₆ о 24.35 5.4 8.3 13.3 40.1 8.9 20Na ₂ SO ₄ P 24.0 10 Na ₂ SO ₄ and 5.4 8.3 13.3 40.1 8.9 10K ₂ SO ₄ q 24.0 4.5 Na ₂ SO ₄ and 5.52 8.84 13.54 40.54 7.21 4.5K ₂ SO ₄ г 24.35 3Na ₂ SO ₄ and 4.64 11.27 17.48 40.85 - 18K ₂ SO ₄ S 25.76

Example 20

The process steps of treating the rapidly absorbable material with an OH-ion-bearing base, which is largely free of toxic constituents, and the silanization are process steps that are carried out essentially on the same basic pattern and therefore presented first and separated.

(a) Surface treatment with OH-ion-bearing bases

A) The support material is heated in an aqueous NaOH solution with pH = 8.4 at 9O ⁰ C for 2 hours. Then the neutral washing with Aqua, bidest. and then the material is dried at about 100 ⁰ C for 120 minutes.

B) The support material is heated in an aqueous Ca (OH) ₂ solution with pH = 8.4 at 80 ° C for 3 hours. The subsequent treatment of the material is analogous to Example A).

This pretreatment was omitted in the selection of the following examples, since the compositions selected showed no significant increases in the active ingredient binding compared to immediately silanized samples in the preliminary experiments.

Example 21

(b) silanization

I) The base pretreated carrier material is incubated with a 1% solution of gamma-aminopropyltriethoxysilane in ethanol / water solvent (1: 1) at 50 ° C for 4 hours. After washing three times with PBS, pH = 7.2, the carrier material was mixed with a 2% glutaraldehyde solution in PBS, incubated for 2 more hours at 37 ° C and washed again three times in PBS.

II) The base pretreated carrier material is incubated with a 1% solution of glycidoxypropyltriethoxysilane in ethanol / water solvent (1: 1) at 50 ° C for 4 hours. After washing three times with PBS, pH = 7.2, the support was prepared for further coupling reactions.

Example 22

(c) Drug carrier coupling

In each case 500 mg of the material of composition d (material 1) and of the material of composition d, which had previously been extracted from sulphate fractions for 5 h at 60 degrees Celsius (material 2), were weighed out in the particle size of 63-200 pm.

Samples according to I) and II) were silanized per material, unsilanized sample material was used as comparison sample. After completion of the individual silanization steps, 5 ml of oxytetracycline (OTC) solution (1 mg / ml) were added. After 4 h of incubation in the refrigerator, the OTC solution was removed using a filter system.

The calculation of the coupled OTC fraction was made on the basis of spectrophotometric measurements by measuring the concentration of the OTC solution before and after incubation at a wavelength of 353 nm. The following results in mg bound OTC to mg granules were obtained:

material

Blank value (silane-free)

Silanisierungnach

0.0027 0.0037

0.0050 0.0060

0.0048 0.0044

Examples 23-26

In each case, 500 mg of the material of Example 22 were mixed with 7 ml human serum albumin solution (2 mg / ml) or 7 ml bovine albumin solution (2 mg / ml) and 5 ml gentamycin solution (2.5 mg / ml) and 5 ml sulfacetamide solution (0.3 mg / ml) at room temperature Incubated for 2 hours. In all cases, similar results were obtained as in Example 22.

Claims (14)

1. A process for the preparation of a resorbable material with coupled active ingredients, characterized in that a mixture consisting of (mass fractions in% 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 SO ₄ and / or K ₂ SO ₄ melts for at least 10 minutes at a temperature of 1200 ⁰ C to 1 580 ⁰ C, the melt at a cooling rate of greater than 150 ° C / min. or less than 35 ° C / min. cooling and the obtained glassy or glassy-crystalline material, which may optionally be crushed and leached, with the active ingredient in the liquid phase over a period of at least 5 minutes incubated, wherein the active ingredient is selected from the group (1) antibiotic drugs such as oxytetracycline , Sulfonamides, gentamycin, quinolone derivatives, or (2) proteins or protein mixtures such as enzymes, albumins, haptoglobins, or (3) antibodies, or (4) antigens or nucleic acids, or (5) cells or viruses. 2. The method according to claim 1, characterized in that the coupling of the active substance after treatment of the material with an OH-ion-bearing base, which is free of toxic accompanying components, and / or an organosilane. 3. The method according to claim 2, characterized in that after the silane treatment, however, takes place before the coupling of the active ingredient, an activation of the material with glutaraldehyde. 4. The method according to claim 1-3, characterized in that the active ingredient is an antibiotic drug of the group oxytetracycline, sulfonamides, gentamycin, quinolone derivatives. 5. The method according to claim 1-3, characterized in that the active ingredient is a protein or protein mixture, in particular an enzyme or enzyme mixture. 6. The method according to claim 1, characterized in that the incubation (coupling) in a period of 5 minutes to 20 hours, preferably up to 120 minutes, at a temperature of 0 ⁰ C to 100 ° C, preferably at room temperature. 7. 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, especially 0.5-10 30-50% P ₂ O ₅ , preferably 32-48, especially 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. 8. The method according to claim 1 or 7, 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 . 9. The method according to claim 7 or 8, characterized in that the spontaneously crystallized material is subjected to a conventional temperature process in the temperature range of about 600 ⁰ C to 1 200 ° C, depending on the chemical composition to increase the crystalline content even further, wherein the crystal phases of rhenanite, mixed crystals of rhenanite, phase "A", mixed crystals of phase "A", phase "X", mixed crystals of phase "X", glaserite and / or crystalline potassium sulfate appear in the rule, however the proportion of the main crystal phases is further increased. 10. 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 ⁰ C to 100 ⁰ C, when the content of Sodium or potassium sulfate is about equal to or greater than 3 parts by weight in% initial amount. 11. resorbable material with coupled active ingredients, characterized in that the mixture before firing the material has the following chemical composition (in parts by mass in% and calculated on 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 rapid solubility carries a chemically-coupled drug, wherein the drug is selected from the group consisting of (1) antibiotic drugs such as oxytetracycline, sulfonamides, gentamycin, quinolone derivatives, or (2) proteins or protein mixtures such as enzymes, albumins , Haptoglobins, or (3) antibodies, or (4) antigens or nucleic acids, or (5) cells or viruses. 12. The material according to claim 11, characterized in that the active ingredient is an antibiotic drug of the group oxytetracycline, sulfonamides, gentamycin, quinolone derivatives. 13. Material according to claim 11, characterized in that the active ingredient is a protein or protein mixture, in particular an enzyme or enzyme mixture. 14. Material according to claim 11 to 13, characterized in that the proportion of the active ingredient glassy or glassy-crystalline material can be replaced by active ingredient-carrying pure tricalcium phosphate or according to DD 258713 surface-treated tricalcium phosphate up to 40%.