Use of composite materials

Abstract

To provide a composition that can be used as a bone substitute material.SOLUTION: The present invention relates to a composition for use in a therapeutic procedure, which comprises calcium sulfate, an alkaline earth carbonate, a binder, and up to 2.5 wt.% gentamicin sulfate based on the total mass of the composition, and to a production method for such a composition.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to the field of orthopedics, and in particular to composite materials for use as bone substitute materials. [Background technology]

[0002] Bone substitute materials can be used to fill bone cavities. In principle, bone cavities can be filled using the patient's own tissue, which, although well tolerated by the patient, is often only available in limited quantities. Therefore, in practice, artificial materials are often used as bone substitute materials for larger bone cavities. Calcium sulfate-containing bone substitute materials are described, for example, in patent documents such as U.S. Patent Application Publication No. 2002110541 (A), U.S. Patent No. 5,807,567 (A), U.S. Patent Application Publication No. 2002197315 (A), U.S. Patent No. 6,652,887 (A), U.S. Patent No. 5,756,127 (A), U.S. Patent No. 5,614,206 (A), and German Patent Application Publication No. 19953771 (C). During surgery, there is a risk of microbial infection as a result of medical intervention, for example, as a result of bone substitute materials or medical devices that have incorporated microorganisms. In other cases, the infection is already present before surgery and there is a risk that the pathogen causing the infection may not be completely removed from the infected tissue during surgery.

[0003] Preferred Embodiments This application describes a bone substitute material and its manufacture. The bone substitute material can preferably contain an antibiotic that is released in a delayed manner from the bone substitute material. Furthermore, therapeutic uses of the bone substitute material are described.

[0004] Preferred embodiments of the present invention are described below.

[0005] In a first embodiment, a first aspect relates to a composition for use in a therapeutic procedure, the composition comprising calcium sulfate, an alkaline earth carbonate, a binder, and greater than 0 to a maximum of 2.5 wt. % gentamicin sulfate, preferably 0.5 to 2.5 wt. % gentamicin sulfate, based on the total weight of the composition.

[0006] In a second embodiment, the use comprises mixing the composition with viable cells in vitro, the mixing preferably forming a homogenous mixture.

[0007] In a third embodiment of the composition for use according to the second embodiment, viable cells are mixed in vitro with the composition in the form of blood, preferably whole blood, and / or in the form of cancellous bone.

[0008] In a fourth embodiment of the composition for use according to the third embodiment, the cancellous bone is autologous cancellous bone or allogeneic cancellous bone.

[0009] In a fifth embodiment of the composition for use according to embodiment 3 or 4, the cancellous bone is present in the form of bone fragments.

[0010] In a sixth embodiment of the composition for use according to the fifth embodiment, the bone particles have an average diameter of between 1 and 10 mm.

[0011] In a seventh embodiment of the composition for use described in any of embodiments 3 to 6, the composition is mixed in vitro with cancellous bone in a weight ratio of "1:0.5" to "1:3".

[0012] In an eighth embodiment of the composition for use according to the third embodiment, the composition is mixed in vitro with blood in a weight ratio of between 1:0.2 and 1:1.

[0013] In a ninth embodiment of the composition for use according to any of embodiments 3 to 8, parts by weight of the composition are mixed in vitro with 0.5 to 3.0 parts by weight of cancellous bone and 0.2 to 0.8 parts by weight of blood.

[0014] In a tenth embodiment of the composition for use according to any of embodiments 3 to 9, the blood is subjected to clotting after being mixed with the composition.

[0015] In an eleventh embodiment of the composition for use according to any of the previous embodiments, the use comprises introducing the composition into a bone defect, such as a bone void.

[0016] In a twelfth embodiment of the composition for use according to any of the previous embodiments, the composition comprises 70 to 80% by weight of calcium sulfate.

[0017] In a thirteenth embodiment of the composition for use according to any of the previous embodiments, the composition comprises 12 to 18% by weight of alkaline earth carbonate.

[0018] In a fourteenth embodiment of the composition for use according to any of the previous embodiments, the composition comprises 7 to 12 wt.% of a binder.

[0019] In a fifteenth embodiment of the composition for use according to any of the previous embodiments, the treatment procedure comprises filling a bone defect caused by trauma, a tumor or an infection with the composition.

[0020] A further aspect is a method for producing a composition comprising the steps of: - grinding calcium sulfate, alkaline earth metal carbonate, a binder, and from greater than 0 to a maximum of 2.5% by weight of gentamicin sulfate, preferably 0.5 to 2.5% by weight of gentamicin sulfate, into a powder; - compressing the powder to form an agglomerate; - breaking down the agglomerates into granules; - fractionating the granules to a desired particle size.

[0021] Further preferred embodiments of the present invention include the following: [Claim 1] A therapeutic composition comprising calcium sulfate, an alkaline earth carbonate, a binder, and from greater than 0 to a maximum of 2.5 wt. % gentamicin sulfate, and from 0.5 to 2.5 wt. % gentamicin sulfate, based on the total mass of the therapeutic composition. [Claim 2] The therapeutic composition of claim 1 , wherein the therapeutic composition comprises viable cells. [Claim 3] 3. The therapeutic composition of claim 2, wherein the viable cells are in the form of blood. [Claim 4] 4. The therapeutic composition of claim 3, wherein the viable cells are in the form of cancellous bone, which can be autologous or allogeneic cancellous bone. [Claim 5] 5. The therapeutic composition of claim 3 or 4, wherein the viable cells are in the form of cancellous bone, which is in the form of bone fragments. [Claim 6] 6. The therapeutic composition of claim 5, wherein the bone particles have an average diameter of 1 to 10 mm. [Claim 7] 5. The therapeutic composition according to claim 4, wherein the weight ratio of said cancellous bone to said therapeutic composition (cancellous bone: therapeutic composition) is "1:0.5" to "1:3". [Claim 8] 4. The therapeutic composition according to claim 3, wherein the weight ratio of the blood to the therapeutic composition (blood:therapeutic composition) is 1:0.2 to 1:1. [Claim 9] 4. The therapeutic composition according to claim 3, wherein each part by weight of the therapeutic composition is mixed in vitro with 0.5 to 3.0 parts by weight of cancellous bone and 0.2 to 0.8 parts by weight of blood. [Claim 10] 4. The therapeutic composition of claim 3, wherein the blood is subjected to clotting after being mixed with the therapeutic composition. [Claim 11] The therapeutic composition according to claim 1 or 2, wherein the therapeutic composition is introduced into a bone defect. [Claim 12] 3. The therapeutic composition according to claim 1, wherein the therapeutic composition contains 70 to 80% by weight of calcium sulfate. [Claim 13] 3. The therapeutic composition according to claim 1, wherein the therapeutic composition comprises 12 to 18% by weight of an alkaline earth carbonate. [Claim 14] 3. The therapeutic composition according to claim 1, wherein the therapeutic composition comprises 7 to 12% by weight of a binder. [Claim 15] The therapeutic composition according to claim 1 or 2 for the treatment of bone defects caused by trauma, tumor or infection. [Claim 16] 3. The therapeutic composition according to claim 1 or 2, wherein the average diameter of the component particles is 1.0 to 7.0 mm, 0.5 to 10 mm, 1 to 3 mm, 2 to 6 mm, 3 to 5 mm, or 3.5 to 4.5 mm. [Claim 17] 3. The therapeutic composition of claim 1, wherein the component particles have an irregular shape and are obtained by breaking down aggregates. DETAILED DESCRIPTION OF THE INVENTION

[0022] As a general rule, with respect to embodiments described herein, elements that "contain" or "comprise" a particular feature (e.g., material), further embodiments are always contemplated in which the element in question consists only of that feature, i.e., does not contain any further components. The terms "comprise" or "comprising" are used herein synonymously with the terms "contain" or "containing."

[0023] In some embodiments, when an element is referred to in the singular, embodiments in which a plurality of these elements are present are also contemplated. The use of a term for a plurality of elements essentially encompasses embodiments in which only a single corresponding element is included.

[0024] Unless otherwise indicated or clearly excluded by the context, it is in principle possible and hereby expressly contemplated that features of different embodiments may also be present in other embodiments described herein. All features described herein in relation to a product, e.g., a composition, are also considered to be applicable to the uses described herein for such products, and vice versa. For the sake of brevity, all such contemplated combinations are not explicitly listed in all cases. Technical solutions known to be equivalent to the features described herein are also intended to be encompassed in principle by the scope of the present invention.

[0025] One aspect of the present invention relates to a composition for use in a therapeutic procedure, the composition comprising calcium sulfate, an alkaline earth carbonate, a binder, and gentamicin sulfate, preferably comprising greater than 0% and up to 2.5% by weight of gentamicin sulfate, based on the total weight of the composition.

[0026] In one embodiment, the composition comprises 0.5-2.5% by weight of gentamicin sulfate, based on the total weight of the composition. In one embodiment, the composition comprises 1.2-2.0% by weight of gentamicin sulfate. In one embodiment, the composition comprises 1.4-1.8% by weight of gentamicin sulfate. In one embodiment, the composition comprises 1.5-1.7% by weight, or 1.55-1.65% by weight of gentamicin sulfate, based on the total weight of the composition. In some embodiments, the composition comprises an effective amount of gentamicin sulfate, including up to 2.5% by weight of gentamicin sulfate, based on the total weight of the composition.

[0027] Gentamicin is an aminoglycoside complex that can be produced by fermenting Micromonospora purpurea or Micromonospora echinospora. Its antibiotic activity is usually achieved as its sulfate salt, gentamicin sulfate. Gentamicin binds to the 30S ribosomal subunit, blocking the transfer of peptidyl-tRNA from the acceptor to the donor, resulting in codon misreading.

[0028] An "effective amount" of gentamicin sulfate can be an amount sufficient to provide a composition described herein that at least reduces the growth rate of a microorganism within the composition compared to a control. In many embodiments, the amount of gentamicin sulfate is sufficient to produce a zone of inhibition having a diameter of at least about 10 mm, typically at least about 15 mm, as measured using the Antibiotic Activity Test according to U.S. Patent No. 5,968,253.

[0029] In some embodiments, compositions according to the present invention contain an amount of gentamicin sulfate that is high enough to produce an antibacterial effect in a patient, but low enough so as not to cause any cytotoxic effects.

[0030] In one embodiment, the composition comprises particles containing the above-mentioned components, i.e., calcium sulfate, alkaline earth carbonate, binder, and gentamicin sulfate. Such compositions are also referred to herein as "granular," and individual particles are also referred to as "granules." Preferably, the calcium sulfate, alkaline earth carbonate, binder, and gentamicin sulfate are present together in the particles. This means that the particles each contain a mixture of the above-mentioned components. Preferably, the mixture is a homogeneous mixture in which the above-mentioned components, particularly calcium sulfate, alkaline earth carbonate, and gentamicin sulfate, are uniformly distributed.

[0031] The particles can have an irregular shape. This means that the particles do not have a perfect spherical or ellipsoidal geometric shape, but have irregular edges on their surface. Such particles can be produced, for example, by breaking up agglomerates. Such irregular shapes make it easier for the particles to bond with each other and, optionally, with further components, for example, to fill bone cavities.

[0032] Bone defects include cavities within bone and are referred to herein as "bone cavities." Such bone cavities can be formed, for example, by injury (also referred to in the art as "trauma"), by infection-related inflammation, or by another disease of the bone. Surgical interventions such as debridement can also cause bone cavities and other bone defects.

[0033] "Agglomerate" is understood herein to mean in particular a form that can be produced by compressing or pressing a powder. An example of an agglomerate is a tablet produced by pressing a powder.

[0034] In some embodiments, the particles have an average diameter of 1.0 to 7.0 mm. In some embodiments, the average diameter of the particles is 0.5 to 10 mm, 1 to 3 mm, 2 to 6 mm, 3 to 5 mm, or 3.5 to 4.5 mm. This average diameter of the particles is conventional in the art and can be determined by fractional screening, as described in more detail herein by way of example.

[0035] In some embodiments, the particles are structured so that the calcium sulfate, alkaline earth carbonate, and gentamicin sulfate components are present together in particles partially or completely surrounded by the binder within the particles. Thus, the composition according to the present invention can include particles including calcium sulfate, alkaline earth carbonate, and gentamicin sulfate particles, the particles being surrounded by the binder. The covering layer formed from the binder around each particle can be, for example, less than 100 μm thick in each case. Such a structure can promote the delayed release of gentamicin sulfate, as described in more detail elsewhere herein.

[0036] In some embodiments, the particles have a substantially compact structure that contains few cavities, for example, the particles may contain no cavities having a diameter greater than 50 μm.

[0037] In one embodiment, the composition comprises 60-90 wt% calcium sulfate, hi some embodiments, the composition comprises 70-80 wt% calcium sulfate, e.g., 70-75 wt%, 75-80 wt%, or 73-77 wt% calcium sulfate.

[0038] In some embodiments, the composition comprises 10-20 wt. % alkaline earth carbonate, e.g., 12-18 wt. % or 14-16 wt. % alkaline earth carbonate. The alkaline earth carbonate can be, for example, magnesium carbonate or calcium carbonate. The calcium carbonate can be crystalline calcium carbonate. The calcium carbonate can be, for example, calcite, aragonite, or dolomite.

[0039] In some embodiments, the calcium sulfate is calcium sulfate dihydrate (CAS No. 10101-41-4), calcium sulfate hemihydrate (CAS No. 10034-76-1), or anhydrous calcium sulfate (CAS No. 7778-18-9). In some embodiments, the calcium sulfate is calcium sulfate dihydrate. Calcium sulfate can exist as a crystalline or amorphous salt.

[0040] In further embodiments, the composition comprises 5-15 wt. % binder, e.g., 7-12 wt. % binder. The binder may be a hydrophobic binder. As used herein, "hydrophobic" means that the binder is not miscible with water. In some embodiments, the binder has a partition coefficient logP (octanol / water) under standard conditions of at least 1.0, at least 5.0, or at least 10.0. It may be advantageous for the binder to have a melting point of at least 45°C. The binder may be, for example, a triglyceride or an alkanol, with the alkanol preferably containing at least 12 carbon atoms. In some embodiments, the alkanol contains at least 13, 14, 15, or 16 carbon atoms.

[0041] Triglycerides contain three carboxylic acids, often referred to as "fatty acids," esterified together with a glycerol molecule. Examples of triglycerides include glycerol tripalmitate (CAS No. 555-44-2), glycerol tristearate (CAS No. 555-43-1), and glycerol trilaurate (CAS No. 538-24-9). In some embodiments, the binder is a saturated triglyceride, i.e., a triglyceride containing only fatty acids with a saturated hydrocarbon content. Such fatty acids do not contain double or triple bonds in the hydrocarbon content. In some embodiments, the triglyceride contains three identical fatty acid residues. In some embodiments, the triglyceride contains only fatty acid residues with an even number of carbon atoms. In some embodiments, the triglyceride contains only straight-chain, unbranched fatty acid residues. The compositions according to the present invention can be a single triglyceride or a mixture of different triglycerides, such as a mixture of glycerol tripalmitate and glycerol tristearate.

[0042] In some embodiments, the calcium sulfate is selected from the group consisting of calcium sulfate dihydrate (CAS No. 10101-41-4), calcium sulfate hemihydrate (CAS No. 10034-76-1), and anhydrous calcium sulfate (CAS No. 7778-18-9). In one embodiment, the calcium sulfate is calcium sulfate dihydrate.

[0043] The compositions described herein are used in treatment procedures.The compositions described herein can be used as bone substitute materials in such treatment procedures.For this purpose, the compositions described herein can be introduced into bone defect.For example, bone defect can be filled with the compositions described herein.The bone defect can be a bone cavity.

[0044] In some embodiments, the treatment procedure involves filling a bone defect caused by trauma, tumor, or infection with a composition. Bone defects caused by trauma can occur due to the action of mechanical forces on the skeletal system, where the impact of the force can destroy bone tissue and, in the case of very large impact forces, can also be divided into bone fragments. Examples of bone defects include comminuted fractures, which are often surgically removed to leave a bone cavity instead of bone fragments. When the bone cavity exceeds a critical size (known as a critical-size defect), it is no longer possible to close the bone cavity by spontaneous bone remodeling without the support of an appropriate filling material. A "critical-size bone defect" is defined in the art and herein as one that can no longer spontaneously heal during the patient's lifetime according to a medical diagnosis. These bone cavities can be filled with the compositions described herein, and optionally with a mixture thereof with blood and / or allogeneic or autologous cancellous bone. Thus, in some embodiments, a treatment procedure involves filling a bone defect having a critical size, for example a bone defect caused by trauma, with a composition described herein.

[0045] Tumor-induced bone defects can occur due to surgical removal of bone tumors, such as osteosarcomas and chondromas, or bone metastases. The resulting bone cavities can also be filled with the compositions according to the invention, or mixtures thereof.

[0046] The compositions described herein can also be used to fill surgically repaired bone cysts.

[0047] Microbial-induced inflammation of bone tissue, sometimes called osteitis or osteomyelitis, can be hematopoietic or traumatic. Such inflammation is often treated by debridement, which involves surgical removal of necrotic and infected tissue. Such debridement usually results in a bone defect. Such bone defects caused by debridement can also be treated with the compositions and mixtures thereof described herein. This treatment includes, for example, filling the bone defect with the compositions described herein or a mixture of such compositions and viable cells, as described in more detail elsewhere herein.

[0048] According to the above explanation, the term "bone defect caused by trauma, tumor or infection" also includes bone defects such as those caused by surgical treatment of conditions caused by trauma, tumor or infection.

[0049] The patient to be treated can be a vertebrate, for example a mammal, or a human.

[0050] The compositions described herein may have a delayed release of the active ingredient, particularly with respect to the gentamicin sulfate contained therein. This means that the gentamicin sulfate is continuously distributed into the aqueous external medium over an extended period of time, for example, over a period of several days to two weeks. These compositions may function as antimicrobial active ingredient depots, where localized distribution of an antimicrobial active ingredient, such as gentamicin sulfate, over a longer period of time is desirable. The compositions may also serve as vehicles for local administration of antimicrobial active ingredients to bone tissue, particularly in the area of ​​bone cavities.

[0051] In the therapeutic procedures described herein, the compositions described herein can be mixed with viable cells. For this purpose, such compositions can be preferably mixed with cells outside the patient's body, i.e., in vitro. In some embodiments, a homogeneous mixture is thus obtained, i.e., the cells are present in a substantially uniform distribution within the mixture. In some embodiments, the viable cells and the composition according to the present invention form a common phase in the mixture from a macroscopic perspective. The mixture thus obtained can be used as a bone substitute material. For example, the mixture can be introduced into a patient's bone defect, particularly a bone cavity, as described herein.

[0052] The viable cells are preferably cells suitable for supporting the healing of bone defects. Examples of such cells are osteoblasts and osteocytes. For example, the compositions described herein can be mixed with blood or cancellous bone. When blood is used, it is preferable to use blood that can clot, such as whole blood. The viable cells can be derived from the same patient treated with the mixture. These are also referred to as "autologous" cells. In some embodiments, cells from other donors can also be used. These are also referred to as "allogeneic" cells. Thus, the compositions described herein can be mixed with autologous or allogeneic blood and / or autologous or allogeneic cancellous bone.

[0053] Where the patient being treated is a human, the cells may preferably be human cells. In a corresponding manner, the cells provided in connection with the compositions described herein for use in treating an animal patient may be derived from the same species as the animal patient.

[0054] The cancellous bone can be mixed with the compositions described herein in the form of bone fragments. Preferably, bone fragments having a length of 1 to 10 mm, such as 2 to 9 mm, 3 to 8 mm, 4 to 7 mm, 1 to 5 mm, or 2 to 4 mm, can be used. To determine this length, the maximum diameter of the bone fragments is decisive in each case, with substantially all bone fragments having a diameter in the range of, for example, 1 to 10 mm.

[0055] The compositions used herein can be mixed with cancellous bone, for example, in a weight ratio of 1:3 to 1:0.5, i.e., one part of the composition described herein is mixed with 0.5 to 3 parts cancellous bone in each case.

[0056] In some embodiments, the compositions described herein are mixed with blood in a weight ratio of 1:0.2 to 1:1, i.e., one part of a composition described herein is mixed with 0.2 to 1 part blood. The blood can be, for example, whole blood. The blood is preferably coagulable. A mixture containing a composition described herein and coagulable blood can preferably be used after coagulation of the blood for therapeutic applications, particularly for filling bone defects, as described herein.

[0057] In some embodiments, the compositions described herein are mixed with both cancellous bone and blood. In this case, 1 part by weight of the composition according to the present invention can be mixed with 0.5 to 3.0 parts by weight of cancellous bone and 0.2 to 0.8 parts by weight of blood, respectively. The mixture formed thereby can then be allowed to undergo clotting of the blood contained therein. After blood clotting has occurred, the mixture can be administered to a patient.

[0058] Viable cells, for example in the form of blood and / or cancellous bone, can be incorporated into compositions according to the invention manually, using a rotary mixer, or using a pneumatic mixer.

[0059] In some embodiments in which the compositions described herein are mixed with blood, the blood wets the surface of the composition after mixing with the composition, which can result in improved binding to or proliferation of patient-specific cells.

[0060] In some embodiments, cells are mixed with the compositions described herein immediately after being removed from the donor and administered to the patient within a short time.For example, this administration can be performed within 1 hour, or within 10 minutes, 20 minutes, or 30 minutes after removing cells from the donor.In one embodiment, the removal of cells from the donor and the administration to the patient are performed in the same surgical procedure.In this case, the patient's own cells are removed from the patient by the attending physician, for example, in the form of cancellous bone and / or blood, mixed with the composition according to the present invention, and then administered to the patient's bone defect area as soon as possible, optionally after blood clotting.

[0061] The compositions according to the invention, as well as their mixtures with viable cells, can be administered to the patient by hand or by a suitable dispensing device, such as a manually operated piston ejector or syringe-like device, in particular in the area of ​​a bone defect, e.g., a bone cavity.

[0062] When using the therapeutic methods of the compositions described herein, it is advantageous if the gentamicin sulfate content does not result in cytotoxic effects. For example, preferably, no cytotoxic effects occur within the area of ​​administration of the composition, e.g., a bone defect. Such cytotoxic effects include, for example, lysis of blood cells, e.g., white blood cells or red blood cells, upon contact with a bone substitute material. This is particularly relevant when the composition is mixed with viable cells in vitro, as described above. The gentamicin sulfate content of the present invention can allow viable cells to maintain their ability to regenerate bone tissue after introduction into the bone cavity of the patient to be treated, which can result in improved therapeutic success. To this end, a gentamicin sulfate content of 2.5% by weight or less, based on the total weight of the composition of the present invention, can be advantageous. In some embodiments, the compositions described herein are non-cytotoxic according to the ISO 10993-5 standard. In some embodiments, the compositions described herein and mixtures thereof described herein are non-cytotoxic according to the in vitro cytotoxicity test of the ISO 10993-5 standard. In some embodiments, the compositions described herein and mixtures thereof described herein are non-cytotoxic according to acute systemic toxicity testing according to the ISO 10993-5 standard.

[0063] Microbial colonization of bone substitute materials can also affect their ability to regenerate bone tissue. Therefore, an effective concentration of gentamicin sulfate can contribute to the improved therapeutic success of the bone substitute materials according to the present invention due to its antibacterial effect. The antibacterial effect of gentamicin sulfate can protect both the bone substitute material and its application site in the patient from microbial colonization.

[0064] The delayed release described herein may also contribute to improved treatment success by preventing microbial colonization and potentially resulting infections over an extended period of time.

[0065] In some embodiments, the compositions or mixtures thereof described herein are capable of acting as a suitable carrier material onto which bone tissue can grow.

[0066] In some embodiments, the compositions or mixtures thereof described herein have osteogenic activity. The term "osteogenic" as used herein refers to the ability of a material to promote and / or accelerate the growth of new bone tissue by one or more mechanisms, such as osteogenesis, osteoconduction, and / or osteoinduction.

[0067] In addition to the above-mentioned components, the compositions according to the present invention may also contain further therapeutic substances (e.g., active ingredients for inducing bone growth such as bone morphogenetic proteins, growth factors, peptides, antivirals, antibiotics, etc.); or monofilament or multifilament structures, films, coatings, membranes (e.g., porous, microporous, absorbable, etc.), foams (e.g., open-cell or closed-cell), screw augmentation, cranial bone reconstruction, and / or combinations thereof. Therapeutic substances may be contained in the compositions according to the present invention. Therapeutic substances may include, but are not limited to, other antibiotics, chemotherapeutic agents, growth factors (especially osteoinductive growth factors), such as bone morphogenetic proteins, endothelial growth factors, insulin growth factors, etc., or combinations thereof. Non-limiting examples of additional antibacterial active ingredients that can be used include: antiamoebic drugs, such as arsutinol, bialamycol, carbason, cephaeline, chlorobetamide, chloroquine, chlorphenoxamide, chlortetracycline, dehydroemetine, dibromopropamidine, diloxanide, diphetalsone, emetine, fumagillin, glaucarubin, glycobiarsol, 8-hydroxy-7-iodo-5-quinolinesulfonic acid, iodochlorhydroxyquin, iodoquinol, paromomycin, phanquinone, polybenzasol, propamidine, quinifamide, cynidazole, sulfarside, teclozan, tetracycline, thiocarbamycin, thiocarbarsone, tinidazole; antibiotics, such as aminoglycosides, Cosides (amikacin, apramycin, arbekacin, bambermycin, butirosin, dibekacin, dihydrostreptomycin, fortimycin (s), isepamicin, kaniamycin, micronomycin, neomycin, neomycin undecylenate, netilmicin, paromomycin, ribostamycin, sisomicin, spectinomycin, streptomycin, tobramycin, trospectomycin, etc.), amphenicols (azidanphenicol, chloramphenicol, florfenicol, thiamphenicol), ansamycins (rifamide, rifampin, rifamycin, rifapentine, rifaximin), lactams (carbacephems, loracarbef), carbapenems (biapenem, imipenem, meropenem,panipenem), cephalosporins (cefaclor, cefadroxil, cefamandole, cefatrizine, cefazedone, cefazolin, cefcapenpoboxil, cefclidin, cefdinir, cefditoren, cefepime, cefetamet, cefixime, cefinenoxin, cefodim, cefonikid, cefoperazone, ceforanide, cefotaxime, cefotiam, cefzopran, cefpimizole, cef Pyramide, cefpirome, cefpodoxime proxetil, cefprozil, cefroxadine, cefsulodin, ceftazidime, cefteram, ceftezole, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime, cefuzonam, cephacetrile sodium, cephalexin, cephaloglycin, cephaloridine, cephalosporin, cephalothin, cephapirin sodium, cephradine, pibcephalexin ), cephamycins (cefbuperazone, cefmetazole, cefminox, cefotetan, cefoxitin), monobactams (aztreonam, carumonam, tigemonam), oxacephenes (flomoxef, moxalactam), penicillins (amdinocillin, amdinocillin pivoxil, amoxicillin, ampicillin, apalcillin, aspoxicillin, azidocillin, azlocillin, bacampicillin, benzyl Penicillinic acid, benzylpenicillin sodium, carbenicillin, carindacillin, clometocillin, cloxacillin, cyclacillin, dicloxacillin, epicillin, fenbenicillin, floxacillin, hetacillin, lenampicillin, metapicillin, methicillin sodium, mezlocillin, nafcillin sodium, oxacillin, penamecillin, penethamate hydroiodide hydriodide), penicillin G benethamine, penicillin G benzathine, penicillin G benzhydrylamine, penicillin G calcium, penicillin G hydrabamine, penicillin G potassium, penicillin G procaine, penicillin N, penicillin O, penicillin V, penicillin V benzathine, penicillin V hydrabamine, penimepicycline, phenethicillin potassium, piperacillin, pivampicillin, propicillin, quinacillin, sulbenicillin, sultamicillin, talampicillin, temocillin, ticarcillin), ritipenem), lincosamides (clindamycin,lincomycin), macrolides (azithromycin, carbomycin, clarithromycin, dirithromycin, erythromycin, erythromycin acystolate, erythromycin estolate, erythromycin glucoheptonate, erythromycin lactobionate, erythromycin propionate, erythromycin stearate, josamycin, eucomycin, midecamycin, miokamycin, oleandomycin, primycin, rokitamycin, rosaramycin, roxithromycin, spiramycin, trolean domycin), polypeptides (amphomycin, bacitracin, capreomycin, colistin, endracidin, enviomycin, fusafungin, gramicidin S, gramicidin(s), mikamycin, polymyxin, pristinamycin, ristocetin, teicoplanin, thiostrepton, tuberactinomycin, tyrocidine, tyrothricin, vancomycin, viomycin, virginiamycin, zinc bacitracin), tetracyclines (apicycline, chlortetracycline, clomocycline, demeclocycline, doxycycline antibacterial agents, such as 2,4-diaminopyrimidines (brodimoprim, tecloxoprim, trimethoprim), nitrofurans (furaltadone, furazolium chloride, nifuraden, nifuratel, nifurforin, nifurpirinol, nifurprazine, nifurtoinol, nitrofurafine), cyclosporine, cyclosporine, cyclohexyl benzoate ... quinolones and analogues (cinoxacin, ciprofloxacin, clinafloxacin, difloxacin, enoxacin, fleroxacin, flumequine, grepafloxacin, lomefloxacin, miroxacin, nadifloxacin, nadixinic acid, norfloxacin, ofloxacin, oxolinic acid, pazufloxacin, pefloxacin, pipemidic acid, piromidic acid, losoxacin, rufloxacin, sparfloxacin, temafloxacin, tosufloxacin, trovafloxacin), sulfonamides (acetylsulfamethoxypyrazine,Benzylsulfamide, chloramine-B, chloramine-T, dichloramine-T, N2-formylsulfisomidine, N4-β-D-glucosylsulfanilamide, mafenide, 4'-(methylsulfamoyl)sulfanilanilide, noprilsulfamide, phthalylsulfacetamide, phthalylsulfathiazole, salazosulfadiimidine, succinylsulfathiazole, sulfabenzamide, sulfacetamide, sulfachlorpyridazine, sulfachrysoidine, sulfacytine, sulfadiazine, sulfadiclamide, sulfa Dimethoxine, sulfadoxine, sulfaethidole, sulfaguanidine, sulfaguanol, sulfalene, sulfaloxine, sulfamerazine, sulfamethel, sulfamethazine, sulfamethizole, sulfamethomidine, sulfamethoxazole, sulfamethoxypyridazine, sulfametrole, sulfamidocrysoidine, sulfamoxole, sulfanilamide, 4-sulfanilamide salicylic acid, N4-sulfanilylsulfanilamide, sulfanilurea, n-sulfanilyl-3,4-xylamide, sulfanilide Ran, sulfapyrazine, sulfaphenazole, sulfaproxyline, sulfapyrazine, sulfapyridine, sulfasomizole, sulfadimazine, sulfathiazole, sulfathiourea, sulfatulamide, sulfisomidine, sulfisoxazole), sulfones (acedapsone, acediasulfone, acetosulfone sodium, dapsone, diazymosulfone, glucosulfone sodium, solasulfone, succylsulfone, sulfanilic acid, p-sulfanylbenzylamine, sulfoxone sodium, thiazol sulfone), clofoctol , hexedine, methenamine, methenamine anhydromethylene citrate, methenamine hiprate, methenamine mandelate, methenamine sulfosalicylate, nitroxoline, taurolidine, xibomol; antileprosy drugs such as acedapsone, acetosulfone sodium, clofazimine, dapsone, diazymosulfone, glucosulfone sodium, hydnocarpic acid, solasulfone, succisulfone, sulfoxone sodium, antifungal agents such as allylamine, butenafine, naftifine, terbinafine, imidazoles (e.g., bifonazole,Butoconazole, colodantoin, chlorimidazole, cloconazole, clotrimazole, econazole, enilconazole, fenticonazole, flutrimazole, isoconazole, ketoconazole, lanoconazole, miconazole, omoconazole, oxiconazole nitrate, sertaconazole, sulconazole, tioconazole), thiocarbamates (tolusylate, tolulindate, tolnaftate), triazolea (fluconazole, itraconazole, saperconazole, terconazole), Acrisol Syn, amorolfine, biphenamine, bromosalicylchloranilide, buclosamide, calcium propionate, chlorphenesin, ciclopirox, cloxiquin, coparaffinate, diamtazole dihydrochloride, exalamide, flucytosine, haletazole, hexetidine, loflucarban, nifuratel, potassium iodide, propionic acid, pyrithione, salicylanilide, sodium propionate, sulbenzine, tenonitrozole, triacetin, ujothion, undecylenic acid, zinc propionate; etc.,

[0068] Other additional antibacterial agents useful in the present invention include p-lactamase inhibitors (e.g., clavulanic acid, sulbactam, tazobactam); chloramphenicol (e.g., azidamphenicol, chloramphenicol, thiafenicol); fusidic acid; synthetic agents (e.g., trimetofrine, optionally in combination with sulfonamides) and nitroimidazoles (e.g., metronidazole, tinidazole, nimorazole); antifungal agents (e.g., capreomycin, clofazimine, dapsone, ethambutol, etc.). antiviral agents (e.g., acrylovir, amantadine, azidothymidine, ganciclovir, idoxuridine, tribavirin, trifluridine, vidarabine); interferons (e.g., interferon a, interferon p); and antiseptics (e.g., chlorhexidine, gentian violet, octenidine, povidone iodine, quaternary ammonium compounds, silver sulfadiazine, triclosan).

[0069] Additional antimicrobial agents may include agents that treat diseases caused by gram-positive and / or gram-negative bacteria. Preferred antibacterial agents include amikacin, tobramycin, vancomycin, and salts thereof.

[0070] Therapeutic agents may further include biological therapeutic agents such as proteins. Proteins that bind to bone can be added to alter the physical properties of the composition, promote resorption, angiogenesis, cell invasion and proliferation, mineralization, bone formation, osteoclast and / or osteoblast growth, etc. Proteins of particular note are the various types of collagen, particularly type I. Other proteins that can be used include osteonectin, bone sialoprotein (Bsp), α-2HS-glycoprotein, bone Gla protein (Bgp), matrix Gla protein, bone phosphoglycoprotein, bone phosphoprotein, bone proteoglycan, protolipids, morphogenetic bone proteins (e.g., BMP-1, -2A, -2B, -3, -3b, -4, -5, -6, -7, -8, -8b, -9, -10, -11, -12, -13, -14, -15), chondrogenic factors, platelet-derived growth factors (PDGF-1, -2), endothelial cell growth factors (ECGF-1, -2a, -2b), skeletal growth factors (IGF-2), insulin-like growth factors (IGF-3), insulin-like growth factors (IGF-4), insulin-like growth factors (IGF-5), insulin-like growth factors (IGF-6), insulin-like growth factors (IGF-7), insulin-like growth factors (IGF-8), insulin-like growth factors (IGF-9), insulin-like growth factors (IGF-10), insulin-like growth factors (IGF-11), insulin-like growth factors (IGF-12), insulin-like growth factors (IGF-13), insulin-like growth factors (IGF-14), insulin-like growth factors (IGF-15 ... These include inflammatory cytokines (IGF-1, IGF-2), fibroblast growth factors (ODGF-1, -2, -3, -4, -5, -6, -7, -8, -9, -10, -11, -12, -13, -14, -15, -16, -17, -18, -19, -20, -21, -22, -23), colony-stimulating factors, transforming growth factors (e.g., TGF-B), vascular endothelial growth factor (VEGF), growth / differentiation factors (GDF-1, -3, -5, -6, -7, -8, -9, -9B, -10, -11, -15, -16), bone morphogenetic proteins (BMP-7, BMP-8, BMP-8b), brown growth hormone, parathormone (PTH), insulin, and calcitonin. Proteins may also include cartilage-associated proteins such as chondrocalcin protein, dentin-associated proteins such as phosphophorin, glycoprotein, and Gla protein, or enamel-associated proteins such as amelognin and enamelin. Structural proteins of interest include fibrin, fibrinogen, keratin, tubulin, elastin, etc. Blood proteins may be used individually or together in plasma or serum (e.g., serum albumin).

[0071] Therapeutic agents may further include non-protein growth factors such as prostaglandins and statins (eg, simvastatin, lovastatin).

[0072] In one embodiment, the therapeutic agent is a growth factor such as a bone morphogenetic protein, endothelial growth factor, insulin-like growth factor, or the like, or a combination thereof.

[0073] Preferably, additional therapeutic agents are optionally used in the compositions described herein in non-cytotoxic amounts.

[0074] A further aspect is a method for producing a composition comprising the steps of: - grinding calcium sulfate, alkaline earth carbonate, binder, and more than 0 to 2.5 wt. % gentamicin sulfate, for example 0.5 to 2.5 wt. % gentamicin sulfate, based on the total weight of the composition, into a powder; - compressing the powder to form an agglomerate; - breaking down the agglomerates into granules; - fractionating the granules to a desired particle size.

[0075] The starting material can be in principle any solid form that can be subjected to grinding.Preferably, grinding bodies, such as grinding balls, can be used during grinding, and the grinding bodies can be made of ceramic materials such as porcelain or corundum.As a result of grinding, powder of the starting material described above is obtained.This powder preferably constitutes a homogenized mixture of the starting material.

[0076] The powder thus obtained can then be compressed. Compression can be carried out by any method conventional and suitable in the art, for example, using a conventional rotary tablet press or an eccentric press. Compression can be carried out, for example, by pressing the powder with a force of at least 30 kN. Compression results in a compact, such as a tablet, obtained from the powder. Such compacts can have a regular shape, for example, a cylindrical, spherical or oval shape. Such compacts are also referred to herein as "agglomerates." An example of an agglomerate is a tablet that can be produced by compressing the powder.

[0077] Granules can be obtained by breaking down agglomerates. Agglomerates can be broken down, for example, by a crushing sieve or a sieve mill, as is known and conventional in the art. The individual granules (i.e., grains) of such granules often have random shapes and sizes. Granules can be fractionated, for example, using a sieve tower, as is conventional in the art and described in the examples below. In this way, granules having a desired particle size fraction can be obtained. The desired particle size is, for example, 1 to 7 mm, as described in more detail elsewhere herein.

[0078] Preferably, the process is carried out under conditions that avoid melting of the binder. To this end, for example, operation can be carried out under ambient conditions below the melting temperature of the binder, and / or the heat generation can be monitored and controlled accordingly using the process steps described above, in particular milling.

[0079] One embodiment relates to granules that can be produced according to the above-described method. The granules can contain calcium sulfate, an alkaline earth carbonate, a binder, and 0.5 to 2.5% by weight of gentamicin sulfate based on the total weight of the composition.

[0080] A further embodiment relates to an agglomerate comprising calcium sulfate, an alkaline earth carbonate, a binder, and greater than 0% to 2.5% by weight of gentamicin sulfate, based on the total weight of the composition. The agglomerate may preferably contain 0.5 to 2.5% by weight, e.g., 1.2 to 2.0%, 1.4 to 1.8%, or 1.5 to 1.7%, or 1.55 to 1.65% by weight of gentamicin sulfate.

[0081] The agglomerates can be produced by compressing the powders, as described in more detail hereinabove. The agglomerates can have a cylindrical shape, for example, with a height of 5 to 15 mm and a diameter of 15 to 40 mm. The agglomerates can also have a spherical or ovoid shape of comparable size.

[0082] The aggregates may optionally be broken down into irregularly shaped granules to obtain the bone substitute materials described herein.

[0083] In some embodiments, the compositions or aggregates described herein contain, for example, 1.6% by weight of gentamicin sulfate. This means that 1.0% by weight of gentamicin base is present in the composition or compacted mixture, with an activity coefficient of gentamicin sulfate, AK=600. An activity coefficient of 600 means that 600 μg of gentamicin base is present in 1 mg of gentamicin sulfate.

[0084] A further aspect of the present invention relates to a composition comprising calcium sulfate, an alkaline earth carbonate, a binder, and from greater than 0 to a maximum of 2.5 wt. % gentamicin sulfate, based on the total weight of the composition.

[0085] A second embodiment of this aspect relates to a composition comprising particles in which calcium sulfate, a binder, an alkaline earth carbonate and gentamicin sulfate are present together.

[0086] In this case, the particles may have irregular shapes which may be produced by breaking up agglomerates.

[0087] The particles can have an average diameter of 1.0 to 7.0 mm, which can be determined by fractional screening.

[0088] The composition may, for example, contain 70 to 80% by weight of calcium sulfate.

[0089] The composition may contain 10 to 20% by weight, or preferably 12 to 18% by weight, of alkaline earth carbonate.

[0090] The composition may contain 5 to 15% by weight, preferably 7 to 12% by weight, of a binder.

[0091] The binder may have a melting point of at least 45°C.

[0092] The binder may be a triglyceride or an alkanol, the alkanol preferably containing at least 12 carbon atoms.

[0093] The calcium sulfate may be selected from the group consisting of calcium sulfate dihydrate, calcium sulfate hemihydrate, and anhydrous calcium sulfate.

[0094] The alkaline earth carbonate may be selected from the group consisting of calcite, aragonite, magnesium carbonate and dolomite.

[0095] A further aspect of the invention relates to a therapeutic procedure in which the compositions described herein are administered to a patient as described herein. [Example]

[0096] The present invention will now be further illustrated by the following examples, but it should be understood that the present invention is not limited to these examples. It will be apparent to those skilled in the art that other equivalent means can be used in place of the features described herein.

[0097] In the following examples, calcium sulfate dihydrate (CS), calcium carbonate (CC), magnesium carbonate (MC), glycerol tripalmitate (GTP), glycerol tristearate (GTS), and gentamicin sulfate ((GS), activity coefficient AC=600) were used, all from Sigma-Aldrich. Glycerol tripalmitate (GTP) was used as a fine powder with a particle size significantly smaller than 1 mm.

[0098] Examples 1-7: Preparation of bone substitute materials The mixtures of Examples 1 to 7 shown in the table were homogenized in a Turbula mixer using porcelain grinding balls for 10 hours. The homogenized mixtures were then compressed in an eccentric tablet press to form cylindrical bodies with a height h = 10 mm and a diameter of 25 mm. The cylindrical bodies were crushed using a vibrating Frewitt crushing sieve, and the resulting granules were fractionated into 1-3 mm and 3-5 mm fractions using a sieve tower. The weight ratios of calcium sulfate dihydrate: calcium carbonate / magnesium carbonate: glycerol tripalmitate / glycerol tristearate were kept constant, and the gentamicin sulfate content was varied between 0.5% and 2.5% by weight.

[0099] [Table 1]

[0100] The in vitro cytotoxicity of the specimens of Examples 1-6 was tested according to ISO 1099-5. The specimens of Examples 1-3, 6 and 7 were non-cytotoxic. The specimens of Examples 4 and 5 showed a cytotoxic effect.

[0101] In the following examples, the compatibility of the bone substitute material according to the invention with whole blood and allogeneic bone particles (allogeneic cancellous bone) was tested.

[0102] Example 8 5.0 g of the 1 to 3 mm fraction granules of Example 2 was mixed with 1.0 mL (approximately 1.0 g) of fresh whole blood (porcine blood) in a basin. After approximately 10 minutes, a gel-like mass was obtained after the whole blood coagulated.

[0103] Example 9 5.0 g of the 1 to 3 mm fraction granules of Example 2 was mixed with 5.0 mL (approximately 5.0 g) of fresh whole blood (porcine blood) in a basin. After approximately 10 minutes, a gel-like mass was obtained after the whole blood coagulated.

[0104] Example 10 5.0 g of the 1-3 mm fraction granules from Example 2 was mixed with 2.5 g of allogeneic bone chips (chip size 2-4 mm) to produce a homogeneous mixture.

[0105] Example 11 5.0 g of the 1-3 mm fraction granules from Example 2 were mixed with 15.0 g of allogeneic bone chips (chip size 2-4 mm). Homogeneous mixtures were similarly prepared.

[0106] Example 12 5.0 g of the 1-3 mm fraction granules from Example 2 was mixed with 5.0 g of allogeneic bone chips (chip size 2-4 mm) and 5.0 mL (approximately 5.0 g) of fresh whole blood (porcine blood). A homogeneous mixture was prepared in the same manner.

Claims

1. A therapeutic composition for the treatment of bone defects caused by trauma, tumor or infection, comprising: the therapeutic composition comprising calcium sulfate, an alkaline earth carbonate, a binder, viable cells, and from greater than 0 to a maximum of 2.5% by weight of gentamicin sulfate based on the total weight of the therapeutic composition; the component particles in the therapeutic composition have irregular shapes and are disintegrated aggregates; said treating comprising mixing said therapeutic composition with said viable cells in vitro; The viable cells consist solely of cells in the form of blood; Therapeutic composition.

2. 2. The therapeutic composition according to claim 1, wherein the weight ratio of the blood to the therapeutic composition (blood:therapeutic composition) is from 1:0.2 to 1:

1.

3. The therapeutic composition further comprises cancellous bone, 2. The therapeutic composition of claim 1, wherein each part by weight of the therapeutic composition is mixed in vitro with 0.5 to 3.0 parts by weight of cancellous bone and 0.2 to 0.8 parts by weight of blood.

4. The therapeutic composition of claim 1 , wherein the blood is subjected to clotting after being mixed with the therapeutic composition.

5. The therapeutic composition of claim 1 or 2, wherein the therapeutic composition is introduced into a bone defect.

6. 3. The therapeutic composition according to claim 1, wherein the therapeutic composition comprises 70 to 80% by weight of calcium sulfate.

7. 3. The therapeutic composition of claim 1, wherein the therapeutic composition comprises 12 to 18% by weight of alkaline earth carbonate.

8. The therapeutic composition of claim 1 or 2, wherein the therapeutic composition comprises 7 to 12% by weight of a binder.

9. 3. The therapeutic composition of claim 1 or 2, wherein the component particles have an average diameter of 1.0 to 7.0 mm, 0.5 to 10 mm, 1 to 3 mm, 2 to 6 mm, 3 to 5 mm, or 3.5 to 4.5 mm.

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