PREPARATION AND FULLY COMPOUNDED STOCK FOR USE IN MEDICAL OR DENTAL APPLICATIONS, MEDICAL OR DENTAL PRODUCT AND USE AND PREPARATION THEREOF

Abstract

According to the invention, a preparation is described which contains at least one calcium compound selected from the group consisting of calcium phosphates, calcium fluorides and calcium fluorophosphates and hydroxyl derivatives and carbonate derivatives of these calcium salts, calcium hydroxides and calcium oxides precipitated using at least one protein component selected from proteins and protein hydrolysates, and at least one crosslinking agent for the protein component and/or non-set cement.

Claims

1. A preparation comprising: at least one calcium compound selected from the group consisting of: calcium phosphates, calcium fluorides and calcium fluorophosphates and hydroxyl derivatives and carbonate derivatives of these calcium salts, calcium hydroxides and calcium oxides, which is precipitated using at least one protein component selected from proteins and protein hydrolysates, and at least one cross-linking agent for the protein component and/or non-set cement.

2. The preparation according to claim 1, wherein the unset cement is selected from the group consisting of calcium silicate cement, calcium phosphate cement, and mixtures thereof, and/or wherein the calcium compound is selected from the group consisting of: Ca(H.sub.2PO.sub.4).sub.2.xH.sub.2O, wherein x is an integer of from 0 to 6, CaHPO.sub.4.xH.sub.2O, wherein x is an integer of from 0 to 6, Ca.sub.8(HPO.sub.4).sub.2(PO.sub.4).sub.4.5H.sub.2O, Ca.sub.3(PO.sub.4).sub.2, Ca.sub.10(PO.sub.4).sub.6(OH).sub.2, Ca.sub.10(PO.sub.4).sub.6F.sub.2, (Ca.sub.10-aM.sub.a) [(PO.sub.4).sub.6-bY.sub.b] [(OH).sub.2-cX.sub.c] wherein M═Na.sup.+, Sr.sub.2+, Mg.sub.2+, Ba.sub.2+, Pb.sub.2+; Y═HPO.sub.4.sup.2−, CO.sub.3.sup.2−; X═F.sup.−, Cl.sup.−, H.sub.2O; wherein a is an integer of from 0 to 10, b is an integer of from 0 to 6, and c is an integer of from 0 to 2, Ca(OH).sub.2 and CaO and/or wherein the protein component is selected from the group consisting of: collagen, keratin, wheat protein, rice protein, soy protein, almond protein and hydrolysates thereof and especially is gelatine and/or wherein the crosslinking agent is selected from the group consisting of: transglutaminase, sortase A, tyrosinase, laccase, peroxidase, lysiloxidase, amine oxidase, glutaraldehyde, (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide/N-hydroxysuccinimide, Genipin, caffeic acid, hexamethylene diisocyanate, proanthocyanidin and formaldehyde.

3. The preparation according to claim 1, wherein the content of crosslinking agent is more than 0 to 25% by mass, in particular more than 0 to 10% by mass and especially more than 0 to 4% by mass, in each case based on the total mass of the preparation.

4. The preparation according to claim 1 further comprising at least one pigment selected from the group consisting of oxides, hydroxides or oxyhydroxides of iron, titanium or zinc and any mixtures thereof and/or further comprising at least one water-soluble fluoride, especially NH.sub.4F, KF or NaF, the content of water-soluble fluoride being in particular more than 0 to 10% by mass, in particular more than 0 to 5% by mass, in each case based on the total mass of the preparation.

5. The preparation according to claim 1 further comprising casein, wherein the casein content is especially more than 0 to 30% by mass, especially more than 0 to 15% by mass, and especially more than 0 to 5% by mass, in each case based on the total mass of the preparation.

6. A ready-mix for use in medical or dental applications, especially for the production of a dental substitute material, a bone substitute material, a root canal sealer, a root filling material, a retrograde filling material, a pulp capping material or a perforation sealing material, comprising: at least one calcium compound selected from the group consisting of: calcium phosphates, calcium fluorides and calcium fluorophosphates and hydroxyl derivatives and carbonate derivatives of these calcium salts, calcium hydroxides and calcium oxides, precipitated using at least one protein component selected from proteins and protein hydrolysates, at least one solvent, especially water, and at least one cross-linking agent for the protein component and/or set and/or non-set cement.

7. The ready-mix of claim 6, wherein the cement is selected from calcium silicate cement, calcium phosphate cement, and mixtures thereof, and/or wherein the calcium compound is selected from the group consisting of: Ca(H.sub.2PO.sub.4).sub.2.xH.sub.2O, wherein x is an integer of from 0 to 6, CaHPO.sub.4.xH.sub.2O, wherein x is an integer of from 0 to 6, Ca.sub.8(HPO.sub.4).sub.2(PO.sub.4).sub.4.5H.sub.2O, Ca.sub.3(PO.sub.4).sub.2, Ca.sub.10(PO.sub.4).sub.6(OH).sub.2, Ca.sub.10(PO.sub.4).sub.6F.sub.2, (Ca.sub.10-aM.sub.a) [(PO.sub.4).sub.6-bY.sub.b] [(OH).sub.2-cX.sub.c] mit M═Na.sup.+, Sr.sup.2+, Mg.sup.2+, Ba.sup.2+, Pb.sup.2+; Y═HPO.sub.4.sup.2−, CO.sub.3.sup.2−; X═F.sup.−, Cl.sup.−, H.sub.2O; wherein a is an integer of from 0 to 10, b is an integer of from 0 to 6 and c is an integer of from 0 to 2, Ca(OH).sub.2und CaO and/or wherein the protein component is selected from the group consisting of: collagen, keratin, wheat protein, rice protein, soy protein, almond protein and hydrolysates thereof, and especially gelatine; and/or wherein the crosslinking agent is selected from the group consisting of: transglutaminase, sortase A, tyrosinase, laccase, peroxidase, lysiloxidase, aminoxidase, glutaraldehyde and (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide/N-hydroxysuccinimide, Genipin, caffeic acid, hexamethylene diisocyanate, proanthocyanidin and formaldehyde, wherein the content of crosslinking agent is especially more than 0 to 25 mass %, especially more than 0 to 10 mass % and especially more than 0 to 4 mass %, in each case based on the total mass of the ready-mix.

8. A medical or dental product, especially for use as a tooth substitute material, a bone substitute material, a root canal sealer, a root filling material, a retrograde filling material, a pulp capping material or a perforation sealing material, comprising: at least one calcium compound selected from the group consisting of: calcium phosphates, calcium fluorides and calcium fluorophosphates and hydroxyl derivatives and carbonate derivatives of these calcium salts, calcium hydroxides and calcium oxides, which is precipitated using at least one protein component selected from proteins and protein hydrolysates, wherein the protein component is crosslinked using at least one crosslinking agent for the protein component and/or wherein the precipitated calcium compound is set with cement.

9. The medical or dental product of claim 8, wherein the cement is selected from the group consisting of calcium silicate cement, calcium phosphate cement, and mixtures thereof, and/or wherein the calcium compound is selected from the group consisting: Ca(H.sub.2PO.sub.4).sub.2.xH.sub.2O, wherein x is an integer of from 0 to 6, CaHPO.sub.4.xH.sub.2O, wherein x is an integer of from 0 to 6, Ca.sub.8(HPO.sub.4).sub.2(PO.sub.4).sub.4.5H.sub.2O, Ca.sub.3(PO.sub.4).sub.2, Ca.sub.10(PO.sub.4).sub.6(OH).sub.2, Ca.sub.10(PO.sub.4).sub.6F.sub.2, (Ca.sub.10-aM.sub.a) [(PO.sub.4).sub.6-bY.sub.b] [(OH).sub.2-cX.sub.c] wherein M═Na.sup.30 , Sr.sup.2+, Mg.sup.2+, Ba.sup.2+, Pb.sup.2+; Y═HPO.sub.4.sup.2−, CO.sub.3.sup.2−; X═F.sup.−, Cl.sup.−, H.sub.2O; wherein a is an integer of from 0 to 10, b is an integer of from 0 to 6 and c is an integer of from 0 to 2, Ca(OH).sub.2 and CaO and/or wherein the protein component is selected from the group consisting of: collagen, keratin, wheat protein, rice protein, soy protein, almond protein and hydrolysates thereof, and especially gelatine; and/or wherein the crosslinking agent is selected from the group consisting of: transglutaminase, sortase A, tyrosinase, laccase, peroxidase, lysiloxidase, aminoxidase, glutaraldehyde and (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide/N-hydroxysuccinimide, Genipin, caffeic acid, hexamethylene diisocyanate, proanthocyanidin and formaldehyde, wherein the content of crosslinking agent is especially more than 0 to 25 mass %, in particular more than 0 to 10 mass % and in particular more than 0 to 4 mass %, each based on the total mass of the medical or dental product.

10. Use of the medical or dental product according to claim 8 as a filling material for filling dental defects and/or bone defects.

11. A process for preparing a medical or dental product, especially a tooth substitute material, a bone substitute material, a root canal sealer, a root filling material, a retrograde filling material, a pulp capping material or a perforation closure material, comprising the steps of: (100): forming a composite of at least one calcium compound selected from the group consisting of: calcium phosphates, calcium fluorides and calcium fluorophosphates and hydroxyl derivatives and carbonate derivatives of these calcium salts, calcium hydroxides and calcium oxides, and at least one protein component selected from proteins and protein hydrolysates; and (200): crosslinking the composite compound using at least one crosslinking agent for the protein component and/or (300): setting the composite compound using unset cement, wherein the cement is especially selected from calcium silicate cement, calcium phosphate cement and mixtures thereof.

Description

[0124] Further details, advantages and features of the present invention will be apparent from the following description of embodiments based on the drawing, wherein:

[0125] FIG. 1 is a process schematic schematizing the process steps for the production of a medical or dental product according to one embodiment,

[0126] FIG. 2 is an overview of curing achieved with different crosslinkers, and

[0127] FIG. 3 is a schematic representation of a test set-up for the production of calcium phosphate-protein component composites.

[0128] FIG. 1 shows a schematic diagram of the steps in a process for producing a medical or dental product according to one embodiment. Medical or dental products especially are dental substitute materials, bone substitute materials, root canal sealers, root filling materials, retrograde filling materials, pulp capping materials or perforation sealing materials.

[0129] The process comprises a first step 100 of forming a composite compound of at least one calcium compound selected from the group consisting of: Calcium phosphates, calcium fluorides and calcium fluorophosphates and hydroxyl derivatives and carbonate derivatives of these calcium salts, calcium hydroxides and calcium oxides and at least one protein component selected from proteins and protein hydrolysates. Herein, the calcium compound is precipitated in the presence of the protein component.

[0130] This may be followed by process step 200, wherein crosslinking of the composite compound using at least one crosslinking agent is carried out. The crosslinking agent is preferably selected from the group consisting of: transglutaminase, sortase A, tyrosinase, laccase, peroxidase, lysiloxidase, aminoxidase, glutaraldehyde and (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide/N-hydroxysuccinimide, genipin, caffeic acid, hexamethylene diisocyanate, proanthocyanidin and formaldehyde, wherein casein may be added additively during crosslinking.

[0131] The material is then cured to obtain the medical product by added or contained water.

[0132] Alternatively or in addition to the process step 200, setting the composite compound with uncured cement to further improve the hardness of the product to be produced, may occur as a process step 300. Preferably, the cement is selected from the goup consisting of calcium silicate cement, calcium phosphate cement and mixtures thereof.

[0133] FIG. 2 shows an overview of hardnesses achieved with different crosslinkers, which were determined according to Vickers HV0.3 with a Zeiss Miniload and Hardsoft measuring system. The hardness measurement was thus performed according to Vickers HV0.3 in each case, see “Metallic materials—Hardness testing according to Vickers—Part 1: Test method (ISO 6507-1:2018); German version EN ISO 6507-1:2018”.

[0134] The figure shows the effect of an aqueous solution of a crosslinker on the hardness of the composite material. Herein, the procedure was that two grams of a wet apatite composite (water content 75%; protein content 5%; apatite content 20%) were crosslinked with 10 ml of a crosslinker solution indicated in the diagram for 24 h. The samples were then centrifuged and dried in an oven at 50° C., cut and polished, and their hardness subsequently was determined at room temperature. The results clearly show that a mixture of transglutaminase (e.g. from Ajinomoto Activa WM after ultrafiltration through a 10000M sieve) and casein provides the best crosslinking properties and thus high hardness. In this context, the mixture of 3% transglutaminase and 1.5% casein should be particularly highlighted, since this, in combination with the apatite composite, results in a hardness of the material which is above the hardness of dentin.

[0135] FIG. 3 is a schematic representation of an experimental set-up for the preparation of calcium phosphate-protein component composites. At least one protein component dissolved in water and a calcium compound are placed in a water bath 3 which is temperature-controlled by a heating device 2. Alternatively, a protein component and a phosphate compound may also be introduced. With the provision that a calcium compound has been introduced, at least one phosphate-containing compound is subsequently added. Provided that a phosphate-containing compound has been submitted, at least one calcium compound is subsequently added. In addition, the pH of the solution can be brought into a desired range and maintained by adding an acid or an alkali. A stirrer 4 is provided in the vessel 1 for stirring at the desired speed.

[0136] In addition to the foregoing written description of the invention, explicit reference is hereby made to the graphic representation of the invention in FIGS. 1 to 3 for supplementary disclosure thereof.

LIST OF REFERENCE NUMBERS

[0137] 1 Vessel [0138] 2 Heating device [0139] 3 Water bath [0140] 4 Stirrer [0141] 100-300 Process steps