EP4009937A1 - Préparation et matériau entièrement composé destiné à être utilisé dans des applications médicales ou dentaires, produit médical ou dentaire et son utilisation et sa préparation - Google Patents

Préparation et matériau entièrement composé destiné à être utilisé dans des applications médicales ou dentaires, produit médical ou dentaire et son utilisation et sa préparation

Info

Publication number
EP4009937A1
EP4009937A1 EP20753297.9A EP20753297A EP4009937A1 EP 4009937 A1 EP4009937 A1 EP 4009937A1 EP 20753297 A EP20753297 A EP 20753297A EP 4009937 A1 EP4009937 A1 EP 4009937A1
Authority
EP
European Patent Office
Prior art keywords
calcium
protein
cement
mass
integer
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP20753297.9A
Other languages
German (de)
English (en)
Inventor
Helmut Cölfen
Elena Sturm
Julian KONSEK
Michael Küllmer
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Gebrueder Brasseler GmbH and Co KG
Original Assignee
Gebrueder Brasseler GmbH and Co KG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Gebrueder Brasseler GmbH and Co KG filed Critical Gebrueder Brasseler GmbH and Co KG
Publication of EP4009937A1 publication Critical patent/EP4009937A1/fr
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K6/00—Preparations for dentistry
    • A61K6/80—Preparations for artificial teeth, for filling teeth or for capping teeth
    • A61K6/849—Preparations for artificial teeth, for filling teeth or for capping teeth comprising inorganic cements
    • A61K6/864—Phosphate cements
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K6/00—Preparations for dentistry
    • A61K6/60—Preparations for dentistry comprising organic or organo-metallic additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K6/00—Preparations for dentistry
    • A61K6/70—Preparations for dentistry comprising inorganic additives
    • A61K6/78—Pigments
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K6/00—Preparations for dentistry
    • A61K6/80—Preparations for artificial teeth, for filling teeth or for capping teeth
    • A61K6/849—Preparations for artificial teeth, for filling teeth or for capping teeth comprising inorganic cements
    • A61K6/853—Silicates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/0047—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L24/0052—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material with an inorganic matrix
    • A61L24/0063—Phosphorus containing materials, e.g. apatite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L27/42—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having an inorganic matrix
    • A61L27/425—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having an inorganic matrix of phosphorus containing material, e.g. apatite
    • C—CHEMISTRY; METALLURGY
    • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
    • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
    • C04B12/00—Cements not provided for in groups C04B7/00 - C04B11/00
    • C04B12/02—Phosphate cements
    • C04B12/025—Phosphates of ammonium or of the alkali or alkaline earth metals
    • C—CHEMISTRY; METALLURGY
    • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
    • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
    • C04B14/00—Use of inorganic materials as fillers, e.g. pigments, for mortars, concrete or artificial stone; Treatment of inorganic materials specially adapted to enhance their filling properties in mortars, concrete or artificial stone
    • C04B14/02—Granular materials, e.g. microballoons
    • C04B14/26—Carbonates
    • C04B14/28—Carbonates of calcium
    • C—CHEMISTRY; METALLURGY
    • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
    • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
    • C04B22/00—Use of inorganic materials as active ingredients for mortars, concrete or artificial stone, e.g. accelerators, shrinkage compensating agents
    • C04B22/06—Oxides, Hydroxides
    • C04B22/062—Oxides, Hydroxides of the alkali or alkaline-earth metals
    • C04B22/064—Oxides, Hydroxides of the alkali or alkaline-earth metals of the alkaline-earth metals
    • C—CHEMISTRY; METALLURGY
    • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
    • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
    • C04B22/00—Use of inorganic materials as active ingredients for mortars, concrete or artificial stone, e.g. accelerators, shrinkage compensating agents
    • C04B22/08—Acids or salts thereof
    • C04B22/10—Acids or salts thereof containing carbon in the anion
    • C—CHEMISTRY; METALLURGY
    • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
    • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
    • C04B22/00—Use of inorganic materials as active ingredients for mortars, concrete or artificial stone, e.g. accelerators, shrinkage compensating agents
    • C04B22/08—Acids or salts thereof
    • C04B22/14—Acids or salts thereof containing sulfur in the anion, e.g. sulfides
    • C—CHEMISTRY; METALLURGY
    • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
    • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
    • C04B22/00—Use of inorganic materials as active ingredients for mortars, concrete or artificial stone, e.g. accelerators, shrinkage compensating agents
    • C04B22/08—Acids or salts thereof
    • C04B22/16—Acids or salts thereof containing phosphorus in the anion, e.g. phosphates
    • C—CHEMISTRY; METALLURGY
    • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
    • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
    • C04B24/00—Use of organic materials as active ingredients for mortars, concrete or artificial stone, e.g. plasticisers
    • C04B24/12—Nitrogen containing compounds organic derivatives of hydrazine
    • C04B24/14—Peptides; Proteins; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
    • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
    • C04B28/00—Compositions of mortars, concrete or artificial stone, containing inorganic binders or the reaction product of an inorganic and an organic binder, e.g. polycarboxylate cements
    • C04B28/02—Compositions of mortars, concrete or artificial stone, containing inorganic binders or the reaction product of an inorganic and an organic binder, e.g. polycarboxylate cements containing hydraulic cements other than calcium sulfates
    • C—CHEMISTRY; METALLURGY
    • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
    • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
    • C04B28/00—Compositions of mortars, concrete or artificial stone, containing inorganic binders or the reaction product of an inorganic and an organic binder, e.g. polycarboxylate cements
    • C04B28/34—Compositions of mortars, concrete or artificial stone, containing inorganic binders or the reaction product of an inorganic and an organic binder, e.g. polycarboxylate cements containing cold phosphate binders
    • C—CHEMISTRY; METALLURGY
    • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
    • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
    • C04B28/00—Compositions of mortars, concrete or artificial stone, containing inorganic binders or the reaction product of an inorganic and an organic binder, e.g. polycarboxylate cements
    • C04B28/34—Compositions of mortars, concrete or artificial stone, containing inorganic binders or the reaction product of an inorganic and an organic binder, e.g. polycarboxylate cements containing cold phosphate binders
    • C04B28/344—Compositions of mortars, concrete or artificial stone, containing inorganic binders or the reaction product of an inorganic and an organic binder, e.g. polycarboxylate cements containing cold phosphate binders the phosphate binder being present in the starting composition solely as one or more phosphates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/12—Materials or treatment for tissue regeneration for dental implants or prostheses
    • C—CHEMISTRY; METALLURGY
    • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
    • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
    • C04B2103/00—Function or property of ingredients for mortars, concrete or artificial stone
    • C04B2103/0001—Living organisms, e.g. microorganisms, or enzymes
    • C—CHEMISTRY; METALLURGY
    • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
    • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
    • C04B2103/00—Function or property of ingredients for mortars, concrete or artificial stone
    • C04B2103/0004—Compounds chosen for the nature of their cations
    • C04B2103/001—Alkaline earth metal or Mg-compounds
    • C—CHEMISTRY; METALLURGY
    • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
    • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
    • C04B2111/00—Mortars, concrete or artificial stone or mixtures to prepare them, characterised by specific function, property or use
    • C04B2111/00474—Uses not provided for elsewhere in C04B2111/00
    • C04B2111/00836—Uses not provided for elsewhere in C04B2111/00 for medical or dental applications

Definitions

  • the present invention relates to a preparation and a ready-mixed mixture for use in medical or dental applications.
  • the present invention also relates to a medical or dental product, its use and its manufacture.
  • Dental prosthesis materials or bone replacement materials used today have the disadvantage that they are not biomimetic or bioinert.
  • the conventional materials differ so much in their composition and structure from the body's own materials that their use creates problems with processing and with long-term stability as well as the biocompatibility of the dental prosthesis or bone replacement materials.
  • the tooth replacement materials or bone replacement materials are therefore often subjected to greater stress, which leads to their high wear.
  • the object is achieved by a preparation which contains at least one calcium compound which is precipitated with at least one protein component selected from proteins and protein hydrolysates and at least one crosslinking agent for the protein component and / or uncured cement.
  • a composite (or a composite compound) is obtained which is characterized by high stability and high chemical similarity to the body's own tooth and bone materials is characterized, since the body's own tooth and bone materials mainly contain calcium phosphates, such as hydroxyapatite in the tooth, and protein compounds.
  • the composite obtained by precipitation is thus already characterized by very good biomimetic properties.
  • the biomimetic or bioinspired properties and in particular the mechanical stability and ability to bind to the body's own tooth or bone materials are increased according to the invention in that the preparation contains at least one crosslinking agent for the protein component and / or cement that has not set.
  • the structure of the composite can additionally be crosslinked after activation of the crosslinking agent. Further connections arise between the binding partner “protein component” and the crosslinking agent. This can significantly increase the mechanical, chemical and biological stability, and thus also the resistance to degradation by macrophages, of the material obtained. In this case, compressive strengths of at least 50 MPa could be achieved for a dental product produced from the preparation according to the invention.
  • the literature gives a compressive strength of 62.2 ⁇ 23.8 MPa for enamel and a compressive strength of 193.7 ⁇ 30.6 MPa for dentine.
  • the compressive strength is determined as specified in the following standard: Dentistry - zinc oxide eugenol cements and eugenol-free zinc oxide cements (ISO 3107: 2011); German version: EN ISO 3107: 2011.
  • a hardness of 70 HV0.3 could be obtained for a dental product made from the preparation by crosslinking the protein component with a crosslinking agent, but without setting the cement, with values of 274.8 ⁇ 18.1 in comparison in the literature for Enamel and values of 65.6 ⁇ 3.9 are given for dentine.
  • the hardness measurement was carried out according to Vickers HV0.3: see “Metallic materials - Vickers hardness test - Part 1: Test method (ISO 6507-1: 2018); German version EN ISO 6507-1: 2018 ".
  • cement that has not set has a similar effect on the mechanical stability, but the increased mechanical stability is not achieved by crosslinking the protein component, but by recrystallization of the calcium compound and the cement after the cement has been activated with a suitable solvent, such as water.
  • a suitable solvent such as water.
  • the cement is added to the preparation in a non-set form. This means that the cement is not yet activated, but after activation it is capable of recrystallization and thus restructuring and compression of the material via the properties described above.
  • the preparation according to the invention is particularly suitable for producing a tooth replacement material, a bone replacement material, a root canal sealer, a root filling material, a retrograde filling material, a pulp capping material or a perforation closure material.
  • the cement that has not set is selected from calcium silicate cement, calcium phosphate cement and mixtures thereof.
  • Calcium silicate cements and calcium phosphate cements are characterized by a high degree of structural similarity to the body's own tooth and bone materials. Calcium phosphate cements are also particularly preferred because of their high chemical similarity to the body's own tooth and bone materials.
  • the calcium compounds mentioned above form stable composites with a protein component which can be easily and stably crosslinked with a crosslinking agent and can be recrystallized very well with cement. Because of their chemical similarity to the body's own tooth or bone materials, calcium compounds containing phosphate groups are particularly preferred among the above calcium compounds.
  • the protein component is selected from collagen, keratin, wheat protein, rice protein, soy protein, almond protein and hydrolysates thereof.
  • the above protein components are highly biocompatible and are therefore characterized by a high level of tolerance.
  • the precipitation reaction with a calcium compound leading to a composite can be brought about very easily and stable composites are obtained.
  • gelatin is preferably used because gelatin is readily available and gives particularly stable composites.
  • gelatin can be further crosslinked very easily using a crosslinking agent.
  • the crosslinking agent is preferably selected from 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.
  • Transglutaminase has proven to be particularly advantageous due to its excellent crosslinking properties, especially when gelatine is used as the protein component.
  • Particularly suitable degrees of crosslinking of the protein component can be obtained by the advantageous further development in which the content of crosslinking agent is more than 0 to 25% by mass, in particular more than 0 to 10% by mass and in particular more than 0 to 4% by mass, in each case based on the total mass of the preparation.
  • the preparation is colored and thus color-matched to its destination.
  • the preparation advantageously contains at least one pigment.
  • the pigment is in particular selected from oxides, hydroxides or oxyhydroxides of iron, titanium or zinc and any mixtures thereof, since these inorganic pigments are characterized by very good compatibility and also by being inert to the ingredients of the preparation which are essential to the invention.
  • the preparation can contain radiopaque to improve the radiopacity.
  • the preparation can also advantageously contain at least one water-soluble fluoride, in particular NH4F, KF or NaF, the water-soluble fluoride content in particular more than 0 to 10% by mass and in particular more than 0 to 5 mass%, each based on the total mass of the preparation.
  • at least one water-soluble fluoride in particular NH4F, KF or NaF, the water-soluble fluoride content in particular more than 0 to 10% by mass and in particular more than 0 to 5 mass%, each based on the total mass of the preparation.
  • casein In the light of a further stabilization of the structure of the preparation, it can also advantageously contain casein, the casein content in particular more than 0 to 30% by mass, in particular more than 0 to 15% by mass, and in particular more than 0 to 5% by mass, each based on the total mass of the preparation.
  • a ready-mixed mixture for use in medical or dental applications is also described.
  • Particularly preferred applications here are the production of a tooth replacement material, a bone replacement material, a root canal sealer, a root filling material, a retrograde filling material, a pulp capping material or a perforation closure material.
  • the finished mixture contains at least one calcium compound selected from 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 with at least one protein component selected from proteins and protein hydrolysates, so that a composite is obtained, at least a solvent, including in particular water, and at least one crosslinking agent for the protein component and / or cement that has set and / or not set.
  • the ready-mixed mixture according to the invention is understood to mean a mixture which is prepared directly for processing, that is to say for the correspondingly intended application.
  • the finished mixture must be processed promptly and, in contrast to the preparation according to the invention, cannot be stored for any length of time.
  • the preferred solvent used is water.
  • the water can be deionized or distilled or double-distilled water, which is also referred to as MilliQ water, for example.
  • the ingredients of the ready-to-use mixture are comparable to those of the preparation described above and used as intended, with the exception that the ready-to-use mixture can contain non-set cement and / or set cement as an alternative or in addition to at least one crosslinking agent.
  • the setting of the cement increases the stability and strength.
  • the set cement is created on contact with a suitable solvent, and in particular through the solvent added to the ready-mixed mixture.
  • the ready-mixed mixture according to the invention is simple and uncomplicated to process and can be reshaped into any medical or dental products or fitted into the body's own defects or cavities.
  • the ingredients contained in the finished mixture which are similar in structure and chemical composition to the body's own tooth or bone materials, result in a highly biocompatible and, moreover, biomimetic or bio-inspired product, which can be combined very well and permanently with the body's own tooth or bone materials.
  • Calcium silicate cement, calcium phosphate cement and mixtures of these cements are therefore also preferred in the ready-to-use mixture according to the invention because of the high structural similarities to the body's own tooth or bone materials, calcium phosphate cement being particularly preferred due to the additional chemical similarity to the body's own tooth or bone materials.
  • the protein component is also advantageously selected from collagen, keratin, wheat protein, rice protein, soy protein, almond protein and hydrolysates thereof and is in particular gelatin.
  • the above protein components are highly biocompatible and are thus characterized by a high level of tolerance.
  • the precipitation reaction with a calcium compound leading to a composite can be brought about very easily and stable composites are obtained.
  • Gelatin is particularly preferred because of its good availability and the formation of particularly stable composites.
  • gelatin can be further crosslinked very easily using a crosslinking agent.
  • the crosslinking agent is also advantageously selected from transglutaminase, sortase A, tyrosinase, laccase, peroxidase, lysiloxidase, amine oxidase, glutaraldehyde and (1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide / N-hydroxysuccinimide, genipin, caffeic acid, hexamethylene diisocyanate, proanthidine and formaldehyde, the content of crosslinking agent being in particular more than 0 to 25% by weight, in particular more than 0 to 10% by weight and in particular more than 0 to 4% by weight, based in each case on the total weight of the finished mixture Set a high degree of crosslinking particularly easily and their processability is very good.
  • a medical or dental product (hereinafter referred to as “product”) is also described which is particularly suitable for use as a tooth replacement material, as a bone replacement material, as a root canal sealer, as a root filling material, as a retrograde filling material, as a pulp capping material or as a perforation closure material characterized by very good compatibility due to high biomimetic or bioinspired properties and thus by permanently good mechanical, chemical and biological properties, in particular long-lasting stability and very good connection properties with the body's own tooth or bone materials.
  • the product according to the invention is very well biocompatible.
  • the product according to the invention contains at least one calcium compound which is selected from 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 with at least one protein component selected from proteins and protein hydrolysates, whereby a composite of the calcium compound and the Protein component is obtained.
  • the protein component is crosslinked by at least one crosslinking agent for the protein component and / or the precipitated calcium compound is bound with cement.
  • the degree of setting can be set as desired.
  • the product according to the invention can be obtained by crosslinking and / or setting the ready-mixed mixture according to the invention.
  • the cement is advantageously selected from calcium silicate cement, calcium phosphate cement and mixtures thereof.
  • the protein component is advantageously selected from collagen, keratin, wheat protein, rice protein, soy protein, almond protein and hydrolyzates thereof and is in particular gelatin.
  • the crosslinking agent is preferably selected from transglutaminase, sortase A, tyrosinase, laccase, peroxidase, lysiloxidase, amine oxidase, glutaraldehyde and (1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide / N-hydroxysuccinimide, genipin, caffeic acid, hexamethylene diisocyanate, Proanthocyanidin and formaldehyde, the content of crosslinking agent being in particular more than 0 to 25% by mass, in particular more than 0 to 10% by mass and in particular more than 0 to 4% by mass, in each case based on the total mass of the medical or dental product Above-mentioned crosslinking agents, transglutamina
  • the use of the medical or dental product disclosed above as a filler material for filling up tooth defects and / or bone defects is also described according to the invention.
  • a method for producing a medical or dental product is also described according to the invention.
  • the medical or dental product can be used like the medical or dental product according to the invention disclosed above and, among them, in particular as a tooth replacement material, as a bone replacement material, as a root canal sealer, as a root filling material, as a retrograde filling material, as a pulp capping material or as a perforation closure material.
  • the method comprises a step of forming a composite compound of at least one calcium compound which is selected from 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 which is selected from proteins and protein hydrolyzates.
  • the composite compound, or in short, the composite is thus obtained by precipitating the at least one calcium compound with the at least one protein component.
  • a crosslinking agent for the protein component is used as the crosslinking agent, which consequently produces crosslinking compounds with the protein component, which strengthen the structure of the medical or dental product and thus increase the mechanical, chemical and biological stability.
  • the setting of the composite compound with cement that has not set takes place in particular by adding a solvent, such as in particular water, which initiates recrystallization of the cement and, depending on the composition, also the calcium compound, which also improves the structure of the medical or dental product and increases its mechanical stability becomes.
  • the method can be implemented easily and without high technical effort and enables the production of a biomimetic and thus a medical or dental product similar in terms of chemical composition and structure to an endogenous tooth or bone material with very good biocompatibility, high mechanical and permanently good stability and very good connectivity with the body's own tooth or bone materials.
  • the cement is preferably selected from calcium silicate cement, calcium phosphate cement and mixtures thereof and is in particular calcium phosphate cement.
  • the apatite-gelatin composite is produced by mixing at least one water-soluble calcium salt with at least one water-soluble phosphate in the presence of a protein, a molar ratio of Ca to P of 1.5: 1 to 1.67: 1 being set, the water-soluble phosphate is in particular NaH 2 P0 4 H 2 0 and wherein the water-soluble calcium salt is in particular CaCl.
  • Example 1 Apatite-gelatin composite
  • gelatin More than 0 to 25 g, in particular 3 g, of gelatin were dissolved in 500 ml of H2O at 45 ° C and then cooled to 25 ° C.
  • the gelatin (general: protein component) can generally be dissolved in a temperature range above 0 ° C to about 70 ° C. 45 ° C have proven to be optimal for quickly obtaining a uniformly dissolved gelatin solution.
  • the pH value of the solution was then adjusted to pH 9, the pH value generally being 7 to 11 in order to obtain apatite in the end.
  • the solution was stirred for about 30 minutes, whereby an attachment of the dissolved ions to the gelatin took place. So to speak, a pre-structuring took place.
  • the particles obtained here had a plate-like structure with a thickness of a few nanometers and an extension of less than 100 nm. A white powder was obtained.
  • the platelets were dried and crosslinked at an elevated temperature, these platelets collapsed and bonded, creating the desired dentin-like structure.
  • a solid tooth-like material was obtained. Without crosslinking of the protein component, the material obtained had a hardness of approx. 25-30 HV0.3. When cross-linked with transglutaminase and casein, a hardness of up to 72 HV0.3 could be achieved.
  • the protein content could be varied over a wide range.
  • the hardness measurement was carried out according to Vickers HV0.3: see “Metallic materials - Vickers hardness test - Part 1: Test method (ISO 6507-1: 2018); German version EN ISO 6507-1: 2018 ".
  • the synthesis of the OCP-gelatin composites was carried out according to the same principle as the synthesis of the apatite composite. The difference here was the order in which calcium and phosphate were added and their molar ratio.
  • 3 g of gelatine also variable from more than 0 to about 25 g were dissolved in 500 ml of H2O at 45 ° C. and then cooled to room temperature.
  • a second solution consisting of 17.64 g CaCh ⁇ hhO (0.12 mol) in 250 ml H2O was prepared (as described above, variable in relation to PCL) and at a constant pH 7 (the pH -Value can be varied in the range from pH 5 to 7.5), the calcium chloride solution is titrated to the phosphate solution at 3 ml / min (variable from 0.1 to 20 ml / min). Thereafter, the solution was either centrifuged off directly and washed or stirred for 24 hours to mature (variable between 1 hour and 365 days) and then centrifuged / washed off and freeze-dried if desired.
  • particles with a thickness of a few nm and an extension of several hundred nm were obtained during freeze-drying, which were templates in the form of a white powder.
  • the protein content could be adjusted very well.
  • Example 4 Amorphous calcium phosphate (ACP) gelatin composite:
  • the gelatin content could be adjusted very well. Contents of 0 to 30% by mass were achieved.
  • FIG. 2 gives an overview of the hardnesses achieved by composites crosslinked with different crosslinkers.
  • the salts were used by grinding in various particle sizes between 100 ⁇ m and 1 nm in order to change the reaction rates and properties of the materials.
  • a proportion of previously synthesized calcium phosphate composite was added and this was then crosslinked with a crosslinker during curing to form an organic supporting network.
  • further additives in order to improve the structure, for example by defoaming or the addition of fluoride, or to increase the X-ray visibility by adding, for example, X-ray opaquers and to adapt the product to the tooth color with a dye.
  • Table Overview of the compounds for the production of calcium phosphate-gelatine composites and dental cements made from calcium phosphate cements and composites.
  • Example 5 Production of biomimetic dental cements based on wet apatite
  • biomimetic dental cement based on wet apatite-gelatin composites in the following:
  • a-tricalcium phosphate (2.26 mmol) with an average particle size in the range of 1-10 ⁇ m were rubbed dry together with 0.042 g of CaO (0.75 mmol) and 0.0252 g of NaF (0.6 mmol).
  • a second mixture consisting of 0.233g of wet apatite-gelatin composite (water content 75%; protein content 5%; apatite content 20%) together with 0.017g transglutaminase (for example "ultrafiltration" from Ajinomoto Activa WM) and 0.0085g casein and 0.15 ml H2O for 20 seconds in the universal mixer mixed up.
  • Example 6 Production of biomimetic dental cements based on freeze-dried apatite-gelatine composites:
  • biomimetic dental cement based on freeze-dried apatite-gelatin composites below:
  • a-tricalcium phosphate (2.26 mmol) with an average particle size in the range of 1-10 ⁇ m were rubbed dry together with 0.042 g of CaO (0.75 mmol) and 0.0252 g of NaF (0.6 mmol).
  • a second mixture consisting of 0.04g freeze-dried apatite-gelatin composite (protein content 20%; apatite content 80%) together with 0.017g transglutaminase (eg “ultrafiltration” from Ajinomoto Activa WM) as well as 0.0085g casein and 0.3 ml Mix the H2O together in the universal mixer for 20 seconds. Both phases were then mixed for 30 seconds in the universal mixer, resulting in a biomimetic filling material that was easy to apply and hardened quickly.
  • Example 7 Production of biomimetic dental cements based on wet
  • the procedure here was that all dry calcium salts, as well as phosphate salts and any added fluorine- or carbonate-containing salts, were ground either before they were mixed or afterwards.
  • the mixing of the dry components was followed by the addition of the wet composite materials and, if necessary to achieve the desired viscosity, water and a gelatin crosslinker. The entire mass was then mixed well again and could then be applied as a filling material.
  • biomimetic dental cement based on wet octacalcium phosphate gelatin composites in the following:
  • Example 8 Production of biomimetic dental cements based on freeze-dried octacalcium phosphate-gelatin composites:
  • biomimetic dental cement based on freeze-dried octacalcium phosphate gelatin composites in the following:
  • a-tricalcium phosphate (2.26 mmol) with an average particle size in the range of 1-10 ⁇ m were used together with 0.044 g of CaO (0.97 mmol) and 0.0252 g of NaF (0.6 mmol) rubbed dry.
  • a second mixture consisting of 0.06g freeze-dried OCP-gelatin composite (protein content 20%; octacalcium phosphate content 80%) together with 0.017g transglutaminase (ultrafiltration from Ajinomoto Activa WM) as well as 0.0085g casein and 0.3 ml HO for 20 seconds long mixed in the universal mixer. Both phases were then mixed together for 30 seconds in the universal mixer, which resulted in an easy-to-apply and fast-curing, biomimetic filling material with an initial pH of 12.
  • the ratio set to apatite by the other salts achieved that in addition to the conversion of the salts to apatite, the composite was also converted to apatite, creating a direct connection of the inorganic components was achieved through the entire system.
  • the material properties could also be further improved by adding fluorine- or carbonate-containing salts.
  • the use of crosslinkers of the protein component which took place in parallel during the addition of the aqueous component, was also advantageous for the formation of the most stable dental cement material possible.
  • biomimetic tooth cement based on wet brushite-gelatin composites in the following:
  • a-tricalcium phosphate (2.26 mmol) with an average particle size in the range from 1 to 10 ⁇ m were rubbed dry together with 0.052 g of CaO (0.97 mmol) and 0.0252 g of NaF (0.6 mmol).
  • a second mixture consisting of 0.25g wet brushite gelatin composite (water content 80%; protein content 1%; octacalcium phosphate content 19%) together with 0.017g transglutaminase (ultrafiltration from Ajinomoto Activa WM) and 0.0085g casein and 0, Mix 15 ml HO for 20 seconds in the universal mixer.
  • biomimetic dental cement based on freeze-dried brushite-gelatin composites in the following:
  • a-tricalcium phosphate (2.26 mmol) with an average particle size in the range of 1-10 ⁇ m were rubbed dry together with 0.052 g of CaO (0.97 mmol) and 0.0252 g of NaF (0.6 mmol).
  • a second mixture consisting of 0.05g freeze-dried brushite-gelatin composite (protein content 5%; brushite content 95%) together with 0.017g transglutaminase (ultrafiltration from Ajinomoto Activa WM) as well as 0.0085g casein and 0.3 ml H2O was used for 20 seconds long mixed in the universal mixer. Both phases were then mixed together for 30 seconds in the universal mixer, which resulted in an easy-to-apply and fast-curing, biomimetic filling material with an initial pH of 12.
  • Example 11 Production of biomimetic dental cements based on wet amorphous calcium phosphate-gelatin composites:
  • amorphous calcium phosphates can cover a very wide range of calcium to phosphate ratios from 1.2 to 1 to 2.2 to 1, the composition of calcium, phosphate, protein components and water was precisely determined for each newly synthesized composite in order to build up based on these results, to coordinate the other calcium and phosphate-containing salts used, with which a calcium to phosphate ratio of 1.5-1.667 to 1 was set.
  • a suitable viscosity could be set by means of the water content of the composites and additionally added water.
  • biomimetic dental cement based on wet amorphous calcium phosphate gelatin composites in the following:
  • a-tricalcium phosphate (2.26 mmol) with an average particle size in the range of 1-10 ⁇ m were rubbed dry together with 0.042 g of CaO (0.75 mmol) and 0.0252 g of NaF (0.6 mmol).
  • a second mixture consisting of 0.233g wet amorphous calcium phosphate-gelatin composite (water content 80%; protein content 4%; calcium phosphate content 16%, Ca / PÜ4 ratio 1.67 to 1) together with 0.017g transglutaminase (e.g.
  • Example 12 Production of biomimetic dental cements based on freeze-dried amorphous calcium phosphate-gelatin composites:
  • biomimetic dental cement based on freeze-dried amorphous calcium phosphate-gelatin composites in the following:
  • a-tricalcium phosphate (2.26 mmol) with an average particle size in the range of 1-10 ⁇ m was rubbed dry together with 0.042 g of CaO (0.75 mmol) and 0.0252 g of NaF (0.6 mmol).
  • a second mixture consisting of 0.04 g of freeze-dried amorphous calcium phosphate-gelatin composite (protein content 20%; calcium phosphate content 80%; Ca / PÜ4 ratio 1.67 to 1) together with 0.017 g transglutaminase (eg "ultrafiltration" from Ajinomoto Activa WM) as well as 0.0085g casein and 0.3 ml H2O are mixed in the universal mixer for 20 seconds. Both phases were then mixed for 30 seconds in the universal mixer, which resulted in an easy-to-apply and fast-curing, biomimetic filling material.
  • Example 13 Production of cements based on calcium phosphate-gelatine composites and calcium silicates
  • Example 14 Reaction of wet apatite-gelatine composites with calcium silicates:
  • Apatite-gelatine composites were hardened by using calcium silicates to such an extent that all of the water bound in the composite was consumed by its setting reaction due to the added cement and the cement was thereby hardened.
  • wet apatite-gelatine composites (in different compositions with regard to protein and water content) were used.
  • Portland cement was added in proportions between 1% by mass and 99% by mass, depending on the water contained, so that a mass that was easy to shape and apply was obtained.
  • a crosslinking agent for the gelatine could be added to the cement mass, which further positively influenced the mechanical properties.
  • Example 15 Reaction of freeze-dried apatite-gelatine composites with calcium silicates:
  • Freeze-dried apatite-gelatine composites were mixed with Portland cement in mixing ratios of 1% -99% (W / W) and mixed with water in proportions of 10-70% by weight, so that a paste-like mass was obtained.
  • the hardening of the cement materials obtained here was due to the simultaneous swelling of the apatite-gelatin composites and the recrystallization or setting of the Portland cement.
  • the addition of a gelatine crosslinker was also advantageous for the mechanical properties (hardness) of the dental cement.
  • 0.0833g Ca2SiC> 4 (0.51 mmol) with an average particle size in the range of 1-1 opm were used together with 0.1667g Ca ß SiOs (0.73mmol) with an average particle size of 1-1 opm and 0.01g NaF rubbed dry.
  • Example 15 Reaction of wet octacalcium phosphate-gelatin composites with calcium silicates:
  • the hardening of the octacalcium phosphate-gelatine composites used by Portland cement was based on two parallel mechanisms.
  • the Portland cement withdrew the water from the OCP-gelatine composite during its setting reaction, which caused the entire mass to harden.
  • the recrystallization of the octacalcium phosphate to apatite could be achieved, since calcium hydroxide was formed during the setting reaction of the Portland cement, which in an aqueous environment contains calcium ions in high excess for the recrystallization of the OCP provided.
  • the reactions taking place at the same time made it possible to achieve a high degree of bonding between the two different starting materials.
  • the organic components could also be hardened by crosslinking the gelatin.
  • 0.0833g Ca 2 Si0 4 (0.51 mmol) with an average particle size in the range of 1-10 pm were used together with 0.1667g Ca ß SiOs (0.73mmol) with an average particle size of 1-1 Opm and 0, 01g NaF rubbed dry.
  • 0.125 g of wet octacalcium phosphate gelatine composites (water content 75%; protein content 5%; OCP content 20%) together with 0.017 g transglutaminase (ultrafiltration from Ajinomoto Activa WM) and 0.0085 g casein and 0.12 ml H2O were im Universal mixer mixed together. Both phases were then mixed for 30 seconds in a universal mixer, which resulted in an easy-to-apply and fast-curing, bio-inspired filling material.
  • Example 17 Freeze-dried octacalcium phosphate-gelatin composites:
  • Freeze-dried octacalcium phosphate-gelatine composites with gelatine concentrations in the range of 1-50% by weight were mixed with Portland cement in mixing ratios of 1-99% by weight (W / W) and mixed with water, so that a pasty mass was obtained.
  • the hardening of the cement materials obtained here took place through the simultaneous swelling of the gelatine components and the recrystallization of the OCP gelatine composites to apatite and the parallel setting of the Portland cement.
  • the addition of a gelatin crosslinking agent was also beneficial for the mechanical properties of the dental cement, as it gave a stable, supporting organic network.
  • a special example of this is the formation of bio-inspired dental cement based on freeze-dried OCP-gelatine composites in combination with calcium silicate below: 0.0833g Ca2SiC> 4 (0.51 mmol) with an average particle size in the range of 1-10 ⁇ m were used together with 0.1667g Ca ß SiOs (0.73mmol) with an average particle size of 1-1 Opm and 0.01g NaF rubbed dry.
  • the hardening of the brushite-gelatine composites used by Portland cement was based on two parallel mechanisms.
  • the Portland cement withdrew the water from the brushite-gelatin composite during its setting reaction, as a result of which the composite part hardened by drying parallel to the hardening of the cement.
  • the composite part hardened by drying parallel to the hardening of the cement.
  • parallel hardening step it was possible to achieve the recrystallization of the brushite to apatite, since calcium hydroxide was formed during the setting reaction of the Portland cement, which in an aqueous environment provided calcium ions in high excess for the recrystallization of the brushite.
  • the simultaneous reactions made it possible to achieve a high degree of bonding between the two different starting materials.
  • the organic components could also be hardened by crosslinking the gelatin.
  • Freeze-dried brushite-gelatine composites were mixed with Portland cement in mixing ratios of 1% by weight to 99% by weight (W / W) and mixed with water so that a pasty mass was obtained.
  • the hardening of the cement materials obtained here took place through the simultaneous swelling and recrystallization of the brushite-gelatin composites and the parallel recrystallization or setting of the Portland cement. During this process, the addition of a gelatin crosslinker was also beneficial for the properties of the dental cement.
  • 0.0833g Ca 2 Si0 4 (0.51 mmol) with an average particle size in the range of 1-10 pm were used together with 0.1667g Ca ß SiOs (0.73mmol) with an average particle size of 1-1 Opm and 0, 01g NaF rubbed dry.
  • 0.04 g of freeze-dried brushite-gelatin composite (protein content 5%; brushite content 95%) together with 0.017 g transglutaminase (ultrafiltration from Ajinomoto Activa WM) and 0.0085 g casein and 0.3 ml H2O were mixed in the universal mixer for 20 seconds. Both phases were then mixed for 30 seconds in a universal mixer, which resulted in an easy-to-apply and fast-curing, bio-inspired filling material.
  • FIG. 1 shows a process scheme schematically illustrating process steps for the production of a medical or dental product according to an embodiment
  • Fig. 2 shows an overview of hardnesses achieved with different crosslinkers
  • FIG. 1 shows a process scheme, schematizing process steps of a process for producing a medical or dental product according to one embodiment.
  • dental prosthesis materials bone replacement materials, root canal sealers, root filling materials, retrograde are particularly suitable Filling materials, pulp capping materials or perforation closure materials are possible.
  • the method comprises a first step 100 of forming a composite compound from at least one calcium compound selected from: 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.
  • the calcium compound is precipitated in the presence of the protein component.
  • Method step 200 can then follow, in which the composite compound is crosslinked with at least one crosslinking agent.
  • the crosslinking agent is preferably selected from: transglutaminase, sortase A, tyrosinase, laccase, peroxidase, lysiloxidase, amine oxidase, glutaraldehyde and (1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide / N-hydroxysuccinimide, genipin, caffeic acid, hexamethylene diisocyanate, proanthocyanate and formaldehyde, it being possible to add casein additively during crosslinking.
  • the material then cures to become a medical product.
  • the composite connection can be set using cement that has not set in order to further improve the hardness of the product to be manufactured.
  • the cement is preferably selected from calcium silicate cement, calcium phosphate cement and mixtures thereof.
  • FIG. 2 shows an overview of hardnesses achieved with different crosslinkers, which were determined according to Vickers HVo, 3 with a Zeiss Miniload and Hardsoft measuring system.
  • the hardness measurement was carried out according to Vickers HV0.3, see “Metallic materials - Vickers hardness test - Part 1: Test method (ISO 6507-1: 2018); German version EN ISO 6507-1: 2018 ".
  • the figure shows what effect an aqueous solution of a crosslinker has on the hardness of the composite material.
  • the procedure was that two grams of a wet apatite composite (water content 75%; protein content 5%; apatite content 20%) were crosslinked with 10ml of a crosslinker solution indicated in the diagram for 24 hours. The samples were then centrifuged and dried in the oven at 50 ° C., cut and polished, and their hardness then determined at room temperature. The results clearly show that a mixture of transglutaminase (e.g. from Ajinomoto Activa WM after Ultrafiltration through 10000M sieve) as well as casein provides the best crosslinking properties and thus high hardness.
  • transglutaminase e.g. from Ajinomoto Activa WM after Ultrafiltration through 10000M sieve
  • FIG. 3 is a schematic representation of an experimental set-up for the production of calcium phosphate-protein component composites. At least one protein component dissolved in water and a calcium compound are placed in a kettle 1, which can be temperature-controlled by a heating device 2. Alternatively, a protein component and a phosphate compound can also be presented. If a calcium compound has been submitted, at least one phosphate-containing compound is then added. If a phosphate-containing compound has been submitted, at least one calcium compound is then added. In addition, the pH value of the solution can be brought into a desired range and maintained by adding an acid or an alkali. In the kettle 1 there is a stirrer 4 which stirs at the desired speed.
  • a stirrer 4 which stirs at the desired speed.

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Abstract

L'invention concerne une préparation qui contient : au moins un composé de calcium, choisis parmi les phosphates de calcium, les fluorures de calcium et les fluorophosphates de calcium et des dérivés hydroxyle et carbonates desdits sels de calcium, hydroxydes de calcium et oxydes de calcium, ledit composé de calcium étant précipité avec au moins un composant protéique, choisi parmi les protéines et les hydrolysats de protéines ; et au moins un agent réticulant pour le composant protéique et/ou le ciment non durci.
EP20753297.9A 2019-08-06 2020-07-27 Préparation et matériau entièrement composé destiné à être utilisé dans des applications médicales ou dentaires, produit médical ou dentaire et son utilisation et sa préparation Pending EP4009937A1 (fr)

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PCT/EP2020/071127 WO2021023547A1 (fr) 2019-08-06 2020-07-27 Préparation et matériau entièrement composé destiné à être utilisé dans des applications médicales ou dentaires, produit médical ou dentaire et son utilisation et sa préparation

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