Classifications

• • 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
  • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
  • A61L27/58—Materials at least partially resorbable by the body
• • 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
  • A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
  • A61L27/46—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with phosphorus-containing inorganic fillers

Definitions

• This invention relates to a composition suitable for use as an impant material in human beings and animals to replace absent bone tissue, and comprising a biocompatible particulate ceramic material as a bone-replacing component and a biodegradable polymeric material.
• a similar material is disclosed in NL-A-7704659.
• the inorganic component or both the inorganic and the organic components are resorbable.
• Other known materials consist virtually entirely of a calcium phosphate compound, for example, hydroxylapatite in the form of hard shapes which prior to use have to be subjected to all sorts of complicated operations, or of a mixture of a calcium phosphate compound with polymers which for example have to harden in the site of implantation, or of loose granulate of, for example, hydroxylapatite .
• a composition suitable for use as an implant material in human beings and animals to replace absent bone tissue comprising a biocompatible, particulate ceramic material as a bone-replacing component and a biodegradable polymeric material, characterized in that the ceramic material is a non-resorbable material, and the biodegradable polymeric material functions as a binder for said ceramic material, the composition being an intimate mixture of, by weight,
• the invention is based on the insight that, after the implantation of the composition according to the invention in the human or animal body the biodegradability of the polymeric material functioning as a binder will ensure that it is broken down in the course of time, and will disappear, leaving a microporous structure of the (bio)ceramic material into which new blood vessels and connective tissue can grow.
• biodegradable polymeric materials suitable for use in the composition according to the invention are the reticulating polymers gelatin A or B, carboxymethyl " cellulose and dextran, which are all polymers of natural origin, but polyethylene glycol, for example, is also suitable Generally speaking, any biodegradable organic compound capable of forming a network or reticulation, and hence capable of functioning as a binder for the biocompatible ceramic material, and which further satisfies the general requirements as imposed in the pharmacopeias, for example, The Netherlands, European and North-American pharmacopeias is suitable for use as an adjuvant in the material according to the present invention.
• gelatin A or B is a polymer made from skin or bones, and satisfies the requirements imposed in the various pharmacopeias. It is a mixture of protein molecules, is biocompatible and biodegradable, and is already being widely applied in injection compositions.
• Carboxymethyl cellulose is a polysaccharide of vegetable origin with a molecular weight of l ⁇ -l ⁇ 6. in the form of the sodium salt this polymer is water-soluble. It satisfies the above requirements and is also frequently being used in injection compositions.
• the polyethylene glycol is a white to off-white viscous composition with a molecular weight of 200-6000 and is also already, being used in pharmaceutical compositions.
• biocompatible, non-resorbable ceramic material for use in the implant material according to this invention will naturally also have to satisfy the general requirements as defined in the pharmacopeias, in particular the above Netherlands, European and North-American pharmacopeias.
• Ceramic materials of the above type which already have found application in practice as an implant material and are also suitable for use as a bone-replacing component in the implant material according to this invention are hydroxylapatite » referred to hereinbefore and, in general a calcium phosphate compound.
• the hydroxylapatite is a white to off-white calcium phosphate compound having the chemical formula Ca o(P ⁇ )6(OH) _
• the compound is a solid and consists of approximately spherica particles with a porosity of between 1 and 50%. Its particle size is about 0.07-0.2 mm.
• the compound is normally purified by treatment with hydrogen peroxide, followed by intensive washing with distilled water. The compound is fully biocompati and not resorbable after implantation in human and animal bone tissues.
• The.more general calcium phosphate compound refers to a compound which is available in the form of a white powder and can be represented by the generic chemical formula Ca x (H y PO z ) .nH2 ⁇ , in which x represents 1, 2 or 3, y is 0, 1 or 2 ; z is 3 or 4; m is 1 or 2; and n represents 0, 1 or 2.
• the compound is a non-toxic, biocompatible material which is often being used as an adjuvant in the pharmaceutical industry and has recently been found to be suitable for use as an implant material.
• Aluminum oxide with the chemical formula Al2 ⁇ 3.nH2 ⁇ also has known applications as an implant material, and is therefore suitable for use in the implant material accordi to the present invention.
• any inorganic or ceramic compound that is biocompatible and non-resorbable and can be processed for preparing the implant material of the invention is suitable for this purpos
• Further examples are Si ⁇ 2-nH2 ⁇ , GeO and GaS.
• the particle size of the ceramic material should not be too large.
• the particle size should not be larger than about 1.5 mm.
• this material has a highly viscous consistency so that it is mouldable by kneading or modelling, but it can also be provided as a shaped material in the form of plates, rods or bars.
• the material according to the invention can be used as such in the case of a bone defect where bone tissue is locally absent and this void is in a form corresponding to the shape of the material.
• the plates, rods or bars are by themselves deformable or breakable.
• the composition according to the invention comprises, by weight, 4-307, of biodegradable polymer and 15-307, water and balance bone-replacing ceramic component.
• the use of less water in the composition increases the risk of the composition being less easy to handle and process, because the binder function of the biodegradable polymeric material is suboptimal.
• composition according to the invention may incorporate more biodegradable polymeric materia
• the implant material has such a viscosity that it can be introduced by means of an injection syringe.
• the invention also relates to a method of producing the composition for use as an implant material, said method being characterized in that a gelled mixture, prepared from the biodegradable polymeric material and water is intimately mixed with the ceramic component, using a high-power, low-spe kneader at a temperature of no more than 60°C, and subjecting the mixture thus produced to an- elevated pressure of at least 10 Mpa at room temperature for at least about 5 minutes.
• a gelled mixture prepared from the biodegradable polymeric material and water is intimately mixed with the ceramic component, using a high-power, low-spe kneader at a temperature of no more than 60°C, and subjecting the mixture thus produced to an- elevated pressure of at least 10 Mpa at room temperature for at least about 5 minutes.
• This biodegradable polymeric material e.g. gelatin, carboxymethyl cellulose, or dextran
• a 807 ethanol solution in water has first been treated with a 807. ethanol solution in water and dried at 110-120°C.
• the treatment with a 807, ethanol solution in water is given because when a less concentrated solution is used, e.g. a 707, ethanol solution in water, the polymeric material may swell unduly
• a gel material is formed, which may take about 2 hours. This process step is completed by homogenizing the gel (material B) .
• material A is slowly added to material B in discrete portions with careful stirring, mixing or kneading.
• a temperature of up to 60°C is permissible, operation at elevated temperature being generally beneficial inasmuch as it facilitates kneading by decreasing the viscosit Taking this circumstance into account, therefore, the mixing operation is preferably carried out at elevated temperature.
• the product produced by the mixing operation described already exhibits a certain coherence, but is in many cases nevertheless too brittle.
• the ultimate composition, produced by mixing with the bone- replacing component is subjected, in a mould, to an elevated pressure of at least about 10 MPa for at least about 5 minutes to produce an end product of sufficient coherence.
• this pressure stage the amount of the pressure and the time for which the pressure is applied are important parameters. It has been found that this stage can be carried out at room temperature, and further that when a given pressur is used it is possible to determine a duration for this treatment after which no appreciable changes in the nature of the material under pressure take place any longer. It can be assumed that the interaction between the particles of ceramic material and the biodegradable polymer, which partly causes the formation of an adsorption bond between the polymer and the ceramic particles, no longer has any effect, or that the bonding process is completed. The product thus obtained is then ready to be packaged and subsequently sterilized, whereafter it can be used.
• the amount of the pressure to be used depends partly upon the nature of the biodegradable adjuvant used. Thus when gelatin is used a preferred pressure range is from 10 to 30 MPa, and in the case of carboxymethyl cellulose a pressure of 75-150 MPa.
• the amount of the pressure to be applied is also selecte with a view to the desired consistency of the implant material
• a pressure of about 455 MPa is used, a product is obtaine which is excellently suitable for being shaped into the implant material in the form of plates, rods or bars.
• a pressure of less than about 150 MPa ensures the production of a product having a good plasticity.
• a pressure is used with a value in the intermediate range of about 150-455 M the plastic properties of the resulting product are not unequivocal or insufficiently so, and such a product is less suitable for use in practice.
• the composition according to the invention is highly viscous and kneadable and can easily be applied with a spatula Accordingly, it is ready for use as an implant material. Owing to the selection of the formulation, the composition according to the invention is hydrophilic and slowly absorbs wound fluid from its surroundings. Owing to the relatively low concentration of polymer, there is a direct contact between the ceramic material and wound fluid, while yet, owing to the pressure step, the ceramic particles, for example apatite particles, are densely packed.
• the implant material according to the invention which has a specific mass ranging from 1.2 x 10 3 and 3.5 x 10 3 kg/m 3 is a product having a greatly improved processabilit , which amply satisfies the requirements imposed thereon in practice.
• fields of application are surgery, traumatology, implantology, orthopedics, paradontology, dental surgery and general dentistry.
• Example III 74 g calcium phosphate (anhydrous) was treated in the manner described in Example I with H2O2 in distilled water. 4 g of the sodium compound of carboxymethyl cellulose was sprinkled onto 22 cm 3 distilled water having a temperature of 60°C. After 2 hours the gel was homogenized. The remainder of the procedure was similar to Example I, except- that the pressure applied was about 152 MPa.
• Example III
• the mass thus obtained was introduced into a disinfected mould and pressed for 5 minutes using room temperature and a pressure of 110 MPa.
• the resulting plates exhibited a brittle fracture when pressed with a spatula.
• Example V Similarly to Example IV, 2 g carboxymethyl cellulose was sprinkled onto 4.3 cm 3 of distilled water, and 13.7 g hydroxylapatite was mixed with the gel.
• Example VI apex restoration.
• Example VII use in capping dental implants.
• Example VI In the same manner as in Example VI, a clinical examinat was made, but now regarding the capping of dental implants. Evaluation etc. was as in Example VI.
• Example II 87. gelatin
• CMC Example III
• Example VIII filling alveolus after extraction.
• Example II In the same way as in Examples VI and VII a clinical examination was made, but now into the applicability for filling the alveolus after extraction. Three patients took part in the examination. In one patient the product of Example I (87, gelatin) was used, and in two patients the product of Example III.
• Example IX In one case in which the product of Example III was used, the results were even so good (as regards maintaining and building jaw bone) that after 6 months a dental implant could be, and was, placed in the site of implantation and hence in the newly-formed bone tissue. Evaluation after a total period of 12 months gave the desired clinical and radiological picture.
• Example IX Example IX

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• 1984
  • 1984-08-17 NL NL8402534A patent/NL8402534A/nl not_active Application Discontinuation
• 1985
  • 1985-08-15 EP EP19850904297 patent/EP0191086A1/de not_active Withdrawn
  • 1985-08-15 WO PCT/NL1985/000033 patent/WO1986001113A1/en not_active Application Discontinuation

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