CA1276558C - Tricalcium phosphate for implant materials - Google Patents
Tricalcium phosphate for implant materialsInfo
- Publication number
- CA1276558C CA1276558C CA000534934A CA534934A CA1276558C CA 1276558 C CA1276558 C CA 1276558C CA 000534934 A CA000534934 A CA 000534934A CA 534934 A CA534934 A CA 534934A CA 1276558 C CA1276558 C CA 1276558C
- Authority
- CA
- Canada
- Prior art keywords
- tricalcium phosphate
- antibiotic
- filler
- implant materials
- pores
- 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.)
- Expired - Fee Related
Links
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
-
- 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
- A61L24/001—Use of materials characterised by their function or physical properties
- A61L24/0015—Medicaments; Biocides
-
- 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
- A61L27/54—Biologically active materials, e.g. therapeutic substances
-
- 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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
- A61L2300/21—Acids
- A61L2300/214—Amino acids
-
- 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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
- A61L2300/406—Antibiotics
-
- 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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/45—Mixtures of two or more drugs, e.g. synergistic mixtures
-
- 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
- A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants
Abstract
Abstract An absorbable porous tricalcium phosphate, in which the pores are sealed with a mixture of an antibiotic and another filler, in particular an amino acid, is parti-cularly advantageous for use in the preparation of bone cements.
Description
Tricalcium phosphate for implant materials The invention relates to a. r.esorbable porous tricalcium phosphate which is suitable as an additive to implant materials based on polyacrylates and/or polymeth-5 acrylates, its pores being filled with a resorbablefiller which is tolerated by the body.
It is known, for example, from German Offenlegungs-schrift 2,905,878 that a tricalcium phosphate which can be ~resorbed in the body can be added to implant materials, in particular bone cements based on polyacrylates and/or polymethacrylates, in order to achieve good osseous fusion of the implant with the surrounding bone tissue. The problem that the pores of a porous tricalcium phosphate must be sealed by a suitable filler in order to avoid the pore system taking up liquid acrylate or methacrylate : monomers and the disadvantages thereby caused during mix-ing of the cement has also already been discussed in German Offenlegungsschrift 2,905,878. The fillers men-tioned there are glycerol, water or aqueous salt or buffer solutions, ethylene glycol, low molecular weight poly-ethylene glycols and lower alcohols, such as ethanol, n-propanol and isopropanol.
In addition to tricalcium phosphate, further addi-tives are proposed or even in fact used for such implant materials, such as, for example, X-ray contrast agents, active compounds, such as, in particular, antibiotics, for controlling infections or fibres for improving the mechani-cal properties of the implant Although each of these additives by itself has a positive influence, there is nevertheless the risk that the mechanical stability and the mixing properties of the bone cement will be adversely influenced by the large number of additives.
" , There WdS therefore the object of discovering a bone cement which is improved in this respect.
It has now been found that a clear improvement can be achieved if a tricalcium phosphate in which the pores -I 5 are filled with a mixture of an antibiotic and another filler is used as an additive.
The invention thus relates to ~ ~esorbable porous tricalcium phosphate which is suitable as an additive to implant materials based on polyacrylate and/or polymeth-10 acrylate, its pores being filled with a resorbable filler tolerated by the body, characterized in that the filler is composed of at least two constituents, one constituent I being an antibiotic.
i The invention also relates to a process for the 15 preparation of a resorbable porous tricalcium phosphate which is suitable as an additive for implant materials based on Polyacrylates and/or polymethacrylates, its pores being filled with a resorbable filler which is tolerated by the body, characterized in that a porous tricalcium I 20 phosphate is brought into contact with the solution of an antibiotic and another filler and the solvent is then removed.
The invention also relates to a precursor for the ! preparation of a bone cement and the implant materials Z5 prepared therefrom, which are characterized in that they contain the tricalcium phosphate according to the inven-tion.
The main advantage of the invention is that both the mixing properties of the bone cement and the mechanical 30 properties r,f the hardened implant are substantially improved by the reduced number of additives. It has furthermore been found, surprisingly, that the release of the antibiotic or antibiotics from an implant according to the invention is significantly improved.
The term tricalcium phosphate used in the present application is to be understood as a generic term -for a number of different materials which are essentially to be described by the chemical formula Ca3(P04)z, the 7655~
calcium : phosphorus ratio approximately being 3 : 2. As well as pure tricalcium phosphates, such as, for example, ct- or ~-whitlockite, it is also intended to include, how-ever, the materials which can be described only approxi-S mately by the formula Ca3(P04)2, such as, for example,apatites or phosphorite. The tricalcium phosphate should in all cases be ~esorbable in the body.
These ma~erials are known per se and can be pre-pared by known processes. These are essentially precipi-tation processes or sintering processes, or a combinationof such processes. Precipitation or sintering processes for the preparation of the calcium phosphates are des-cribed in the standard works of inorganic chemistry, for example Gmelin. Starting materials which are used here are as a rule soluble calcium salts and soluble phosphates, or, for the sintering process, for example CaO, Ca(OH)2, CaC03 and CaHP04, which are sintered together with P20s or with one another.
Tricalcium phosphates obtained by precipitation processes are particularly preferably used in the present invention These are as a rule relatively soft and have a large pore volume of the order of about 0~3-0.5 ml/g.
The resorption of these materials obtained by precipita-tion is as a rule better than that of sintered materials.
According to the invention, the pores of these tricalcium phosphates are sealed with a mixture of an antibiotic and another filler. Aminoglycoside antibiotics, and in particular gentamicin, are preferably used as the antibiotics for this. Clindamycin and lincomycin and com-binations of antibiotics, such as, for example, gentamicin with clindamycin, are furthermore also preferred.
Other fillers are in principle all the physio-logically tolerated substances which can be resorbed by the body and are immiscible with the acrylate monomers.
Thus, for example, the alcohols already mentioned in German Offenlegungsschrift 2,905,878, such as, for example, glycerol, ethylene glycol and low molecular weight poly-ethylene glycols, or sugars, such as, for example, glucose '7~i5~
or sucrose, sugar alcohols, such as, for example, mannitol or sorbitol, proteins and degradation products thereof, such as, for example, collagen, gelatine or elastin, and, in particular, also aminoacids, such as, for example, 5 valine, histidine, leucine, isoleucine, threonine, argin-ine, lysine and alanine, can be used. Threonine and arginine are particularly preferably used.
Although the pore volume of a selected tricalcium phosphate is fixed, the amount of fillers can be varied 10 within relatively wide limits without the hollow space system of the tricalcium phosphate taking up monomers during mixing of the bone cement. This shows that evid-ently the entire pore volume of the tricalcium phosphate 1 does not have to be filled with the fillers, but that it ! 15 is evidently sufficient to seal the pores externally by the fillers.
Thus, if a precipitated tricalcium phosphate which has a relatively high pore volume is used, about 2-20, in particular about 5-15% by weight of antibiotic and about O.S-5, in particular about 0.8-3.2% by weight of the other I filler are employed. Only if a liquid filler, such as, ¦ for example, glycerol, is used is up to about 30% by weight ¦ thereof employed.
These fillers are applied to the tricalcium phos-25 phate by methods which are known per se. Thus, for ex-ample, the tricalcium phosphate can be impregnated with ~ a solution of the fillers and the solvent can then be I evaporated. In order to achieve intensive penetration of the solution into the pore system of the tricalcium phos-30 phate, it i5 possible, for example, either to carry out this operation under increased pressure or to evacuate the tricalcium phosphate powder before the addition of the filler solution. Possible solvents for the fillers are both organic solvents and, in particular, water or aqueous 35 buffer solutions with a physiological pH.
A particularly advantageous product is obtained by spray-drying. Since the tricalcium phosphate prefer-ably employed has a very small particle size in the range ~76~58 of about 2-300 ~m, in particular about 20-200 ~m, suspen-sions of the tricalcium phosphate in a solution of the fillers can be spray-dried by customary methods. The con-ditions to be applied here, such as concentration of the suspension, temperature and pressure, are familiar to the expert and can if necessary be optimized in respect of the particular components used by a few preliminary experi-ments in accordance with methods described in textbooks, such as, for example, in Sucker, Fuchs and Speiser "Pharmazeutische rechnologie" ("Pharmaceutical Technology"), Georg-Thieme-Verlag, Stuttgart, 1978.
The tricalcium phosphate particles obtained as a free-flowing powder by one of these methods can be used directly or after sterilization, for example by irradia-tion or gassing with ethylene oxide, in the preparation o-f bone cements. The known bone cements are prepared by mixing about two parts of a fine-particled prepolymer, in particular polymethyl methacrylate or a copolymer of methyl acrylate and methyl methacrylate, containing a polymerization catalyst (for example dibenzoyl peroxide) with about one part of the liquid monomer, for example acrylic acid or methyl methacrylate or mixtures thereof, containing an accelerator (for example dimethyl-p-tolui-dine) to gi~e a mass which can be shaped and which is implanted in the body and hardens there. Such bone cements are commercially available, for example, under the tradename PalacosR.
Bone cements with the tricalcium phosphate accord-ing to the invention are prepared in an analogous manner by either mixing the three constituents of prepolymer, tricalcium phosphate and monomer or first admixing one of the other two constituents to the tricalcium phosphate.
The commercially available form of the bone cement will preferably be such that the solid and liquid con-stituents are indeed separate but are in a ready-to-use pack in amounts matched to one another. A ratio of about 40 9 of solid to 20 ml of liquid monomer is preferably maintained here. The proportion of tricalcium phosphate 1~76~51~
according to the invention in the solid component is as a rule about 5-30, in particular about 8-20% by weight.
In addition to the tricalcium phosphate according to the invention, other additives can be admixed to the S solid component. Thus, for example, another tricalcium phosphate content without fillers, such as, for example, an essentially pore-free sintered apatite, or an X-ray contrast agent, such as, for example, zirconium dioxide, can be admixed in amounts of 0-20% by weight. The latter cor;stituent can be dispensed with, however, if the tri-calcium phosphate components already effect sufficient X-ray contrast. To improve the mechanica( properties of the implant, it is also possible to add fibre constituents, such as, for example, carbon fibres, glass fibres or fibres of plastic, such as, for example, those of poly-I methyl methacrylate or Aramite, in amounts of about 0-30%
¦ by weight. The solid component can additionally also con-tain other materials, such as, in particular, bioactive I glass ceramics, in amounts of 0-50% by weight. However the j 20 solid component is in all cases chosen so that the ratio of 1 40 9 of solid to 20 ml of monomer is essentially observed, ¦ that is to say as the content of other additives increases ¦ the content of the prepolymer decreases.
It has already been mentioned that compared with an implant material to which a pulverulent antibiotic has been added, the release of the antibiotic from an implant material according to the invention is significantly improved. A release which is improved by a factor of 5-10 is in fact found. A very useful and advantageous new tri-calcium phosphate component is thus available for thepreparation of bone cements.
Example 1 97.6 g of tricalcium phosphate (E. Merck, Darm-stadt~ Cat. No. 2194) with a particle size of less than 63 ~m are suspended in a solution, brought to pH 7.4, of 0.8 9 of L-arginine and 1.6 g of gentamicin sulfate and the suspension is sprayed in a spray-drying unit (nozzle pressure: 2 bar; air flow 380 m3/hour; intake temperature:
~6'~
200C; discharge temperature: 65C).
Example Z
The procedure followed is analogous to Example 1, but 1.6 9 of L-arginine and 96.8 9 of tricalcium phosphate S are employed.
Example 3 The procedure followed is analogous to Example 1, but 1.6 9 of L-arginine, 4.0 9 of gentamicin and 94.4 9 of tricalcium phosphate are employed.
Example 4 The procedure followed is analogous to Example 1, but 1.6 9 of L-arginine, 8.0 9 of gentamicin and 90.4 9 of tricalcium phosphate are employed.
Example S
The procedure followed is analogous to Example 1, but 1.6 9 of L-arginine, 16.0 9 of gentamicin and 82.4 9 of tricalcium phosphate are employed.
Example 6 The procedure followed is analogous to Example 1, but 5.0 9 of L--arginine, 8.0 9 of gentamicin and 87 9 of tricalcium phosphate are employed.
Examples 7-12 f The procedure followed is analogous to Examples 1-6, but L-threonine is employed instead of L-arginine.
It is known, for example, from German Offenlegungs-schrift 2,905,878 that a tricalcium phosphate which can be ~resorbed in the body can be added to implant materials, in particular bone cements based on polyacrylates and/or polymethacrylates, in order to achieve good osseous fusion of the implant with the surrounding bone tissue. The problem that the pores of a porous tricalcium phosphate must be sealed by a suitable filler in order to avoid the pore system taking up liquid acrylate or methacrylate : monomers and the disadvantages thereby caused during mix-ing of the cement has also already been discussed in German Offenlegungsschrift 2,905,878. The fillers men-tioned there are glycerol, water or aqueous salt or buffer solutions, ethylene glycol, low molecular weight poly-ethylene glycols and lower alcohols, such as ethanol, n-propanol and isopropanol.
In addition to tricalcium phosphate, further addi-tives are proposed or even in fact used for such implant materials, such as, for example, X-ray contrast agents, active compounds, such as, in particular, antibiotics, for controlling infections or fibres for improving the mechani-cal properties of the implant Although each of these additives by itself has a positive influence, there is nevertheless the risk that the mechanical stability and the mixing properties of the bone cement will be adversely influenced by the large number of additives.
" , There WdS therefore the object of discovering a bone cement which is improved in this respect.
It has now been found that a clear improvement can be achieved if a tricalcium phosphate in which the pores -I 5 are filled with a mixture of an antibiotic and another filler is used as an additive.
The invention thus relates to ~ ~esorbable porous tricalcium phosphate which is suitable as an additive to implant materials based on polyacrylate and/or polymeth-10 acrylate, its pores being filled with a resorbable filler tolerated by the body, characterized in that the filler is composed of at least two constituents, one constituent I being an antibiotic.
i The invention also relates to a process for the 15 preparation of a resorbable porous tricalcium phosphate which is suitable as an additive for implant materials based on Polyacrylates and/or polymethacrylates, its pores being filled with a resorbable filler which is tolerated by the body, characterized in that a porous tricalcium I 20 phosphate is brought into contact with the solution of an antibiotic and another filler and the solvent is then removed.
The invention also relates to a precursor for the ! preparation of a bone cement and the implant materials Z5 prepared therefrom, which are characterized in that they contain the tricalcium phosphate according to the inven-tion.
The main advantage of the invention is that both the mixing properties of the bone cement and the mechanical 30 properties r,f the hardened implant are substantially improved by the reduced number of additives. It has furthermore been found, surprisingly, that the release of the antibiotic or antibiotics from an implant according to the invention is significantly improved.
The term tricalcium phosphate used in the present application is to be understood as a generic term -for a number of different materials which are essentially to be described by the chemical formula Ca3(P04)z, the 7655~
calcium : phosphorus ratio approximately being 3 : 2. As well as pure tricalcium phosphates, such as, for example, ct- or ~-whitlockite, it is also intended to include, how-ever, the materials which can be described only approxi-S mately by the formula Ca3(P04)2, such as, for example,apatites or phosphorite. The tricalcium phosphate should in all cases be ~esorbable in the body.
These ma~erials are known per se and can be pre-pared by known processes. These are essentially precipi-tation processes or sintering processes, or a combinationof such processes. Precipitation or sintering processes for the preparation of the calcium phosphates are des-cribed in the standard works of inorganic chemistry, for example Gmelin. Starting materials which are used here are as a rule soluble calcium salts and soluble phosphates, or, for the sintering process, for example CaO, Ca(OH)2, CaC03 and CaHP04, which are sintered together with P20s or with one another.
Tricalcium phosphates obtained by precipitation processes are particularly preferably used in the present invention These are as a rule relatively soft and have a large pore volume of the order of about 0~3-0.5 ml/g.
The resorption of these materials obtained by precipita-tion is as a rule better than that of sintered materials.
According to the invention, the pores of these tricalcium phosphates are sealed with a mixture of an antibiotic and another filler. Aminoglycoside antibiotics, and in particular gentamicin, are preferably used as the antibiotics for this. Clindamycin and lincomycin and com-binations of antibiotics, such as, for example, gentamicin with clindamycin, are furthermore also preferred.
Other fillers are in principle all the physio-logically tolerated substances which can be resorbed by the body and are immiscible with the acrylate monomers.
Thus, for example, the alcohols already mentioned in German Offenlegungsschrift 2,905,878, such as, for example, glycerol, ethylene glycol and low molecular weight poly-ethylene glycols, or sugars, such as, for example, glucose '7~i5~
or sucrose, sugar alcohols, such as, for example, mannitol or sorbitol, proteins and degradation products thereof, such as, for example, collagen, gelatine or elastin, and, in particular, also aminoacids, such as, for example, 5 valine, histidine, leucine, isoleucine, threonine, argin-ine, lysine and alanine, can be used. Threonine and arginine are particularly preferably used.
Although the pore volume of a selected tricalcium phosphate is fixed, the amount of fillers can be varied 10 within relatively wide limits without the hollow space system of the tricalcium phosphate taking up monomers during mixing of the bone cement. This shows that evid-ently the entire pore volume of the tricalcium phosphate 1 does not have to be filled with the fillers, but that it ! 15 is evidently sufficient to seal the pores externally by the fillers.
Thus, if a precipitated tricalcium phosphate which has a relatively high pore volume is used, about 2-20, in particular about 5-15% by weight of antibiotic and about O.S-5, in particular about 0.8-3.2% by weight of the other I filler are employed. Only if a liquid filler, such as, ¦ for example, glycerol, is used is up to about 30% by weight ¦ thereof employed.
These fillers are applied to the tricalcium phos-25 phate by methods which are known per se. Thus, for ex-ample, the tricalcium phosphate can be impregnated with ~ a solution of the fillers and the solvent can then be I evaporated. In order to achieve intensive penetration of the solution into the pore system of the tricalcium phos-30 phate, it i5 possible, for example, either to carry out this operation under increased pressure or to evacuate the tricalcium phosphate powder before the addition of the filler solution. Possible solvents for the fillers are both organic solvents and, in particular, water or aqueous 35 buffer solutions with a physiological pH.
A particularly advantageous product is obtained by spray-drying. Since the tricalcium phosphate prefer-ably employed has a very small particle size in the range ~76~58 of about 2-300 ~m, in particular about 20-200 ~m, suspen-sions of the tricalcium phosphate in a solution of the fillers can be spray-dried by customary methods. The con-ditions to be applied here, such as concentration of the suspension, temperature and pressure, are familiar to the expert and can if necessary be optimized in respect of the particular components used by a few preliminary experi-ments in accordance with methods described in textbooks, such as, for example, in Sucker, Fuchs and Speiser "Pharmazeutische rechnologie" ("Pharmaceutical Technology"), Georg-Thieme-Verlag, Stuttgart, 1978.
The tricalcium phosphate particles obtained as a free-flowing powder by one of these methods can be used directly or after sterilization, for example by irradia-tion or gassing with ethylene oxide, in the preparation o-f bone cements. The known bone cements are prepared by mixing about two parts of a fine-particled prepolymer, in particular polymethyl methacrylate or a copolymer of methyl acrylate and methyl methacrylate, containing a polymerization catalyst (for example dibenzoyl peroxide) with about one part of the liquid monomer, for example acrylic acid or methyl methacrylate or mixtures thereof, containing an accelerator (for example dimethyl-p-tolui-dine) to gi~e a mass which can be shaped and which is implanted in the body and hardens there. Such bone cements are commercially available, for example, under the tradename PalacosR.
Bone cements with the tricalcium phosphate accord-ing to the invention are prepared in an analogous manner by either mixing the three constituents of prepolymer, tricalcium phosphate and monomer or first admixing one of the other two constituents to the tricalcium phosphate.
The commercially available form of the bone cement will preferably be such that the solid and liquid con-stituents are indeed separate but are in a ready-to-use pack in amounts matched to one another. A ratio of about 40 9 of solid to 20 ml of liquid monomer is preferably maintained here. The proportion of tricalcium phosphate 1~76~51~
according to the invention in the solid component is as a rule about 5-30, in particular about 8-20% by weight.
In addition to the tricalcium phosphate according to the invention, other additives can be admixed to the S solid component. Thus, for example, another tricalcium phosphate content without fillers, such as, for example, an essentially pore-free sintered apatite, or an X-ray contrast agent, such as, for example, zirconium dioxide, can be admixed in amounts of 0-20% by weight. The latter cor;stituent can be dispensed with, however, if the tri-calcium phosphate components already effect sufficient X-ray contrast. To improve the mechanica( properties of the implant, it is also possible to add fibre constituents, such as, for example, carbon fibres, glass fibres or fibres of plastic, such as, for example, those of poly-I methyl methacrylate or Aramite, in amounts of about 0-30%
¦ by weight. The solid component can additionally also con-tain other materials, such as, in particular, bioactive I glass ceramics, in amounts of 0-50% by weight. However the j 20 solid component is in all cases chosen so that the ratio of 1 40 9 of solid to 20 ml of monomer is essentially observed, ¦ that is to say as the content of other additives increases ¦ the content of the prepolymer decreases.
It has already been mentioned that compared with an implant material to which a pulverulent antibiotic has been added, the release of the antibiotic from an implant material according to the invention is significantly improved. A release which is improved by a factor of 5-10 is in fact found. A very useful and advantageous new tri-calcium phosphate component is thus available for thepreparation of bone cements.
Example 1 97.6 g of tricalcium phosphate (E. Merck, Darm-stadt~ Cat. No. 2194) with a particle size of less than 63 ~m are suspended in a solution, brought to pH 7.4, of 0.8 9 of L-arginine and 1.6 g of gentamicin sulfate and the suspension is sprayed in a spray-drying unit (nozzle pressure: 2 bar; air flow 380 m3/hour; intake temperature:
~6'~
200C; discharge temperature: 65C).
Example Z
The procedure followed is analogous to Example 1, but 1.6 9 of L-arginine and 96.8 9 of tricalcium phosphate S are employed.
Example 3 The procedure followed is analogous to Example 1, but 1.6 9 of L-arginine, 4.0 9 of gentamicin and 94.4 9 of tricalcium phosphate are employed.
Example 4 The procedure followed is analogous to Example 1, but 1.6 9 of L-arginine, 8.0 9 of gentamicin and 90.4 9 of tricalcium phosphate are employed.
Example S
The procedure followed is analogous to Example 1, but 1.6 9 of L-arginine, 16.0 9 of gentamicin and 82.4 9 of tricalcium phosphate are employed.
Example 6 The procedure followed is analogous to Example 1, but 5.0 9 of L--arginine, 8.0 9 of gentamicin and 87 9 of tricalcium phosphate are employed.
Examples 7-12 f The procedure followed is analogous to Examples 1-6, but L-threonine is employed instead of L-arginine.
Claims (8)
1. Resorbable porous tricalcium phosphate which is suitable as an additive to implant materials based on polyacrylates and/or polymethacrylates, its pores being filled with a resorbable filler tolerated by the body, characterized in that the filler is composed of at least two constituents, one constituent being an antibiotic.
2. Tricalcium phosphate according to Claim 1, charac-terized in that it contains an aminoacid, in addition to the antibiotic.
3. Tricalcium phosphate according to Claim 1 or 2, characterized in that it contains an aminoglycoside anti-biotic as the antibiotic.
4. Process for the preparation of a resorbable porous tricalcium phosphate which is suitable as an addi-tive for implant materials based on polyacrylate and/or polymethacrylate, its pores being filled with a resorb-able filler which is tolerated by the body, characterized in that a porous tricalcium phosphate is brought into contact with the solution of an antibiotic and another filler and the solvent is then removed.
5. Process according to Claim 4, characterized in that the tricalcium phosphate is suspended in the solution of an antibiotic and another filler and the suspension is then spray-dried.
6. Process according to Claim 4 or 5, characterized in that an aminoglycoside antibiotic is used as the anti-biotic and an aminoacid is used as the other filler.
7. Precursor for the preparation of a bone cement which contains a pulverulent solid component based on polyacrylate and/or polymethacrylate and a liquid monomer component in a ready-to-use pack unit, characterized in that the solid component contains 5-30% by weight of tri-calcium phosphate according to Claim 1.
8. Implant materials, in particular bone cements based on polyacrylates and/or polymethacrylates, charac-terized in that they contain 3-20% by weight of a trical-cium phosphate according to Claim 1.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19863613213 DE3613213A1 (en) | 1986-04-18 | 1986-04-18 | TRICALCIUMPHOSPHATE FOR IMPLANTATION MATERIALS |
| DEP3613213.6 | 1986-04-18 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1276558C true CA1276558C (en) | 1990-11-20 |
Family
ID=6299037
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000534934A Expired - Fee Related CA1276558C (en) | 1986-04-18 | 1987-04-16 | Tricalcium phosphate for implant materials |
Country Status (12)
| Country | Link |
|---|---|
| US (1) | US4869906A (en) |
| EP (1) | EP0242672B1 (en) |
| JP (1) | JP2552483B2 (en) |
| KR (1) | KR950003699B1 (en) |
| AT (1) | ATE81785T1 (en) |
| AU (1) | AU603356B2 (en) |
| CA (1) | CA1276558C (en) |
| DE (2) | DE3613213A1 (en) |
| ES (1) | ES2044855T3 (en) |
| HU (1) | HU198384B (en) |
| IE (1) | IE59765B1 (en) |
| ZA (1) | ZA872762B (en) |
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| DE3885261T2 (en) * | 1987-12-21 | 1994-04-21 | Asahi Optical Co Ltd | Process for the production of a substrate coated with apatite. |
| EP0388480A1 (en) * | 1989-03-20 | 1990-09-26 | Siemens Aktiengesellschaft | Implantable stimulation electrode |
| DE4033291A1 (en) * | 1990-10-19 | 1992-04-23 | Draenert Klaus | MATERIAL AND METHOD FOR THE PRODUCTION THEREOF |
| DE4113021C2 (en) * | 1991-04-20 | 1995-01-26 | Carus Carl Gustav | Resorbable phosphate glasses and resorbable phosphate glass ceramics, process for their preparation and use |
| DE4143239A1 (en) * | 1991-12-31 | 1993-07-01 | Joerg Dipl Chem Schierholz | PHARMACEUTICAL ACTIVE SUBSTANCES CONTAINING AN IMPLANTABLE DEVICE FROM A POLYMERIC MATERIAL AND METHOD FOR THE PRODUCTION THEREOF |
| SE510491C2 (en) * | 1993-08-18 | 1999-05-31 | Coripharm Gmbh & Co | Cement for medical use and manufacture and use of the cement |
| US5591453A (en) * | 1994-07-27 | 1997-01-07 | The Trustees Of The University Of Pennsylvania | Incorporation of biologically active molecules into bioactive glasses |
| US5817327A (en) * | 1994-07-27 | 1998-10-06 | The Trustees Of The University Of Pennsylvania | Incorporation of biologically active molecules into bioactive glasses |
| US6075067A (en) * | 1994-08-15 | 2000-06-13 | Corpipharm Gmbh & Co | Cement for medical use, method for producing the cement, and use of the cement |
| DE59711025D1 (en) * | 1996-09-30 | 2003-12-24 | Degudent Gmbh | Polymerizable dental material and use of apatite fillers in the dental material |
| DE19713229A1 (en) * | 1997-04-01 | 1998-10-08 | Merck Patent Gmbh | Bone cement paste containing antibiotics |
| WO1998058602A1 (en) * | 1997-06-20 | 1998-12-30 | Alfred Farrington | Bone grafting material |
| AUPO907697A0 (en) * | 1997-09-09 | 1997-10-02 | Day, Robert Edward | Chemical supplementation of bone |
| JP4215884B2 (en) * | 1998-03-23 | 2009-01-28 | 日本特殊陶業株式会社 | Calcium phosphate cement and calcium phosphate cement composition |
| DE19813614A1 (en) * | 1998-03-27 | 1999-09-30 | Merck Patent Gmbh | Bio-cements with improved properties |
| US6155812A (en) * | 1998-07-15 | 2000-12-05 | Biomet, Inc | Cement mold for a temporary implant |
| US6361731B1 (en) | 1998-07-15 | 2002-03-26 | Biomet, Inc. | Method of forming a temporary implant |
| US6458162B1 (en) * | 1999-08-13 | 2002-10-01 | Vita Special Purpose Corporation | Composite shaped bodies and methods for their production and use |
| US6949251B2 (en) | 2001-03-02 | 2005-09-27 | Stryker Corporation | Porous β-tricalcium phosphate granules for regeneration of bone tissue |
| TW200400062A (en) | 2002-04-03 | 2004-01-01 | Mathys Medizinaltechnik Ag | Kneadable, pliable bone replacement material |
| DE10227935B4 (en) * | 2002-06-21 | 2007-10-04 | Heraeus Kulzer Gmbh | Process for the preparation of an antibiotic coating of porous bodies and use |
| EP1614403B2 (en) | 2003-03-14 | 2014-06-18 | Depuy Spine, Inc. | Hydraulic device for the injection of bone cement in percutaneous vertebroplasty |
| US8066713B2 (en) | 2003-03-31 | 2011-11-29 | Depuy Spine, Inc. | Remotely-activated vertebroplasty injection device |
| ITFI20030105A1 (en) * | 2003-04-14 | 2004-10-15 | Italmed Di Galli Giovanna E Pacini Gigliola S N C | COMPOSITION FOR DENTAL USE FOR BONE REGENERATION |
| US8415407B2 (en) | 2004-03-21 | 2013-04-09 | Depuy Spine, Inc. | Methods, materials, and apparatus for treating bone and other tissue |
| WO2006011152A2 (en) | 2004-06-17 | 2006-02-02 | Disc-O-Tech Medical Technologies, Ltd. | Methods for treating bone and other tissue |
| US8579908B2 (en) | 2003-09-26 | 2013-11-12 | DePuy Synthes Products, LLC. | Device for delivering viscous material |
| DE102004016883A1 (en) * | 2004-04-06 | 2005-10-27 | Coripharm Medizinprodukte Gmbh & Co. Kg. | A method for producing a bone implant material with improved mechanical strength on the basis of shaped bodies of porous implant material and implant material produced by the method |
| WO2005114322A2 (en) | 2004-05-12 | 2005-12-01 | Massachusetts Institute Of Technology | Manufacturing process, such as three-dimensional printing, including solvent vapor filming and the like |
| US9220595B2 (en) | 2004-06-23 | 2015-12-29 | Orthovita, Inc. | Shapeable bone graft substitute and instruments for delivery thereof |
| US9381024B2 (en) | 2005-07-31 | 2016-07-05 | DePuy Synthes Products, Inc. | Marked tools |
| US9918767B2 (en) | 2005-08-01 | 2018-03-20 | DePuy Synthes Products, Inc. | Temperature control system |
| DE102005040429A1 (en) * | 2005-08-25 | 2007-03-01 | Heraeus Kulzer Gmbh | Drug release system and its use |
| US8360629B2 (en) | 2005-11-22 | 2013-01-29 | Depuy Spine, Inc. | Mixing apparatus having central and planetary mixing elements |
| CN101516412B (en) | 2006-09-14 | 2014-02-12 | 德普伊斯派尔公司 | Bone cement and use method thereof |
| AU2007311451A1 (en) | 2006-10-19 | 2008-04-24 | Depuy Spine, Inc. | Fluid delivery system |
| FR2911508B1 (en) * | 2007-01-19 | 2012-11-09 | Kasios | BONE SUBSTITUTE BASED ON PHOSPHOCALCIUM CEMENT |
| US20090131867A1 (en) | 2007-11-16 | 2009-05-21 | Liu Y King | Steerable vertebroplasty system with cavity creation element |
| US9510885B2 (en) | 2007-11-16 | 2016-12-06 | Osseon Llc | Steerable and curvable cavity creation system |
| US20090131886A1 (en) | 2007-11-16 | 2009-05-21 | Liu Y King | Steerable vertebroplasty system |
| US8206143B2 (en) * | 2007-12-13 | 2012-06-26 | Biomet Manufacturing Corp. | Modular articulating cement spacer |
| US20100298832A1 (en) | 2009-05-20 | 2010-11-25 | Osseon Therapeutics, Inc. | Steerable curvable vertebroplasty drill |
| SG181156A1 (en) * | 2009-12-04 | 2012-07-30 | Agency Science Tech & Res | Nanostructured material formulated with bone cement for effective antibiotic delivery |
| EP2512537B1 (en) * | 2009-12-18 | 2015-08-26 | Howmedica Osteonics Corp. | Dual paste direct injectable bone cement precursor systems and methods of making same |
| WO2011137377A1 (en) | 2010-04-29 | 2011-11-03 | Dfine, Inc. | System for use in treatment of vertebral fractures |
| CA2798710C (en) | 2010-05-11 | 2019-08-27 | Venkat R. Garigapati | Organophosphorous, multivalent metal compounds, & polymer adhesive interpenetrating network compositions & methods |
| ES2714701T3 (en) | 2010-11-10 | 2019-05-29 | Stryker European Holdings I Llc | Process for the preparation of a polymeric bone foam |
| CA2861357C (en) * | 2011-01-19 | 2022-08-23 | Laboratory Skin Care, Inc. | Topical minocycline compositions and methods of using the same |
| WO2012158527A2 (en) | 2011-05-13 | 2012-11-22 | Howmedica Osteonics | Organophosphorous & multivalent metal compound compositions & methods |
| US8834772B2 (en) | 2011-12-07 | 2014-09-16 | Biomet Manufacturing, Llc | Antimicrobial methacrylate cements |
| ES2951010T3 (en) | 2016-02-01 | 2023-10-17 | Schierholz Joerg Michael | Implantable health products, procedure for their preparation and use thereof |
| JP2019534130A (en) | 2016-10-27 | 2019-11-28 | ディーファイン，インコーポレイティド | Articulated osteotome with cement delivery channel |
| US11116570B2 (en) | 2016-11-28 | 2021-09-14 | Dfine, Inc. | Tumor ablation devices and related methods |
| WO2018107036A1 (en) | 2016-12-09 | 2018-06-14 | Dfine, Inc. | Medical devices for treating hard tissues and related methods |
| WO2018129180A1 (en) | 2017-01-06 | 2018-07-12 | Dfine, Inc. | Osteotome with a distal portion for simultaneous advancement and articulation |
| EP3876856A4 (en) | 2018-11-08 | 2022-10-12 | Dfine, Inc. | Tumor ablation device and related systems and methods |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2320373B2 (en) * | 1973-04-21 | 1978-04-06 | Merck Patent Gmbh, 6100 Darmstadt | Antibiotic agent and its use as a plastic surgical material |
| AR216922A1 (en) * | 1976-11-11 | 1980-02-15 | Merck Patent Gmbh | PROCEDURE FOR THE MANUFACTURE OF A SURGICAL ENVIRONMENT |
| DE2843963A1 (en) * | 1978-10-09 | 1980-04-24 | Merck Patent Gmbh | BODY-RESORBABLE SHAPED MATERIAL BASED ON COLLAGEN AND THEIR USE IN MEDICINE |
| DE2905878A1 (en) * | 1979-02-16 | 1980-08-28 | Merck Patent Gmbh | IMPLANTATION MATERIALS AND METHOD FOR THEIR PRODUCTION |
| DE3325111A1 (en) * | 1983-07-12 | 1985-01-24 | Merck Patent Gmbh, 6100 Darmstadt | IMPLANTATION MATERIALS |
| JPS6024848A (en) * | 1983-07-20 | 1985-02-07 | 株式会社未来科学研究所 | Composition using natural calcium hydroxide apatite |
| JPS60106459A (en) * | 1983-11-15 | 1985-06-11 | 三菱マテリアル株式会社 | Calcium phosphate filler |
| JPS60142857A (en) * | 1983-12-29 | 1985-07-29 | 住友セメント株式会社 | Bone cement composition |
| DE3513938A1 (en) * | 1985-04-18 | 1986-10-23 | Merck Patent Gmbh, 6100 Darmstadt | CYTOSTATIC-CONTAINING PHARMACADEPOT |
-
1986
- 1986-04-18 DE DE19863613213 patent/DE3613213A1/en not_active Withdrawn
-
1987
- 1987-04-03 ES ES87104975T patent/ES2044855T3/en not_active Expired - Lifetime
- 1987-04-03 DE DE8787104975T patent/DE3782357D1/en not_active Expired - Fee Related
- 1987-04-03 AT AT87104975T patent/ATE81785T1/en active
- 1987-04-03 EP EP87104975A patent/EP0242672B1/en not_active Expired - Lifetime
- 1987-04-08 AU AU71168/87A patent/AU603356B2/en not_active Ceased
- 1987-04-15 KR KR1019870003588A patent/KR950003699B1/en not_active IP Right Cessation
- 1987-04-16 ZA ZA872762A patent/ZA872762B/en unknown
- 1987-04-16 CA CA000534934A patent/CA1276558C/en not_active Expired - Fee Related
- 1987-04-16 IE IE101987A patent/IE59765B1/en not_active IP Right Cessation
- 1987-04-17 US US07/039,254 patent/US4869906A/en not_active Expired - Lifetime
- 1987-04-17 JP JP62093463A patent/JP2552483B2/en not_active Expired - Lifetime
- 1987-04-17 HU HU871715A patent/HU198384B/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| KR870009729A (en) | 1987-11-30 |
| KR950003699B1 (en) | 1995-04-17 |
| ZA872762B (en) | 1987-11-25 |
| JP2552483B2 (en) | 1996-11-13 |
| DE3613213A1 (en) | 1987-10-22 |
| IE59765B1 (en) | 1994-03-23 |
| ATE81785T1 (en) | 1992-11-15 |
| AU603356B2 (en) | 1990-11-15 |
| JPS62254764A (en) | 1987-11-06 |
| HU198384B (en) | 1989-10-30 |
| EP0242672A3 (en) | 1990-01-17 |
| DE3782357D1 (en) | 1992-12-03 |
| IE871019L (en) | 1987-10-18 |
| EP0242672A2 (en) | 1987-10-28 |
| ES2044855T3 (en) | 1994-01-16 |
| AU7116887A (en) | 1987-10-22 |
| US4869906A (en) | 1989-09-26 |
| HUT44169A (en) | 1988-02-29 |
| EP0242672B1 (en) | 1992-10-28 |
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| Date | Code | Title | Description |
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| MKLA | Lapsed |