ZA200006034B - Biologically degradable cement exhibiting improved properties. - Google Patents
Biologically degradable cement exhibiting improved properties. Download PDFInfo
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- ZA200006034B ZA200006034B ZA200006034A ZA200006034A ZA200006034B ZA 200006034 B ZA200006034 B ZA 200006034B ZA 200006034 A ZA200006034 A ZA 200006034A ZA 200006034 A ZA200006034 A ZA 200006034A ZA 200006034 B ZA200006034 B ZA 200006034B
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- South Africa
- Prior art keywords
- tcp
- mixture according
- cag
- mixture
- phosphate
- Prior art date
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- 239000004568 cement Substances 0.000 title claims description 36
- 230000001747 exhibiting effect Effects 0.000 title 1
- 239000001506 calcium phosphate Substances 0.000 claims description 68
- 239000000203 mixture Substances 0.000 claims description 68
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims description 57
- 229910000391 tricalcium phosphate Inorganic materials 0.000 claims description 48
- 235000019731 tricalcium phosphate Nutrition 0.000 claims description 48
- 229940078499 tricalcium phosphate Drugs 0.000 claims description 48
- 239000002245 particle Substances 0.000 claims description 29
- 210000000988 bone and bone Anatomy 0.000 claims description 20
- 229910019142 PO4 Inorganic materials 0.000 claims description 18
- 239000011575 calcium Substances 0.000 claims description 14
- 239000000843 powder Substances 0.000 claims description 12
- 239000003242 anti bacterial agent Substances 0.000 claims description 11
- 239000004480 active ingredient Substances 0.000 claims description 10
- 239000000645 desinfectant Substances 0.000 claims description 10
- 239000000463 material Substances 0.000 claims description 10
- 239000011734 sodium Substances 0.000 claims description 10
- 239000011777 magnesium Substances 0.000 claims description 9
- 229910000389 calcium phosphate Inorganic materials 0.000 claims description 8
- 235000011010 calcium phosphates Nutrition 0.000 claims description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 7
- 239000010452 phosphate Substances 0.000 claims description 7
- 229910052749 magnesium Inorganic materials 0.000 claims description 5
- 229910052708 sodium Inorganic materials 0.000 claims description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
- 239000007943 implant Substances 0.000 claims description 4
- 150000002484 inorganic compounds Chemical class 0.000 claims description 4
- 229910010272 inorganic material Inorganic materials 0.000 claims description 4
- 101100283604 Caenorhabditis elegans pigk-1 gene Proteins 0.000 claims description 3
- 241001286462 Caio Species 0.000 claims description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 230000003115 biocidal effect Effects 0.000 claims description 3
- VSIIXMUUUJUKCM-UHFFFAOYSA-D pentacalcium;fluoride;triphosphate Chemical compound [F-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O VSIIXMUUUJUKCM-UHFFFAOYSA-D 0.000 claims description 3
- OJYGBLRPYBAHRT-UHFFFAOYSA-N alphachloralose Chemical compound O1C(C(Cl)(Cl)Cl)OC2C(O)C(C(O)CO)OC21 OJYGBLRPYBAHRT-UHFFFAOYSA-N 0.000 claims description 2
- 229910052586 apatite Inorganic materials 0.000 claims description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 2
- 235000010216 calcium carbonate Nutrition 0.000 claims description 2
- 239000006072 paste Substances 0.000 claims description 2
- 239000007900 aqueous suspension Substances 0.000 claims 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims 1
- 235000019700 dicalcium phosphate Nutrition 0.000 claims 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 12
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 12
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 12
- 229940038472 dicalcium phosphate Drugs 0.000 description 12
- 229940088710 antibiotic agent Drugs 0.000 description 9
- 238000002156 mixing Methods 0.000 description 7
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical group [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 7
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 6
- 229930182566 Gentamicin Natural products 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 229960002518 gentamicin Drugs 0.000 description 6
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 6
- 239000007788 liquid Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- RDEIXVOBVLKYNT-VQBXQJRRSA-N (2r,3r,4r,5r)-2-[(1s,2s,3r,4s,6r)-4,6-diamino-3-[(2r,3r,6s)-3-amino-6-(1-aminoethyl)oxan-2-yl]oxy-2-hydroxycyclohexyl]oxy-5-methyl-4-(methylamino)oxane-3,5-diol;(2r,3r,4r,5r)-2-[(1s,2s,3r,4s,6r)-4,6-diamino-3-[(2r,3r,6s)-3-amino-6-(aminomethyl)oxan-2-yl]o Chemical compound OS(O)(=O)=O.O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H](CC[C@@H](CN)O2)N)[C@@H](N)C[C@H]1N.O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H](CC[C@H](O2)C(C)N)N)[C@@H](N)C[C@H]1N.O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N RDEIXVOBVLKYNT-VQBXQJRRSA-N 0.000 description 4
- RDEIXVOBVLKYNT-HDZPSJEVSA-N (2r,3r,4r,5r)-2-[(1s,2s,3r,4s,6r)-4,6-diamino-3-[(2r,3r,6s)-3-amino-6-[(1r)-1-aminoethyl]oxan-2-yl]oxy-2-hydroxycyclohexyl]oxy-5-methyl-4-(methylamino)oxane-3,5-diol;(2r,3r,4r,5r)-2-[(1s,2s,3r,4s,6r)-4,6-diamino-3-[(2r,3r,6s)-3-amino-6-(aminomethyl)oxan-2 Chemical compound OS(O)(=O)=O.O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H](CC[C@@H](CN)O2)N)[C@@H](N)C[C@H]1N.O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H](CC[C@H](O2)[C@@H](C)N)N)[C@@H](N)C[C@H]1N.O1[C@H]([C@@H](C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N RDEIXVOBVLKYNT-HDZPSJEVSA-N 0.000 description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 4
- 239000012620 biological material Substances 0.000 description 4
- 229910052791 calcium Inorganic materials 0.000 description 4
- 238000002513 implantation Methods 0.000 description 4
- 238000012545 processing Methods 0.000 description 4
- 244000052616 bacterial pathogen Species 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 230000002950 deficient Effects 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 238000005755 formation reaction Methods 0.000 description 3
- 239000003102 growth factor Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 102000007350 Bone Morphogenetic Proteins Human genes 0.000 description 2
- 108010007726 Bone Morphogenetic Proteins Proteins 0.000 description 2
- 206010031252 Osteomyelitis Diseases 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 2
- UFUVLHLTWXBHGZ-MGZQPHGTSA-N [(2r,3r,4s,5r,6r)-6-[(1s,2s)-2-chloro-1-[[(2s,4r)-1-methyl-4-propylpyrrolidine-2-carbonyl]amino]propyl]-4,5-dihydroxy-2-methylsulfanyloxan-3-yl] dihydrogen phosphate Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](OP(O)(O)=O)[C@@H](SC)O1 UFUVLHLTWXBHGZ-MGZQPHGTSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000036760 body temperature Effects 0.000 description 2
- 229940112869 bone morphogenetic protein Drugs 0.000 description 2
- 229960001139 cefazolin Drugs 0.000 description 2
- MLYYVTUWGNIJIB-BXKDBHETSA-N cefazolin Chemical compound S1C(C)=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 MLYYVTUWGNIJIB-BXKDBHETSA-N 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 229960002291 clindamycin phosphate Drugs 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 239000010419 fine particle Substances 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000000750 progressive effect Effects 0.000 description 2
- 150000003180 prostaglandins Chemical class 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- GBNXLQPMFAUCOI-UHFFFAOYSA-H tetracalcium;oxygen(2-);diphosphate Chemical compound [O-2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O GBNXLQPMFAUCOI-UHFFFAOYSA-H 0.000 description 2
- VAZJLPXFVQHDFB-UHFFFAOYSA-N 1-(diaminomethylidene)-2-hexylguanidine Chemical compound CCCCCCN=C(N)N=C(N)N VAZJLPXFVQHDFB-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 229940123208 Biguanide Drugs 0.000 description 1
- 208000010392 Bone Fractures Diseases 0.000 description 1
- GHXZTYHSJHQHIJ-UHFFFAOYSA-N Chlorhexidine Chemical compound C=1C=C(Cl)C=CC=1NC(N)=NC(N)=NCCCCCCN=C(N)N=C(N)NC1=CC=C(Cl)C=C1 GHXZTYHSJHQHIJ-UHFFFAOYSA-N 0.000 description 1
- HECLRDQVFMWTQS-UHFFFAOYSA-N Dicyclopentadiene Chemical compound C1C2C3CC=CC3C1C=C2 HECLRDQVFMWTQS-UHFFFAOYSA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010031264 Osteonecrosis Diseases 0.000 description 1
- 208000037581 Persistent Infection Diseases 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000001251 acridines Chemical class 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 229940126575 aminoglycoside Drugs 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000012062 aqueous buffer Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 150000004283 biguanides Chemical class 0.000 description 1
- 239000003462 bioceramic Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 239000002639 bone cement Substances 0.000 description 1
- 239000000316 bone substitute Substances 0.000 description 1
- 238000001354 calcination Methods 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 229960003260 chlorhexidine Drugs 0.000 description 1
- -1 chlorhexidine and Chemical class 0.000 description 1
- 229960004714 clindamycin palmitate Drugs 0.000 description 1
- OYSKUZDIHNKWLV-PRUAPSLNSA-N clindamycin palmitate Chemical compound O1[C@H](SC)[C@H](OC(=O)CCCCCCCCCCCCCCC)[C@@H](O)[C@@H](O)[C@H]1[C@@H]([C@H](C)Cl)NC(=O)[C@H]1N(C)C[C@H](CCC)C1 OYSKUZDIHNKWLV-PRUAPSLNSA-N 0.000 description 1
- 239000011362 coarse particle Substances 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 238000001804 debridement Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- CGMRCMMOCQYHAD-UHFFFAOYSA-J dicalcium hydroxide phosphate Chemical compound [OH-].[Ca++].[Ca++].[O-]P([O-])([O-])=O CGMRCMMOCQYHAD-UHFFFAOYSA-J 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229910052816 inorganic phosphate Inorganic materials 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- ZBGPYVZLYBDXKO-HILBYHGXSA-N netilmycin Chemical compound O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@]([C@H](NC)[C@@H](O)CO1)(C)O)NCC)[C@H]1OC(CN)=CC[C@H]1N ZBGPYVZLYBDXKO-HILBYHGXSA-N 0.000 description 1
- 210000000963 osteoblast Anatomy 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 235000011837 pasties Nutrition 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 238000002271 resection Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 230000008467 tissue growth Effects 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
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
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/02—Surgical adhesives or cements; Adhesives for colostomy devices containing inorganic materials
Description
® WO 99/49306 PCT/EP99/01738
Bio-cements having improved properties
The invention relates to biodegradable calcium phosphate cements, in particular mixtures of calcium phosphate-containing powders of different stoichio- metric composition having improved properties. The mixtures according to the invention all comprise tricalcium phosphate (TCP) and one or more other phosphate-containing inorganic compounds of different composition, the TCP content being present in a well defined particle size range.
Naturally occurring bone material consists of calcium phosphate having the hydroxylapatite structure.
However, the composition of bone minerals does not correspond to the ideal stoichiometric composition of crystalline hydroxylapatite (Ca;o(P0;)s(0OH),) but as a rule has a nonstoichiometric composition which is due to the incorporation of other anions, such as carbonate or hydrogen phosphate, instead of orthophosphate, but also of other cations, such as sodium, potassium or magnesium, instead of calcium.
Biodegradable calcium phosphate cements (CaP) are attracting more and more interest in traumatology and orthopaedics owing to the limited availability of autogenous bone and the problem of the bioburden with allogenic bone. A disadvantage of many available synthetic bone substitutes based on calcium and phosphorus is essentially that they are not degradable.
For some years it has been possible to prepare synthetic bone material which is based on hydroxyl- apatite-like calcium phosphate compounds and, owing to its qualitative and structural similarity, is very similar to natural bone. It is thus possible to avoid the known disadvantages which may arise through the acquisition of natural autogenous or heterogeneous bone. Furthermore, these materials have the advantage that they withstand mechanical loads virtually just as well as natural bones, which suggests their use in the case of more major bone defects or bone fractures.
! 4 The main components of these materials are, for example, tricalcium phosphate (TCP), dicalcium phosphate (DCP) and tetracalcium phosphate (TTCP), which, in the presence of water, react to give hydroxylapatite, the end product of the cement formation reaction. Since hydroxylapatite formed in this manner has formed in an aqueous environment, it resembles the biological apatites far more than the hydroxylapatite which is produced at high temperatures.
Such cements are therefore osteotransductive and hence very suitable for the repair and reconstruction of bones. They are rapidly integrated into bone structures and then converted into new bone tissue by the cellular activity of the osteoblasts.
Depending on the condition, essentially the following solids can occur in the system Ca(OH). - HiPO, - H,0:
Ca (H;PO,) 2 -H20 (MCPM)
CaHPO, (DCP)
CaHPOQ, - 2H,0 (DCPD)
Cag (HPQ,) 5 {PO4) 4 - 5H,0 (OCP)
Cas (HPO4) (P04) sOH (CDA)
Caio (POs) 6 (OH) 2 (PHA)
Cas (POy) 2+ H,0 (ACP)
Cas (POy) 2 (a, B-TCP)
Such cements are disclosed, for example, in
Us 4,518,430, US 4,612,053, US 4,678,355, US 4,880,610,
Us 5,053,212, US 5,152,836, US 5,605,713, EP 0 416 761,
EP 0 543 765, EP 0 664 133 or WO 96/36562.
The prior art furthermore discloses a cement consisting of o-TCP and fB-TCP and a small amount, serving as a crystallization nucleus, of precipitated hydroxylapatite (PHA) whose setting behaviour has been investigated (Jansen et al., J Mat Sc: Mat Med 6 (1995) 653-657). The following is a general equation for the reaction of a-TCP with water: po o ah 30-Cas (POs) > + HO — Cag (HPO,) (PO,) sOH and the following for the reaction with dicalcium phosphate (DCP): 2CaHPO, + 20-Caz (P04): + 5 HO — Cag (HPO,) 2 (PO4)4-5H,0.
The hardening of the initially pasty mixture takes place by the intermeshing of the calcium- deficient hydroxylapatite crystals precipitated during the setting process.
The properties of the known hydroxylapatites or calcium phosphate cements, in particular their physio- logical acceptance, acquired biocabsorbability and the ability to be replaced by newly generated natural bone tissue or stimulation of the growth thereof, and some of their physical properties, such as, for example, compressive strength and hardening times, depend on the more or less pronounced crystallinity, on the particle size and on the porosity which can be achieved during the preparation.
Thus, different biocements were obtained, for example, by adding CaHPO; or CaCO; or CaHPO, together with CaCO; to a mixture of «-TCP and B-TCP (Khairoun et al., Biomaterials, 10 (1997) 1535-1539). The compres- sive strength of certain compositions which was obtained after hardening was in the region of 30 MPa and hence in the region of trabecular human bone (Driessens et al., Bioceramics 10 (1997) 279-282), but the achievement of these high compressive strength values took 15 to 30 hours in spite of the use of customary hardening accelerators, which however is too long for use in traumatclogy and orthopaedics for the purpose of early stability and load bearing. In these cases, the «o,B-TCP mixture had been milled in such a way that about 60% to 70% of the powder had a particle size of less than 8 um and the remainder of the particles had a size of less than about 35 pum.
! ® Thus, there is still interest in the development of bone cements which have various properties to meet the different requirements. The present invention provides such cements having particular properties. The problem on which the invention was based was specifically whether novel cements having improved properties can be obtained by variation of the milling of the particle size of a TCP mixture together with admixtures of other inorganic phosphate compounds. :
The present invention thus relates to a mixture of powders which are suitable for the preparation of absorbable calcium phosphate cements and, in addition to tricalcium phosphate (TCP), comprise at least one further other phosphate-containing inorganic compound, which is characterized in that the TCP particles have the following particle size distribution: 30-90%: 0.1-40 pm and 10-70%: 40-300 um.
That a certain proportion of fine particles (about 1-40 um) and very fine particles (0.1-1 pm) must be present in addition to a certain proportion of coarse particles (40-300 um) is to be regarded as essential to the invention.
The mixtures according to the invention must always contain TCP. TCP occurs mainly in two different crystal modifications, a and fp. According to the invention, the mixtures comprise «a-TCP, it being possible to admix up to 60% of P-TCP. The invention thus relates to a mixture in which 40 to 100% of the
TCP present is in the a-form (a-TCP) and 0 to 60% is in the B-form (P-TCP). Where the term TCP is used above or below, this mixture of a- and B-TCP is, by definition, always meant.
The invention relates in particular to those mixtures in which 30 to 70% of the TCP particles have a particle size of 0.1 to 7 um. The invention furthermore
’ o relates to those mixtures in which 10 to 60% of the TCP particles have a particle size of 40 to 100 um.
Corresponding mixtures which have the following particle size distribution of the TCP particles are particularly preferred: 30-50%: 1-7 um 20-40%: 7-40 pm and 10-50%: 40-100 pm.
It was found that not only does the particle size of the TCP particles or their particle size distribution have an advantageous effect but that the size and property of the remaining phosphate-containing compounds in the mixture also play a role. According to the invention, at least 50% of these non-TCP particles should have a size between 10 and 100 pm. In general, these particles, too, may not be milled either tco fine or too coarse. The proportion of these non-TCP compounds in the mixtures according to the invention is 1-85%, preferably 5 to 60%.
Suitable compounds which can be mixed with TCP are in general all inorganic compounds which comprise calcium and phosphate. Particularly suitable compounds are disclosed in EP 543 765. The compounds which are selected from the following group are preferred:
Ca (H;PO4),-H0O, CaHPO,, CaHPO,-2H;0, Cag{HPO4),(P0O,)4-5H0,
Cay (HPO,) (POs) sOH, Ca, (POs) ¢ (OH) 2, carbonate-containing apatite, CaCO;, Ca (OH),, MgHPO,-3H0, Mg; (PO,;)., CaNaPOy,
CaiiNa (POs) ,, CaKPO,, CayP0,Cl, CayNaK(PO,),, Cajo(P0s)sClsy,
ZnHPO, - 4H,0 and Zn; (PO) ,, in particular from the group:
Cag (HPO,) 2 (POy) 4 - 5H,0, Cai (POs) (OH) 2, CaHPO; and CaCO;.
In summary, the mixtures having the following composition are particularly suitable:
- 6 ~ ! ® (1) TCP: 90-99% Cai (POs) 6 (OH) 5: 1-10%; (ii) TCP: 90-99% Cag (HPO); (PO4) 4-5H,0: 1-10%; (iii) TCP: 70-99% Cayo (POs) (OH): 1-10%,
CaCO;: 10-20%; (iv) TCP: 70-99% Cag (HPO, ) 5 (PO4) 4-5H,0:1-10%,
CaCO3: 10-20%; (v) TCP: 40-99% Caio (POs) (OH): 1-10%,
CaHPO,: 1-50%; (vi) TCP: 40-99% Cag (HPO) 5 (P04) 4-5H,0: 1-10%,
CaHPO,: 1-50%; (vi) TCP: 20-99% Cayo (POs) 6 (OH) 2: 1-10%,
CaHPO,: 1-50%, CaCO;: 1-20%; (vii) TCP: 20-99% Cag (HPO,) » (PO4) 4+ 5H,0: 1-10%,
CaHPO,: 1-50%, CaCO;: 1-20%.
The mixtures according to the present invention can, if desired, also contain known hardening accelerators. Disodium hydrogen phosphate is preferred here.
Furthermore, it was found that the TCP- containing bio-cements of the present invention are particularly advantageous if the content of magnesium in the starting materials is not more than about 0.13% and the content of sodium not more than about 0.2%.
The implantation of biomaterials in the human or animal body always involves the risk of populating these inanimate materials with germs, because these materials initially have no vascular supply and therefore cannot be protected by the immune system. It is therefore desirable to add antibiotics, for example from the aminoglycosides, such as gentamicin, or cefazolin, clindamycin palmitate, in particular clindamycin phosphate, or disinfectants to the biomaterials for their own temporary protection from population with germs, to avoid population with germs during the implantation. This gives rise to the next object, to demonstrate that antibiotics and/or disinfectants are not only mixed into the cements but are also eluted therefrom. Furthermore, mixing in
! ® antibiotics and/or disinfectants should not adversely affect the mechanical properties or the processing properties of the cements, for example with respect to the hardening times, in accordance with the intended use. Suitable disinfectants are acridines, in particular biguanides, such as chlorhexidine and, here in turn, in particular polyhexanidum (Lavasept®) .
Furthermore, by the mixing in and progressive release of antibiotics and/or disinfectants from absorbable calcium phosphate cements, this biomaterial can, after surgical debridement, be implanted in areas with a risk of infection. Moreover, the treatment of osteomyelitis, which is characterized by chronic infection and osteonecrosis, ig facilitated because it may be possible to remedy the osteomyelitis by a single operation.
Furthermore, it is desirable to mix with absorbable biocements further pharmaceutical active ingredients which have a very wide range of actions, for example increase the cellular activity of the bone surrounding the cement, to achieve increased absorption of the cement and replacement thereof by endogenous bone or formation of a composite of endogenous bone and unabsorbed portions of the cement, or active ingredients in the sense of chemotherapeutics which prevent the loosening of a stabilizing cement filling after tumour resection by tumour cells remaining in the vicinity.
Examples of such suitable pharmaceutical active ingredients are growth factors, such as FGF (Fibroblast
Growth Factor), BMP (Bone Morphogenetic Protein) or
TGF-P (Tissue Growth Factor), or other active ingredients, such as prostaglandins or substances which influence the prostaglandin metabolism, active ingredients which interact with the metabolism of the thyroid glands or pithyroid glands, or even chemcotherapeutics, such as, for example, methotrexate.
It has now been found that admixing such substances leads to corresponding hardened biocements which, owing
! ® to their structure, are capable of releasing these active ingredients into the environment within a few or several days after implantation.
The invention thus also relates to mixtures which additionally contain one or more pharmaceutical active ingredients or one or more disinfectants.
For implantation or injection, the mixtures according to the invention must be mixed with an agueous liquid so that setting or formation of apatite structures or apatite-like materials occurs according to the equation mentioned at the outset. As a result, advantageous properties are obtained after the powder mixtures are mixed with the aqueous liquids. These properties are characterized in that the paste obtained after the mixing of solid and liquid phase permit, in a temperature-dependent manner, certain processing possi- bilities, such as modelling and injectability, at certain time intervals. Suitable aqueous liquids are, for example, physiological saline solution, body fluids, such as blood or serum, or aqueous buffers.
In principle, the additives, such as pharmacological active ingredients or hardening accelerators, can not only be mixed with the TCP powder but also added in aqueous solution to the biocement to be stirred. This is then present as a creamy suspension or paste that can easily be introduced into the intended sites or defective bone structures.
Thus, the invention also relates to a corresponding mixture in the form of an aqueous solution, paste or suspension and its use for the preparation of biodegradable implantable synthetic bone materials.
The stirred and setting mixtures according to the invention are distinguished in particular by a desired compressive strength of 30 MPa or more, which, depending on the composition of the mixture according to the invention, is reached after only very short hardening times between two and ten, preferably between three and six, hours, whereas in the prior art, in the
' ® case of mixtures having a slightly changed composition, hardening times of 15 to 30 hours as a rule and the strength is only slightly above 30 MPa. Within these longer hardening times, compressive strengths as high as 40 to 50 MPa can be achieved in the case of the mixtures according to the invention.
The figures are explained briefly below.
Fig. 1: Antibiotic elution from biocement D
Batches:
I. 1 g of cement + 0.7 ml of Refobacin 120; 0.7 g thereof / 20 ml of buffer (= 20 mg)
IT. 1 ml of Med. 65-agar + 0.7 wml of Refobacin 120/20 ml of buffer
III. 1 g of cement + 0.7 ml of cefazolin 60 mg/ml, 1.04 g thereof / 20 ml of buffer (= 25.7 mg)
IV. 1 g of cement + 0.7 ml of netilmycin 60 mg/ml, 1.15 g/20 ml of buffer (= 28.4 mg)
Vv. 1 g of cement + 0.7 ml of clindamycin phosphate 60 mg/ml, 0.99 g / 20 ml of buffer (= 24.5 mg)
Elution in 1/15 M phosphate buffer, pH 7.4, 37°C
Paragraphs [sic] I to V correspond to the identically denoted curves in the figure.
Fig. 2: Gentamicin release from H-, B-, F- and D-cement
Release in ug
C - 10 -
Er FU FE FE PE
Cement H B F D
Buffer 20 20 20 20
Gentamicin in % | 4.2 4.2 4.2 4.2
Additive Na,HPQO, Na,HPO, Na, HPO, Na,HPQO,
Day 1 249.13 308.28 238.91 302.06
Day 2 18.93 21.35 29.55 22.16
Day 3 7.05 8.96 12.30 14.02
Day 4 6.63 7.20 9.05 12.64
Day 5 3.91 4.14 6.44 9.44
Day 6 4.05 4.07 5.15 7.95
Day 7 2.53 3.57 5.13 6.71
Day 8 1.83 2.96 2.55 3.74
Day 9 1.39 3.75 2.96 4.55
Day 10 1.86 3.20 2.75 3.99
The numbers of the mixtures correspond to the identically denoted curves.
Example 1: a-TCP was prepared by a calcination process at 1350°C for 4 hours, and subsequent ccoling in room air, of a 2:1 molar mixture of CaHPO, and CaCO;. The reaction product obtained contained less than 10% of PB-TCP.
The o-TCP was milled, sieved and mixed in such a way that about 50% had a particle size between 0.1 and 7 pm, about 25% between 7 and 25 um and a further 25% between 25 and 80 um. The OCP was prepared by the method of LeGeros (Calzif. Tiss. Int. 37 (1985) 194- 197).
The properties of the following cement mixtures were demonstrated by way of example:
Below, the meanings are as follows:
Biocement H: Mixture of a-TCP and PHA
Biocement F: Mixture of a-TCP, DCP and PHA
! ® Biocement D: Mixture of a-TCP, DCP, CaCO; and
PHA
Biocement H-OCP: Mixture of a-TCP and OCP
Biocement F-OCP: Mixture of a-TCP, DCP and OCP
Biocement D-OCP: Mixture of o-TCP, DCP, CaCO; and
OCP
Biocement a-TCP DCP CaCO; PHA OCP a-TCP 20 - - - -
H 20 - - 0.40 -
H-OCP 20 - - - 1.00
F 14 6.0 - 0.40 -
F-0OCP 14 6.0 - - 1.00
D 14 6.0 2.0 0.40 -
D-OCP 14 6.0 2.0 - 1.00
The numerical data of the mixing ratios are in grammes. The liquid used for mixing the powders is a 4% solution of Na,HPO; in water. The liquid/powder ratio is 0.30 ml/g of powder.
The initial hardening (ti) and the time until reaching the final hardness (tg) were determined at room temperature (20+1°C) and at 37+1°C according to
ASTM standard by means of Gilmoore needles.
The compressor strength was determined using a
Lloyd type LR50K material tester after immersion for 1, 2, 4, 18 and 65 hours in Ringer's solution. The reaction product was determined by means of X-ray diffractometry.
For the preparation of the bio-cements F,
F-OCP, D and D-OCP, whose common feature is the admixing of DCP, a particularly preferred DCP is one whose Ca/P ratio is > 1.45.
Example 2:
Antibiotics/disinfectants in liquid formulation and as solid were mixed into the cements obtained, and the release behaviour was determined. The elution solution
¢ 1d used was a phosphate buffer according to Sbdérensen, pH 7.4 at 37°C.
The hardening properties of mixtures of cements with antibiotics/disinfectants were determined according to ASTM standards.
X-ray diffractometry showed that CaHPO, in the cements F-OCP and D-OCP did not react and, in spite of the additional OCP as a crystallization nucleus, formed a calcium-deficient hydroxylapatite.
Setting times (min.) as tt; and tf at 20°C and 37°C (standard deviation)
Biocement t; (20°C) t; (37°C) te (20°C) te (37°C) o-TCP 31 (1) 4.5 (0.25) 51 (1) 7 (0.5)
H 19 (1) 3.25 (0.25) 40 (1) 6 (0.5)
H-0OCP 17.5 (1) 3.25 (0.25) 35 (1) 6 (0.5)
F 5.75 (0.25) 3.25 (0.25) 16 (1) 9 (0.5)
F-OCP 10 (0.5) 3.5 (0.25) 16.5 (1) 4.5 (0.25)
D 9.75 (0.5) 3.5 (0.25) 19 (1) 8.25 (0.5)
D-OCP 11.5 (0.5) 3 (0.25) 22 (1) 6.5 (0.5)
Compressor strength after 1, 2, 4, 18 and 65 hours
Biocement 1 h 2 h 4 h 18 h 65 h a-TCP 10 (1) 18 (1) 31 (2) - 32 (3)
H 11 (1) 20 (1) 38 (2) 40 (4) 41 (5)
H-OCP 13 (1) 18 (2) 37 (3) 40 (5) -
F 11 (1) 18 (3) 28 (3) 31 (4) 39 (2)
F-OCP 11 (1) 29 (1) 32 (2) 42 (3) 41 (2)
D 10 (2) 16 (1) 26 (2) 45 (5) 47 (2)
D-QCP 10 (1) 16 (2) 23 (1) 45 (3) 47 (6)
The results show that the object of the invention has been achieved. The initial and final hardening time is shortened in comparison with «o-TCP (with 10% P-TCP content) by adding OCP and PHA. The shift of the kinetics of hardening towards shorter times is particularly pronounced at low temperature,
JH
' ® whereas at body temperature the effect 1s only very slight. This is particularly advantageous for the processing properties of the cement obtained because sufficiently long processing time is ensured at room temperature whereas the hardening at body temperature is not too short and hence the cement introduced can still be modelled. The data on the compressor strength of the biocements demonstrated here by way of example show that the final strength is generally reached after 6 hours and that the Dbiocement D and D-OCP achieve strengths of up to 50 MPa.
Example 3:
The next of object of the invention, namely the mixing in and progressive release of active ingredients from the cements, for example of an antibiotic for implant protection or for fighting infection, is also shown below to have been achieved.
The kinetics of release of the biocement D chosen by way of example and containing various antibiotics as well as the kinetics of release of various biocements containing gentamicin are shown in Figures 1 and 2.
By mixing in antibiotics/disinfectants, the kinetics of hardening or the strength is not adversely affected in relation to the desired effect of the release of antibiotics. The results of using biocement H, F and D with gentamicin sulphate powder in a 1liquid/powder ratio of 0.30 with the use of Na;HPO, or gentamicin sulphate solution as liguid at 37°C are shown as an example. The stated strength values were determined after 20 hours. The values t; and ty are measured in minutes and relate to the measurements using the
Gilmoore needle. The cohesion time (CT) was measured at room temperature and is stated in minutes.
! ® Measured values determined using gentamicin sulphate powder 120 mg / 5 g of cement
Biocement ts oF CT F (MPa) t; te CT F (MPa) without gentamicin with gentamicin
H 3.5 6 6 40+4 8 14 1.5 3743
F 3.5 5 3.5 31+4 7.5 9.5 1.5 39+3
D 4 5.5 1.5 4545 5 8 1.5 41+1
Measured values determined using gentamicin sulphate as solution (Refobacin 120®) without the use of Na,HPO, and only with Na,HPO, )
Biocement ty te CT F (MPa) oi te CT F (MPa)
Refobacin 120® Na,HPO,
H 7 12 < 2 48+4 3.5 +6 6 40+4
EF 3.5 5 3.5 31+4 7.5 9.5 1.5 3943
D 4 5.5 1.5 45+5 5 8 1.5 41+1
Example 4:
Preparation of TCP with starting materials
In the preparation of TCP, the percentage content of o/fp TCP is substantially influenced by the percentages by weight of Mg and Na in the starting substances but also by the relative Ca/P ratio. The following table gives an overview of the effect of Mg and Na on the phase composition of TCP: $Mg $Na £B-TCP 0.11 0.12 5 0.39 0.10 70 0.25 0.022 35 0.23 0.025 25 <0.0005 0.0024 <5 <0.0005 0.0029 <5 <0.0005 0.0013 <5 0.062 0.0081 <5 0.11 0.72 100 ood
° - 15 - ) 0.0024 0.20 <5 0.13 0.20 <5
Claims (21)
1. Mixture of powders suitable for the preparation of absorbable calcium phosphate cements, comprising tricalcium phosphate (TCP) and at least one further other phosphate-containing inorganic compound, charac- terized in that the TCP particles have the following particle size distribution: 30-90%: 0.1-40 pm and 10-70%: 40-300 pm.
2. Mixture according to Claim 1, characterized in that 30-70% of the TCP particles have a particle size of between 0.1 and 7 um.
3. Mixture according to Claim 1, characterized in that at least 10-60% of the TCP particles have a particle size of between 40 and 100 um.
4. Mixture according to Claim 1, characterized in that the TCP particles have the following particle size distribution: 30-50%: 1-7 pm 20-40%: 7-40 pm and 10-50%: 40-100 pm.
5. Mixture according to any of Claims 1 to 4, characterized in that at least 50% of the remaining particles have a particle size of between 10 and 100 um.
6. Mixture according to any of Claims 1 to 5, characterized in that 40 to 100% of the TCP is present in the a-form (a-TCP) and 0 to 60% in the B form (B- TCP) . .
7. Mixture according to any of Claims 1 to 6, characterized in that the proportion of said other
) ® phosphate-containing compounds is 1 to 85% of the total mixture.
8. Mixture according to any of Claims 1 to 7, characterized in that at least one other phosphate- containing compound was selected from the group: Ca (H,;PO4) ,-H,O, CaHPO,, CaHPQ,-2H,0, Cag(HPO,); (P04) 4-5H,0, Cag (HPO) (PQ4) OH, Cap (P04) ¢ (OH) 2, carbonate-containing apatite, CaCO;, Ca (OH),, MgHPOC,-3H,0, Mg; (P0O4),, CaNaPO,, CaiNa (PQ;),, CaKPO,;, CapP0.Cl, CaNaK(PQ;),, Caip{(PQ4)eClsz, ZnHPO, -4H,0 and Zn; (P04) 5.
9. Mixture according to Claim 8, characterized in that at least one other phosphate-containing compound was selected from the group: Cag (HPO4) 2 (PO4) 4 5H,0, Cayo (P04) (OH),, CaHPO, and CaCO;.
10. Mixture according to Claim 9 in a total composition selected from the following group: (i) TCP: 90-99% Caio (PO4)¢ (OH) 2: 1-10%; (ii) TCP: 90-99% Cag (HPO) 2 (POy4) 4-5H;0: 1-10%; (iii) TCP: 70-99% Ca10(PO4)e(OH)2: 1-10%, CaCO3: 10-20%; (iv) TCP: 70-99% Cag (HPO) 2 (POy4) 4-5H,0:1-10%, CaCO;: 10-20%; (v) TCP: 40-99% Cag (P04) (OH) 2: 1-10%, CaHPO,: 1-50%; (vi) TCP: 40-99% Cag (HPQ,) 2 (POs) 4 5Hz0: 1-10%, CaHPO4: 1-50%; (vi) TCP: 20-99% Cag (POs) (OH) 2: 1-10%, CaHPO,: 1-50%, CaCOs: 1-20%; (vii) TCP: 20-99% Cag (HPO) 2 (PO4) 4-5H,0: 1-10%, CaHPO,: 1-50%, CaCO;: 1-20%.
11. Mixture according to any of Claims 1 to 10, characterized in that the percentage content of magnesium and sodium in the starting components does not exceed a value of 0.13 (Mg) and 0.2 (Na), regpectively.
' » r & ETE
12. Mixture according to any of Claims 1 to 11, characterized in that it additionally comprises a setting accelerator.
13. Mixture according to any of Claims 1 to 12, characterized in that it additionally comprises a pharmaceutical active ingredient.
14. Mixture according to Claim 13, characterized in that it comprises an antibiotic or disinfectant.
15. Mixture according to any of Claims 1 to 14, characterized in that it is present in the form of an aqueous solution, suspension or paste.
16. Bicdegradable implant, produced from a hardened mixture according to Claim 15.
17. The use of a mixture according to Claim 15 for the preparation of biodegradable implantable synthetic bone materials.
18. A mixture according to Claim 1, substantially as herein described and illustrated.
19. An implant according to Claim 16, substantially as herein described and illustrated.
20. Use according to Claim 17, substantially as herein described and illustrated.
21. A new mixture, new implant, or new use of a mixture according to Claim 15, substantially as herein described. AMENDED SHEET
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19813614A DE19813614A1 (en) | 1998-03-27 | 1998-03-27 | Bio-cements with improved properties |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ZA200006034B true ZA200006034B (en) | 2001-08-10 |
Family
ID=7862589
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200006034A ZA200006034B (en) | 1998-03-27 | 2000-10-26 | Biologically degradable cement exhibiting improved properties. |
Country Status (10)
| Country | Link |
|---|---|
| EP (1) | EP1066065A1 (en) |
| JP (1) | JP2002509766A (en) |
| CN (1) | CN1295485A (en) |
| AU (1) | AU2933699A (en) |
| CA (1) | CA2325740A1 (en) |
| DE (1) | DE19813614A1 (en) |
| HU (1) | HUP0101520A3 (en) |
| PL (1) | PL342733A1 (en) |
| WO (1) | WO1999049906A1 (en) |
| ZA (1) | ZA200006034B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1153621A1 (en) * | 2000-05-12 | 2001-11-14 | MERCK PATENT GmbH | Biocements based on a mixture of TCP-PHA with improved compressive strength |
| JP2004511320A (en) | 2000-10-16 | 2004-04-15 | ユニバーシテイ・オブ・サウス・カロライナ | Biocompatible cement containing reactive calcium phosphate nanoparticles and methods of making and using said cement |
| JP2002291866A (en) * | 2001-04-03 | 2002-10-08 | Ngk Spark Plug Co Ltd | Calcium phosphate cement powder and calcium phosphate cement |
| DE10249625B4 (en) * | 2002-10-21 | 2005-08-04 | BAM Bundesanstalt für Materialforschung und -prüfung | Powder mixture for resorbable calcium phosphate biocements and their use |
| AU2006287478B2 (en) | 2005-09-09 | 2012-02-02 | Agnovos Healthcare, Llc | Composite bone graft substitute cement and articles produced therefrom |
| EP2077126A1 (en) * | 2008-01-07 | 2009-07-08 | Graftys | Analgesic apatitic calcium-phosphate cement |
| JP5478872B2 (en) * | 2008-11-05 | 2014-04-23 | 国立大学法人東北大学 | Artificial aggregate |
| MX351724B (en) * | 2012-01-31 | 2017-10-26 | Univ Toledo | Injectable, biodegradable bone cements and methods of making and using same. |
| US9487443B2 (en) * | 2014-03-14 | 2016-11-08 | Ricoh Company, Ltd. | Layer stack formation powder material, powder layer stack formation hardening liquid, layer stack formation material set, and layer stack object formation method |
| CN106587681B (en) * | 2016-12-06 | 2019-04-12 | 南昌大学 | A kind of preparation method of green construction material-biology cement |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4668295A (en) * | 1985-04-25 | 1987-05-26 | University Of Dayton | Surgical cements |
| DE3613213A1 (en) * | 1986-04-18 | 1987-10-22 | Merck Patent Gmbh | TRICALCIUMPHOSPHATE FOR IMPLANTATION MATERIALS |
| US5569442A (en) * | 1994-11-04 | 1996-10-29 | Norian Corporation | Reactive tricalcium phosphate compositions and uses |
-
1998
- 1998-03-27 DE DE19813614A patent/DE19813614A1/en not_active Withdrawn
-
1999
- 1999-03-17 JP JP2000540868A patent/JP2002509766A/en active Pending
- 1999-03-17 WO PCT/EP1999/001738 patent/WO1999049906A1/en not_active Application Discontinuation
- 1999-03-17 CA CA002325740A patent/CA2325740A1/en not_active Abandoned
- 1999-03-17 PL PL99342733A patent/PL342733A1/en unknown
- 1999-03-17 HU HU0101520A patent/HUP0101520A3/en unknown
- 1999-03-17 AU AU29336/99A patent/AU2933699A/en not_active Abandoned
- 1999-03-17 EP EP99910351A patent/EP1066065A1/en not_active Withdrawn
- 1999-03-17 CN CN99804569.1A patent/CN1295485A/en active Pending
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Also Published As
| Publication number | Publication date |
|---|---|
| DE19813614A1 (en) | 1999-09-30 |
| AU2933699A (en) | 1999-10-18 |
| HUP0101520A2 (en) | 2001-11-28 |
| PL342733A1 (en) | 2001-07-02 |
| CN1295485A (en) | 2001-05-16 |
| EP1066065A1 (en) | 2001-01-10 |
| WO1999049906A1 (en) | 1999-10-07 |
| HUP0101520A3 (en) | 2001-12-28 |
| JP2002509766A (en) | 2002-04-02 |
| CA2325740A1 (en) | 1999-10-07 |
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