JP2012519641A - ガリウムがドープされたリン酸カルシウム化合物 - Google Patents
ガリウムがドープされたリン酸カルシウム化合物 Download PDFInfo
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- JP2012519641A JP2012519641A JP2011552440A JP2011552440A JP2012519641A JP 2012519641 A JP2012519641 A JP 2012519641A JP 2011552440 A JP2011552440 A JP 2011552440A JP 2011552440 A JP2011552440 A JP 2011552440A JP 2012519641 A JP2012519641 A JP 2012519641A
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- JP
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- Prior art keywords
- gallium
- calcium phosphate
- compound
- doped
- phosphate compound
- 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.)
- Granted
Links
- 239000001506 calcium phosphate Substances 0.000 title claims abstract description 76
- 235000011010 calcium phosphates Nutrition 0.000 title claims abstract description 68
- 229910000389 calcium phosphate Inorganic materials 0.000 title claims abstract description 67
- -1 Calcium phosphate compound Chemical class 0.000 title claims abstract description 58
- 229910052733 gallium Inorganic materials 0.000 title claims abstract description 55
- GYHNNYVSQQEPJS-UHFFFAOYSA-N Gallium Chemical compound [Ga] GYHNNYVSQQEPJS-UHFFFAOYSA-N 0.000 title claims abstract description 53
- 239000011575 calcium Substances 0.000 claims abstract description 53
- 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 abstract description 50
- 238000004519 manufacturing process Methods 0.000 claims abstract description 41
- 150000001875 compounds Chemical class 0.000 claims abstract description 32
- 238000000034 method Methods 0.000 claims abstract description 18
- 239000004568 cement Substances 0.000 claims abstract description 13
- 239000000203 mixture Substances 0.000 claims abstract description 11
- 239000007787 solid Substances 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- 239000012620 biological material Substances 0.000 claims abstract description 6
- 150000004677 hydrates Chemical class 0.000 claims abstract description 5
- 229910052791 calcium Inorganic materials 0.000 claims description 20
- 239000000243 solution Substances 0.000 claims description 19
- CHPZKNULDCNCBW-UHFFFAOYSA-N gallium nitrate Chemical compound [Ga+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O CHPZKNULDCNCBW-UHFFFAOYSA-N 0.000 claims description 18
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 17
- 150000002259 gallium compounds Chemical class 0.000 claims description 14
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 10
- 229940044658 gallium nitrate Drugs 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 6
- AJNVQOSZGJRYEI-UHFFFAOYSA-N digallium;oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Ga+3].[Ga+3] AJNVQOSZGJRYEI-UHFFFAOYSA-N 0.000 claims description 6
- 229910001195 gallium oxide Inorganic materials 0.000 claims description 6
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 5
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Substances OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- 238000005245 sintering Methods 0.000 claims description 4
- ZHJGWYRLJUCMRT-UHFFFAOYSA-N 5-[6-[(4-methylpiperazin-1-yl)methyl]benzimidazol-1-yl]-3-[1-[2-(trifluoromethyl)phenyl]ethoxy]thiophene-2-carboxamide Chemical compound C=1C=CC=C(C(F)(F)F)C=1C(C)OC(=C(S1)C(N)=O)C=C1N(C1=C2)C=NC1=CC=C2CN1CCN(C)CC1 ZHJGWYRLJUCMRT-UHFFFAOYSA-N 0.000 claims description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 238000001354 calcination Methods 0.000 claims description 3
- 229940043430 calcium compound Drugs 0.000 claims description 3
- 150000001674 calcium compounds Chemical class 0.000 claims description 3
- YEEGWNXDUZONAA-UHFFFAOYSA-K 5-hydroxy-2,8,9-trioxa-1-gallabicyclo[3.3.2]decane-3,7,10-trione Chemical compound [Ga+3].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O YEEGWNXDUZONAA-UHFFFAOYSA-K 0.000 claims description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 claims description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims description 2
- JJBNCYLBHKHXAH-UHFFFAOYSA-N O.O.O.[Ga] Chemical compound O.O.O.[Ga] JJBNCYLBHKHXAH-UHFFFAOYSA-N 0.000 claims description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 2
- VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 claims description 2
- 239000001639 calcium acetate Substances 0.000 claims description 2
- 235000011092 calcium acetate Nutrition 0.000 claims description 2
- 229960005147 calcium acetate Drugs 0.000 claims description 2
- 239000001110 calcium chloride Substances 0.000 claims description 2
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 2
- WUKWITHWXAAZEY-UHFFFAOYSA-L calcium difluoride Chemical compound [F-].[F-].[Ca+2] WUKWITHWXAAZEY-UHFFFAOYSA-L 0.000 claims description 2
- 229910001634 calcium fluoride Inorganic materials 0.000 claims description 2
- FYWVTSQYJIPZLW-UHFFFAOYSA-K diacetyloxygallanyl acetate Chemical compound [Ga+3].CC([O-])=O.CC([O-])=O.CC([O-])=O FYWVTSQYJIPZLW-UHFFFAOYSA-K 0.000 claims description 2
- 229910021513 gallium hydroxide Inorganic materials 0.000 claims description 2
- 229910000373 gallium sulfate Inorganic materials 0.000 claims description 2
- UPWPDUACHOATKO-UHFFFAOYSA-K gallium trichloride Chemical compound Cl[Ga](Cl)Cl UPWPDUACHOATKO-UHFFFAOYSA-K 0.000 claims description 2
- SBDRYJMIQMDXRH-UHFFFAOYSA-N gallium;sulfuric acid Chemical compound [Ga].OS(O)(=O)=O SBDRYJMIQMDXRH-UHFFFAOYSA-N 0.000 claims description 2
- 230000001376 precipitating effect Effects 0.000 claims description 2
- HECLRDQVFMWTQS-UHFFFAOYSA-N Dicyclopentadiene Chemical compound C1C2C3CC=CC3C1C=C2 HECLRDQVFMWTQS-UHFFFAOYSA-N 0.000 claims 1
- 150000002258 gallium Chemical class 0.000 claims 1
- ZIMMUTZCWZAVJS-UHFFFAOYSA-M hydroxy(oxo)gallane Chemical compound O[Ga]=O ZIMMUTZCWZAVJS-UHFFFAOYSA-M 0.000 claims 1
- 239000002243 precursor Substances 0.000 claims 1
- LFULEKSKNZEWOE-UHFFFAOYSA-N propanil Chemical compound CCC(=O)NC1=CC=C(Cl)C(Cl)=C1 LFULEKSKNZEWOE-UHFFFAOYSA-N 0.000 claims 1
- 230000008569 process Effects 0.000 abstract description 3
- 210000000988 bone and bone Anatomy 0.000 description 11
- 235000019731 tricalcium phosphate Nutrition 0.000 description 9
- 150000002500 ions Chemical class 0.000 description 8
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- 229940078499 tricalcium phosphate Drugs 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 7
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [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
- 208000001132 Osteoporosis Diseases 0.000 description 6
- RBLGLDWTCZMLRW-UHFFFAOYSA-K dicalcium;phosphate;dihydrate Chemical compound O.O.[Ca+2].[Ca+2].[O-]P([O-])([O-])=O RBLGLDWTCZMLRW-UHFFFAOYSA-K 0.000 description 6
- 239000007943 implant Substances 0.000 description 6
- 239000000523 sample Substances 0.000 description 6
- 229910021642 ultra pure water Inorganic materials 0.000 description 6
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- 239000000376 reactant Substances 0.000 description 5
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- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 229910019142 PO4 Inorganic materials 0.000 description 4
- 229910052586 apatite Inorganic materials 0.000 description 4
- XAAHAAMILDNBPS-UHFFFAOYSA-L calcium hydrogenphosphate dihydrate Chemical compound O.O.[Ca+2].OP([O-])([O-])=O XAAHAAMILDNBPS-UHFFFAOYSA-L 0.000 description 4
- ZCCIPPOKBCJFDN-UHFFFAOYSA-N calcium nitrate Chemical compound [Ca+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O ZCCIPPOKBCJFDN-UHFFFAOYSA-N 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 210000002997 osteoclast Anatomy 0.000 description 4
- 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 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 4
- 239000010452 phosphate Substances 0.000 description 4
- 235000021317 phosphate Nutrition 0.000 description 4
- 239000000047 product Substances 0.000 description 4
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- 208000010191 Osteitis Deformans Diseases 0.000 description 3
- 210000002449 bone cell Anatomy 0.000 description 3
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 3
- 150000001768 cations Chemical class 0.000 description 3
- 230000002950 deficient Effects 0.000 description 3
- 229940095079 dicalcium phosphate anhydrous Drugs 0.000 description 3
- 230000000705 hypocalcaemia Effects 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 239000003002 pH adjusting agent Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical group [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 208000006386 Bone Resorption Diseases 0.000 description 2
- 208000020084 Bone disease Diseases 0.000 description 2
- 206010061728 Bone lesion Diseases 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
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- 230000010072 bone remodeling Effects 0.000 description 2
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- ZBZJARSYCHAEND-UHFFFAOYSA-L calcium;dihydrogen phosphate;hydrate Chemical compound O.[Ca+2].OP(O)([O-])=O.OP(O)([O-])=O ZBZJARSYCHAEND-UHFFFAOYSA-L 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
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- 229910000388 diammonium phosphate Inorganic materials 0.000 description 2
- 235000019838 diammonium phosphate Nutrition 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000010304 firing Methods 0.000 description 2
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- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
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- CKHJYUSOUQDYEN-UHFFFAOYSA-N gallium(3+) Chemical compound [Ga+3] CKHJYUSOUQDYEN-UHFFFAOYSA-N 0.000 description 1
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- DWRNSCDYNYYYHT-UHFFFAOYSA-K gallium(iii) iodide Chemical compound I[Ga](I)I DWRNSCDYNYYYHT-UHFFFAOYSA-K 0.000 description 1
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- 125000005341 metaphosphate group Chemical group 0.000 description 1
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- QSUVHYRUWBKUKW-UHFFFAOYSA-H tetracalcium;diphosphate Chemical compound [Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QSUVHYRUWBKUKW-UHFFFAOYSA-H 0.000 description 1
- 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 1
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Images
Classifications
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- A—HUMAN NECESSITIES
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Abstract
Description
骨は、バイオポリマー、特にコラーゲン、及び、(Ca,Mg,Na,M)10(PO4,CO3,HPO4)6(OH,Cl)2と見積もられる、炭酸ヒドロキシアパタイトとして同定された無機成分を含む混合物である。
それに存在する全身投与経路の結果として、ガリウムは、骨材料に対する低レベルの吸収を示し、副作用の潜在性が高い。
本発明は、新規のガリウムがドープされたリン酸カルシウム化合物を提供する。本発明者らは、驚くべきことに、Ga(III)イオンをリン酸カルシウム化合物中に包含させることが可能であることを示す。さらに、かかるガリウム修飾されたリン酸カルシウム化合物がインサイチュ(in situ)においてガリウムを放出可能であることを示す。
第一の態様において、本発明は、式(I):
で表される、ガリウムがドープされたリン酸カルシウム化合物及びその塩、それらの水和物、並びにそれらの混合物に関する。
第二の態様において、本発明は、上記のガリウムがドープされたリン酸カルシウム化合物の製造方法に関する。
(a)適量のガリウム化合物の存在下で、リン酸カルシウムを炭酸カルシウムと接触させ;
(b)当該混合物を焼結してガリウムがドープされたリン酸カルシウム化合物を形成し;そして
(c)前記ガリウムがドープされたリン酸カルシウム化合物を回収すること
を含む、前記方法に関する。
(a)カルシウム化合物及び好適量のガリウム化合物を含有する水溶液を調製するステップ;
(b)ステップ(a)で得られた溶液のpHを、必要であれば、8.5〜12、好ましくは9〜11、より好ましくは9〜9.5に調節するステップ;
(c)前記溶液に好適量のリン酸化合物を添加するステップ;
(d)前記溶液のpHを7.0〜12、好ましくは7.5〜9、より好ましくは7.5〜8に調整することによってガリウムがドープされたリン酸カルシウム化合物を析出させるステップ;そして
(e)前記析出したガリウムがドープされたリン酸カルシウム化合物を溶液から分離するステップ
から成るステップを含む。
実施例1:固体状態反応による、ガリウムがドープされたリン酸カルシウムの製造
乳鉢中で、以下の等式を使用して、(Ca+Ga)/Pモル比が所望のx値に相当するように計算された量の炭酸カルシウム及び酸化ガリウムを、無水リン酸カルシウム(0.174mol)と共にしっかりと混合した。
(Ca+Ga)/Pモル比が1.5である製造物のために、0.444gの硝酸ガリウム(Aldrich,MW=390)及び2.685gの硝酸カルシウム四水和物(MW=236)の混合物を、125mlの超純水を含有するビーカー中で溶解した。
Claims (15)
- 式(I)の化合物において、0<x≦0.85である、請求項1に記載のガリウムがドープされたリン酸カルシウム化合物。
- 式(I)の化合物が、Ca10.125Ga0.25(PO4)7;Ca9.75Ga0.5(PO4)7;Ca9.375Ga0.75(PO4)7;及びCa9.27Ga0.82(PO4)7から成る群から選択される、請求項1又は2に記載のガリウムがドープされたリン酸カルシウム化合物。
- 式(I)の化合物が、Ga含量に応じて以下の範囲:a=10.31〜10.44Å、c=37.15〜37.5Å、α=90°;β=90°及びγ=120°で変化する格子パラメーターを有するR3c空間群で少なくとも部分的に結晶化される、請求項1又は2に記載のガリウムがドープされたリン酸カルシウム化合物。
- 式(I)のガリウムがドープされたリン酸カルシウム化合物の製造のための固体状態での製造方法であって、以下のステップ:
(a)適量のガリウム化合物の存在下で、リン酸カルシウムを炭酸カルシウムと接触させ;
(b)当該混合物を焼結してガリウムがドープされたリン酸カルシウム化合物を形成し;そして
(c)前記ガリウムがドープされたリン酸カルシウム化合物を回収すること
を含む、前記方法。 - ステップ(a)において使用される前記リン酸カルシウムが、DCPA、DCPD、又はそれらの混合物である、請求項5に記載の方法。
- ステップ(a)において使用される前記ガリウム化合物が酸化ガリウムである、請求項5又は6に記載の方法。
- ガリウムがドープされたリン酸カルシウム化合物の製造のための溶液中での製造方法であって、以下のステップ:
(a)カルシウム化合物及び好適量のガリウム化合物を含有する水溶液を調製し;
(b)ステップ(a)で得られた溶液のpHを、必要であれば8.5〜12に調節し;
(c)前記溶液に好適量のリン酸化合物を添加し;
(d)得られた溶液のpHを7.0〜12に調整することによって、ガリウムがドープされたリン酸カルシウム化合物を析出させ;そして
(e)析出したガリウムがドープされたリン酸カルシウム化合物を溶液から分離すること
を含む、前記方法。 - ステップ(a)における前記ガリウム塩が、酢酸ガリウム、炭酸ガリウム、クエン酸ガリウム、塩化ガリウム、フッ化ガリウム、ギ酸ガリウム、硝酸ガリウム、シュウ酸ガリウム、硫酸ガリウム、水酸化ガリウム、酸化ガリウムヒドロキシドから成る群から選択される、請求項8に記載の方法。
- ステップ(a)における前記カルシウム固体前駆体が、硝酸カルシウム四水和物、酢酸カルシウム、塩化カルシウム及びフッ化カルシウムから成る群から選択される、請求項8又は9に記載の方法。
- 前記リン酸化合物がリン酸水素アンモニウムである、請求項8〜10のいずれか1項に記載の方法。
- ステップ(d)が37〜80℃で行われる、請求項8〜11のいずれか1項に記載の方法。
- 得られたガリウムがドープされたリン酸カルシウム化合物のその後の焼成をさらに含む、請求項8〜12のいずれか1項に記載の方法。
- (Ca+Ga)/Pモル比が1.3〜1.67であり、ガリウム含量が4.5重量%以下である、請求項8〜12のいずれか1項に記載の方法によって得られうる、ガリウムがドープされたリン酸カルシウム化合物。
- 生体材料、特に自己凝結性リン酸カルシウムセメント(CPC)の製造のための、請求項1〜4及び14のいずれか1項に記載のガリウムがドープされたリン酸カルシウム化合物の使用。
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EP09305194A EP2228079A1 (en) | 2009-03-03 | 2009-03-03 | Gallium-doped phosphocalcic compounds |
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PCT/EP2010/052721 WO2010100209A1 (en) | 2009-03-03 | 2010-03-03 | Gallium-doped phosphocalcic compounds |
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JP6206880B2 (ja) * | 2012-08-16 | 2017-10-04 | 学校法人中部大学 | 骨修復材料及びその製造方法 |
CN106693073A (zh) * | 2017-01-06 | 2017-05-24 | 中国科学院上海光学精密机械研究所 | 镓掺杂的无定形磷酸钙生物活性纳米材料的制备方法 |
US10537661B2 (en) | 2017-03-28 | 2020-01-21 | DePuy Synthes Products, Inc. | Orthopedic implant having a crystalline calcium phosphate coating and methods for making the same |
CN114344563B (zh) * | 2022-01-28 | 2023-04-18 | 河南科技大学 | 一种具有抗菌和促成骨性能的材料及其制备方法 |
CN114949342A (zh) * | 2022-05-30 | 2022-08-30 | 山东大学齐鲁医院 | 一种促进骨再生的复合三斜钙磷石/无定形磷酸钙骨水泥 |
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JPH07500823A (ja) * | 1991-10-22 | 1995-01-26 | マリンクロッド・インコーポレイテッド | 医療診断イメージング用処理アパタイト粒子 |
WO2001049327A2 (en) * | 2000-01-03 | 2001-07-12 | Hku/Hantak Ortho-Technology Limited | Bioactive and osteoprorotic bone cement |
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