KR101017815B1 - Calcium Phosphate Particle Manufacture Methods for Solution Growth Method - Google Patents
Calcium Phosphate Particle Manufacture Methods for Solution Growth Method Download PDFInfo
- Publication number
- KR101017815B1 KR101017815B1 KR1020080041103A KR20080041103A KR101017815B1 KR 101017815 B1 KR101017815 B1 KR 101017815B1 KR 1020080041103 A KR1020080041103 A KR 1020080041103A KR 20080041103 A KR20080041103 A KR 20080041103A KR 101017815 B1 KR101017815 B1 KR 101017815B1
- Authority
- KR
- South Korea
- Prior art keywords
- calcium
- phosphate
- aqueous solution
- calcium phosphate
- particles
- Prior art date
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- 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 title claims abstract description 53
- 239000001506 calcium phosphate Substances 0.000 title claims abstract description 52
- 235000011010 calcium phosphates Nutrition 0.000 title claims abstract description 52
- 229910000389 calcium phosphate Inorganic materials 0.000 title claims abstract description 51
- 239000002245 particle Substances 0.000 title claims abstract description 41
- 238000000034 method Methods 0.000 title claims abstract description 36
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 19
- 239000007864 aqueous solution Substances 0.000 claims abstract description 70
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims abstract description 17
- 239000000945 filler Substances 0.000 claims abstract description 5
- 239000003937 drug carrier Substances 0.000 claims abstract description 4
- 229960001714 calcium phosphate Drugs 0.000 claims description 45
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- ZCCIPPOKBCJFDN-UHFFFAOYSA-N calcium nitrate Chemical compound [Ca+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O ZCCIPPOKBCJFDN-UHFFFAOYSA-N 0.000 claims description 18
- 238000003756 stirring Methods 0.000 claims description 14
- 239000011575 calcium Substances 0.000 claims description 12
- 238000000746 purification Methods 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
- 210000000988 bone and bone Anatomy 0.000 claims description 7
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 150000007529 inorganic bases Chemical class 0.000 claims description 6
- 150000007530 organic bases Chemical class 0.000 claims description 6
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 4
- 239000000920 calcium hydroxide Substances 0.000 claims description 4
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims description 4
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 claims description 4
- 235000011007 phosphoric acid Nutrition 0.000 claims description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 4
- 239000001488 sodium phosphate Substances 0.000 claims description 4
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 4
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 claims description 4
- 241000700605 Viruses Species 0.000 claims description 3
- 238000011049 filling Methods 0.000 claims description 3
- 239000001226 triphosphate Substances 0.000 claims description 3
- 235000011178 triphosphate Nutrition 0.000 claims description 3
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 claims description 3
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 3
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 3
- RMBBSOLAGVEUSI-UHFFFAOYSA-H Calcium arsenate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-][As]([O-])([O-])=O.[O-][As]([O-])([O-])=O RMBBSOLAGVEUSI-UHFFFAOYSA-H 0.000 claims description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 2
- BCZXFFBUYPCTSJ-UHFFFAOYSA-L Calcium propionate Chemical compound [Ca+2].CCC([O-])=O.CCC([O-])=O BCZXFFBUYPCTSJ-UHFFFAOYSA-L 0.000 claims description 2
- UEZVMMHDMIWARA-UHFFFAOYSA-N Metaphosphoric acid Chemical compound OP(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-N 0.000 claims description 2
- 229910021529 ammonia Inorganic materials 0.000 claims description 2
- LFVGISIMTYGQHF-UHFFFAOYSA-N ammonium dihydrogen phosphate Chemical compound [NH4+].OP(O)([O-])=O LFVGISIMTYGQHF-UHFFFAOYSA-N 0.000 claims description 2
- 150000008064 anhydrides Chemical class 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
- 229940103357 calcium arsenate Drugs 0.000 claims description 2
- 235000010376 calcium ascorbate Nutrition 0.000 claims description 2
- 239000011692 calcium ascorbate Substances 0.000 claims description 2
- 229940047036 calcium ascorbate Drugs 0.000 claims description 2
- 239000004301 calcium benzoate Substances 0.000 claims description 2
- 235000010237 calcium benzoate Nutrition 0.000 claims description 2
- 229910001622 calcium bromide Inorganic materials 0.000 claims description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 2
- 239000001110 calcium chloride Substances 0.000 claims description 2
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 2
- FNAQSUUGMSOBHW-UHFFFAOYSA-H calcium citrate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O FNAQSUUGMSOBHW-UHFFFAOYSA-H 0.000 claims description 2
- 239000001354 calcium citrate Substances 0.000 claims description 2
- 229960004256 calcium citrate Drugs 0.000 claims description 2
- WGEFECGEFUFIQW-UHFFFAOYSA-L calcium dibromide Chemical compound [Ca+2].[Br-].[Br-] WGEFECGEFUFIQW-UHFFFAOYSA-L 0.000 claims description 2
- 239000004227 calcium gluconate Substances 0.000 claims description 2
- 229960004494 calcium gluconate Drugs 0.000 claims description 2
- 235000013927 calcium gluconate Nutrition 0.000 claims description 2
- MKJXYGKVIBWPFZ-UHFFFAOYSA-L calcium lactate Chemical compound [Ca+2].CC(O)C([O-])=O.CC(O)C([O-])=O MKJXYGKVIBWPFZ-UHFFFAOYSA-L 0.000 claims description 2
- 239000001527 calcium lactate Substances 0.000 claims description 2
- 229960002401 calcium lactate Drugs 0.000 claims description 2
- 235000011086 calcium lactate Nutrition 0.000 claims description 2
- BRPQOXSCLDDYGP-UHFFFAOYSA-N calcium oxide Chemical compound [O-2].[Ca+2] BRPQOXSCLDDYGP-UHFFFAOYSA-N 0.000 claims description 2
- 239000000292 calcium oxide Substances 0.000 claims description 2
- ODINCKMPIJJUCX-UHFFFAOYSA-N calcium oxide Inorganic materials [Ca]=O ODINCKMPIJJUCX-UHFFFAOYSA-N 0.000 claims description 2
- 239000004330 calcium propionate Substances 0.000 claims description 2
- 235000010331 calcium propionate Nutrition 0.000 claims description 2
- 239000000378 calcium silicate Substances 0.000 claims description 2
- 229910052918 calcium silicate Inorganic materials 0.000 claims description 2
- BLORRZQTHNGFTI-ZZMNMWMASA-L calcium-L-ascorbate Chemical compound [Ca+2].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] BLORRZQTHNGFTI-ZZMNMWMASA-L 0.000 claims description 2
- NEEHYRZPVYRGPP-UHFFFAOYSA-L calcium;2,3,4,5,6-pentahydroxyhexanoate Chemical compound [Ca+2].OCC(O)C(O)C(O)C(O)C([O-])=O.OCC(O)C(O)C(O)C(O)C([O-])=O NEEHYRZPVYRGPP-UHFFFAOYSA-L 0.000 claims description 2
- HZQXCUSDXIKLGS-UHFFFAOYSA-L calcium;dibenzoate;trihydrate Chemical compound O.O.O.[Ca+2].[O-]C(=O)C1=CC=CC=C1.[O-]C(=O)C1=CC=CC=C1 HZQXCUSDXIKLGS-UHFFFAOYSA-L 0.000 claims description 2
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 claims description 2
- 239000000969 carrier Substances 0.000 claims description 2
- 238000002316 cosmetic surgery Methods 0.000 claims description 2
- 150000004677 hydrates Chemical class 0.000 claims description 2
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 claims description 2
- 239000000347 magnesium hydroxide Substances 0.000 claims description 2
- 229910001862 magnesium hydroxide Inorganic materials 0.000 claims description 2
- 238000001742 protein purification Methods 0.000 claims description 2
- FQENQNTWSFEDLI-UHFFFAOYSA-J sodium diphosphate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]P([O-])(=O)OP([O-])([O-])=O FQENQNTWSFEDLI-UHFFFAOYSA-J 0.000 claims description 2
- VKFFEYLSKIYTSJ-UHFFFAOYSA-N tetraazanium;phosphonato phosphate Chemical compound [NH4+].[NH4+].[NH4+].[NH4+].[O-]P([O-])(=O)OP([O-])([O-])=O VKFFEYLSKIYTSJ-UHFFFAOYSA-N 0.000 claims description 2
- RYCLIXPGLDDLTM-UHFFFAOYSA-J tetrapotassium;phosphonato phosphate Chemical compound [K+].[K+].[K+].[K+].[O-]P([O-])(=O)OP([O-])([O-])=O RYCLIXPGLDDLTM-UHFFFAOYSA-J 0.000 claims description 2
- 235000013337 tricalcium citrate Nutrition 0.000 claims description 2
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 claims 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims 3
- 229910001424 calcium ion Inorganic materials 0.000 claims 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims 2
- GVALZJMUIHGIMD-UHFFFAOYSA-H magnesium phosphate Chemical compound [Mg+2].[Mg+2].[Mg+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O GVALZJMUIHGIMD-UHFFFAOYSA-H 0.000 claims 2
- 239000004137 magnesium phosphate Substances 0.000 claims 2
- 229910000157 magnesium phosphate Inorganic materials 0.000 claims 2
- 229960002261 magnesium phosphate Drugs 0.000 claims 2
- 235000010994 magnesium phosphates Nutrition 0.000 claims 2
- XPPKVPWEQAFLFU-UHFFFAOYSA-N diphosphoric acid Chemical compound OP(O)(=O)OP(O)(O)=O XPPKVPWEQAFLFU-UHFFFAOYSA-N 0.000 claims 1
- ATGAWOHQWWULNK-UHFFFAOYSA-I pentapotassium;[oxido(phosphonatooxy)phosphoryl] phosphate Chemical compound [K+].[K+].[K+].[K+].[K+].[O-]P([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O ATGAWOHQWWULNK-UHFFFAOYSA-I 0.000 claims 1
- 229910000160 potassium phosphate Inorganic materials 0.000 claims 1
- 235000011009 potassium phosphates Nutrition 0.000 claims 1
- 229940005657 pyrophosphoric acid Drugs 0.000 claims 1
- 229940001496 tribasic sodium phosphate Drugs 0.000 claims 1
- 239000000243 solution Substances 0.000 abstract description 19
- 229910019142 PO4 Inorganic materials 0.000 abstract description 17
- 239000010419 fine particle Substances 0.000 abstract description 17
- 239000010452 phosphate Substances 0.000 abstract description 16
- 230000002378 acidificating effect Effects 0.000 abstract description 15
- 159000000007 calcium salts Chemical class 0.000 abstract description 15
- 239000002994 raw material Substances 0.000 abstract description 15
- 239000000126 substance Substances 0.000 abstract description 6
- 230000008859 change Effects 0.000 abstract description 5
- 230000008901 benefit Effects 0.000 abstract description 2
- 229920006395 saturated elastomer Polymers 0.000 abstract description 2
- 239000003826 tablet Substances 0.000 abstract 1
- 235000021317 phosphate Nutrition 0.000 description 16
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 15
- 239000011148 porous material Substances 0.000 description 14
- 150000007524 organic acids Chemical class 0.000 description 11
- 150000007522 mineralic acids Chemical class 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 230000002776 aggregation Effects 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 239000008187 granular material Substances 0.000 description 5
- 235000005985 organic acids Nutrition 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 238000001878 scanning electron micrograph Methods 0.000 description 5
- 239000004254 Ammonium phosphate Substances 0.000 description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 4
- 229910000148 ammonium phosphate Inorganic materials 0.000 description 4
- 235000019289 ammonium phosphates Nutrition 0.000 description 4
- 229960005069 calcium Drugs 0.000 description 4
- 229910052791 calcium Inorganic materials 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 description 4
- 235000019700 dicalcium phosphate Nutrition 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000001694 spray drying Methods 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 238000004220 aggregation Methods 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- CGMRCMMOCQYHAD-UHFFFAOYSA-J dicalcium hydroxide phosphate Chemical compound [OH-].[Ca++].[Ca++].[O-]P([O-])([O-])=O CGMRCMMOCQYHAD-UHFFFAOYSA-J 0.000 description 3
- 239000002270 dispersing agent Substances 0.000 description 3
- -1 hydroxyapatite Chemical compound 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000005054 agglomeration Methods 0.000 description 2
- 229910052586 apatite Inorganic materials 0.000 description 2
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 2
- OABQFEHDVMFLLE-UHFFFAOYSA-L calcium;dihydrogen phosphate;dihydrate Chemical compound O.O.[Ca+2].OP(O)([O-])=O.OP(O)([O-])=O OABQFEHDVMFLLE-UHFFFAOYSA-L 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000006911 nucleation Effects 0.000 description 2
- 238000010899 nucleation Methods 0.000 description 2
- 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 2
- 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 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 229920000747 poly(lactic acid) Polymers 0.000 description 2
- 239000004626 polylactic acid Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000000638 solvent extraction Methods 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 1
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 210000004102 animal cell Anatomy 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000003637 basic solution Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- GPEKFYQYRNWUML-UHFFFAOYSA-L calcium (3-hydroxy-2-oxopropyl) phosphate Chemical compound [Ca+2].OCC(=O)COP([O-])([O-])=O GPEKFYQYRNWUML-UHFFFAOYSA-L 0.000 description 1
- 229940059251 calcium bromide Drugs 0.000 description 1
- 229940087373 calcium oxide Drugs 0.000 description 1
- 229960003340 calcium silicate Drugs 0.000 description 1
- 229940095672 calcium sulfate Drugs 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000010924 continuous production Methods 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 239000003479 dental cement Substances 0.000 description 1
- 229940075110 dibasic magnesium phosphate Drugs 0.000 description 1
- MHJAJDCZWVHCPF-UHFFFAOYSA-L dimagnesium phosphate Chemical compound [Mg+2].OP([O-])([O-])=O MHJAJDCZWVHCPF-UHFFFAOYSA-L 0.000 description 1
- 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
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001476 gene delivery Methods 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000012567 medical material Substances 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 239000006259 organic additive Substances 0.000 description 1
- 230000011164 ossification Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- KFHHGNBIPJDZPH-UHFFFAOYSA-D pentamagnesium [oxido(phosphonatooxy)phosphoryl] phosphate Chemical compound [Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[O-]P([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O.[O-]P([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O KFHHGNBIPJDZPH-UHFFFAOYSA-D 0.000 description 1
- HWGNBUXHKFFFIH-UHFFFAOYSA-I pentasodium;[oxido(phosphonatooxy)phosphoryl] phosphate Chemical compound [Na+].[Na+].[Na+].[Na+].[Na+].[O-]P([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O HWGNBUXHKFFFIH-UHFFFAOYSA-I 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920002635 polyurethane Polymers 0.000 description 1
- 239000004814 polyurethane Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 229920002379 silicone rubber Polymers 0.000 description 1
- 239000004945 silicone rubber Substances 0.000 description 1
- 235000019832 sodium triphosphate Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229940062627 tribasic potassium phosphate Drugs 0.000 description 1
- 229940116269 uric acid Drugs 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
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Abstract
본 발명은 인산칼슘 세립 및 미립자의 제조 방법에 대한 것으로, 보다 상세하게는 용액 성장법을 이용하여 균일한 사이즈의 인산칼슘 세립 및 미립자를 제조하는 방법에 관한 것이다. The present invention relates to a method for producing calcium phosphate fine particles and fine particles, and more particularly to a method for producing calcium phosphate fine particles and fine particles of uniform size using a solution growth method.
본 발명의 용액 성장법은 포화 상태를 과포화 상태로 인위적으로 만들어 목적하고자하는 물질을 생성하는 방법으로 본 발명에서는 칼슘염 및 인산염이 포함되어 있는 산성의 수용액을 제조한 다음 수용액의 pH에 변화를 주어 포화 상태가 되도록 조절을 하고 온도 변화 방법을 이용하여 과포화 상태로 만들어 인산칼슘이 생성되게 하는 것으로 본 발명에 의하면 0.1㎛ ~ 300㎛의 크기를 갖는 인산칼슘 입자를 제조 할 수 있다. 또한 목적하는 크기의 입자를 선택적으로 균일하게 제조 할 수 있으며 기초한 원료보다 순도가 높은 생성물을 얻을 수 있다는 장점이 있다. The solution growth method of the present invention is a method of artificially making the saturated state into a supersaturated state to produce a desired substance. In the present invention, an acidic aqueous solution containing calcium salt and phosphate is prepared, and then the pH of the aqueous solution is changed. According to the present invention, the calcium phosphate particles having a size of 0.1 μm to 300 μm may be manufactured by adjusting the saturation state to make the supersaturated state by using a temperature change method to produce calcium phosphate. In addition, the particles of the desired size can be selectively and uniformly produced, and there is an advantage in that a product with higher purity than the raw material can be obtained.
인산칼슘, 충진재, 정제용, 약물 담체, 용액 성장 Calcium phosphate, filler, tablet, drug carrier, solution growth
Description
인산칼슘은 인체의 치아와 뼈를 구성하고 있는 무기질 성분으로서, 생체 적합성과 무독성으로 우수한 생체 친화성을 가지고 있다. 또한 골 형성 유도 능력이 우수하고 중간층 없이 뼈와 직접 결합하고 신생골를 유입하고 성장시킨다. 따라서 인산칼슘은 생체 이식재료로서 널리 사용되고 있다. 또한 하이드록시아파아타이트와 같은 인산칼슘은 세라믹화하거나 입자 자체를 응용하여 인공 관절, 골충전재, 인공골, 인공치근, 경피 단자, 치과용 충전용, 치과용 시멘트 등에도 이용되고 있다. 또한 PLGA(Poly Lactic-co-Glycolic Acid), PLA(Poly Lactic Acid)나 실리콘 고무 또는 폴리우레탄 등의 고분자 의료용 재료에 생체 활성을 부여하기 위한 첨가재로서 사용된다. 뿐만 아니라 우수한 중금속 흡착 및 제거율, 아미노산 및 단백질의 분리 및 정제, 알콜류의 탈수, 핵산의 분리, 과산화물의 흡착 등의 다양한 물리.화학적 성질을 가지고 있다. 따라서 바이오산업 특히 생명공학 관련 분야에서도 응용될 수 있다. 예를 들면 동물 세포 배양용, DNA나 RNA의 정제용, 바이러스 정제용, 단백질 의약품 정제용, 단백질 의약품의 약물 담체용(유전자 전달용, 항생 제, 서방형, 이식형, 주사형, DNA나 RNA 치료용, 암세포 타켓용, 흡입형 등)으로 매우 유망한 재료이다. 상기와 같은 분야에 응용되기 위해서 가장 중요한 것은 미세한 입자경과 균일한 입도 분포이다. Calcium phosphate is an inorganic component that constitutes the teeth and bones of the human body, and has excellent biocompatibility with biocompatibility and nontoxicity. In addition, the ability to induce bone formation is excellent, it directly binds to bone without the middle layer and introduces and grows new bone. Therefore, calcium phosphate is widely used as a living implant material. In addition, calcium phosphate, such as hydroxyapatite, has been used in artificial joints, bone filling materials, artificial bones, artificial roots, transdermal terminals, dental fillings, dental cements, etc. by ceramicization or application of particles themselves. It is also used as an additive for imparting bioactivity to polymer medical materials such as PLGA (Poly Lactic-co-Glycolic Acid), PLA (Poly Lactic Acid), silicone rubber or polyurethane. In addition, it has various physical and chemical properties such as excellent heavy metal adsorption and removal rate, separation and purification of amino acids and proteins, dehydration of alcohols, separation of nucleic acids and adsorption of peroxides. Therefore, it can be applied in the bio industry, especially in the field of biotechnology. For example, animal cell culture, DNA or RNA purification, virus purification, protein drug purification, protein drug drug carrier (for gene delivery, antibiotics, sustained release, implantable, injectable, DNA or RNA) Therapeutic, cancer cell target, inhalation type). The most important for the application in the above fields is the fine particle diameter and uniform particle size distribution.
용액 성장법은 일반적으로 물질의 과포화도를 이용하여 결정을 얻어내는 방법으로 균일한 입자를 얻기 위해서 많이 사용되고 있다. 과포화도를 얻어내는 방법에 따라 크게 온도 변화, 용매 추출, 순환의 세가지 방법으로 분류할 수 있다. 온도 변화의 경우 거의 용액의 냉각에 의해서 아주 드물게는 가열에 의해 결정을 얻는 방법이고, 용매 추출은 보통 증발에 의해서 이루어지나 용매를 첨가하여 결정을 얻는 방법이다. 순환 방법은 산업체에서 선호하는 방식으로 용매가 원료로부터 종자로 흐르게 하는 이중 온도 시스템으로 연속 과정으로 사용할 수 있다. 또한 용액 성장법은 기초한 원료보다 순도가 높은 원료를 얻을 수 있다는 장점도 있다. The solution growth method is generally used to obtain uniform particles by obtaining crystals using the supersaturation degree of a substance. Depending on the method of obtaining supersaturation, it can be classified into three methods: temperature change, solvent extraction, and circulation. In the case of temperature change, crystals are obtained by heating the solution very rarely by heating, and solvent extraction is usually performed by evaporation, but by adding solvent, crystals are obtained. The circulating method can be used as a continuous process in a dual temperature system in which the solvent flows from the raw material to the seed in a manner preferred by the industry. In addition, the solution growth method has an advantage of obtaining a raw material having a higher purity than the raw material based on it.
인산칼슘 입자 특히 과립을 제조하기 위한 방법으로는 미국특허 제4836994호, 미국특허 제5858318호 및 미국특허 제5205928호와 같은 분무 건조법(Spray Dryer)있다. 하지만 분무건조 방법을 이용하여 과립을 제조할 경우 결합제, 가소제, 분산제 등의 유기첨가제와 분말의 혼합비 및 슬러리 농도 등의 화학적인 문제와 분무기의 회전속도, 내부 온도, 노즐의 선택 등의 기계적인 문제를 해결해야 하는 문제가 있었다. 그리고 분무 건조방법의 경우 출발 원료로 사용되는 인산칼슘 특히 하이드록시아파타이트를 제조하는 공정이 추가 되어야 한다는 것이다. 따라서 분무 건조법의 단점을 극복하고자 용액에서 과립을 제조하는 방법으로는 국내특허 제0498759호 및 국내특허 제0687892호가 있다. 하지만 분무 건조법과 마찬가지로 국내 특허 제0498759호의 출발 원료인 인산팔칼슘, 비정질인산칼슘, 수산화인산칼슘, 국내 특허 제0687892호의 출발 원료인 인산일수소칼슘무수화물과 인산일수소칼슘이수화물을 제조하는 공정이 별도로 필요하다. 또한 원료로 사용되는 인산팔칼슘, 비정질인산칼슘, 수산화인산칼슘, 인산일수소칼슘무수화물, 인산일수소칼슘무수화물의 용해도가 낮기 때문에 용해량이 적어 제조되는 수산화아파타이트의 양이 매우 적다. 또한 과립을 얻기 위한 pH의 범위가 좁다는 문제점이 있다. ( 국내특허 제0498759호 - pH 6.5 ~ 7.5 , 국내특허 제0687892호 - pH 6.0 ~ 8.5 ) Methods for preparing calcium phosphate particles, particularly granules, include a spray dryer such as US Pat. No. 4,388,994, US Pat. No. 5,858,318 and US Pat. However, when manufacturing granules by spray drying, chemical problems such as the mixing ratio and slurry concentration of organic additives such as binders, plasticizers, and dispersants and slurry concentrations, and mechanical problems such as rotation speed, internal temperature, and nozzle selection of the sprayer There was a problem that needs to be solved. In the case of spray drying, a process of preparing calcium phosphate, especially hydroxyapatite, which is used as a starting material should be added. Therefore, Korean Patent No. 0498759 and Korean Patent No. 0687892 are methods for preparing granules in solution to overcome the disadvantages of the spray drying method. However, as in the spray drying method, a process for preparing palcalcium phosphate, amorphous calcium phosphate, calcium hydroxide phosphate, starting material of Korean Patent No. 0498759, calcium monohydrogen phosphate anhydrous and calcium dihydrogen phosphate dihydrate which are starting materials of Korean Patent No. 0687892. This is necessary separately. In addition, since the solubility of palcalcium phosphate, amorphous calcium phosphate, calcium hydroxide phosphate, calcium monohydrogen phosphate anhydride and calcium monohydrogen phosphate anhydride is low, the amount of apatite produced is small because of low solubility. In addition, there is a problem in that the pH range for obtaining granules is narrow. (Korean Patent No. 0498759-pH 6.5 ~ 7.5, Domestic Patent No. 0687892-pH 6.0 ~ 8.5)
따라서 본 발명에서는 상기의 문제점을 해결하기 위해 별도의 출발 원료를 제조하지 않는 간단한 공정을 통하여 목적하고자 하는 입자를 다량으로 제조하는 것이다. 그리고 본 발명의 방법으로 제조 시 출발 원료를 제조하기 위한 공정을 생략할 수 있다. 뿐만 아니라 출발 원료(국내 특허 제0498759호의 인산팔칼슘, 비정질인산칼슘, 수산화인산칼슘, 국내 특허 제0687892호의 인산일수소칼슘무수화물, 인산일수소칼슘이수화물)를 제조 시 화학 합성의 특성상 미반응되어 버려지는 원료가 발생된다. 하지만 본 발명의 방법으로 제조 시 원료 합성에 사용되지 못하고 버려지는 원료가 없기 때문에 경제적인 비용 절감 효과를 얻을 수 있다. 또한 제조하는 pH 범위가 매우 넓고 높아지기 때문에 합성이 용이할 뿐만 아니라 세립 및 미립의 입자를 용이하게 제조할 수 있다. Therefore, in the present invention to solve the above problems is to prepare a large amount of the desired particles through a simple process that does not prepare a separate starting raw material. And the process for producing the starting raw material at the time of manufacture by the method of the present invention can be omitted. In addition, unreacted nature of the chemical synthesis in the preparation of starting raw materials (palmium phosphate, amorphous calcium phosphate, calcium hydroxide phosphate, calcium monohydrogen phosphate anhydrous, calcium dihydrogen phosphate dihydrate) of Korean Patent No. 0498759 The raw material which becomes waste is generated. However, since there is no raw material that cannot be used for raw material synthesis during manufacturing and discarded by the method of the present invention, an economic cost reduction effect can be obtained. In addition, since the pH range to be prepared is very wide and high, not only the synthesis is easy but also fine particles and fine particles can be easily produced.
상기 과제를 해결하기 위하여 많은 예의 검토를 거쳐 본 발명에 이르렀다. In order to solve the said subject, through the examination of many examples, the present invention was reached.
즉, 본 발명에 따른 인산칼슘은 상기 과제를 해결하기 위하여 (A) 칼슘염 및 인산염 함유 물질 또는 이들의 혼합물과 무기산 및 유기산 또는 이들의 혼합물로 이루어진 수용액을 제조하는 단계; (B) 상기 (A) 단계의 칼슘 및 인산염이 용해된 산성의 수용액을 교반하면서 염기성 원료 또는 염기성의 수용액을 첨가하여 약산성에서 강알칼리성의 수용액을 제조하는 단계; (C) 상기 B 단계의 수용액을 교반하면서 수용액의 온도를 상승시켜 인산칼슘입자를 제조하는 단계; (D) 상기 C단계 후 수용액에서 얻어진 인산칼슘을 여과하여 건조하는 단계로 구성되고 상기 과정들로 인산칼슘 입자를 제조하는 것을 특징으로 한다. That is, the calcium phosphate according to the present invention comprises the steps of (A) preparing an aqueous solution consisting of calcium salts and phosphate-containing substances or mixtures thereof and inorganic acids and organic acids or mixtures thereof; (B) adding a basic raw material or a basic aqueous solution while stirring the acidic aqueous solution in which calcium and phosphate are dissolved in step (A) to prepare a strong alkaline aqueous solution in weak acidity; (C) preparing calcium phosphate particles by raising the temperature of the aqueous solution while stirring the aqueous solution of step B; (D) comprising the step of filtering and drying the calcium phosphate obtained in the aqueous solution after step C, characterized in that to produce calcium phosphate particles by the above processes.
본 발명의 (A) 단계는 칼슘염 및 인산염을 함유한 물질 또는 이들의 혼합물과 무기산 및 유기산 또는 이들의 혼합물로 이루어진 수용액을 제조하는 것이다. 상기의 수용액을 제조하기 위한 방법으로는 두 가지가 있다. 첫 번째 방법은 칼슘염 및 인산염의 농도가 각각 0,005M ~ 3M이 되도록 수용액을 제조한 후 무기산 및 유기산 또는 혼합물을 0.01M ~ 10M이 되도록 첨가하여 교반시킨다. 두 번째 방법은 무기산 및 유기산 또는 혼합물의 농도를 0.01M ~ 10M이 되도록 제조한 수용액에 칼슘염 및 인산염의 농도가 0,005M ~ 3M이 되도록 칼슘염 및 인산염의 공급원을 첨가하여 교반시키는 것이다. 이 때 칼슘염 및 인산염의 농도는 각각 0.01M ~ 0.5M로, 산의 농도는 0.1M ~ 2M로 하는 것이 가장 바람직하다. 또한 단계 A에서 칼슘염과 인산염의 농도비, 즉 Ca/P 몰 비는 1.0 ~ 2.0으로 하며 가장 바람직한 Ca/P 몰 비는 1.5~1.7이다. 상기의 (A) 단계의 수용액을 제조하기 위한 방법들에서 두 번째 방법이 제조가 쉽고 칼슘염, 인산염 및 산성의 농도를 조절하는 것이 용이하다. Step (A) of the present invention is to prepare an aqueous solution consisting of a substance containing calcium salt and phosphate or a mixture thereof and an inorganic acid and an organic acid or a mixture thereof. There are two methods for preparing the aqueous solution. In the first method, an aqueous solution is prepared such that the concentration of calcium salt and phosphate is 0,005M to 3M, respectively, and then the inorganic and organic acids or mixtures are added and stirred to 0.01M to 10M. The second method is to add and stir a source of calcium salt and phosphate so that the concentration of the calcium salt and phosphate is 0,005M to 3M in the aqueous solution prepared so that the concentration of the inorganic acid and the organic acid or the mixture is 0.01M ~ 10M. At this time, it is most preferable that the concentration of calcium salt and phosphate is 0.01M to 0.5M, and the concentration of acid to 0.1M to 2M, respectively. In addition, in step A, the concentration ratio of calcium salt and phosphate, that is, the Ca / P molar ratio is 1.0 to 2.0, and the most preferable Ca / P molar ratio is 1.5 to 1.7. In the methods for preparing the aqueous solution of step (A), the second method is easy to manufacture and it is easy to control the concentration of calcium salt, phosphate and acid.
(A) 단계의 칼슘염의 공급원으로는 수산화칼슘, 탄산칼슘, 염화칼슘, 질산칼슘, 산화칼슘, 황산칼슘, 규산칼슘, 글루콘산칼슘, 비산칼슘, 아세트산칼슘, 브롬화칼슘, 글리세론인산칼슘, 젖산칼슘, 구연산칼슘, 프로피온산칼슘, 안식향산칼슘, 아스코르빈산칼슘 및 그들의 무수화물 및 수화물로 구성된 군에서 선택하여 사용한다. 인산염의 공급원으로는 오르토인산, 오산화인, 제일인산암모늄, 제이인산암모늄, 메타인산, 피로인산, 제이인산나트륨, 삼인산, 사인산, 제이인산칼륨, 제이인산마그네슘, 제삼인삼칼륨, 제삼인산나트륨, 제일인산나트륨, 제일인산칼륨, 염화포스포릴, 폴리메타인산, 제삼인산마그네슘으로 구성된 군에서 선택하여 사용한다. 그리고 무기산으로는 염산, 탄산, 질산, 황산, 과염소산으로 구성하는 군에서 선택되고, 유기산은 시트르산, 아세트산, 카르복시산, 말산, 젖산, 옥살산, 부티르산, 요 산 및 술폰산으로 구성하는 군에서 선택하여 사용하면 된다. Sources of calcium salt in step (A) include calcium hydroxide, calcium carbonate, calcium chloride, calcium nitrate, calcium oxide, calcium sulfate, calcium silicate, calcium gluconate, calcium arsenate, calcium acetate, calcium bromide, calcium glycerone phosphate, calcium lactate, It is selected from the group consisting of calcium citrate, calcium propionate, calcium benzoate, calcium ascorbate and their anhydrides and hydrates. Sources of phosphates include orthophosphoric acid, phosphorus pentoxide, ammonium monophosphate, ammonium diphosphate, metaphosphoric acid, pyrophosphate, sodium diphosphate, triphosphate, triphosphate, potassium diphosphate, dibasic magnesium phosphate, tribasic potassium phosphate, sodium triphosphate, It is selected from the group consisting of sodium monophosphate, potassium monophosphate, phosphoryl chloride, polymethic acid, and magnesium triphosphate. The inorganic acid is selected from the group consisting of hydrochloric acid, carbonic acid, nitric acid, sulfuric acid, perchloric acid, and the organic acid is selected from the group consisting of citric acid, acetic acid, carboxylic acid, malic acid, lactic acid, oxalic acid, butyric acid, uric acid and sulfonic acid. do.
(B) 단계는 상기의 (A) 단계에서 제조된 칼슘염 및 인산염이 포함되어 있는 산성의 수용액을 염기성 원료를 이용하여 약산성내지 강알칼리성의 수용액으로 바꾸어 주는 것이다. 본 단계에서도 수용액의 pH를 조절하기 위한 방법으로 산성의 수용액을 교반하면서 무기염기나 유기염기 또는 이들의 화합물을 직접 첨가하는 방법과 무기염기나 유기염기 또는 이들의 화합물을 이용하여 염기성 수용액을 제조하고 이 염기성 용액을 (A) 단계의 산성의 수용액에 혼합하는 방법이 있다. 본 발명에서 가장 바람직한 방법은 후자로 산성의 수용액을 교반하면서 염기성 수용액을 첨가하면 목적하는 pH를 정확하게 맞추는 것이 용이하다. 이때의 약산성 및 강알칼리성이 되는 수용액의 pH는 pH 6.0 ~ pH 14.0으로 본 발명에 따르면 pH 8.0 ~ pH 12.0이 가장 적당하다. pH가 맞지 않으면 불균일하게 불규칙한 입자들이 얻어지며 적정 pH는 칼슘염 및 인산염의 농도, 무기산이나 유기산의 종류, 염기성 수용액의 농도에 따라 영향을 받으며 이중 칼슘염의 농도와 유기산의 농도에 가장 큰 영향을 받는다. 유기산 특히 카르복실기를 함유하고 있는 유기산의 경우 인산칼슘의 결정 성장을 억제하는 역할을 하기 때문에 포화상태에서 과포화상태에 의한 핵생성 시 보다 균일한 미립의 인산칼슘을 입자를 얻을 수 있다. pH 조절을 위한 염기성 공급원의 첨가량은 (A) 단계의 산성 수용액의 농도에 의해 영향을 받는다. 이 때 (A)단계의 칼슘염 및 인산염, 무기산, 유기산 및 그들의 화합물이 함유된 산성의 수용액의 농도에 따라 다르다. 직접 염기성 원료를 첨가하면서 pH Meter를 확인하면서 목적하는 pH로 조절하면 된다. 무기염기나 유기염기 및 그들의 화합물로 이루어진 수용액을 사용할 경우는 0.01M ~ 10M의 수용액을 사용하면 되며 가장 적당하게는 무기산의 경우 0.2M ~ 2M, 유기산의 경우 0.2M ~ 1M, 유기염기 및 무기염기 화합물의 경우는 0.5M ~ 1M의 수용액을 사용하면 된다. Step (B) is to change the acidic aqueous solution containing the calcium salt and phosphate prepared in step (A) to a weakly acidic to strongly alkaline aqueous solution using a basic raw material. In this step, a method for adjusting the pH of the aqueous solution is prepared by directly adding an inorganic base or an organic base or a compound thereof while stirring an acidic aqueous solution, and preparing a basic aqueous solution using an inorganic base or an organic base or a compound thereof. There is a method of mixing this basic solution with the acidic aqueous solution of step (A). The most preferred method in the present invention is the latter, it is easy to accurately adjust the desired pH by adding a basic aqueous solution while stirring the acidic aqueous solution. At this time, the pH of the aqueous solution becomes weakly acidic and strongly alkaline is pH 6.0 ~ pH 14.0 according to the present invention is the most suitable pH 8.0 ~ pH 12.0. If the pH is not correct, irregularly irregular particles are obtained, and the optimum pH is affected by the concentration of calcium salt and phosphate, the type of inorganic acid or organic acid, and the concentration of basic aqueous solution, and is most affected by the concentration of calcium salt and organic acid. . In the case of organic acids, especially organic acids containing carboxyl groups, they inhibit the growth of calcium phosphate crystals. Thus, particles of fine grained calcium phosphate can be obtained when nucleation occurs due to supersaturation in saturated state. The amount of basic source added for pH control is influenced by the concentration of the acidic aqueous solution of step (A). This depends on the concentration of the calcium salt and the phosphate, inorganic acid, organic acid and acidic aqueous solution containing the compound of step (A). The pH can be adjusted to the desired pH while adding basic raw materials. When using an aqueous solution composed of inorganic or organic bases and compounds thereof, an aqueous solution of 0.01M to 10M may be used. Most preferably, 0.2M to 2M for inorganic acids, 0.2M to 1M for organic acids, organic bases and inorganic bases. In the case of a compound, 0.5M-1M aqueous solution may be used.
(B) 단계에 사용되는 염기성 공급원인 무기 염기로는 수산화나트륨, 수산화칼륨, 암모니아, 수산화리듐, 수산화칼슘, 수산화마그네슘으로 구성된 군에서 선택되고, 유기염기로는 트리스히드록시메틸아미노메탄, 비스2-히드록시에틸아미노트리히드로 메틸메탄으로 구성된 군에서 선택된다. Inorganic bases used as the basic source for step (B) are selected from the group consisting of sodium hydroxide, potassium hydroxide, ammonia, lithium hydroxide, calcium hydroxide and magnesium hydroxide, and as organic bases, trishydroxymethylaminomethane, bis2- Hydroxyethylaminotrihydro methylmethane.
상기의 (A) 단계 및 (B) 단계에서 수용액의 온도는 0~30℃로 하는 것이 적당하고 상온과 유사한 20℃ ~ 28℃가 가장 바람직하다. 또한 (B) 단계의 pH를 조절한 수용액은 pore size가 1㎛ ~ 0.1㎛인 여과 필터를 사용하여 여과하거나 원심분리기를 이용하여 10,000 RPM이상으로 원심 분리하여 수용액만 얻는 것이 바람직하다. In the above steps (A) and (B), the temperature of the aqueous solution is preferably 0 to 30 ° C, and most preferably 20 ° C to 28 ° C, which is similar to room temperature. In addition, it is preferable to obtain the aqueous solution by adjusting the pH of step (B) using a filter having a pore size of 1 μm to 0.1 μm or by centrifuging at 10,000 RPM or more using a centrifuge.
(C)단계에서는 (B) 단계에서 적절한 pH로 조절된 수용액을 교반하면서 수용액의 온도를 상승시켜 인산칼슘 입자를 얻는 과정으로 수용액의 온도는 50℃ ~ 200℃로 하여 최소 10분에서 42시간까지 반응시킨다. 가장 바람직한 수용액의 온도를 70℃ ~ 120℃로 하여 1시간 ~ 5시간 반응시키는 것이다. 이와 같은 공정은 용액 성장법에서 매우 드물게 사용하는 방법으로 포화된 용액을 과포화상태로 만들기 위해 온도 변화를 주는 것, 즉 온도를 올려 과포화상태로 만드는 것이다. 상기에서 생성되는 인산칼슘 입자의 크기에 가장 큰 영향을 주는 것은 칼슘 농도와 용액의 pH로 칼슘 농도가 높을수록, 또한 pH가 높아질수록 생성되는 입자의 크기는 작아진다. 이는 칼슘 농도 및 pH가 높아질수록 결정핵의 생성 속도가 빨라지기 때문에 단시간에 많 은 양의 인산칼슘 결정핵이 생성된다. 따라서 결정핵이 성장할 시간 및 조건이 되지 않기 때문에 생성되는 인산칼슘 입자의 크기는 작다. In step (C), the temperature of the aqueous solution is increased to obtain calcium phosphate particles by stirring the aqueous solution adjusted to the appropriate pH in step (B). The temperature of the aqueous solution is 50 ° C. to 200 ° C. for at least 10 minutes to 42 hours. React. The temperature of the most preferable aqueous solution is made into 70 degreeC-120 degreeC, and is made to react for 1 hour-5 hours. Such a process is very rarely used in the solution growth method, in which a saturated solution is subjected to a temperature change to make a supersaturated solution, that is, a temperature is raised to a supersaturated state. The biggest influence on the size of the calcium phosphate particles produced above is the calcium concentration and the pH of the solution, the higher the calcium concentration, and the higher the pH, the smaller the size of the particles produced. The higher the calcium concentration and pH, the faster the rate of nucleation is produced, so a large amount of calcium phosphate nucleus is produced in a short time. Therefore, the size of the calcium phosphate particles produced is small because it is not the time and conditions for the growth of the nuclei.
(D) 단계는 수용액에 생성된 인산칼슘을 여과 및 건조하는 단계로서 생성된 세립 및 미립자를 여과를 통하여 얻는다. 이때 여과하는 방법으로 필터를 하거나 원심분리기를 사용하면 된다. 여과 시 생성된 인산칼슘 입자의 크기에 따라 여과 방법을 및 필터 페이퍼의 기공 사이즈를 선택하여 사용하여야 한다. 원심 분리를 이용한 분리는 입자 크기에 따라 1,000 RPM ~ 10,000 RPM의 속도로 여과를 하면 된다. 본 발명으로 얻어지는 인산칼슘은 목적하는 입자 사이즈에 따라 다르지만 0.1㎛ ~ 300㎛로 비교적 넓은 범위의 입자를 선택하여 균일하게 제조할 수 있다. 또한 5㎛ 이하의 미립의 입자의 경우 건조하면서 입자간의 응집이 발생할 수 있다. 만약 이러한 응집이 응용하는데 영향이 없다면 그대로 사용하면 된다. 하지만 제품 응용 시 응집 상태가 문제가 된다면 응집 최소화를 위한 방법으로 (D) 단계의 여과 과정 전에 인산칼슘 입자가 생성된 수용액에 분산제를 첨가하고 여과를 수행한 후에 건조를 하고 분산제의 제거를 위해 300℃ ~ 1300℃로 열처리하면 미립자의 응집을 막을 수 있으며 800℃ ~ 900℃에서 열처리하는 것이 가장 바람직하다. Step (D) is a step of filtering and drying the calcium phosphate produced in the aqueous solution to obtain the fines and fine particles produced through filtration. In this case, the filter may be filtered or a centrifuge may be used. The filtration method and the pore size of the filter paper should be used according to the size of the calcium phosphate particles produced during the filtration. Separation by centrifugation can be performed at 1,000 to 10,000 RPM depending on the particle size. Calcium phosphate obtained by the present invention can be produced uniformly by selecting a relatively wide range of particles from 0.1 μm to 300 μm, depending on the desired particle size. In addition, in the case of fine particles of 5 μm or less, aggregation between particles may occur while drying. If this aggregation does not affect the application, it can be used as it is. However, if the agglomeration state is a problem in the application of the product, as a method for minimizing the agglomeration, dispersant is added to the aqueous solution in which calcium phosphate particles are formed before the filtration process in step (D), followed by filtration, followed by drying to remove the dispersant. When the heat treatment at ℃ ~ 1300 ℃ can prevent the aggregation of fine particles, heat treatment at 800 ℃ ~ 900 ℃ is most preferred.
따라서 본 발명의 결과물인 0.1㎛ ~ 300㎛ 크기의 인산칼슘 입자를 치아 및 골 충진재, 성형외과용 필러, 단백질 정제용, DNA 정제용, RNA 정제용, 바이러스 정제용, 분석용 담체, 약물 담체 등으로 사용할 수 있다. Therefore, calcium phosphate particles having a size of 0.1 μm to 300 μm as a result of the present invention may be used for filling tooth and bone fillers, plastic surgery fillers, protein purification, DNA purification, RNA purification, virus purification, analytical carriers, drug carriers, and the like. Can be used as
본 발명은 다음과 같은 효과가 있다. The present invention has the following effects.
세립 및 미립의 인산칼슘을 제조하기 위한 별도의 출발 원료를 제조할 필요가 없어 제조 공정이 매우 간단하다. 또한 출발 원료의 제조 시 화학 반응의 특성상 사용할 수 없어 버려지는 원료가 없어 제조 비용의 절감 효과가 있다. 따라서 제조 공정에 따른 합성 비용 및 설비 비용을 절감할 수 있다. 그리고 세립 및 미립의 인산칼슘 특히 수산화아파타이트를 제조하는데 있어서 그 제조 범위가 pH 6.0 ~ pH 14까지 매우 넓은 범위에서 제조할 수 있어 미립에서 과립의 매우 균일한 입자를 제조할 수가 있다. The production process is very simple since there is no need to prepare separate starting materials for the production of fine and fine calcium phosphates. In addition, there is no raw material that can not be used due to the nature of the chemical reaction during the production of the starting raw material can reduce the manufacturing cost. Therefore, the synthesis cost and equipment cost according to the manufacturing process can be reduced. In addition, in the preparation of fine and fine calcium phosphate, especially apatite hydroxide, the production range can be prepared in a very wide range from pH 6.0 to pH 14, thereby producing very uniform particles of granules in fine particles.
본 발명의 하기 실시예는 본 발명을 보다 명확하게 표현하기 위한 목적으로 기재될 뿐 본 발명의 내용이 하기 실시예에 한정되는 것은 아니다. The following examples of the present invention are described for the purpose of more clearly expressing the present invention, but the contents of the present invention are not limited to the following examples.
< 실시예 1 >≪ Example 1 >
1000ml의 증류수에 시트르산 0.35M, 질산칼슘 17mM 및 인산나트륨 10mM이 되도록 정량하여 수용액을 제조하였다. (Ca/P 몰비 1.7) 제조한 수용액을 교반하면서 pH가 pH 10이 될 때까지 1M의 수산화나트륨 수용액을 첨가하였다. pH 10으로 조절한 수용액은 필터(기공 사이즈 0.2㎛)를 이용하여 여과하고 수용액의 온도가 80℃가 되도록 하고 3시간 동안 교반하였다. 3시간 후 필터(기공 사이즈 0.1㎛)한 후 건조하여 인산칼슘 미립자를 얻었다. An aqueous solution was prepared by quantifying 1000 ml of distilled water to 0.35M citric acid, 17 mM calcium nitrate, and 10 mM sodium phosphate. (Ca / P molar ratio 1.7) 1M sodium hydroxide aqueous solution was added until the pH became pH 10, stirring the prepared aqueous solution. The aqueous solution adjusted to pH 10 was filtered using a filter (pore size 0.2 μm), the temperature of the aqueous solution was 80 ℃ and stirred for 3 hours. 3 hours later, the filter (pore size 0.1 micrometer) was dried, and calcium phosphate microparticles | fine-particles were obtained.
< 실시예 2 >≪ Example 2 >
1000ml의 증류수에 질산칼슘 15mM 및 인산암모늄 10mM이 되도록 정량한 후 용액을 교반하면서 아세트산 30ml을 첨가하여 산성의 수용액을 제조하였다. (Ca/P 몰비 1.50) 제조된 수용액을 교반하면서 pH가 pH 7.15가 될 때까지 0.25M의 수산화나트륨 수용액을 첨가하였다. pH 7.15로 조절한 수용액은 필터(기공 사이즈 0.2㎛)를 이용하여 여과하고 수용액의 온도가 70℃가 되도록 하고 5시간 동안 교반하였다. 5시간 후 필터(기공 사이즈 1㎛)한 후 건조하여 인산칼슘 미립자를 얻었다. An acidic aqueous solution was prepared by adding 30 ml of acetic acid while stirring the solution to 1000 mM distilled water to 15 mM calcium nitrate and 10 mM ammonium phosphate. (Ca / P molar ratio 1.50) While stirring the prepared aqueous solution, 0.25M aqueous sodium hydroxide solution was added until the pH became pH 7.15. The aqueous solution adjusted to pH 7.15 was filtered using a filter (pore size 0.2 μm), the temperature of the aqueous solution was 70 ℃ and stirred for 5 hours. After 5 hours, the resultant was dried with a filter (pore size of 1 μm) to obtain calcium phosphate fine particles.
< 실시예 3 ><Example 3>
0.25M의 시트르산 1000ml에 0.835M의 질산칼슘 및 0.05M의 인산암모늄이 되도록 정량하여 산성의 수용액을 제조하였다.(Ca/P 몰비 1.67) 제조한 수용액을 교반하면서 pH가 pH 7이 될 때까지 1M의 수산화나트륨 수용액을 첨가하였다. pH 7로 조절한 수용액은 필터(기공 사이즈 0.2㎛)를 이용하여 여과하고 수용액의 온도가 90℃가 되도록 하고 1시간 동안 교반하였다. 1시간 후 필터(기공 사이즈 0.1㎛)한 후 건조하여 인산칼슘 미립자를 얻었다. An acidic aqueous solution was prepared by quantifying 1,000 ml of 0.25M citric acid to 0.835M calcium nitrate and 0.05M ammonium phosphate (Ca / P molar ratio of 1.67) while stirring the prepared aqueous solution until the pH reached pH 7 Aqueous sodium hydroxide solution was added. The aqueous solution adjusted to pH 7 was filtered using a filter (pore size 0.2 μm), the temperature of the aqueous solution was 90 ℃ and stirred for 1 hour. After 1 hour, the resultant was filtered (pore size 0.1 μm) and dried to obtain calcium phosphate fine particles.
< 실시예 4 ><Example 4>
0.25M의 염산 1000ml에 16.7mM의 질산칼슘 및 10mM의 인산나트륨이 되도록 정량하여 산성의 수용액을 제조하였다.(Ca/P 몰비 1.67) 제조한 수용액을 교반하면서 pH가 pH 7이 될 때까지 0.2M의 트리스히드록시메틸아미노메탄 수용액을 첨가하였다. pH 7로 조절한 수용액은 필터(기공 사이즈 0.2㎛)를 이용하여 여과하고 수용액의 온도가 70℃가 되도록 하고 5시간 동안 교반하였다. 5시간 후 필터(기공 사이즈 1㎛)한 후 건조하여 인산칼슘 미립자를 얻었다. An acidic aqueous solution was prepared by quantifying 1000 ml of 0.25 M hydrochloric acid to 16.7 mM calcium nitrate and 10 mM sodium phosphate. (Ca / P molar ratio 1.67) 0.2 M until the pH reached pH 7 while stirring the prepared aqueous solution. Trishydroxymethylaminomethane aqueous solution was added. The aqueous solution adjusted to pH 7 was filtered using a filter (pore size 0.2 μm), the temperature of the aqueous solution was 70 ℃ and stirred for 5 hours. After 5 hours, the resultant was dried with a filter (pore size of 1 μm) to obtain calcium phosphate fine particles.
< 실시예 5 ><Example 5>
0.1M의 염산 100ml에 0.4M의 시트르산 900ml을 혼합한 수용액에 질산칼슘이 17.5mM , 인산나트륨이 10mM이 되도록 정량하여 산성의 수용액을 제조하였다. (Ca/P 몰비 1.75) 제조한 수용액을 교반하면서 pH가 pH 11.5가 될 때까지 1M의 수산화나트륨 수용액을 첨가하였다. pH 11.5로 조절한 수용액은 필터(기공 사이즈 0.2㎛)를 이용하여 여과하고 수용액의 온도가 90℃가 되도록 하고 2시간 동안 교반하였다. 2시간 후 필터(기공 사이즈 0.1㎛)한 후 건조하여 인산칼슘 미립자를 얻었다. An acidic aqueous solution was prepared by quantifying 100 ml of 0.1 M hydrochloric acid in an aqueous solution of 0.4 ml of citric acid 900 ml, so that calcium nitrate was 17.5 mM and sodium phosphate was 10 mM. (Ca / P molar ratio 1.75) While stirring the prepared aqueous solution, 1M sodium hydroxide aqueous solution was added until pH became pH 11.5. The aqueous solution adjusted to pH 11.5 was filtered using a filter (pore size 0.2 μm), the temperature of the aqueous solution was 90 ℃ and stirred for 2 hours. After 2 hours, the resultant was dried with a filter (pore size of 0.1 μm) to obtain calcium phosphate fine particles.
< 실시예 6 ><Example 6>
0.4M의 시트르산 1000ml에 각각 질산칼슘 0.167M , 인산암모늄 0.1M (a 용액) 및 질산칼슘 16.7mM , 인산암모늄 10mM (b 용액)이 되도록 정량하여 각각의 산성의 수용액을 제조하였다. 염기성 수용액으로 0.4M , 1M의 수산화나트륨 수용액을 제조하였다. (a) 및 (b) 수용액을 교반하면서 pH를 아래와 같이 조절하였다.Each acidic aqueous solution was prepared by quantifying to 0.4 ml of 0.4 M citric acid to 0.167 M of calcium nitrate, 0.1 M of ammonium phosphate (a solution) and 16.7 mM of calcium nitrate, 10 mM of ammonium phosphate (b solution), respectively. 0.4 M and 1 M aqueous sodium hydroxide solution were prepared as the basic aqueous solution. The pH was adjusted as follows while stirring (a) and (b) aqueous solution.
상기와 같이 제조한 수용액들을 필터(기공 사이즈 0.2㎛)를 이용하여 여과하고 수용액의 온도가 80℃가 되도록 하고 5시간 동안 교반하였다. 5시간 후 필터(기공 사이즈 0.1㎛)한 후 건조하여 인산칼슘 미립자를 얻었다. 그 결과 칼슘염의 농도 및 pH가 높을수록 더 미세하고 균일한 인산칼슘 미립자가 생성되었다. The aqueous solution prepared as described above was filtered using a filter (pore size 0.2 μm) and the solution was stirred at 80 ° C. for 5 hours. After 5 hours, the resultant was dried with a filter (pore size of 0.1 μm) to obtain calcium phosphate fine particles. As a result, the higher the calcium salt concentration and pH, the finer and more uniform calcium phosphate particles were produced.
도 1은, 실시예 1에 의해 제조된 인산칼슘의 X-선 회절 분석 결과를 나타내었다. Figure 1 shows the results of X-ray diffraction analysis of calcium phosphate prepared in Example 1.
도 2는, 실시예 1에 의해 제조된 인산칼슘 입자의 주사전자현미경 사진을 나타내었다. Figure 2 shows a scanning electron micrograph of the calcium phosphate particles prepared in Example 1.
도 3은, 실시예 2에 의해 제조된 인산칼슘 입자의 주사전자현미경 사진을 나타내었다. Figure 3 shows a scanning electron micrograph of the calcium phosphate particles prepared in Example 2.
도 4는, 실시예 3에 의해 제조된 인산칼슘 입자의 주사전자현미경 사진을 나타내었다. Figure 4 shows a scanning electron micrograph of the calcium phosphate particles prepared in Example 3.
도 5는, 실시예 4에 의해 제조된 인산칼슘 입자의 주사전자현미경 사진을 나타내었다. Figure 5 shows a scanning electron micrograph of the calcium phosphate particles prepared in Example 4.
도 6은, 실시예 5에 의해 제조된 인산칼슘 입자의 주사전자현미경 사진을 나타내었다. Figure 6 shows a scanning electron micrograph of the calcium phosphate particles prepared in Example 5.
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