WO1995027437A1 - Microfluidization of calcium/oxyanion-containing particles - Google Patents
Microfluidization of calcium/oxyanion-containing particles Download PDFInfo
- Publication number
- WO1995027437A1 WO1995027437A1 PCT/US1994/003276 US9403276W WO9527437A1 WO 1995027437 A1 WO1995027437 A1 WO 1995027437A1 US 9403276 W US9403276 W US 9403276W WO 9527437 A1 WO9527437 A1 WO 9527437A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- particles
- apatite
- preparing
- oxyanion
- calcium
- Prior art date
Links
- 239000002245 particle Substances 0.000 title claims abstract description 294
- 239000011575 calcium Substances 0.000 title claims description 62
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 title claims description 53
- 229910052791 calcium Inorganic materials 0.000 title claims description 53
- 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 abstract description 89
- 229910052586 apatite Inorganic materials 0.000 claims abstract description 88
- 238000000034 method Methods 0.000 claims abstract description 74
- 239000011248 coating agent Substances 0.000 claims abstract description 53
- 238000002059 diagnostic imaging Methods 0.000 claims abstract description 31
- 238000002595 magnetic resonance imaging Methods 0.000 claims abstract description 26
- 150000003839 salts Chemical class 0.000 claims abstract description 22
- 238000000576 coating method Methods 0.000 claims abstract description 16
- 238000009295 crossflow filtration Methods 0.000 claims abstract description 11
- DBVJJBKOTRCVKF-UHFFFAOYSA-N Etidronic acid Chemical group OP(=O)(O)C(O)(C)P(O)(O)=O DBVJJBKOTRCVKF-UHFFFAOYSA-N 0.000 claims description 32
- 239000000203 mixture Substances 0.000 claims description 32
- 239000011572 manganese Substances 0.000 claims description 29
- 239000002243 precursor Substances 0.000 claims description 28
- 230000005298 paramagnetic effect Effects 0.000 claims description 19
- 229910021645 metal ion Inorganic materials 0.000 claims description 17
- 229910052751 metal Inorganic materials 0.000 claims description 16
- 239000002184 metal Substances 0.000 claims description 16
- 210000000056 organ Anatomy 0.000 claims description 11
- 150000001875 compounds Chemical class 0.000 claims description 10
- 238000003384 imaging method Methods 0.000 claims description 10
- 229910019142 PO4 Inorganic materials 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 9
- 239000010452 phosphate Substances 0.000 claims description 9
- 210000001519 tissue Anatomy 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 8
- 210000004185 liver Anatomy 0.000 claims description 7
- 210000004369 blood Anatomy 0.000 claims description 6
- 239000008280 blood Substances 0.000 claims description 6
- 150000001450 anions Chemical class 0.000 claims description 5
- 238000011033 desalting Methods 0.000 claims description 5
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 claims description 5
- 210000000952 spleen Anatomy 0.000 claims description 5
- WAEMQWOKJMHJLA-UHFFFAOYSA-N Manganese(2+) Chemical group [Mn+2] WAEMQWOKJMHJLA-UHFFFAOYSA-N 0.000 claims description 4
- 150000007942 carboxylates Chemical class 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 3
- DUYCTCQXNHFCSJ-UHFFFAOYSA-N dtpmp Chemical compound OP(=O)(O)CN(CP(O)(O)=O)CCN(CP(O)(=O)O)CCN(CP(O)(O)=O)CP(O)(O)=O DUYCTCQXNHFCSJ-UHFFFAOYSA-N 0.000 claims description 3
- PTMHPRAIXMAOOB-UHFFFAOYSA-N phosphoramidic acid Chemical group NP(O)(O)=O PTMHPRAIXMAOOB-UHFFFAOYSA-N 0.000 claims description 3
- 230000002285 radioactive effect Effects 0.000 claims description 3
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 claims description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 claims description 2
- VTLYFUHAOXGGBS-UHFFFAOYSA-N Fe3+ Chemical compound [Fe+3] VTLYFUHAOXGGBS-UHFFFAOYSA-N 0.000 claims description 2
- 230000001588 bifunctional effect Effects 0.000 claims 3
- 125000000524 functional group Chemical group 0.000 claims 3
- 150000004697 chelate complex Chemical class 0.000 claims 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical group OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 claims 1
- 150000001412 amines Chemical class 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 18
- 239000007787 solid Substances 0.000 abstract description 10
- 238000002604 ultrasonography Methods 0.000 abstract description 4
- 239000000463 material Substances 0.000 abstract description 3
- 239000000243 solution Substances 0.000 description 43
- 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 38
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 36
- 239000002585 base Substances 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 18
- 239000000725 suspension Substances 0.000 description 18
- 229910052748 manganese Inorganic materials 0.000 description 17
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 14
- 239000002002 slurry Substances 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 10
- 229910052786 argon Inorganic materials 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- MIVBAHRSNUNMPP-UHFFFAOYSA-N manganese(II) nitrate Inorganic materials [Mn+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O MIVBAHRSNUNMPP-UHFFFAOYSA-N 0.000 description 8
- 238000000746 purification Methods 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- YDONNITUKPKTIG-UHFFFAOYSA-N [Nitrilotris(methylene)]trisphosphonic acid Chemical compound OP(O)(=O)CN(CP(O)(O)=O)CP(O)(O)=O YDONNITUKPKTIG-UHFFFAOYSA-N 0.000 description 7
- 230000001965 increasing effect Effects 0.000 description 7
- 239000006228 supernatant Substances 0.000 description 7
- 238000009826 distribution Methods 0.000 description 6
- ZCCIPPOKBCJFDN-UHFFFAOYSA-N calcium nitrate Inorganic materials [Ca+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O ZCCIPPOKBCJFDN-UHFFFAOYSA-N 0.000 description 5
- 238000007872 degassing Methods 0.000 description 5
- 229910000388 diammonium phosphate Inorganic materials 0.000 description 5
- 239000012530 fluid Substances 0.000 description 5
- 230000007935 neutral effect Effects 0.000 description 5
- 239000008188 pellet Substances 0.000 description 5
- 239000012266 salt solution Substances 0.000 description 5
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 239000003446 ligand Substances 0.000 description 4
- 229910001960 metal nitrate Inorganic materials 0.000 description 4
- 230000003647 oxidation Effects 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
- 230000002572 peristaltic effect Effects 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 238000004220 aggregation Methods 0.000 description 3
- 230000002776 aggregation Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000001506 calcium phosphate Substances 0.000 description 3
- 229910000389 calcium phosphate Inorganic materials 0.000 description 3
- 235000011010 calcium phosphates Nutrition 0.000 description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 150000002739 metals Chemical class 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 238000010951 particle size reduction Methods 0.000 description 3
- 238000000527 sonication Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 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 description 3
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 description 2
- 239000004254 Ammonium phosphate Substances 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 229910017974 NH40H Inorganic materials 0.000 description 2
- 229920005654 Sephadex Polymers 0.000 description 2
- 239000012507 Sephadex™ Substances 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- 229910000148 ammonium phosphate Inorganic materials 0.000 description 2
- 235000019289 ammonium phosphates Nutrition 0.000 description 2
- -1 apatites Inorganic materials 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 235000011089 carbon dioxide Nutrition 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 239000002872 contrast media Substances 0.000 description 2
- 238000010908 decantation Methods 0.000 description 2
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000005291 magnetic effect Effects 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 239000012521 purified sample Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- 238000000108 ultra-filtration Methods 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- 210000001835 viscera Anatomy 0.000 description 2
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 241000237074 Centris Species 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 101100536354 Drosophila melanogaster tant gene Proteins 0.000 description 1
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 description 1
- QCWXUUIWCKQGHC-UHFFFAOYSA-N Zirconium Chemical compound [Zr] QCWXUUIWCKQGHC-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 238000002583 angiography Methods 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 229910052797 bismuth Inorganic materials 0.000 description 1
- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- BFGKITSFLPAWGI-UHFFFAOYSA-N chromium(3+) Chemical compound [Cr+3] BFGKITSFLPAWGI-UHFFFAOYSA-N 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 230000002844 continuous effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- 229940039227 diagnostic agent Drugs 0.000 description 1
- 238000002405 diagnostic procedure Methods 0.000 description 1
- 238000012631 diagnostic technique Methods 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
- 239000003814 drug Substances 0.000 description 1
- IOIFRTZBJMZZFO-UHFFFAOYSA-N dysprosium(3+) Chemical compound [Dy+3] IOIFRTZBJMZZFO-UHFFFAOYSA-N 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- JHFPQYFEJICGKC-UHFFFAOYSA-N erbium(3+) Chemical compound [Er+3] JHFPQYFEJICGKC-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- RJOJUSXNYCILHH-UHFFFAOYSA-N gadolinium(3+) Chemical compound [Gd+3] RJOJUSXNYCILHH-UHFFFAOYSA-N 0.000 description 1
- 229960005219 gentisic acid Drugs 0.000 description 1
- 229910052735 hafnium Inorganic materials 0.000 description 1
- VBJZVLUMGGDVMO-UHFFFAOYSA-N hafnium atom Chemical compound [Hf] VBJZVLUMGGDVMO-UHFFFAOYSA-N 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 239000001307 helium Substances 0.000 description 1
- 229910052734 helium Inorganic materials 0.000 description 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
- SCKNFLZJSOHWIV-UHFFFAOYSA-N holmium(3+) Chemical compound [Ho+3] SCKNFLZJSOHWIV-UHFFFAOYSA-N 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000012216 imaging agent Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 229910052747 lanthanoid Inorganic materials 0.000 description 1
- 150000002602 lanthanoids Chemical class 0.000 description 1
- 229910052746 lanthanum Inorganic materials 0.000 description 1
- FZLIPJUXYLNCLC-UHFFFAOYSA-N lanthanum atom Chemical compound [La] FZLIPJUXYLNCLC-UHFFFAOYSA-N 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 229910052750 molybdenum Inorganic materials 0.000 description 1
- 239000011733 molybdenum Substances 0.000 description 1
- QEFYFXOXNSNQGX-UHFFFAOYSA-N neodymium atom Chemical compound [Nd] QEFYFXOXNSNQGX-UHFFFAOYSA-N 0.000 description 1
- 229910052758 niobium Inorganic materials 0.000 description 1
- 239000010955 niobium Substances 0.000 description 1
- GUCVJGMIXFAOAE-UHFFFAOYSA-N niobium atom Chemical compound [Nb] GUCVJGMIXFAOAE-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000003186 pharmaceutical solution Substances 0.000 description 1
- 239000007971 pharmaceutical suspension Substances 0.000 description 1
- 229920005646 polycarboxylate Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- WCWKKSOQLQEJTE-UHFFFAOYSA-N praseodymium(3+) Chemical compound [Pr+3] WCWKKSOQLQEJTE-UHFFFAOYSA-N 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 229910052712 strontium Inorganic materials 0.000 description 1
- CIOAGBVUUVVLOB-UHFFFAOYSA-N strontium atom Chemical compound [Sr] CIOAGBVUUVVLOB-UHFFFAOYSA-N 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229910052715 tantalum Inorganic materials 0.000 description 1
- GUVRBAGPIYLISA-UHFFFAOYSA-N tantalum atom Chemical compound [Ta] GUVRBAGPIYLISA-UHFFFAOYSA-N 0.000 description 1
- HKCRVXUAKWXBLE-UHFFFAOYSA-N terbium(3+) Chemical compound [Tb+3] HKCRVXUAKWXBLE-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 239000010937 tungsten Substances 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
- AWSFICBXMUKWSK-UHFFFAOYSA-N ytterbium(3+) Chemical compound [Yb+3] AWSFICBXMUKWSK-UHFFFAOYSA-N 0.000 description 1
- 229910052726 zirconium Inorganic materials 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
- A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
- A61K49/225—Microparticles, microcapsules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/32—Manganese; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
- A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
- A61K49/1821—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
- A61K49/1824—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles
- A61K49/1827—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle
- A61K49/1833—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with a small organic molecule
- A61K49/1842—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with a small organic molecule the small organic molecule being a phosphate or a phosphonate, not being a phospholipid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B90/00—Instruments, implements or accessories specially adapted for surgery or diagnosis and not covered by any of the groups A61B1/00 - A61B50/00, e.g. for luxation treatment or for protecting wound edges
- A61B90/39—Markers, e.g. radio-opaque or breast lesions markers
- A61B2090/3925—Markers, e.g. radio-opaque or breast lesions markers ultrasonic
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B90/00—Instruments, implements or accessories specially adapted for surgery or diagnosis and not covered by any of the groups A61B1/00 - A61B50/00, e.g. for luxation treatment or for protecting wound edges
- A61B90/39—Markers, e.g. radio-opaque or breast lesions markers
- A61B2090/3954—Markers, e.g. radio-opaque or breast lesions markers magnetic, e.g. NMR or MRI
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B90/00—Instruments, implements or accessories specially adapted for surgery or diagnosis and not covered by any of the groups A61B1/00 - A61B50/00, e.g. for luxation treatment or for protecting wound edges
- A61B90/39—Markers, e.g. radio-opaque or breast lesions markers
Definitions
- This invention relates to the preparation of calci ⁇ um/oxyanion-containing particles for use in medical diag ⁇ nostic imaging, such as magnetic resonance imaging ("MRI"), ultrasound, and X-ray.
- MRI magnetic resonance imaging
- the present inven ⁇ tion is directed to the use of a microfluidizer for the preparation of calcium/oxyanion-containing particles having a uniform small ( ⁇ 5 ⁇ m) size distribution.
- the present invention also includes the use of tangential flow filtra ⁇ tion for particle purification.
- contrast agents in diagnostic medicine is rapidly growing.
- X-ray diagnostics for example, increased contrast of internal organs, such as the kidneys, the urinary tract, the digestive tract, the vascular system of the heart (angiography) , etc.
- a contrast agent which is substantially radiopaque.
- increased contrast of internal organs and tissues may be obtained by adminis ⁇ tering compositions containing paramagnetic metal species which increase the relaxivity of surrounding protons.
- improved contrast is obtained by administering compositions having acoustic impedances different than that of blood and other tissues. Often it is desirable to image or treat a specific organ or tissue.
- hydroxylapatite (sometimes referred to as "hydroxylapatite”) .
- stoichiometric hydroxyapatite Ca 10 (OH) 2 (P0 4 ) 6
- Useful apatite particles may also be prepared by replacing calcium with paramagnetic metal ions.
- Other apatite derivatives are prepared by replacing the OH " with simple anions, including F “ , Br", I " , or ⁇ [C0 3 2 -] .
- Various techniques for controlling the particle size for certain calcium phosphate-containing compounds are disclosed in copending application Serial No. 07/948,540.
- apatite particles Due to the small size and nature of apatite particles, they tend to aggregate. Particle aggregation may be inhibited by coating the particles with coating agents, while agglomerated particles may be disrupted by mechanical or chemical means and then coated with a coating agent having an affinity for the apatite.
- One preferred method of obtaining small, uniformly sized, manganese-doped apatite particles is to dropwise add a degassed solution of (NH 4 ) 2 HP0 4 and NH 4 OH into a rapidly stirring degassed solution of Ca(N0 3 ) 2 «4H 2 0 and Mn(N0 3 ) 2 *6H 2 0.
- the resulting apatite particles are then reacted with a solution of 1-hydroxyethane-l, 1-diphosphonic acid (HEDP) .
- the smaller particles are separated from larger particles by repeated centrifuging and collection of the supernatant.
- the present invention provides methods of preparing calcium/oxyanion-containing particles, including apatites and apatite precursors, using a microfluidizer.
- the particles thus prepared are for use in medical diagnostic imaging, such as magnetic resonance imaging, X-ray, and ultrasound applications.
- the desired calcium/oxyanion- containing particles are synthesized, passed through a microfluidizer, and purified to remove excess base, salts, and other materials used to synthesize the particles.
- the microfluidizer causes two high pressure streams to interact at ultra high velocities in a precisely defined microchan ⁇ nel. Use of the microfluidizer results in significant reduction in the average particle size. Purifying the particles, preferably using tangential flow filtration, as well as coating the particles, improves particle stability.
- FIG. 1 is a graphical representation of the particle size distribution of manganese-doped hydroxyapatite parti ⁇ cles prepared according to Example 8, before and after passing through a microfluidizer.
- Figure 2 is a graphical representation of the osmolal- ity of a particulate suspension after sequential passes through a tangential flow filtration system as described in Example 8.
- the present invention provides methods for preparing calcium/oxyanion-containing particles, including apatites and apatite precursors, especially hydroxyapatite, having uniform, small ( ⁇ 5 ⁇ m) particle size and uniform distribu ⁇ tion through use of a microfluidizer.
- calcium/oxyanion-containing particles include calcium phosphate minerals, apatites, and apatite precursors of the general formula Ca n M m X r Y s , where M is a paramagnetic metal ion, radiopaque metal ion, radioactive metal ion, or stoichiometric mixture of metal ions, X is a simple anion, Y is an oxyanion including tetrahedral oxyanions, carbonate, or mixtures thereof, m is from 0 to 10, n is from-1 to 10, s is ⁇ 1, and r is adjusted as needed to provide charge neutrality.
- apatite precursors include compounds within the scope of the above general formula having one or more amorphous phases which, when sintered, may become crystalline apatites.
- Possible paramagnetic metal ions which can be used in the calcium/oxyanion-containing particles of the present invention include: chromium(III) , manganese (II) , iron(II), iron(III), praseodymium(III) , neodymium(III) , samari- um(III), ytterbium(III) , gadolinium(III) , terbium(III) , dysprosium(III) , holmium(III) , erbium(III), or mixtures of these with each other or with alkali or alkaline earth metals.
- radiopaque heavy metals such as bismuth, tungsten, tantalum, hafnium, lanthanum and the lanthanides, barium, molybdenum, niobium, zirconium, and strontium may also be incorporated into particles to provide X-ray contrast.
- the radiopaque metals are incorporated into the calcium/oxyanion-containing particles in the same manner as paramagnetic metal ions.
- Typical simple anions which can be used in the calci ⁇ um/oxyanion-containing particles of the present invention include: OH “ , F “ , Br “ I “ , [C0 3 2" ], or mixtures thereof.
- the tetrahedral oxyanions used in the present invention may optionally include radiopaque metals or radioactive metals. Suitable tetrahedral oxyanions are nonoxidizing and stable to hydrolysis. Examples of suitable tetrahedral oxyanions for use in the present invention include: P0 4 3" , As0 4 3" , W0 4 2" , Mo0 4 2" , V0 4 3” , SiO-- 4" , and Ge0 4 4" . Phosphate is a currently preferred tetrahedral oxyanion.
- organ specific imaging or therapy of the liver or gastrointestinal tract is obtained.
- apatite particles having a size in the range from about 5 n to about 5 ⁇ m are injected into the vascular system, the particles collect in the liver or spleen (the RES system) because a normal function of these organs is to purify the blood of foreign particles.
- the particles Once the particles have collected in the liver or spleen, these organs may be imaged by the desired medical diagnostic imaging technique.
- calci- um/oxyanion containing particles are treated to be paramag- netic, radiopaque, or echogenic.
- paramagnetic metal species may be incorporated into the particles to improve magnetic resonance contrast
- radiopaque species may be incorporated to provide X-ray contrast.
- Particle density, and corresponding echogenic characteristics can be controlled to impart low or high acoustic impedance relative to blood.
- the calcium/oxyanion-containing parti ⁇ cles may also be fluorinated to form stable, nontoxic compositions useful for 19 F imaging. The presence of a paramagnetic metal species in these particles may reduce 19 F and proton relaxivity, thereby enhancing MRI, MRS, or MRSI.
- Hydroxyapatite doped with a paramagnetic metal can be prepared by mixing a basic (pH 10-12) phosphate solution with a calcium/paramagnetic metal solution at native pH.
- Antioxidants such as gentisic acid and ascorbic acid, added during or after apatite particle synthesis may also be used to prevent metal ion oxidation.
- Reducing agents such as NaBH 4
- Paramagnetic particles may also be prepared by adsorb ⁇ ing paramagnetic metal ions onto the particle.
- manganese can be adsorbed to hydroxyapatite particles by taking a slurry of hydroxyapatite and adding Mn(N0 3 ) 2 with stirring. Applying energy, such as ultrasonic power or heat, to the resulting mixture may also facilitate the reaction.
- the resulting mixture can be separated by either centrifugation and decantation or by filtration. Any excess manganese may be removed by washing with large amounts of water.
- the manganese adsorbed particles can then be stabilized against oxidation and particle agglomer ⁇ ation with a suitable coating agent. The same procedure may be used with other paramagnetic cations.
- the amount of manganese adsorbed onto the particle surface, as a percent- age of the total calcium in the particle, is in the range from about 0.1% to about 50%. Such particles exhibit very high relaxivities and rapid liver enhancement in magnetic resonance imaging studies.
- a microfluidizer such as those produced by Microfluidics Corporation, Newton, Massachu ⁇ setts, causes two high pressure fluid streams to interact at ultra high velocity. It is postulated that shear, impact and cavitation forces act on the fluid streams to achieve submicron particle reduction with uniform distribu ⁇ tion. Fluid pressures typically range from 2000 psi to 30,000 psi with some production size microfluidizers capable of handling pressures up to 40,000 psi.
- Stabilized calcium/oxyanion-containing particles including apatites and apatite precursors, are desirable for in vivo use as medical diagnostic imaging agents. Such particles tend to aggregate. Although the reasons calci ⁇ um/oxyanion-containing particles aggregate is not fully understood, it has been found that several different coating agents are able to inhibit particle aggregation.
- these particles may be stabilized by treatment with coating agents such as di- and polyphosphonate-con ⁇ taining compounds or their salts, such as 1-hydroxyethane- 1,1-diphosphonate (HEDP) , pyrophosphate, aminophosphonates; carboxylates and polycarboxylate-containing compounds such as oxalates and citrates; alcohols and polyalcohol-contain ⁇ ing compounds; compounds containing one or more phosphate, sulfate, or sulfonate moiety; and biomolecules such as peptides, proteins, antibodies, and lipids all have been shown to inhibit particle aggregation.
- coating agents such as di- and polyphosphonate-con ⁇ taining compounds or their salts, such as 1-hydroxyethane- 1,1-diphosphonate (HEDP) , pyrophosphate, aminophosphonates; carboxylates and polycarboxylate-containing compounds such as oxalates and citrates; alcohols and
- particle relaxivity When used in magnetic resonance imaging, particle relaxivity is enhanced by allowing more water accessible to the particle surface. By limiting particle size and increasing the available surface area, relaxivity may be improved.
- Typical coating techniques are identified in International Publication Numbers WO 85/02772, WO 91/02811, and European Publication Number EP 0343934, which are incorporated by reference.
- agglomerated particles may be disrupted by mechanical or chemical means and then coated with polymers such as carbohydrates, proteins, and synthetic polymers.
- Dextran having a molecular weight in the range from about 10,000 to about 40,000 is one currently pre- ferred coating material.
- Albumin and surfactants, such as tween 80 have also been used to reduce particle aggrega ⁇ tion.
- apatite coating agents are their ability to modify the particle surface charge, or zeta potential. It will be appreciated that the calcium phosphate- containing particles within the scope of the present invention may be coated before, during, or after passage through the microfluidizer. When coated during passage through the microfluidizer, one fluid stream is the coating agent, while the other fluid stream is the particulate stream.
- the currently preferred mechanical means for reducing particle size is microfluidization, but other means such as heating, sonication, other forms of particle energization, such as irradiation, and chemical means, such as pH modifi- cation or combinations of these types of treatment, such as pH modification, combined with sonication may be used.
- the calcium/oxyanion-containing particles of this invention may be formulated into diagnostic compositions for parenteral administration.
- parenteral formulations advantageously contain a sterile aqueous solution or suspension of treated apatite or apatite precursor particles according to this invention.
- suitable pharmaceutical solutions and suspensions are known in the art.
- Such solutions also may contain pharmaceutically acceptable buffers and, optionally, electrolytes such as sodium chloride.
- Paren- teral compositions may be injected directly or mixed with a large volume parenteral composition for systemic adminis ⁇ tration.
- the diagnostic compositions of this invention are used in a conventional manner in medical diagnostic imaging procedures such as magnetic resonance, X-ray, and ultra ⁇ sound imaging.
- the diagnostic compositions are adminis ⁇ tered in a sufficient amount to provide adequate visualiza ⁇ tion, to a warm-blooded animal either systemically or locally to an organ or tissues to be imaged, then the animal is subjected to the medical diagnostic procedure.
- Such doses may vary widely, depending upon the diagnostic technique employed as well as the organ to be imaged.
- Example 1 is offered to further illus ⁇ trate the present invention. These examples are intended to be purely exemplary and should not be viewed as a limitation on any claimed embodiment.
- Example 1
- Manganese containing hydroxyapatite particles were prepared by the following general procedure. A procedure is described for particles containing 10% Mn (compared to the total metal content) but other percentages are also applicable. Into a 1 L erlenmeyer flask were placed 10.5 g of
- the entire reaction mixture was centrifuged at one time at 2400 rpm for 15 minutes. The supernatant was discarded and the solid residue in each tube resuspended in water. The slurry was re-centrifuged at 2400 rpm and the milky supernatant was collected. The solid was resuspended twice more and centrifuged at 2400 rpm. The three washes were combined and centrifuged at 7000 rpm for 30 minutes. The resulting solid pellet was separated from the superna- tant by decantation, and the pellet was washed (D.I. H 2 0) and centrifuged three times, and the supernatants were discarded. After washing, the solid pellet was suspended in 30 mL of D.I.. H 2 0.
- the preparation was stored at room temperature for one month.
- the particle size was analyzed and found to be 280 nm (2.9 chi squared, 0.31 coefficient of variance) .
- the particulate suspension was passed through a microfluidizer at approximately 5000 psi. After one pass through the microfluidizer, the particle size was reduced to 125 nm (0.43 chi squared, 0.35 coefficient of variance) . After another pass through the microfluidizer at a pressure of approximately 10,000 psi, the size did not change signifi ⁇ cantly, 144 nm (0.20 chi squared, 0.28 coefficient of variance) . At three hours and 36 hours after passing through the microfluidizer, the particle size remained essentially constant at 159 nm and 148 nm, respectively.
- Manganese containing hydroxyapatite particles were prepared according to the procedure of Example 1, except that the particles were not purified by centrifuging, decanting, and washing, but left in the base and salt solution.
- the particulate suspension (average size > 1 ⁇ m, chi squared > 20) was passed through a microfluidizer at approximately 5000 psi. After one pass through the micro ⁇ fluidizer, the particle size was 87 nm (2.3 chi squared, 0.41 coefficient of variance) . After five passes through the microfluidizer at pressures from 5000 psi to 7000 psi, the particle size was 89 nm (0.88 chi squared, 0.37 coeffi ⁇ cient of variance) .
- the resulting particles were too small to pellet at 2400 rpm and were left in the base and salts. There was no indication that multiple passes through the microfluidizer made smaller particles, but it appears the uniformity was increased. Twenty hours after passing through the micro ⁇ fluidizer the particle size has increased to 713 nm (21.1 chi squared, 0.53 coefficient of variance) . Although the chi squared was large, indicating a poor fit to a gaussian distribution, the coefficient of variance was small with 99% of the particles less than 2 ⁇ m and 75% less than 825 nm. The relaxivity (R of these particles 2 hours after formation was approximately 22 mM "1 s "1 .
- Manganese containing hydroxyapatite particles were prepared according to the procedure of Example 1, except that the particles were not coated with HEDP and were not purified by centrifuging, decanting, and washing, but left in the base and salt solution.
- the particulate suspension was passed as one stream into a microfluidizer.
- the other microfluidizer stream consisted of a HEDP solution prepared according to the procedure of Example 1.
- the two streams passed through the microfluidizer at a pressure of 10,000 psi.
- the resulting particulate suspension had a particle size of 70 nm (2.4 chi squared, 0.42 coefficient of vari- ance) .
- the particles were not purified from base and salts.
- Unpurified into Neutral HEDP Solution Manganese containing hydroxyapatite particles were prepared according to the procedure of Example 1, except that the particles were not coated with HEDP and were not purified by centrifuging, decanting, and washing, but left in the base and salt solution.
- the particulate suspension was passed through a microfluidizer at 10,000 psi and into a beaker of neutral HEDP.
- the neutral HEDP solution was prepared from 8.3 mL of a 60% solution HEDP (neutral form) in 25 mL of D.I. water.
- the resulting particulate solution had an average particle size of 1333 nm (7.3 chi squared, 0.40 coefficient of variance) . Two hours after formation, the particle size was 884 nm (8.3 chi squared, 0.46 coefficient of variance) .
- the results suggest that the use of acidic HEDP is useful in the formation of small particles and the neutral form of HEDP may be used when larger particles are desired.
- Examples 1-4 indicate that the particle size of manganese doped hydroxyapatite may be substantially reduced by the shear, impact and cavitation forces present within the microfluidizer.
- Manganese containing hydroxyapatite particles were prepared according to the procedure of Example 1, except that the particles were not coated with HEDP and the particles were washed free of base and salts by centrifug- ing three times at 2400 rpm. Degassed water was used to wash the pelleted particles following centrifuging.
- ATMP solution was prepared by mixing 0.0027 moles or 1.6 mL of a 50% aqueous solution with 25 mL D.I. H 2 0 and degassing for 30 minutes -under argon.
- the ATMP solution was added dropwise to the washed particles resulting in a "white" slurry.
- the slurry was passed through a microfluidizer at 10,000 psi. After passing through the microfluidizer, the particles had an estimated size of 84 nm (1.3 chi squared, 0.52 coefficient of variance) . There was some oxidation of manganese with time as evident from a brown appearance in the particles. After six days there were two populations of particles, 46 nm and >2 ⁇ m. The percentages of each component could not be determined due to the limits of the particle analyzer and settling of the larger particles.
- Manganese containing hydroxyapatite particles were prepared according to the procedure of Example 1, except that the particles were not coated with HEDP and were not purified by centrifuging, decanting, and washing, but left in the base and salt solution.
- An HEDP solution prepared according to the procedure of Example 1 was added dropwise to the particles.
- the particle size before passing through a microfluidizer was 1498 nm (13.4 chi squared, 0.93 coefficient of variance) . After passing the particulate suspension through the microfluidizer at 10,000 psi the particle size was 62 nm (0.27 chi squared, 0.47 coefficient of variance) .
- the particle size of the S-10 purified sample was 100 nm (0.40 chi squared, 0.38 coefficient of variance) .
- the size of the particles that -were passed through the microfluidizer but were not purified and stored in the base solution increased to 744 nm (4.22 chi squared, 0.57 coefficient of variance) .
- the S-10 purified fraction had a particle size of 77 nm (0.65 chi squared, 0.44 coeffi ⁇ cient of variance) .
- Manganese containing hydroxyapatite particles were prepared according to the procedure of Example 1, except that the particles were not coated with HEDP and were not purified by centrifuging, decanting, and washing, but left in the base and salt solution.
- An ATMP solution was prepared by mixing 0.0027 moles or 1.6 mL of a 50% aqueous solution with 25 mL D.I. H 2 0 and degassing for 30 minutes under argon. The ATMP solution was added dropwise to the particles. The particle size before passing through a microfluidizer was 1465 nm and difficult to analyze due to settling.
- the particle size was 85 nm (0.58 chi squared, 0.41 coefficient of variance) .
- the particulate suspension was divided into two parts. One part was passed through a Sephadex 10 (S-10) desalting column to remove base, salts, and excess ligand. The remaining part of the particulate suspension was retained as a control. Following S-10 purification, the particle size was 67 nm (0.25 chi squared, 0.44 coefficient of variance) . Six days later, the particle size of the S-10 purified sample was 131 nm (0.60 chi squared, 0.39 coeffi ⁇ cient of variance) .
- apatite particles are stabilized better with removal of the base, salts, and excess phosphonate.
- the particles tend to grow at a fast rate when stored in the reaction solution, but growth of purified particles is either stopped or inhibit ⁇ ed.
- growth of purified particles is either stopped or inhibit ⁇ ed.
- Manganese containing hydroxyapatite particles were prepared by the following general procedure. A procedure is described for particles containing 10% Mn but other percentages are also applicable.
- Two thirds of the reaction mixture was passed through a microfluidizer at 10,000 psi.
- the particle size before passing through a microfluidizer was 800 nm (27 chi squared, 0.92 coefficient of variance) .
- the particle size was 53 nm (2.2 chi squared, 0.48 coefficient of variance) .
- the particulate suspension was then purified to remove base, salts, and excess ligand by passing it through a tangential flow filtration (sometimes referred to as "ultrafiltration") system.
- the tangential flow filtra ⁇ tion system was obtained from Koch Membrane Systems, Inc., Wilmington, Massachusetts. After each filtration pass, the osmolality was measured. A total of 10 filtration passes were made followed by a 3-fold concentration step.
- the particle size was 67 nm (0.43 chi squared, 0.44 coefficient of variance) .
- the size of the particles that were passed through the microfluidizer but were not purified and stored in the base solution increased to 744 nm (4.22 chi squared, 0.57 coefficient of variance) .
- the filtered fraction had a particle size of 82 nm (2.7 chi squared, 0.41 coefficient of variance) .
- the results of this Example are illustrated graphical ⁇ ly in Figures 1 and 2.
- Calcium hydroxyapatite particles are prepared by the following procedure: A solution containing 6.5 g of (NH 4 ) 2 HP0 4 in 120 mL of
- D.I. water is treated with 60 mL of concentrated NH 4 0H followed by 90 mL of D.I. water. The resulting solution is stirred for 3 hours at room temperature.
- the pH of the reaction mixture is decreased from 9.53 to 8.50 with 169 ml of 1 N HCl .
- Manganese nitrate, Mn(N0 3 ) 2 »6H 2 0 (2.10 g) is added to the hydroxyapatite mixture and stirred for 1 hour and 15 minutes. The color of the slurry is pale tan.
- the mixture is passed through a tangential flow filter to remove excess manganese nitrate from the apatite particles.
- the HEDP treated hydroxyapatite particulate suspension is passed through a microfluidizer at a pressure of 5000 psi.
- the particulate suspension is then purified to remove base, salts, and excess ligand by passing it through a tangential flow filtration system.
- This example describes the general preparation of hydroxyapatite particles having a functionalized coating agent where the functionalized coating agent is defined as one with the ability to bind tightly to the particles and contains a pendant group to which other organic biomole- cules or organic may be attached.
- the particles are prepared by adding 0.1 to 100 mole % of an appropriate coating agent to a slurry of Mn(II) substituted hydroxyapa- tite with 0.1 to 100 mole % Mn based on the Ca used in the reaction. The mixture is stirred from 1 to 360 minutes at temperatures in the range from 4°C to 100°C.
- the particu ⁇ late suspension is passed through a microfluidizer at a pressure in the range from 2000 to 20,000 psi, and the solid separated from the supernatant and purified from excess ions and coating agent by tangential flow filtra ⁇ tion.
- the solid may be treated with a metal salt (0.01 to 10 mole% based on the total metal in the preparation) . This is especially appropriate if the coating agent con- tains a pendant chelating group designed to capture and hold tightly the metal when subjected to .in vitro and/or in vivo solutions.
- the resultant solid is purified to remove loosely attached coating agent or free metal/coating agent complex by tangential flow filtration.
- Calcium hydroxyapatite is prepared by the following procedure and treated with the polyphosphonate, diethylene- triaminepenta(methylenephosphonic acid) (abbreviated
- a basic ammonium phosphate solution is prepared using 6.34 g of (NH 4 ) 2 HP0 4 in 120 mL of D.I. water. Concentrated ammonium hydroxide (60 mL) is added followed by 90 ml of D.I. water. The mixture is stirred for 4 hours at room temperature.
- a solution of 19.0 g of Ca(N0 3 ) 2 »4H 2 0 in 468 mL of D.I. water is placed in a 3-neck 1 L round bottom flask.
- the reaction setup includes a mechanical stirrer, water cooled and low temperature (dry ice/isopropanol) condenser ar ⁇ rangement, and a rubber septum.
- the solution is heated to reflux with rapid stirring.
- the basic phosphate solution is added dropwise with a peristaltic pump over one hour. The heat is removed after the addition is complete and the reaction mixture stirred overnight at room temperature.
- the reaction mixture is passed through a microfluidizer at a pressure of 5000 psi and purified by tangential flow filtration.
- the present invention provides an improved method for preparing solid calcium phosphate-containing particles for medical diagnostic applications having a controlled particle size distribution and good yield.
Abstract
Description
Claims
Priority Applications (16)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US07/948,540 US5344640A (en) | 1991-10-22 | 1992-09-22 | Preparation of apatite particles for medical diagnostic imaging |
CA002120130A CA2120130A1 (en) | 1991-10-22 | 1992-10-21 | Treated apatite particles for medical diagnostic imaging |
AU28864/92A AU674291B2 (en) | 1991-10-22 | 1992-10-21 | Treated apatite particles for medical diagnostic imaging |
PCT/US1992/009032 WO1993007905A2 (en) | 1991-10-22 | 1992-10-21 | Treated apatite particles for medical diagnostic imaging |
EP92922461A EP0610333B1 (en) | 1991-10-22 | 1992-10-21 | Treated apatite particles for medical diagnostic imaging |
JP5507914A JPH07500823A (en) | 1991-10-22 | 1992-10-21 | Processed apatite particles for medical diagnostic imaging |
US08/038,329 US5342609A (en) | 1991-10-22 | 1993-03-29 | Microfluidization of calcium/oxyanion-containing particles |
US08/047,129 US5407659A (en) | 1991-10-22 | 1993-04-13 | Treated calcium/oxyanion-containing particles for medical diagnostic imaging |
JP7526296A JPH09511520A (en) | 1994-04-11 | 1994-04-11 | Microfluidization of particles containing calcium / oxyanions |
EP94915769A EP0755222A4 (en) | 1994-04-11 | 1994-04-11 | Microfluidization of calcium/oxyanion-containing particles |
AU67664/94A AU6766494A (en) | 1994-04-11 | 1994-04-11 | Microfluidization of calcium/oxyanion-containing particles |
PCT/US1994/003276 WO1995027437A1 (en) | 1991-10-22 | 1994-04-11 | Microfluidization of calcium/oxyanion-containing particles |
US08/271,921 US5468465A (en) | 1991-10-22 | 1994-07-06 | Treated apatite particles for x-ray diagnostic imaging |
US08/249,776 US5419892A (en) | 1991-10-22 | 1994-07-26 | Microfluidization of calcium/oxyanion-containing particles |
FI964057A FI964057A0 (en) | 1994-04-11 | 1996-10-10 | Microfluidization of particles of calcium / oxyanion |
NO964317A NO964317D0 (en) | 1994-04-11 | 1996-10-10 | Microfluidization of calcium / oxyanion-containing particles |
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
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US78432591A | 1991-10-22 | 1991-10-22 | |
US07/948,540 US5344640A (en) | 1991-10-22 | 1992-09-22 | Preparation of apatite particles for medical diagnostic imaging |
US08/038,329 US5342609A (en) | 1991-10-22 | 1993-03-29 | Microfluidization of calcium/oxyanion-containing particles |
PCT/US1994/003276 WO1995027437A1 (en) | 1991-10-22 | 1994-04-11 | Microfluidization of calcium/oxyanion-containing particles |
US08/271,921 US5468465A (en) | 1991-10-22 | 1994-07-06 | Treated apatite particles for x-ray diagnostic imaging |
US08/249,776 US5419892A (en) | 1991-10-22 | 1994-07-26 | Microfluidization of calcium/oxyanion-containing particles |
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WO1998047532A1 (en) * | 1997-04-24 | 1998-10-29 | Nycomed Imaging As | Embolus therapy using insoluble microparticles or vesicles containing contrast agents |
WO2005006356A1 (en) * | 2003-07-10 | 2005-01-20 | Micromod Partikeltechnologie Gmbh | Magnetic nanoparticles having improved magnetic properties |
US7691285B2 (en) | 2003-07-10 | 2010-04-06 | Micromod Partikeltechnologie Gmbh | Magnetic nanoparticles having improved magnetic properties |
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