CN106927441B - 一种孔径可控的空心羟基磷灰石微球、制备方法及其应用 - Google Patents
一种孔径可控的空心羟基磷灰石微球、制备方法及其应用 Download PDFInfo
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- 229910052588 hydroxylapatite Inorganic materials 0.000 title claims abstract description 89
- 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 title claims abstract description 89
- 239000004005 microsphere Substances 0.000 title claims abstract description 70
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims abstract description 96
- 229910000019 calcium carbonate Inorganic materials 0.000 claims abstract description 48
- 239000002243 precursor Substances 0.000 claims abstract description 25
- 238000001027 hydrothermal synthesis Methods 0.000 claims abstract description 16
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000013078 crystal Substances 0.000 claims abstract description 6
- 239000000243 solution Substances 0.000 claims description 27
- 238000001556 precipitation Methods 0.000 claims description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 19
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 19
- 229910021642 ultra pure water Inorganic materials 0.000 claims description 15
- 239000012498 ultrapure water Substances 0.000 claims description 15
- 238000005406 washing Methods 0.000 claims description 14
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 13
- 239000011575 calcium Substances 0.000 claims description 13
- 229910052791 calcium Inorganic materials 0.000 claims description 13
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- 239000007788 liquid Substances 0.000 claims description 11
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 10
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 8
- 239000000908 ammonium hydroxide Substances 0.000 claims description 8
- 239000011148 porous material Substances 0.000 claims description 8
- 238000009938 salting Methods 0.000 claims description 8
- 239000000470 constituent Substances 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- 238000005119 centrifugation Methods 0.000 claims description 6
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical group [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- 239000001488 sodium phosphate Substances 0.000 claims description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 5
- FTOAOBMCPZCFFF-UHFFFAOYSA-N 5,5-diethylbarbituric acid Chemical compound CCC1(CC)C(=O)NC(=O)NC1=O FTOAOBMCPZCFFF-UHFFFAOYSA-N 0.000 claims description 4
- 239000000872 buffer Substances 0.000 claims description 4
- 239000007853 buffer solution Substances 0.000 claims description 4
- 150000005323 carbonate salts Chemical class 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical group [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- SNRUBQQJIBEYMU-UHFFFAOYSA-N dodecane Chemical compound CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 claims description 3
- 239000012266 salt solution Substances 0.000 claims description 3
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 229960002319 barbital Drugs 0.000 claims description 2
- GHXRKGHKMRZBJH-UHFFFAOYSA-N boric acid Chemical compound OB(O)O.OB(O)O GHXRKGHKMRZBJH-UHFFFAOYSA-N 0.000 claims description 2
- 239000000337 buffer salt Substances 0.000 claims description 2
- 159000000007 calcium salts Chemical class 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 claims description 2
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical group [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 claims description 2
- 235000019838 diammonium phosphate Nutrition 0.000 claims description 2
- 229910000388 diammonium phosphate Inorganic materials 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 2
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 2
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical group [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical group [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 2
- 235000011008 sodium phosphates Nutrition 0.000 claims description 2
- OTNVGWMVOULBFZ-UHFFFAOYSA-N sodium;hydrochloride Chemical compound [Na].Cl OTNVGWMVOULBFZ-UHFFFAOYSA-N 0.000 claims description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical group [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims 1
- 238000005660 chlorination reaction Methods 0.000 claims 1
- SEGLCEQVOFDUPX-UHFFFAOYSA-N di-(2-ethylhexyl)phosphoric acid Chemical group CCCCC(CC)COP(O)(=O)OCC(CC)CCCC SEGLCEQVOFDUPX-UHFFFAOYSA-N 0.000 claims 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical group [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 claims 1
- GRHBQAYDJPGGLF-UHFFFAOYSA-N isothiocyanic acid Chemical compound N=C=S GRHBQAYDJPGGLF-UHFFFAOYSA-N 0.000 claims 1
- 229910052938 sodium sulfate Inorganic materials 0.000 claims 1
- 235000011152 sodium sulphate Nutrition 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 15
- 229940079593 drug Drugs 0.000 abstract description 10
- RCEAADKTGXTDOA-UHFFFAOYSA-N OS(O)(=O)=O.CCCCCCCCCCCC[Na] Chemical compound OS(O)(=O)=O.CCCCCCCCCCCC[Na] RCEAADKTGXTDOA-UHFFFAOYSA-N 0.000 abstract description 7
- 230000015556 catabolic process Effects 0.000 abstract description 7
- 238000006731 degradation reaction Methods 0.000 abstract description 7
- 230000000694 effects Effects 0.000 abstract description 5
- 230000007246 mechanism Effects 0.000 abstract description 2
- 239000000693 micelle Substances 0.000 abstract description 2
- 238000013268 sustained release Methods 0.000 abstract description 2
- 239000012730 sustained-release form Substances 0.000 abstract description 2
- 125000003277 amino group Chemical group 0.000 abstract 1
- 238000012925 biological evaluation Methods 0.000 abstract 1
- 239000000700 radioactive tracer Substances 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 18
- 238000011026 diafiltration Methods 0.000 description 16
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 229910052697 platinum Inorganic materials 0.000 description 10
- 239000004094 surface-active agent Substances 0.000 description 10
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 9
- 238000002156 mixing Methods 0.000 description 9
- 239000002953 phosphate buffered saline Substances 0.000 description 9
- 230000005540 biological transmission Effects 0.000 description 8
- 238000010586 diagram Methods 0.000 description 8
- -1 sodium dialkyl sulfate Chemical class 0.000 description 6
- NQTSTBMCCAVWOS-UHFFFAOYSA-N 1-dimethoxyphosphoryl-3-phenoxypropan-2-one Chemical compound COP(=O)(OC)CC(=O)COC1=CC=CC=C1 NQTSTBMCCAVWOS-UHFFFAOYSA-N 0.000 description 5
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000000101 transmission high energy electron diffraction Methods 0.000 description 5
- 239000012901 Milli-Q water Substances 0.000 description 4
- 229910052586 apatite Inorganic materials 0.000 description 4
- 229910000397 disodium phosphate Inorganic materials 0.000 description 4
- 235000019800 disodium phosphate Nutrition 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- VSIIXMUUUJUKCM-UHFFFAOYSA-D pentacalcium;fluoride;triphosphate Chemical compound [F-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O VSIIXMUUUJUKCM-UHFFFAOYSA-D 0.000 description 4
- 238000012545 processing Methods 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 230000033228 biological regulation Effects 0.000 description 3
- 231100000135 cytotoxicity Toxicity 0.000 description 3
- 230000003013 cytotoxicity Effects 0.000 description 3
- 238000002354 inductively-coupled plasma atomic emission spectroscopy Methods 0.000 description 3
- 238000005070 sampling Methods 0.000 description 3
- 239000004575 stone Substances 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 235000019738 Limestone Nutrition 0.000 description 2
- DMGNFLJBACZMRM-UHFFFAOYSA-N O[P] Chemical compound O[P] DMGNFLJBACZMRM-UHFFFAOYSA-N 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000001464 adherent effect Effects 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000004140 cleaning Methods 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 239000006028 limestone Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- UWSONZCNXUSTKW-UHFFFAOYSA-N 4,5-Dimethylthiazole Chemical compound CC=1N=CSC=1C UWSONZCNXUSTKW-UHFFFAOYSA-N 0.000 description 1
- 229910014497 Ca10(PO4)6(OH)2 Inorganic materials 0.000 description 1
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 description 1
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical group [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- LFVGISIMTYGQHF-UHFFFAOYSA-N ammonium dihydrogen phosphate Chemical compound [NH4+].OP(O)([O-])=O LFVGISIMTYGQHF-UHFFFAOYSA-N 0.000 description 1
- 229910000387 ammonium dihydrogen phosphate Inorganic materials 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000009514 concussion Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- CGMRCMMOCQYHAD-UHFFFAOYSA-J dicalcium hydroxide phosphate Chemical compound [OH-].[Ca++].[Ca++].[O-]P([O-])([O-])=O CGMRCMMOCQYHAD-UHFFFAOYSA-J 0.000 description 1
- KCIDZIIHRGYJAE-YGFYJFDDSA-L dipotassium;[(2r,3r,4s,5r,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] phosphate Chemical compound [K+].[K+].OC[C@H]1O[C@H](OP([O-])([O-])=O)[C@H](O)[C@@H](O)[C@H]1O KCIDZIIHRGYJAE-YGFYJFDDSA-L 0.000 description 1
- WBZKQQHYRPRKNJ-UHFFFAOYSA-L disulfite Chemical compound [O-]S(=O)S([O-])(=O)=O WBZKQQHYRPRKNJ-UHFFFAOYSA-L 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 238000000703 high-speed centrifugation Methods 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000005297 material degradation process Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 235000019837 monoammonium phosphate Nutrition 0.000 description 1
- 201000011216 nasopharynx carcinoma Diseases 0.000 description 1
- 239000011574 phosphorus Chemical group 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
- C01B25/00—Phosphorus; Compounds thereof
- C01B25/16—Oxyacids of phosphorus; Salts thereof
- C01B25/26—Phosphates
- C01B25/32—Phosphates of magnesium, calcium, strontium, or barium
- C01B25/325—Preparation by double decomposition
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
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- C01P2002/70—Crystal-structural characteristics defined by measured X-ray, neutron or electron diffraction data
- C01P2002/72—Crystal-structural characteristics defined by measured X-ray, neutron or electron diffraction data by d-values or two theta-values, e.g. as X-ray diagram
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- C01P2002/80—Crystal-structural characteristics defined by measured data other than those specified in group C01P2002/70
- C01P2002/82—Crystal-structural characteristics defined by measured data other than those specified in group C01P2002/70 by IR- or Raman-data
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- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2004/00—Particle morphology
- C01P2004/01—Particle morphology depicted by an image
- C01P2004/03—Particle morphology depicted by an image obtained by SEM
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- C01P2004/34—Spheres hollow
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Abstract
本发明提供了一种孔径可控的空心羟基磷灰石微球,微球的粒径在400nm‑7000nm之间,微球表面为刺状结构,微球内为空心结构,晶型为羟基磷灰石。该微球的制备方法主要分为:碳酸钙前体的制备、水热反应和罗丹明标记,同时还探究了其在载药缓释领域的应用。本发明探究了不同浓度的十二烷基硫酸钠所制备微球的载药效率、降解速率和释放规律,总结得出当十二烷基硫酸钠浓度为其临界胶束浓度时,所得空心羟基磷灰石微球可获得最为理想的载药及释药效果。其次,本专利创新性地通过连结于空心羟基磷灰石微球表面的氨基基团,实现了其与罗丹明染料的结合,使该载药微球体系在生物学性能评价和作用机制研究中更易于定位及示踪。
Description
技术领域
本发明属于生物医药材料技术领域,尤其是涉及一种孔径可控的空心羟基磷灰石微球、制备方法及其应用。
背景技术
羟基磷灰石[Ca10(PO4)6(OH)2,简称HA]是人体骨额、牙齿等硬组织的主要无机成分,具有良好的生物相容性、生物活性、无毒副作用、无免疫反应等优点,植入体内后可以促进新骨的生长,已经被广泛的应用于人体硬组织替代材料和修复材料。空心羟基磷灰石作为一种新型无机载体材料,已成为生物学、制药学和材料科学交叉领域中的研究重点。
羟基磷灰石制备过程中,加入表面活性剂制备空心碳酸钙前体,通过水热反应形成空心的羟基磷灰石已成为一种比较成熟的制备方法。Y.-J.Guo等人应用碳酸钙做前体,通过水热反应合成羟基磷灰石。但现有技术中制得的空心羟基磷灰石孔径不可控,造成载药量不能够灵活调控。
发明内容
有鉴于此,本发明旨在提出一种孔径可控的空心羟基磷灰石微球、制备方法及其应用,制备过程中通过改变表面活性剂的用量进而影响羟基磷灰石微球的孔径大小、孔壁厚度和结晶度,从而实现对微球的载药量、降解速率和药物释放规律的灵活调控。
为达到上述目的,本发明提出一种孔径可控的空心羟基磷灰石微球,包括羟基磷灰石微球本体,所述羟基磷灰石微球本体为圆球形结构,羟基磷灰石微球本体的粒径在400nm-7000nm之间,其表面为刺状结构,羟基磷灰石微球本体内为空心结构,孔壁厚度为300-2000nm,所述空心结构的平均孔径在100-1000nm之间,晶型为羟基磷灰石。
本发明的另一目的在于提出一种上述孔径可控的空心羟基磷灰石微球的制备方法,包括如下步骤:
步骤A、碳酸钙前体的制备:
将浓度为0.1mol/L-0.5mol/L的可溶性钙盐溶液与浓度为0.1mg/mL-30mg/mL的十二烷基硫酸钠的水溶液等体积混合,半小时后向混合液中加入0.2mol/L的可溶性碳酸盐溶液,碳酸盐溶液的体积与钙盐溶液的体积相等,搅拌1.5小时,过滤得到碳酸钙沉淀,用超纯水和无水乙醇先后洗涤碳酸钙沉淀,最后将洗涤后的碳酸钙沉淀于120℃下干燥24小时;
步骤B、水热反应:
将步骤A中的得到的碳酸钙前体和可溶性磷酸盐溶液混合,控制钙元素与磷元素的摩尔比为1.67:1,用氨水将混合液的pH值调至10-11,在水热反应釜中200℃下反应24小时,离心分离,即得到羟基磷灰石微球,并用超纯水和无水乙醇先后对微球进行洗涤,最后将洗涤后的羟基磷灰石微球于120℃下干燥24小时;
步骤C、罗丹明标记:
将步骤B中得到羟基磷灰石微球分散在pH值为7.4的缓冲溶液中,加入0.05mg/ml的罗丹明异硫氰酸盐溶液,持续搅拌4小时,在不小于9000rpm的转速下离心收集产物,并用超纯水和无水乙醇先后洗涤多次,即得到罗丹明标记的羟基磷灰石微球。
优选的,步骤A中所述可溶性钙盐溶液为氯化钙溶液,可溶性碳酸盐溶液为碳酸钠溶液。
优选的,步骤B中所述可溶性磷酸盐水溶液为磷酸钠、磷酸氢二钠、磷酸二氢钠、磷酸氢二钾、磷酸二氢钾、磷酸钾、磷酸氢二铵或磷酸二氢铵中的一种。
优选的,步骤B中所述氨水的质量百分浓度为33%。
优选的,所述步骤C所述的缓冲盐溶液为磷酸缓冲盐溶液、巴比妥钠-盐酸缓冲液、Tris-HCl缓冲液或者硼酸-硼砂缓冲液中的一种。
本发明制备的一种孔径可控的空心羟基磷灰石微球可将其应用于载药缓释领域。
相对于现有技术,本发明所述的一种孔径可控的空心羟基磷灰石微球、制备方法及其应用具有以下优势:
(1)可以通过调控表面活性剂的浓度,对载药体系的载药量、药物释放速率实现灵活的调控;
(2)具有良好的生物兼容性和可降解性,可安全应用与生物医学领域;
(3)载药体系在不同酸碱度下表现出截然不同的降解速率和药物释放规律,可应用于选择性地作用在特定体液环境中;
(4)可方便地负载包括荧光染料在内的各种示踪成分,用于材料的生物学性能评价和作用机制研究。
附图说明
图1为实施例1中碳酸钙前体的扫描电子显微镜图(标尺为2μm);
图2为实施例1中碳酸钙前体的透射电子显微镜图(标尺为1μm);
图3为实施例2中碳酸钙前体的扫描电子显微镜图(标尺为3μm);
图4为实施例2中碳酸钙前体的透射电子显微镜图(标尺为1μm);
图5为实施例3中碳酸钙前体的扫描电子显微镜图(标尺为2μm);
图6为实施例3中碳酸钙前体的透射电子显微镜图(标尺为1μm);
图7为实施例4中碳酸钙前体的扫描电子显微镜图(标尺为3μm);
图8为实施例4中碳酸钙前体的透射电子显微镜图(标尺为1μm);
图9为实施例1中羟基磷灰石微球的扫描电子显微镜图(标尺为4μm);
图10为实施例2中羟基磷灰石微球的扫描电子显微镜图(标尺为1μm);
图11为实施例3中羟基磷灰石微球的扫描电子显微镜图(标尺为3μm);
图12为实施例4中羟基磷灰石微球的扫描电子显微镜图(标尺为3μm);
图13为实施例1中羟基磷灰石微球的透射电子显微镜图及相对应的SAED衍射图样(标尺为1μm);
图14为实施例2中羟基磷灰石微球的透射电子显微镜图及相对应的SAED衍射图样(标尺为1μm);
图15为实施例3中羟基磷灰石微球的透射电子显微镜图及相对应的SAED衍射图样(标尺为1μm);
图16为实施例4中羟基磷灰石微球的透射电子显微镜图及相对应的SAED衍射图样(标尺为1μm);
图17为实施例1-4中制得的的羟基磷灰石微球的傅氏转换红外线光谱图;
图18为实施例1-4中制得的的羟基磷灰石微球的X射线衍射谱图;
图19为实施例1中制得的空心羟基磷灰石微球的粒径分布图;
图20为实施例2中制得的空心羟基磷灰石微球的粒径分布图;
图21为实施例3中制得的空心羟基磷灰石微球的粒径分布图;
图22为实施例4中制得的空心羟基磷灰石微球的粒径分布图;
图23为实施例5中载顺铂的羟基磷灰石微球处理FaDu细胞后细胞的扫描电镜图(标尺为10μm);
图24为实施例5中载顺铂的羟基磷灰石微球处理FaDu细胞后细胞的高倍扫描电镜图(标尺为1μm);
图25为实施例5中未负载顺铂的羟基磷灰石微球处理FaDu细胞后细胞的扫描电镜图(标尺为10μm);
图26为实施例5中未负载顺铂的羟基磷灰石微球处理FaDu细胞后细胞的高倍扫描电镜图(标尺为200nm);
图27为实施例5中不同孔径的空心羟基磷灰石微球的载药量柱状图;
图28为实施例6中pH为3时药物释放曲线;
图29为实施例6中pH为5时药物释放曲线;
图30为实施例6中pH为7时药物释放曲线;
图31为实施例7中pH为3时的降解曲线;
图32为实施例7中pH为5时的降解曲线;
图33为实施例7中pH为7时的降解曲线;
图34为实施例8中不同孔径的羟基磷灰石微球分别在24h和72h时FaDu细胞存活率的柱状图。
具体实施方式
除有定义外,以下实施例中所用的技术术语具有与本发明所属领域技术人员普遍理解的相同含义。以下实施例中所用的试验试剂,如无特殊说明,均为常规生化试剂;所述实验方法,如无特殊说明,均为常规方法。
下面结合实施例及图1-34来详细说明本发明。
一种孔径可控的空心羟基磷灰石微球,包括羟基磷灰石微球本体,所述羟基磷灰石微球本体为圆球形结构,羟基磷灰石微球本体的粒径在400nm-7000nm之间,其表面为刺状结构,羟基磷灰石微球本体内为空心结构,孔壁厚度为300-2000nm,所述空心结构的平均孔径在100-1000nm之间,晶型为羟基磷灰石。
实施例1
步骤A、碳酸钙前体的制备:
取浓度为0.2mol/L的氯化钙溶液250mL与浓度为1mg/mL的十二烷基硫酸钠溶液250mL混合,半小时后向混合液中加入0.2mol/L的碳酸钠溶液250mL,搅拌1.5小时,过滤得到碳酸钙沉淀,用超纯水滤洗碳酸钙沉淀8次,再用无水乙醇滤洗碳酸钙沉淀2次,最后将洗涤后的碳酸钙沉淀于120℃下干燥24小时;
步骤B、水热反应:
取步骤A中的得到的碳酸钙前体1g和0.2mol/L磷酸氢二钠溶液混合,控制钙元素与磷元素的摩尔比为1.67,用质量百分浓度为33%的氨水将混合液的PH值调至10.3,在含有聚四氟乙烯内衬的水热反应釜中200℃下反应24小时,离心分离,即得到羟基磷灰石微球,先用超纯水洗涤5次,再用无水乙醇洗涤3次,最后将洗涤后的羟基磷灰石微球于120℃下干燥24小时;
步骤C、罗丹明标记:
将步骤B中得到羟基磷灰石微球10mg分散在5mL、pH值为7.4的磷酸缓冲盐溶液中,再加入1mg/ml的罗丹明异硫氰酸盐的甲醇溶液250μL,持续搅拌4小时,在9000rpm的转速下离心收集产物,先用超纯水滤洗2次,再用无水乙醇滤洗2次,即得洁净的罗丹明标记的羟基磷灰石微球。
实施例2
步骤A、碳酸钙前体的制备:
取浓度为0.2mol/L的氯化钙溶液250mL与浓度为2.33mg/mL的十二烷基硫酸钠溶液250mL混合,半小时后向混合液中加入0.2mol/L的碳酸钠溶液250mL,搅拌1.5小时,过滤得到碳酸钙沉淀,用超纯水滤洗碳酸钙沉淀8次,再用无水乙醇滤洗碳酸钙沉淀2次,最后将洗涤后的碳酸钙沉淀于120℃下干燥24小时;
步骤B、水热反应:
取步骤A中的得到的碳酸钙前体1g和0.2mol/L磷酸氢二钠溶液混合,控制钙元素与磷元素的摩尔比为1.67,用质量百分浓度为33%的氨水将混合液的PH值调至10.9,在含有聚四氟乙烯内衬的水热反应釜中200℃下反应24小时,离心分离,即得到羟基磷灰石微球,先用超纯水洗涤5次,再用无水乙醇洗涤3次,最后将洗涤后的羟基磷灰石微球于120℃下干燥24小时;
步骤C、罗丹明标记:
将步骤B中得到羟基磷灰石微球10mg分散在5mL、pH值为7.4的磷酸缓冲盐溶液中,再加入1mg/ml的罗丹明异硫氰酸盐的甲醇溶液250μL,持续搅拌4小时,在11000rpm的转速下离心收集产物,先用超纯水滤洗2次,再用无水乙醇滤洗2次,即得洁净的罗丹明标记的羟基磷灰石微球。
实施例3
步骤A、碳酸钙前体的制备:
取浓度为0.2mol/L的氯化钙溶液250mL与浓度为4.66mg/mL的十二烷基硫酸钠溶液250mL混合,半小时后向混合液中加入0.2mol/L的碳酸钠溶液250mL,搅拌1.5小时,过滤得到碳酸钙沉淀,用超纯水滤洗碳酸钙沉淀8次,再用无水乙醇滤洗碳酸钙沉淀2次,最后将洗涤后的碳酸钙沉淀于120℃下干燥24小时;
步骤B、水热反应:
取步骤A中的得到的碳酸钙前体1g和0.2mol/L磷酸氢二钠溶液混合,控制钙元素与磷元素的摩尔比为1.67,用质量百分浓度为33%的氨水将混合液的PH值调至11.0,在含有聚四氟乙烯内衬的水热反应釜中200℃下反应24小时,离心分离,即得到羟基磷灰石微球,先用超纯水洗涤5次,再用无水乙醇洗涤3次,最后将洗涤后的羟基磷灰石微球于120℃下干燥24小时;
步骤C、罗丹明标记:
将步骤B中得到羟基磷灰石微球10mg分散在5mL、pH值为7.4的磷酸缓冲盐溶液中,再加入1mg/ml的罗丹明异硫氰酸盐的甲醇溶液250μL,持续搅拌4小时,在10000rpm的转速下离心收集产物,先用超纯水滤洗2次,再用无水乙醇滤洗2次,即得洁净的罗丹明标记的羟基磷灰石微球。
实施例4
步骤A、碳酸钙前体的制备:
取浓度为0.2mol/L的氯化钙溶液250mL与浓度为10mg/mL的十二烷基硫酸钠溶液250mL混合,半小时后向混合液中加入0.2mol/L的碳酸钠溶液250mL,搅拌1.5小时,过滤得到碳酸钙沉淀,用超纯水滤洗碳酸钙沉淀8次,再用无水乙醇滤洗碳酸钙沉淀2次,最后将洗涤后的碳酸钙沉淀于120℃下干燥24小时;
步骤B、水热反应:
取步骤A中的得到的碳酸钙前体1g和0.2mol/L磷酸氢二钠溶液混合,控制钙元素与磷元素的摩尔比为1.67,用质量百分浓度为33%的氨水将混合液的PH值调至11.0,在含有聚四氟乙烯内衬的水热反应釜中200℃下反应24小时,离心分离,即得到羟基磷灰石微球,先用超纯水洗涤5次,再用无水乙醇洗涤3次,最后将洗涤后的羟基磷灰石微球于120℃下干燥24小时;
步骤C、罗丹明标记:
将步骤B中得到羟基磷灰石微球10mg分散在5mL、pH值为7.4的磷酸缓冲盐溶液中,再加入1mg/ml的罗丹明异硫氰酸盐的甲醇溶液250μL,持续搅拌4小时,在9000rpm的转速下离心收集产物,先用超纯水滤洗2次,再用无水乙醇滤洗2次,即得洁净的罗丹明标记的羟基磷灰石微球。
由图1-16可以看出,随十二烷基硫酸钠浓度的增大,空心碳酸钙微球的孔径显著增大,孔壁显著变薄,同时粒径也有所增大。基于该碳酸钙前体的水热反应所获得之羟基磷灰石微球亦发生相应趋势的变化。同时,结合SAED衍射图样可知,随着十二烷基硫酸钠用量的增加,所制备的羟基磷灰石微球中晶体的结晶度有所下降(如图13-16所示)。
如图18所示,对实施例1-4中制得的羟基磷灰石微球进行了X射线衍射测试进行了相对结晶度的计算,对应实施例1-4分别标记为组A、B、C、D,计算结果如下:A组的相对结晶度为77.29%,B组的相对结晶度为76.5%,C组的相对结晶度为44.53%,D组的相对结晶度为47.61%,进一步说明随着十二烷基硫酸钠用量的增加,所制备的羟基磷灰石微球中晶体的结晶度下降。
表1是通过EDX表征的实施例1、实施例2、实施例3和实施例4中制得空心羟基磷灰石微球的各元素含量组成。
表1EDX表征各组空心羟基磷灰石的元素组成
实施例5
载药量实验:
(1)将实施例1、实施例2、实施例3、实施例4中制得的空心羟基磷灰石微球重悬于0.4mg/mL的顺铂溶液中,并分别标记为组A、B、C、D;
(2)震荡15秒后,于37℃,300rpm的摇床中避光震荡24小时;
(3)先用超纯水过滤洗涤2次,再用无水乙醇过滤洗涤2次,高速离心获得载顺铂的羟基磷灰石微球;
(4)用电感耦合等离子体发射光谱仪(ICP-OES)测上清液中铂含量,然后根据公式(1)计算出载药量。
载药量(%)=(Pt对照组-Pt上清液)/Pt对照组×100% (1)
如图27所示,通过载药量柱状图的对比可以明显看出,C组的载药量最高,对应实施例3中制备过程中表面活性剂十二烷基硫酸钠溶液的浓度为4.66mg/mL。
实施例6
不同酸碱环境中药物释放实验:
(1)分别用pH值为3,5,7的磷酸缓冲盐溶液溶解实施例1-4中制得的羟基磷灰石微球,并分别标记为组A、B、C、D;
(2)震荡15秒后,放在37℃摇床上,以200rpm的速度震荡72小时;
(3)分别在6小时,12小时,24小时,36小时,48小时,72小时,1周,两周,一个月后各取4mL取样待测;
(4)在每个样品中加入4mL对应pH值的磷酸缓冲盐溶液;
(5)用电感耦合等离子体发射光谱仪(ICP-OES)检测待测溶液中的铂和钙的浓度,结果如图28-30所示。
实施例7
不同酸碱环境中材料降解实验:
(1)分别用pH值为3,5,7的磷酸缓冲盐溶液溶解实施例1-4中制得的羟基磷灰石微球,并分别标记为组A、B、C、D;
(2)震荡15秒后,放在37℃摇床上,以200rpm的速度震荡72小时;
(3)分别在6小时,12小时,24小时,36小时,48小时,72小时,1周,两周,一个月后各取4mL取样待测;
(4)每次取样后,补入4mL对应浓度的磷酸缓冲盐溶液;
(5)用ICP-OES检测待测溶液中的钙浓度。
如图28-33所示,在三种不同的pH值情况下,不同孔径的空心羟基磷灰石微球的释放药物的量与降解量都有所不同,分别对应前期制备过程中所使用的表面活性剂十二烷基硫酸钠溶液的浓度不同,达到了通过调控表面活性剂用量进而调控药物释放的目的。
实施例8
细胞毒性实验:
(1)在96孔板中每孔接种5000个FaDu细胞(一种鼻咽癌鳞状细胞癌细胞系);
(2)经过24小时的贴壁后,实施例5中制得的4组相同浓度载顺铂的空心羟基磷灰石微球作用于细胞,并标记为组A、B、C、D;
(3)24小时和72小时后分别用MTT法检测细胞毒性(MTT:[3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐])。
如图23-26所示,载顺铂的羟基磷灰石微球处理FaDu细胞后的细胞较未负载顺铂的羟基磷灰石微球处理FaDu细胞后的细胞外形发生明显变化,细胞壁缩小,细胞质减小且不贴壁,失去原有的鹅卵石外形。
MTT法可检测出细胞存活率,由图34所示,等量的A、B、C、D四组羟基磷灰石微球作用于细胞时,C组作用的细胞存活率最低,即C组细胞毒性最强。
综上所述,表面活性剂用量过少,无法形成空心微球,载药量过低,而表面活性剂用量过多,则会影响羟基磷灰石的形成,前体壁过薄而导致破碎。因此控制表面活性剂的用量,调控空心羟基磷灰石微球的形成,进一步控制药物释放量,从而使药物达到更好的作用效果。从本发明的实施例中可以看出,当表面活性剂在临界胶束浓度时,载药效果最好。
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (5)
1.一种孔径可控的空心羟基磷灰石微球的制备方法,其特征在于:包括如下步骤:
步骤A、碳酸钙前体的制备:
将浓度为0.1mol/L-0.5mol/L的可溶性钙盐溶液与浓度为0.1mg/mL-30mg/mL的十二烷基硫酸钠的水溶液等体积混合,半小时后向混合液中加入0.2mol/L的可溶性碳酸盐溶液,碳酸盐溶液的体积与钙盐溶液的体积相等,搅拌1.5小时,过滤得到碳酸钙沉淀,用超纯水和无水乙醇先后洗涤碳酸钙沉淀,最后将洗涤后的碳酸钙沉淀于120℃下干燥24小时,制得碳酸钙前体;
步骤B、水热反应:
将步骤A中的得到的碳酸钙前体和可溶性磷酸盐溶液混合,控制钙元素与磷元素的摩尔比为1.67:1,用氨水将混合液的pH值调至10.0-11.0,在水热反应釜中200℃下反应24小时,离心分离,即得到羟基磷灰石微球,并用超纯水和无水乙醇先后对微球进行洗涤,最后将洗涤后的羟基磷灰石微球于120℃下干燥24小时;
步骤C、罗丹明标记:
将步骤B中得到羟基磷灰石微球分散在pH值为7.4的缓冲溶液中,加入0.05mg/ml的罗丹明异硫氰酸盐溶液,持续搅拌4小时,在不小于9000rpm的转速下离心收集产物,并用超纯水和无水乙醇先后洗涤多次,即得到罗丹明标记的羟基磷灰石微球;
该羟基磷灰石微球为圆球形结构,羟基磷灰石微球的粒径在400nm-7000nm之间,其表面为刺状结构,羟基磷灰石微球内为空心结构,孔壁厚度为300-2000nm,所述空心结构的平均孔径在100-1000nm之间,晶型为羟基磷灰石。
2.根据权利要求1所述的制备方法,其特征在于:步骤A中所述可溶性钙盐溶液为氯化钙溶液,可溶性碳酸盐溶液为碳酸钠溶液。
3.根据权利要求1所述的制备方法,其特征在于:步骤B中所述可溶性磷酸盐水溶液为磷酸钠、磷酸氢二钠、磷酸二氢钠、磷酸氢二钾、磷酸二氢钾、磷酸钾、磷酸氢二铵或磷酸二氢铵中的一种。
4.根据权利要求1所述的制备方法,其特征在于:步骤B中所述氨水的质量百分浓度为33%。
5.根据权利要求1所述的制备方法,其特征在于:步骤C中所述的缓冲盐溶液为磷酸缓冲盐溶液、巴比妥钠-盐酸缓冲液、Tris-HCl缓冲液或者硼酸-硼砂缓冲液中的一种。
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