WO2014094345A1 - 纳米羟基磷灰石/壳聚糖的制备方法 - Google Patents
纳米羟基磷灰石/壳聚糖的制备方法 Download PDFInfo
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- WO2014094345A1 WO2014094345A1 PCT/CN2013/000754 CN2013000754W WO2014094345A1 WO 2014094345 A1 WO2014094345 A1 WO 2014094345A1 CN 2013000754 W CN2013000754 W CN 2013000754W WO 2014094345 A1 WO2014094345 A1 WO 2014094345A1
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- Prior art keywords
- chitosan
- nano
- phosphate
- hydroxyapatite
- nanohydroxyapatite
- Prior art date
Links
- 229920001661 Chitosan Polymers 0.000 title claims abstract description 63
- 229910052588 hydroxylapatite Inorganic materials 0.000 title claims abstract description 56
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 20
- 239000000203 mixture Substances 0.000 claims abstract description 16
- 239000000725 suspension Substances 0.000 claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 10
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229940057995 liquid paraffin Drugs 0.000 claims abstract description 7
- 239000000243 solution Substances 0.000 claims description 27
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 18
- 239000007787 solid Substances 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- 229910019142 PO4 Inorganic materials 0.000 claims description 8
- 239000010452 phosphate Substances 0.000 claims description 8
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 claims description 7
- 229910001424 calcium ion Inorganic materials 0.000 claims description 7
- 238000004945 emulsification Methods 0.000 claims description 7
- 239000000843 powder Substances 0.000 claims description 7
- 239000011575 calcium Substances 0.000 claims description 6
- 159000000007 calcium salts Chemical class 0.000 claims description 6
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical group [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 5
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims description 5
- 150000002500 ions Chemical class 0.000 claims description 5
- 239000012982 microporous membrane Substances 0.000 claims description 5
- 239000001488 sodium phosphate Substances 0.000 claims description 5
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical group [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 5
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 claims description 4
- 150000002484 inorganic compounds Chemical class 0.000 claims description 4
- 229910010272 inorganic material Inorganic materials 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 claims description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 claims description 3
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 3
- 229910000397 disodium phosphate Inorganic materials 0.000 claims description 3
- 235000019800 disodium phosphate Nutrition 0.000 claims description 3
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 3
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 3
- 229940049964 oleate Drugs 0.000 claims description 3
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 3
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 3
- 235000011008 sodium phosphates Nutrition 0.000 claims description 3
- 239000004254 Ammonium phosphate Substances 0.000 claims description 2
- LKDRXBCSQODPBY-AMVSKUEXSA-N L-(-)-Sorbose Chemical compound OCC1(O)OC[C@H](O)[C@@H](O)[C@@H]1O LKDRXBCSQODPBY-AMVSKUEXSA-N 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 claims description 2
- 229910000148 ammonium phosphate Inorganic materials 0.000 claims description 2
- 235000019289 ammonium phosphates Nutrition 0.000 claims description 2
- 150000008064 anhydrides Chemical class 0.000 claims description 2
- 229910052586 apatite 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
- 238000005119 centrifugation Methods 0.000 claims description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 2
- 235000019797 dipotassium phosphate Nutrition 0.000 claims description 2
- 229910000396 dipotassium phosphate Inorganic materials 0.000 claims description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims 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 claims description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [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
- 239000012266 salt solution Substances 0.000 claims description 2
- 239000004575 stone Substances 0.000 claims description 2
- 229910000406 trisodium phosphate Inorganic materials 0.000 claims description 2
- 235000019801 trisodium phosphate Nutrition 0.000 claims description 2
- 239000013049 sediment Substances 0.000 claims 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims 1
- 125000005211 alkyl trimethyl ammonium group Chemical group 0.000 claims 1
- LFVGISIMTYGQHF-UHFFFAOYSA-N ammonium dihydrogen phosphate Chemical compound [NH4+].OP(O)([O-])=O LFVGISIMTYGQHF-UHFFFAOYSA-N 0.000 claims 1
- 229910000387 ammonium dihydrogen phosphate Inorganic materials 0.000 claims 1
- DCAYPVUWAIABOU-UHFFFAOYSA-N hexadecane Chemical compound CCCCCCCCCCCCCCCC DCAYPVUWAIABOU-UHFFFAOYSA-N 0.000 claims 1
- 235000019837 monoammonium phosphate Nutrition 0.000 claims 1
- 239000002131 composite material Substances 0.000 abstract description 16
- 238000002156 mixing Methods 0.000 abstract description 14
- NWGKJDSIEKMTRX-AAZCQSIUSA-N Sorbitan monooleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 0.000 abstract description 6
- 239000002245 particle Substances 0.000 abstract description 6
- 229950004959 sorbitan oleate Drugs 0.000 abstract description 4
- 238000004132 cross linking Methods 0.000 abstract description 2
- 239000003995 emulsifying agent Substances 0.000 abstract description 2
- 239000004530 micro-emulsion Substances 0.000 abstract description 2
- 238000001291 vacuum drying Methods 0.000 abstract description 2
- 238000010923 batch production Methods 0.000 abstract 1
- 238000005406 washing Methods 0.000 abstract 1
- 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 18
- 239000000463 material Substances 0.000 description 8
- 238000010521 absorption reaction Methods 0.000 description 7
- 229940085991 phosphate ion Drugs 0.000 description 5
- 210000000988 bone and bone Anatomy 0.000 description 4
- 150000004676 glycans Chemical class 0.000 description 4
- 238000000593 microemulsion method Methods 0.000 description 4
- 238000002441 X-ray diffraction Methods 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- USJRHIYLKAMMSO-UHFFFAOYSA-M hexadecanoyl(trimethyl)azanium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC(=O)[N+](C)(C)C USJRHIYLKAMMSO-UHFFFAOYSA-M 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 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
- 238000005303 weighing Methods 0.000 description 3
- 238000003917 TEM image Methods 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 239000002086 nanomaterial Substances 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 229920002101 Chitin Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- -1 anhydride oleate Chemical class 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 238000005452 bending Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000003592 biomimetic effect Effects 0.000 description 1
- 239000000316 bone substitute Substances 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 238000003501 co-culture Methods 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000006196 deacetylation Effects 0.000 description 1
- 238000003381 deacetylation reaction Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000010419 fine particle Substances 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000002122 magnetic nanoparticle Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 210000000963 osteoblast Anatomy 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000004627 transmission electron microscopy Methods 0.000 description 1
Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/20—Compounding polymers with additives, e.g. colouring
- C08J3/205—Compounding polymers with additives, e.g. colouring in the presence of a continuous liquid phase
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/24—Crosslinking, e.g. vulcanising, of macromolecules
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
- C08K3/00—Use of inorganic substances as compounding ingredients
- C08K3/32—Phosphorus-containing compounds
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
- C08L5/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2305/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2301/00 or C08J2303/00
- C08J2305/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
- C08K3/00—Use of inorganic substances as compounding ingredients
- C08K3/32—Phosphorus-containing compounds
- C08K2003/321—Phosphates
- C08K2003/325—Calcium, strontium or barium phosphate
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
- C08K2201/00—Specific properties of additives
- C08K2201/011—Nanostructured additives
Definitions
- the invention relates to a preparation method of nano hydroxyapatite/chitosan, belonging to the technical field of inorganic nano materials.
- Nano-hydroxyapatite has good biocompatibility and biological activity and is widely used in the repair and replacement of bone tissue, but the material is too brittle, thus limiting its bone replacement at the bearing site.
- Shell Polysaccharide (CS) is a polysaccharide with a cation after deacetylation of chitin. It has natural degradability, is non-toxic, harmless, non-irritating, biocompatible, and suitable for various tissues and cells. Adhesion and proliferation have various excellent properties such as promotion. If n-HA and CS are made into composite materials, the new materials are expected to improve their mechanical properties in addition to excellent biocompatibility, so there is much room for development in the field of bone substitute materials.
- n-HA/CS composites are one of the research hotspots in the field of biomedical materials.
- the book Thein-Han has obtained a porous scaffold with a pore size of 50 ⁇ 120 ⁇ by freeze-drying method, n-HA. It can be evenly distributed in the CS matrix. There is a chemical interaction between n-HA and CS.
- the mechanical properties of the composite are greatly improved after co-culture with pre-osteoblasts (MC 3T3-E1 ).
- HA/CS composite materials are micron-sized materials, or materials in which nano-HA is dispersed and distributed in micron-sized CS.
- nano-hydroxyapatite with particle width and long diameter at the nanometer scale can be easily prepared.
- the method of chitosan composites is rare.
- the inverse microemulsion method has attracted attention because of its high thermodynamic stability, fine particle size, uniformity, and simple operation. For example, Zhu et al.
- the object of the present invention is to overcome the deficiencies in the prior art and provide a preparation method of nano hydroxyapatite/chitosan, which can be easily prepared by a reverse microemulsion method to obtain a particle width and a long diameter at a nanometer scale. Nano-hydroxyapatite/chitosan.
- the preparation method of the nano hydroxyapatite/chitosan has the following steps:
- the nano hydroxyapatite has a width of 5 to 100 nm and a length of 15 to 800 nm ; and the nano hydroxyapatite/chitosan has a width of 10 to 300 nm and a length of 20 to 990 nm.
- the nano hydroxyapatite is synthesized by the following method: mixing a phosphate solution, a calcium salt solution and a hexadecanoyltrimethylammonium bromide solution (CTAB) to obtain a reaction system in which Ca 2+ is Ca 2+
- the concentration of ions is 0.08 ⁇ 500 ⁇ 1 ⁇
- the concentration of phosphate ions is 0.048 ⁇ 300 mmoH 1
- the concentration of CTAB is mol-L 1
- the molar ratio of calcium ion to phosphate ion is 5:3
- the reaction is carried out for 12 to 96 hours, and the pH is adjusted to be maintained at 8 to 14 ;
- the obtained product is centrifuged and centrifuged to obtain a microporous membrane.
- the solid obtained by filtration was washed alternately with water and absolute ethanol for 2 to 20 times, and then dried under vacuum at 30 to 80 ° C to obtain a nano-hydroxyapatite powder.
- the phosphate is a water-soluble inorganic compound containing a phosphate, a hydrogen phosphate or a dihydrogen phosphate in the formula.
- the phosphate is sodium phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate, trisodium phosphate, potassium phosphate, potassium hydrogen phosphate, potassium dihydrogen phosphate, ammonium phosphate, ammonium hydrogen phosphate or dihydrogen phosphate. Ammonium.
- the calcium salt is a water-soluble inorganic compound containing calcium ions.
- the calcium salt is calcium chloride.
- the method for preparing the nano hydroxyapatite/chitosan composite material according to the invention comprises uniformly mixing the nano hydroxyapatite with the chitosan acetic acid solution, mixing the mixture with the liquid paraffin, and adding the emulsifier span80 ( Sorbitol anhydride oleate), after the system is fully emulsified, glutaraldehyde is added to carry out cross-linking reaction, and the obtained suspension is collected by centrifugation, washed and vacuum-dried to obtain nano-hydroxyapatite/chitosan composite. material.
- emulsifier span80 Sorbitol anhydride oleate
- the preparation method of the reversed-phase microemulsion of the nano-hydroxyapatite/chitosan composite material provided by the invention has the particle width and the long diameter of the obtained product in the nanometer scale range, and the product has good shape and crystallinity.
- the method has simple preparation process, low cost and is suitable for mass production, and has important application value in the field of biomedicine.
- Figure 1 is a transmission electron micrograph of nano-hydroxyapatite.
- Figure 2 is a transmission electron micrograph of nano-hydroxyapatite/chitosan particles.
- Figure 3 is an infrared spectrum of nano-hydroxyapatite, chitosan and nano-hydroxyapatite/chitosan, wherein the abscissa is the wave number in cm ⁇
- Figure 4 is an X-ray diffraction spectrum of nano-hydroxyapatite, chitosan and nano-hydroxyapatite/chitosan, wherein the abscissa is 2 ⁇ angle, that is, the angle of diffraction of the diffraction spectrometer, the unit is °;
- Embodiment 1 A method for preparing nano hydroxyapatite/chitosan, comprising the following process steps:
- the nano-hydroxyapatite and nano-hydroxyapatite/chitosan were respectively subjected to morphology analysis by transmission electron microscopy (JEM-2100, Japan JEOL Co., Ltd.), as shown in FIG. 1 and FIG. 2, the nano-hydroxyphosphate
- the stone has a width of 5 to 100 nm and a length of 15 to 800 nm; and the nano-hydroxyapatite/chitosan has a width of 10 to 300 nm and a length of 20 to 990 nm.
- Nano-hydroxyapatite, chitosan and nano-hydroxyapatite/chitosan were respectively analyzed by infrared spectroscopy using Fourier transform infrared spectrometer (FTLA2000-104, ABB Bbomem, Canada).
- FTLA2000-104 Fourier transform infrared spectrometer
- the obtained spectrum is shown in Fig. 3.
- the absorption peak at 472, 566, 597, 632, 962 cm' 1 is caused by the deformation vibration of ⁇ 0 4 3 ⁇
- the absorption peak at 1039-1097 cm' 1 is caused by the antisymmetric stretching vibration of ⁇ 0 4 3 —
- the absorption peak appearing near 3428 cm' 1 is the NH stretching vibration absorption peak of OH and -NH 2 . Infrared diffraction pattern analysis confirmed that the obtained product was indeed nano-hydroxyapatite/chitosan.
- the nano-hydroxyapatite, chitosan and nano-hydroxyapatite/chitosan were respectively analyzed by X-ray diffraction analyzer, and the obtained spectrum is shown in Fig. 4.
- 2 ⁇ 25. 9°, 31
- the diffraction peaks at 8°, 32. 8°, 34°, 39. 8°, 49. 4°, and 53. 1 ° correspond to (002), (211), (300) of nano-hydroxyapatite, respectively. , (202), (310), (321), and (004) crystal faces.
- Embodiment 2 A method for preparing nano hydroxyapatite/chitosan, comprising the following process steps:
- the nano-hydroxyapatite has a width of 5 to 100 nm and a length of 15 to 800 nm; and the nano-hydroxyapatite/chitosan has a width of 10 to 300 nm and a length of 20 to 990 nm.
- Embodiment 3 A method for preparing nano hydroxyapatite/chitosan, comprising the following process steps:
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Inorganic Chemistry (AREA)
- Materials For Medical Uses (AREA)
- Cosmetics (AREA)
Abstract
本发明涉及一种纳米羟基磷灰石/壳聚糖复合材料的制备方法，将纳米羟基磷灰石与壳聚糖的乙酸溶液进行均匀混合后，将混合物与液体石蜡混合，再加入乳化剂span80（山梨糖醇酐油酸酯），待体系充分乳化后，再加入戊二醛进行交联反应，所得悬浮液经离心分离、洗涤真空干燥后收集，即得到纳米羟基磷灰石/壳聚糖复合材料。本发明所提供的纳米羟基磷灰石/壳聚糖复合材料的反相微乳液制备方法，所得产品颗粒宽度及长径均在纳米尺度范围内，产品形貌规则、结晶性好。该方法制备工艺简单，成本低廉，适于批量生产，在生物医学领域有着重要的应用价值。
Description
纳米羟基磷灰石 /壳聚糖的制备方法
技术领域
本发明涉及一种纳米羟基磷灰石 /壳聚糖的制备方法， 属于无机纳米材料技 术领域。
背景技术
纳米羟基磷灰石 （n-HA) 具有良好的生物相容性和生物活性， 被广泛应用 于骨骼组织的修复与替代技术， 但该材料脆性太大， 因而限制了其在承载部位 骨替换与骨修补中的应用。 壳聚说糖（CS ) 是甲壳素脱乙酰化后带有阳离子的多 糖， 具有天然可降解性， 对人体及组织无毒、 无害、 无刺激、 生物相容性良好、 对多种组织细胞的黏附和增殖具有促进作用等多种优良特性。 如将 n-HA与 CS 制成复合材料， 新材料除具备优良的生物相容性之外还可有望改善其力学性能， 因而在骨替代材料领域有较大的发展空间。 针对 n-HA/CS复合材料所开展的研 究是目前生物医学材料领域的研究热点之一，如书 Thein-Han等采用冻干法制得了 孔隙大小为 50〜120 μ πι的多孔支架， n-HA可在 CS基质中均匀分布，在 n-HA 与 CS之间存在着化学相互作用， 复合后材料的机械性能有了较大幅度的提升， 与前成骨细胞（MC 3T3-E1 )共培养的实验结果表明， 与纯 CS相比， 复合材料 具有更好的细胞亲合性， 同时也能更好地促进细胞的增殖 [Thein-Han W. W.; Misra R. D. K.， Biomimetic chitosan-nanohydroxyapatite composite scaffolds for bone tissue engineering, ACTA BIOMATERIALIA, 2009， 5(4): 1182—1197.]。
目前所制备的 HA/CS复合材料多为微米级材料， 或为纳米 HA分散分布在 微米级的 CS中的材料， 目前能够简便地制备颗粒宽度及长径均在纳米尺度的纳 米羟基磷灰石 /壳聚糖复合材料的方法并不多见。 在制备纳米材料的技术中， 反 相微乳液法因其具有热力学稳定性高、 粒径细小、 均匀、 操作简单等特点而备 受瞩目。如 Zhu等利用反相微乳液法制备了 CS包覆的磁性纳米粒子并成功地将 其用作抗癌药物 5-氟尿嘧啶的药物载体 [Zhu Longzhang; Ma Jingwei; Jia Nengqin; Zhao Yu; Shen Hebai, COLLOIDS AND SURFACES B: BIOINTERFACES, 2009, 68(1): 1 - 6.] c
但目前尚缺少采用反相微乳液法成功制备颗粒宽度及长径均在纳米尺度的 纳米羟基磷灰石 /壳聚糖复合材料的简便制备方法， 如能成功制备， 则将有望在 很大程度上拓展纳米羟基磷灰石 /壳聚糖复合材料在生物医学领域的应用前景。 发明内容
本发明的目的是克服现有技术中存在的不足， 提供一种纳米羟基磷灰石 /壳 聚糖的制备方法， 能够采用反相微乳液法简便地制备得到颗粒宽度与长径均在 纳米尺度的纳米羟基磷灰石 /壳聚糖。
按照本发明提供的技术方案， 所述纳米羟基磷灰石 /壳聚糖的制备方法， 特 征是， 包括以下工艺步骤：
( 1 )将 0.05〜1.5g壳聚糖粉末溶于 5~500mL质量百分浓度为 1~5%的乙酸
水溶液中， 得到壳聚糖溶液；
(2)称取 0.05〜1.5g纳米羟基磷灰石粉末， 与步骤 （1 )得到的壳聚糖溶 液混合， 得到混合物； 将混合物与 100~500mL液体石蜡混合均匀， 再加入 1〜 15mL山梨糖醇酐油酸酯， 进行乳化， 乳化时间为 0.2~50小时； 再加入 l〜15mL 质量百分浓度为 10~50%的戊二醛溶液， 在 30〜95°C的水浴中反应 5〜24小时， 得到悬浮液； 将悬浮液经离心机离心得到固体沉积物， 得到的固体沉积物用氯 仿和无水乙醇交替洗涤 2~20次，再在 30〜80°C真空干燥，得到所述的纳米羟基 磷灰石 /壳聚糖。
所述纳米羟基磷灰石的宽度为 5〜100nm， 长度为 15〜800nm; 所述纳米羟 基磷灰石 /壳聚糖的宽度为 10〜300nm， 长度为 20〜990nm。
所述纳米羟基磷灰石采用以下方法合成得到： 将磷酸盐溶液、 钙盐溶液和 十六垸基三甲基溴化铵溶液 （CTAB) 混合， 得到反应体系， 在该反应体系中 Ca2+离子的浓度为 0.08~500 ηιιηο1·ΐ 磷酸根离子的浓度为 0.048~300 mmoH1, CTAB 的浓度为
mol-L 1, 且钙离子与磷酸根离子的摩尔比为 5:3； 反应 12〜96小时， 并调节 pH值保持在 8〜14; 将得到的产物经离心机离 心后由微孔滤膜过滤,将过滤得到的固体用水和无水乙醇进行交替洗涤 2〜20次， 再在 30〜80°C真空干燥得到纳米羟基磷灰石粉末。
在一个具体实施方式中， 所述磷酸盐为分子式中含有磷酸根、 磷酸氢根或 磷酸二氢根的易溶于水的无机化合物。
在一个具体实施方式中， 所述磷酸盐为磷酸钠、 磷酸氢钠、 磷酸二氢钠、 磷酸三钠、 磷酸钾、 磷酸氢钾、 磷酸二氢钾、 磷酸铵、 磷酸氢铵或磷酸二氢铵。
在一个具体实施方式中， 所述钙盐为含有钙离子的易溶于水的无机化合物。 在一个具体实施方式中， 所述钙盐为氯化钙。
本发明所述的纳米羟基磷灰石 /壳聚糖复合材料的制备方法将纳米羟基磷灰 石与壳聚糖的乙酸溶液进行均匀混合后， 将混合物与液体石蜡混合， 再加入乳 化剂 span80 (山梨糖醇酐油酸酯）， 待体系充分乳化后， 再加入戊二醛进行交联 反应， 所得悬浮液经离心分离、 洗涤真空干燥后收集， 即得到纳米羟基磷灰石 / 壳聚糖复合材料。 本发明所提供的纳米羟基磷灰石 /壳聚糖复合材料的反相微乳 液制备方法， 所得产品颗粒宽度及长径均在纳米尺度范围内， 产品形貌规则、 结晶性好。 该方法制备工艺简单， 成本低廉， 适于批量生产， 在生物医学领域 有着重要的应用价值。
说明书附图
图 1为纳米羟基磷灰石的透射电镜相片。
图 2为纳米羟基磷灰石 /壳聚糖颗粒的透射电镜相片。
图 3为纳米羟基磷灰石、 壳聚糖和纳米羟基磷灰石 /壳聚糖的红外光谱图， 其中， 横坐标为波数， 单位为 cm^
图 4为纳米羟基磷灰石、 壳聚糖和纳米羟基磷灰石 /壳聚糖的 X射线衍射谱 图， 其中， 横坐标为 2Θ角， 即衍射谱仪扫描的角度， 单位为 °；
具体实施方式
下面结合具体实施例对本发明作进一步说明。
实施例一： 一种纳米羟基磷灰石 /壳聚糖的制备方法， 包括以下工艺步骤：
( 1 )合成纳米羟基磷灰石： 将磷酸钠溶液、 氯化钙溶液和十六烷基三甲基 溴化铵溶液（CTAB)混合， 得到反应体系， 在该反应体系中 Ca2+离子的浓度为 Ο.ΟδπιπιοΙ-υ1, 磷酸根离子的浓度为 0.048ηιιηο1·ΐ CTAB的浓度为 8><1θ ηο1· L-1, 且钙离子与磷酸根离子的摩尔比为 5:3; 反应 12〜96小时， 并调节 ρΗ值保 持在 8;将得到的产物经离心机离心后由 0.22 μ ιη的微孔滤膜过滤，将过滤得到 的固体用水和无水乙醇进行交替洗涤 2次， 再在 30°C真空干燥过夜得到纳米羟 基磷灰石粉末；
(2)将 0.05g壳聚糖粉末溶于 5mL质量百分浓度为 1%的乙酸水溶液中， 得到壳聚糖溶液；
(3 )称取 0.05g步骤（1 )得到的纳米羟基磷灰石粉末或市售产品， 与步骤 (2)得到的壳聚糖溶液混合， 得到混合物； 将混合物与 100 mL液体石蜡混合 均勾， 再加入 lmL山梨糖醇酐油酸酯， 进行乳化， 乳化时间为 0.2小时； 再加 入 lmL质量百分浓度为 10%的戊二醛溶液， 在 30°C的水浴中反应 24小时， 得 到悬浮液； 将悬浮液经离心机离心得到固体沉积物， 得到的固体沉积物用氯仿 和无水乙醇交替洗涤 2次， 再在 30°C真空干燥过夜， 得到所述的纳米羟基磷灰 石 /壳聚糖；
将纳米羟基磷灰石和纳米羟基磷灰石 /壳聚糖分别用透射电电镜 (JEM-2100, 日本 JEOL公司）进行形貌分析， 如图 1、 图 2所示， 所述纳米羟 基磷灰石的宽度为 5〜100 nm， 长度为 15〜800 nm; 所述纳米羟基磷灰石 /壳聚 糖的宽度为 10〜300 nm, 长度为 20〜990 nm。
再将纳米羟基磷灰石、 壳聚糖和纳米羟基磷灰石 /壳聚糖分别用傅立叶转换 红外光谱仪（FTLA2000-104, 加拿大 ABB Bbomem公司）进行红外光谱分析， 所得图谱如图 3所示， 图中 472， 566, 597, 632, 962 cm'1处的吸收峰为 Ρ04 3· 的变形振动引起， 1039-1097 cm'1处的吸收峰为 Ρ04 3—的反对称伸缩振动引起，这 些都是纳米羟基磷灰石的特征吸收峰。 1653cm'1处为壳聚糖中酰胺的 C=0的伸 缩振动吸收峰（酰胺 I谱带）， 1599cm'1处的肩峰为胺基的弯曲振动吸收峰（酰 胺 II谱带） ， 而在 3428cm'1附近出现的吸收峰为 O-H及 -NH2的 N-H伸縮振动 吸收峰。 红外衍射图谱分析证实， 得到的产品确为纳米羟基磷灰石 /壳聚糖。
将纳米羟基磷灰石、 壳聚糖和纳米羟基磷灰石 /壳聚糖分别用 X射线衍射分 析仪进行物相分析， 所得图谱如图 4所示， 图中 2Θ= 25. 9° 、 31. 8° 、 32. 8° 、 34° 、 39. 8° 、 49. 4° 、 53. 1 ° 处的衍射峰分别对应于纳米羟基磷灰石的（ 002)、 ( 211) 、 ( 300) 、 ( 202) 、 ( 310) 、 ( 321) 以及（004)晶面。 图中 2Θ= 12·2° 、 20.1 ° 处的两个峰是壳聚糖的特征衍射峰， 当形成复合材料后， 由于相对含量发 生了变化， 所以与纯的纳米羟基磷灰石及壳聚糖材料相比， 复合材料相应的衍 射峰强度有所下降， 但各衍射峰的出峰位置及各峰之间的相对强度仍保持不变。 X射线衍射图谱的分析结果同样证实了得到的产品确为纳米羟基磷灰石 /壳聚
实施例二： 一种纳米羟基磷灰石 /壳聚糖的制备方法， 包括以下工艺步骤：
( 1 )合成纳米羟基磷灰石： 将磷酸氢钠溶液、 氯化钙溶液和十六垸基三甲 基溴化铵溶液（CTAB)混合， 得到反应体系， 在该反应体系中 Ca2+离子的浓度 为 500mmol*L ，磷酸根离子的浓度为 300mmol，L , CTAB的浓度为 10.5 1θ ηο1 •Ι 且钙离子与磷酸根离子的摩尔比为 5:3; 反应 96小时， 并调节 ρΗ值保持 在 14; 将得到的产物经离心机离心后由 0.22 μ πι的微孔滤膜过滤， 将过滤得到 的固体用水和无水乙醇进行交替洗涤 20次，再在 80°C真空干燥过夜得到纳米羟 基磷灰石粉末；
(2)将 1.5g壳聚糖粉末溶于 500mL质量百分浓度为 5%的乙酸水溶液中， 得到壳聚糖溶液；
(3 )称取 1.5g步骤 （1 ) 得到的纳米羟基磷灰石粉末或市售产品， 与步骤 (2)得到的壳聚糖溶液混合，得到混合物；将混合物与 500mL液体石蜡混合均 匀， 再加入 15mL山梨糖醇酐油酸酯， 进行乳化， 乳化时间为 50小时； 再加入 15mL质量百分浓度为 50%的戊二醛溶液， 在 95°C的水浴中反应 5小时， 得到 悬浮液； 将悬浮液经离心机离心得到固体沉积物， 得到的固体沉积物用氯仿和 无水乙醇交替洗涤 20次， 再在 80°C真空干燥过夜，得到所述的纳米羟基磷灰石 /壳聚糖； 所述纳米羟基磷灰石的宽度为 5〜100nm， 长度为 15〜800nm; 所述纳 米羟基磷灰石 /壳聚糖的宽度为 10〜300nm， 长度为 20〜990nm。
实施例三： 一种纳米羟基磷灰石 /壳聚糖的制备方法， 包括以下工艺步骤：
( 1 )合成纳米羟基磷灰石： 将磷酸二氢钠溶液、 氯化钙溶液和十六垸基三 甲基溴化铵溶液（CTAB)混合， 得到反应体系， 在该反应体系中 Ca2+离子的浓 度为 10 mmol-L 1, 磷酸根离子的浓度为 6 mmol-L"1, CTAB的浓度为 9X10"4 mol •Ι 且钙离子与磷酸根离子的摩尔比为 5:3; 反应 36小时， 并调节 ρΗ值保持 在 10; 将得到的产物经离心机离心后由 0.22 μ πι的微孔滤膜过滤， 将过滤得到 的固体用水和无水乙醇进行交替洗涤 10次，再在 50°C真空干燥过夜得到纳米羟 基磷灰石粉末；
(2)将 lg壳聚糖粉末溶于 250mL质量百分浓度为 2%的乙酸水溶液中， 得到壳聚糖溶液；
(3 )称取 lg步骤（1 )得到的纳米羟基磷灰石粉末或巿售产品，与步骤（2) 得到的壳聚糖溶液混合， 得到混合物； 将混合物与 200mL液体石蜡混合均匀， 再加入 10mL山梨糖醇酐油酸酯，进行乳化，乳化时间为 20小时；再加入 10mL 质量百分浓度为 20%的戊二醛溶液，在 50°C的水浴中反应 12小时，得到悬浮液; 将悬浮液经离心机离心得到固体沉积物， 得到的固体沉积物用氯仿和无水乙醇 交替洗涤 10次， 再在 50Ό真空干燥过夜， 得到所述的纳米羟基磷灰石 /壳聚糖; 所述纳米羟基磷灰石的宽度为 5〜100nm， 长度为 15〜800nm; 所述纳米羟基磷 灰石 /壳聚糖的宽度为 10〜300nm， 长度为 20〜990nm。
Claims
1、一种纳米羟基磷灰石 /壳聚糖的制备方法，其特征是，包括以下工艺步骤:
( 1 )将 0.05〜1.5g壳聚糖粉末溶于 5~500mL质量百分浓度为 1~5%的乙酸 水溶液中， 得到壳聚糖溶液；
(2)称取 0.05〜1.5g纳米羟基磷灰石粉末， 与步骤 （1 )得到的壳聚糖溶 液混合， 得到混合物； 将混合物与 100~500mL液体石蜡混合均匀， 再加入 1〜 15mL山梨糖醇酐油酸酯， 进权行乳化， 乳化时间为 0.2~50小时； 再加入 l~15mL 质量百分浓度为 10~50%的戊二醛溶液， 在 30〜95°C的水浴中反应 5〜24小时， 得到悬浮液； 将悬浮液经离心机离心得到固体沉积物， 得到的固体沉积物用氯 仿和无水乙醇交替洗涤 2〜20次，再在 30〜80°C真空干燥，得到所述的纳米羟基 磷灰石 /壳聚糖。
2、如权利要求 1所述的纳米羟基磷灰石 /壳聚糖的制备方法， 其特征是： 所 述纳米羟基磷灰石的宽度为 5〜100nm， 长度为 15〜800nm; 所述纳米羟基磷灰 石 /壳聚糖的宽度为 10〜300nm， 长度为 20〜990n书m。
3、如权利要求 1所述的纳米羟基磷灰石 /壳聚糖的制备方法， 其特征是： 所 述纳米羟基磷灰石采用以下方法合成得到： 将磷酸盐溶液、 钙盐溶液和十六烷 基三甲基溴化铵溶液（CTAB)混合， 得到反应体系， 在该反应体系中 Ca2+离子 的浓度为 0.08〜500 mmol-L 1, 磷酸根离子的浓度为 0.048~300 mmol-L 1, CTAB 的浓度为 Sx lO^lO^x lO"4 mol-L-1, 且钙离子与磷酸根离子的摩尔比为 5:3; 反 应 12〜96小时， 并调节 pH值保持在 8〜14； 将得到的产物经离心机离心后由 微孔滤膜过滤， 将过滤得到的固体用水和无水乙醇进行交替洗涤 2〜20次， 再在 30〜80°C真空干燥得到纳米羟基磷灰石粉末。
4、如权利要求 3所述的纳米羟基磷灰石 /壳聚糖的制备方法， 其特征是： 所 述磷酸盐为分子式中含有磷酸根、 磷酸氢根或磷酸二氢根的易溶于水的无机化 合物。
" 5、如权利要求 4所述的纳米羟基磷灰石 /壳聚糖的制备方法， 其特征是： 所 述磷酸盐为磷酸钠、 磷酸氢钠、 磷酸二氢钠、 磷酸三钠、 磷酸钾、 磷酸氢钾、 磷酸二氢钾、 磷酸铵、 磷酸氢铵或磷酸二氢铵。
6、如权利要求 3所述的纳米羟基磷灰石 /壳聚糖的制备方法， 其特征是： 所 述钙盐为含有钙离子的易溶于水的无机化合物。
7、如权利要求 6所述的纳米羟基磷灰石 /壳聚糖的制备方法， 其特征是： 所 述钙盐为氯化钙。
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| CN105417516A (zh) * | 2015-12-18 | 2016-03-23 | 瓮福（集团）有限责任公司 | 一种饲料级磷酸二氢钙生产方法 |
| CN105597155A (zh) * | 2015-12-30 | 2016-05-25 | 湖北赛罗生物材料有限责任公司 | 一锅法制备羟基磷灰石-天然高分子纳米复合物的方法 |
| EP3341327A4 (en) * | 2015-08-26 | 2019-04-24 | Honeywell International Inc. | PARTICULATE HYDROXYAPATITE COMPOSITIONS AND METHODS OF PREPARATION THEREOF |
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| CN103495204B (zh) * | 2013-09-11 | 2014-08-13 | 山西医科大学 | 负载细胞外全基质的壳聚糖/纳米羟基磷灰石缓释微球及其制备方法 |
| CN107050523A (zh) * | 2016-12-23 | 2017-08-18 | 江南大学 | 一种新型β‑磷酸三钙/壳聚糖复合仿生水凝胶的制备方法 |
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