CN105641801B - 一种多孔羟基磷灰石/明胶复合微针阵列贴片及其制备方法 - Google Patents
一种多孔羟基磷灰石/明胶复合微针阵列贴片及其制备方法 Download PDFInfo
- Publication number
- CN105641801B CN105641801B CN201610109651.3A CN201610109651A CN105641801B CN 105641801 B CN105641801 B CN 105641801B CN 201610109651 A CN201610109651 A CN 201610109651A CN 105641801 B CN105641801 B CN 105641801B
- Authority
- CN
- China
- Prior art keywords
- gelatin
- compounded
- porous hydroxyapatite
- patch
- micropin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 229910052588 hydroxylapatite Inorganic materials 0.000 title claims abstract description 49
- 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 49
- 238000002360 preparation method Methods 0.000 title claims abstract description 31
- 108010010803 Gelatin Proteins 0.000 claims abstract description 39
- 239000008273 gelatin Substances 0.000 claims abstract description 39
- 229920000159 gelatin Polymers 0.000 claims abstract description 39
- 235000019322 gelatine Nutrition 0.000 claims abstract description 39
- 235000011852 gelatine desserts Nutrition 0.000 claims abstract description 39
- 239000003814 drug Substances 0.000 claims abstract description 24
- 229940079593 drug Drugs 0.000 claims abstract description 22
- 239000000463 material Substances 0.000 claims abstract description 18
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 15
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 8
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract 3
- 239000000203 mixture Substances 0.000 claims description 44
- 239000000243 solution Substances 0.000 claims description 40
- 235000011837 pasties Nutrition 0.000 claims description 32
- 239000011259 mixed solution Substances 0.000 claims description 16
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 claims description 12
- 238000007605 air drying Methods 0.000 claims description 9
- 238000009423 ventilation Methods 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 8
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 6
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 claims description 6
- 102000004877 Insulin Human genes 0.000 claims description 6
- 108090001061 Insulin Proteins 0.000 claims description 6
- 239000001110 calcium chloride Substances 0.000 claims description 6
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 6
- 229960002713 calcium chloride Drugs 0.000 claims description 6
- 235000011148 calcium chloride Nutrition 0.000 claims description 6
- 229960002897 heparin Drugs 0.000 claims description 6
- 229920000669 heparin Polymers 0.000 claims description 6
- 229940125396 insulin Drugs 0.000 claims description 6
- 239000001488 sodium phosphate Substances 0.000 claims description 6
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 6
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical group [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 6
- IBFYXTRXDNAPMM-BVTMAQQCSA-N Geniposide Chemical compound O([C@@H]1OC=C([C@@H]2[C@H]1C(=CC2)CO)C(=O)OC)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O IBFYXTRXDNAPMM-BVTMAQQCSA-N 0.000 claims description 5
- IBFYXTRXDNAPMM-FZEIBHLUSA-N Geniposide Natural products COC(=O)C1=CO[C@@H](O[C@H]2O[C@@H](CO)[C@H](O)[C@@H](O)[C@@H]2O)[C@H]2[C@@H]1CC=C2CO IBFYXTRXDNAPMM-FZEIBHLUSA-N 0.000 claims description 5
- VGLLGNISLBPZNL-RBUKDIBWSA-N arborescoside Natural products O=C(OC)C=1[C@@H]2C([C@H](O[C@H]3[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O3)OC=1)=C(CO)CC2 VGLLGNISLBPZNL-RBUKDIBWSA-N 0.000 claims description 5
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 claims description 4
- 239000011575 calcium Substances 0.000 claims description 4
- MKJXYGKVIBWPFZ-UHFFFAOYSA-L calcium lactate Chemical compound [Ca+2].CC(O)C([O-])=O.CC(O)C([O-])=O MKJXYGKVIBWPFZ-UHFFFAOYSA-L 0.000 claims description 4
- 239000001527 calcium lactate Substances 0.000 claims description 4
- 229960002401 calcium lactate Drugs 0.000 claims description 4
- 235000011086 calcium lactate Nutrition 0.000 claims description 4
- 229910019142 PO4 Inorganic materials 0.000 claims description 3
- 239000004227 calcium gluconate Substances 0.000 claims description 3
- 229960004494 calcium gluconate Drugs 0.000 claims description 3
- 235000013927 calcium gluconate Nutrition 0.000 claims description 3
- NEEHYRZPVYRGPP-UHFFFAOYSA-L calcium;2,3,4,5,6-pentahydroxyhexanoate Chemical compound [Ca+2].OCC(O)C(O)C(O)C(O)C([O-])=O.OCC(O)C(O)C(O)C(O)C([O-])=O NEEHYRZPVYRGPP-UHFFFAOYSA-L 0.000 claims description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 3
- 239000010452 phosphate Substances 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 102000008186 Collagen Human genes 0.000 claims description 2
- 108010035532 Collagen Proteins 0.000 claims description 2
- 102000004190 Enzymes Human genes 0.000 claims description 2
- 108090000790 Enzymes Proteins 0.000 claims description 2
- 229920001436 collagen Polymers 0.000 claims description 2
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 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
- 229940088598 enzyme Drugs 0.000 claims description 2
- 239000000413 hydrolysate Substances 0.000 claims description 2
- 229920005573 silicon-containing polymer Polymers 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 235000019738 Limestone Nutrition 0.000 claims 1
- DMGNFLJBACZMRM-UHFFFAOYSA-N O[P] Chemical compound O[P] DMGNFLJBACZMRM-UHFFFAOYSA-N 0.000 claims 1
- 150000001718 carbodiimides Chemical class 0.000 claims 1
- 238000005119 centrifugation Methods 0.000 claims 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 claims 1
- 235000019797 dipotassium phosphate Nutrition 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 239000006028 limestone Substances 0.000 claims 1
- 238000004321 preservation Methods 0.000 claims 1
- 230000035515 penetration Effects 0.000 abstract description 3
- 206010033675 panniculitis Diseases 0.000 abstract description 2
- 210000004304 subcutaneous tissue Anatomy 0.000 abstract description 2
- 229920002521 macromolecule Polymers 0.000 abstract 2
- 230000029087 digestion Effects 0.000 abstract 1
- 238000001647 drug administration Methods 0.000 abstract 1
- 239000003640 drug residue Substances 0.000 abstract 1
- 230000000694 effects Effects 0.000 abstract 1
- 210000001519 tissue Anatomy 0.000 abstract 1
- 231100000331 toxic Toxicity 0.000 abstract 1
- 230000002588 toxic effect Effects 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 7
- 230000008901 benefit Effects 0.000 description 5
- 239000003462 bioceramic Substances 0.000 description 5
- ZNZYKNKBJPZETN-WELNAUFTSA-N Dialdehyde 11678 Chemical compound N1C2=CC=CC=C2C2=C1[C@H](C[C@H](/C(=C/O)C(=O)OC)[C@@H](C=C)C=O)NCC2 ZNZYKNKBJPZETN-WELNAUFTSA-N 0.000 description 4
- 238000003763 carbonization Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 3
- 239000002131 composite material Substances 0.000 description 3
- -1 e.g. Chemical compound 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 229910052710 silicon Inorganic materials 0.000 description 3
- 239000010703 silicon Substances 0.000 description 3
- 210000003491 skin Anatomy 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 238000010586 diagram 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
- 229910000388 diammonium phosphate Inorganic materials 0.000 description 2
- 235000019838 diammonium phosphate Nutrition 0.000 description 2
- RAABOESOVLLHRU-UHFFFAOYSA-N diazene Chemical compound N=N RAABOESOVLLHRU-UHFFFAOYSA-N 0.000 description 2
- 229910000071 diazene Inorganic materials 0.000 description 2
- 229910000397 disodium phosphate Inorganic materials 0.000 description 2
- 229910010272 inorganic material Inorganic materials 0.000 description 2
- 239000011147 inorganic material Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000011505 plaster Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 229910001069 Ti alloy Inorganic materials 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 229960005069 calcium Drugs 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 239000003431 cross linking reagent Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 210000005093 cutaneous system Anatomy 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 239000004205 dimethyl polysiloxane Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 238000000703 high-speed centrifugation Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000009738 saturating Methods 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 230000008023 solidification Effects 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000008467 tissue growth Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/02—Inorganic materials
- A61L31/028—Other inorganic materials not covered by A61L31/022 - A61L31/026
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/04—Macromolecular materials
- A61L31/043—Proteins; Polypeptides; Degradation products thereof
- A61L31/045—Gelatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/16—Biologically active materials, e.g. therapeutic substances
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
- A61L2300/252—Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/003—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles having a lumen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0038—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles having a channel at the side surface
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0053—Methods for producing microneedles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M2202/00—Special media to be introduced, removed or treated
- A61M2202/07—Proteins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M2205/00—General characteristics of the apparatus
- A61M2205/02—General characteristics of the apparatus characterised by a particular materials
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Heart & Thoracic Surgery (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Vascular Medicine (AREA)
- Surgery (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Molecular Biology (AREA)
- Dermatology (AREA)
- Medical Informatics (AREA)
- Anesthesiology (AREA)
- Hematology (AREA)
- Media Introduction/Drainage Providing Device (AREA)
Abstract
本发明涉及一种多孔羟基磷灰石/明胶复合微针阵列贴片及其制备方法。所述复合微针阵列贴片包括高分子柔性贴片和位于贴片上的多孔羟基磷灰石/明胶复合微针;所述高分子柔性贴片由高分子材料和交联稳定剂制成;所述多孔羟基磷灰石/明胶复合微针由羟基磷灰石、明胶和交联稳定剂组成;多孔羟基磷灰石/明胶复合微针集成阵列位于交联明胶柔性贴片。本发明的多孔羟基磷灰石/明胶复合微针阵列贴片可用于蛋白质类药物的包埋,具有药物的负载率较高,针体底部贴片无药物残留,大大提高了给药效率以及给药精确度;另外,针体进入皮下组织的部分可迅速溶解并且随后完全降解,被组织消化吸收,无毒副作用。本发明的多孔羟基磷灰石/明胶复合微针阵列贴片制备工艺条件简单,价格低廉,适合大批量生产,可广泛应用于蛋白质类大分子药物透皮给药领域。
Description
技术领域
本发明涉及一种多孔羟基磷灰石/明胶复合微针阵列贴片及其制备方法,属于微针透皮给药设备技术领域。
背景技术
微针透皮给药系统具有注射和透皮给药的双重优势,具有快速、方便、无痛和微创的优点,更为重要的是,患者可根据实际药物需求及时的实现终止给药。自20世纪90年代末首次将实心硅微针阵列芯片用于药物经皮释放的研究以来,经皮微针药物导入的研究取得了较大进展。微针透皮给药是由数十至数百空心或实心微针(针长约50~900μm)组成1~2cm2的透皮贴片帖于皮肤,通过刺穿皮肤最外层,使药物进入体内。微针透皮给药中,由于能避免胃酸极端pH、消化酶降解、肠蠕动清除和肠上皮吸收等多重屏障,对于大分子药物的传递具有显著优势。
制作微针的材料主要有无机和高分子材料两大类。无机微针材料(如,硅、钛合金、玻璃等)具有良好的机械强度,目前在临床上得到一定范围的应用。但无机材料微针在使用过程中,针体可能会在皮肤内断裂。由于不能降解及与生物体相容性差等问题会有引起感染的危险,且制作成本也很高。虽然以纯高分子基材制备的微针也具有较高的强度并可穿透表皮,但与无机材料微针相比,其强度和硬度还是相对较低;此外,制备过程中有机溶剂(溶解高分子材料)和合成小分子试剂(如,交联剂等)的使用和残留可能对人体有害。
生物陶瓷是近年来发展的一类重要生物功能材料,具有在高温高湿环境下有良好的机械强度和稳定性;可以精确复制模具形状并能在温和条件下实现固化;此外,表面积、孔隙率和降解速率则可用于调控药物的释放速率。以生物陶瓷和高分子材料作为主体材料制备的微针具有独特的优势:其中生物陶瓷的结晶性为微针提供足够的刚性;而有机高分子材料能使生物陶瓷纳米颗粒紧密粘结,同时由于吸收细胞间隙液而溶胀和降解,在结晶的生物陶瓷颗粒间形成持续、流畅的微通道,使药物快速得到渗透和释放。
发明内容
本发明的目的是针对现有技术的不足,公开了一种多孔羟基磷灰石/明胶复合微针阵列贴片及其制备方法。该方法具有反应条件温和、制备步骤简单、操作方便等优点。
本发明通过下述技术方案得以解决:
一种多孔羟基磷灰石/明胶复合微针阵列贴片及其制备方法,其特征在于,所述复合微针阵列贴片包括交联明胶柔性贴片和位于贴片上的多孔羟基磷灰石/明胶复合微针;所述交联明胶柔性贴片由明胶和交联稳定剂制成;所述多孔羟基磷灰石/明胶复合微针由羟基磷灰石、明胶和交联稳定剂组成。多孔羟基磷灰石/明胶复合微针集成阵列位于交联明胶柔性贴片;所述多孔羟基磷灰石/明胶复合微针内包埋固态蛋白质类大分子药物。
所述多孔羟基磷灰石/明胶复合微针为圆锥形或类圆锥形,整体高度200~1000μm,微针顶部直径伟5~20μm,微针底部直径伟300~500μm,贴片厚度500~1000μm。
所述多孔羟基磷灰石的前驱体材料选自水溶性钙盐和水溶性磷酸盐。水溶性钙盐,如,葡萄糖酸钙、乳酸钙、氯化钙;水溶性磷酸盐,如,磷酸钠、磷酸氢钠、磷酸氢二铵、磷酸氢钾。控制钙/磷摩尔比为1.67。
所述明胶选自动物胶原的水解产物。
所述交联稳定剂为戊二醛、碳化二亚胺、京尼平中的一种或几种。
所述多孔羟基磷灰石/明胶复合微针中羟基磷灰石、明胶和交联稳定剂的重量比例为10-60:15-45:0.01-0.5。
所述固态蛋白质类大分子药物选自胰岛素、肝素、酶或其它组织生长因子。
所述制备方法具体步骤如下:1)室温下,在表面洁净的聚二甲基硅氧烷微针模板模腔上方滴加羟基磷灰石前驱体材料、明胶、交联稳定剂和蛋白质类大分子药物组成的糊状混合物,高速离心处理5~10min,待糊状混合物填满模腔后,移除模板表面多余的糊状混合物;2)室温下,在上述含药后的模腔上方滴加明胶和交联稳定剂组成的混合溶液;3)待混合溶液完全覆盖模腔表面后,将微针模板置于通风处自然风干,脱模,脱模后的微针贴片置于低温密封保存备用。
与现有技术相比,本发明上述一种多孔羟基磷灰石/明胶复合微针阵列贴片及其制备方法,以羟基磷灰石和生物可降解材料明胶作为微针的主体材料,可使微针保持生物安全性的前提下具有足够的强度和硬度。由于微针独特的多孔结构,在皮下组织中,微针可吸收细胞液快速溶胀性,为药物微孔通道的快速形成和药物的渗透释放提供了便捷途径。此外,可根据生产需要,通过调节模板微孔大小、形状,设计不同的微针模板,并具有反应条件温和、制备步骤简单、操作方便等优点。
附图说明
图1为多孔羟基磷灰石/明胶复合微针阵列贴片制备流程示意图。
图2为本发明的方法制备多孔羟基磷灰石/明胶复合材料的红外光谱图。
图3为本发明的方法制备多孔羟基磷灰石/明胶复合材料的X射线衍射图。
图4为本发明的方法制备多孔羟基磷灰石/明胶复合材料的透射电镜(TEM)图。
图5为本发明的方法制备多孔羟基磷灰石/明胶复合微针扫描电镜(SEM)图。
图6为包埋胰岛素的多孔羟基磷灰石/明胶复合微针阵列贴片的药物释放曲线。
图7为包埋肝素的多孔羟基磷灰石/明胶复合微针阵列贴片的药物释放曲线。
具体实施方式
下面通过实施例对本发明具体的描述,应当指出:以下所述仅是本发明的优选实施方式,对于本技术领域的技术人员来说,在不脱离本发明的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
实施例1:
图1为多孔羟基磷灰石/明胶复合微针阵列贴片制备流程示意图。具体制备步骤如下:
(1)将液态聚二甲基硅氧烷预聚物和固化剂按质量比10:1混合后,浇注在微针硅片基底上,之后先抽真空去除气泡,然后恢复到正常大气压下,在60℃下加热5h,脱模可制得微针模板。
(2)将1.11g的氯化钙和2.14g Na2HPO4·12HO分别溶解在15mL浓度为15%的明胶水溶液中,得到溶液A和溶液B。将溶液B缓慢滴加到溶液A,调节混合溶液pH=8后,在室温下充分搅拌,水份挥发至约10mL得到糊状混合物C。
(3)在糊状混合物C中加入100μL浓度为2.5%的戊二醛后,搅拌均匀后将其浇注到步骤(1)所制的微针模板中,3000rpm离心处理5min,待糊状混合物填满模腔后,移除模板表面多余的糊状混合物。
(4)室温下,在上述的模腔上方滴加10mL浓度为10%明胶和120μL浓度为1.25%戊二醛组成的混合溶液。
(5)待混合溶液完全覆盖模腔表面后,将微针模板置于通风处自然风干,脱模,脱模后的微针贴片置于低温密封保存备用。
所制备的微针通过红外光谱(图2)和X射线衍射分析(图3),确定其组成和结构;结合通过透射电镜分析(图4),进一步确定羟基磷灰石的晶体结构。通过扫描电镜分析(图5),可发现所制备的微针具有多孔结构。
实施例2:
(1)微针模板制备同实施例1。
(2)将6.16g的乳酸钙和4.28g Na2HPO4·12HO分别溶解在13mL浓度为15%的明胶水溶液中,得到溶液A和溶液B。将溶液B缓慢滴加到溶液A,调节混合溶液pH=8后,在室温下充分搅拌,水份挥发至约12mL得到糊状混合物C。
(3)在糊状混合物C中加入100μL浓度为1.25%的戊二醛和3mg胰岛素后,搅拌均匀后将其浇注到步骤(1)所制的微针模板上,而后放置在真空干燥器中真空处理5min,去除微针模腔中的空气,待糊状混合物填满模腔后,移除模板表面多余的糊状混合物。
(4)室温下,在上述的模腔上方滴加10mL浓度为15%明胶和240μL浓度为1.25%戊二醛组成的混合溶液。
(5)待混合溶液完全覆盖模腔表面后,将微针模板置于通风处自然风干,脱模,脱模后的微针贴片置于低温密封保存备用,药物释放曲线如图6所示。
实施例3:
(1)微针模板制备同实施例1。
(2)将3.33g的氯化钙和2.376g磷酸氢二铵分别溶解在10mL浓度为15%的明胶水溶液中,得到溶液A和溶液B。将溶液B缓慢滴加到溶液A,调节混合溶液pH=8后,在室温下充分搅拌,水份挥发至约15mL得到糊状混合物C。
(3)在糊状混合物C中加入1mL浓度为1.5%的碳化二亚胺和4mg肝素后,搅拌均匀后将其浇注到步骤(1)所制的微针模板中,1000rpm离心处理10min,待糊状混合物填满模腔后,移除模板表面多余的糊状混合物。
(4)室温下,在上述的模腔上方滴加10mL浓度为10%明胶和0.5mL浓度为1.5%京尼平组成的混合溶液。
(5)待混合溶液完全覆盖模腔表面后,将微针模板置于通风处自然风干,脱模,脱模后的微针贴片置于低温密封保存备用,药物释放曲线如图7所示。
实施例4:
(1)微针模板制备同实施例1。
(2)将2.22g的氯化钙和1.968g磷酸钠分别溶解在10mL浓度为6%的明胶水溶液中,得到溶液A和溶液B。将溶液B缓慢滴加到溶液A,调节混合溶液pH=8后,在室温下充分搅拌,水份挥发至约10mL得到糊状混合物C。
(3)在糊状混合物C中加入1.5mL浓度为1.5%的京尼平和2.5mg胰岛素后,搅拌均匀后将其浇注到步骤(1)所制的微针模板中,2000rpm离心处理5min,待糊状混合物填满模腔后,移除模板表面多余的糊状混合物。
(4)室温下,在上述的模腔上方滴加10mL浓度为15%明胶和1mL浓度为1.5%碳化二亚胺组成的混合溶液。
(5)待混合溶液完全覆盖模腔表面后,将微针模板置于通风处自然风干,脱模,脱模后的微针贴片置于低温密封保存备用。
实施例5:
(1)微针模板制备同实施例1。
(2)将11.12g的葡萄糖酸钙和2.44g磷酸钠分别溶解在10mL浓度为5%的明胶水溶液中,得到溶液A和溶液B。将溶液B缓慢滴加到溶液A,调节混合溶液pH=8后,在室温下充分搅拌,水份挥发至约10mL得到糊状混合物C。
(3)在糊状混合物C中加入1mL浓度为1.5%的京尼平和2.5mg胰岛素后,搅拌均匀后将其浇注到步骤(1)所制的微针模板中,5000rpm离心处理5min,待糊状混合物填满模腔后,移除模板表面多余的糊状混合物。
(4)室温下,在上述的模腔上方滴加10mL浓度为10%明胶和100μL浓度为2.5%戊二醛组成的混合溶液。
(5)待混合溶液完全覆盖模腔表面后,将微针模板置于通风处自然风干,脱模,脱模后的微针贴片置于低温密封保存备用。
实施例6:
(1)微针模板制备同实施例1。
(2)将6.66的氯化钙和8.16g磷酸氢二钾分别溶解在10mL浓度为8%的明胶水溶液中,得到溶液A和溶液B。将溶液B缓慢滴加到溶液A,调节混合溶液pH=8后,在室温下充分搅拌,水份挥发至约10mL得到糊状混合物C。
(3)在糊状混合物C中加入480uL浓度为1.5%的碳化二亚胺和2.5mg肝素后,而后放置在真空干燥器中真空处理8min,去除微针模腔中的空气,待糊状混合物填满模腔后,用疏水性较好的材料再进行进一步的压实,之后移除模板表面多余的糊状混合物。
(4)室温下,在上述的模腔上方滴加10mL浓度为10%明胶和300μL浓度为2.5%碳化二亚胺组成的混合溶液。
(5)待混合溶液完全覆盖模腔表面后,将微针模板置于通风处自然风干,脱模,脱模后的微针贴片置于低温密封保存备用。
实施例7:
(1)微针模板制备同实施例1。
(2)将9.17的乳酸钙和2.43g磷酸二氢钾分别溶解在15mL浓度为15%的明胶水溶液中,得到溶液A和溶液B。将溶液B缓慢滴加到溶液A,调节混合溶液pH=8后,在室温下充分搅拌,水份挥发至约10mL得到糊状混合物C。
(3)在糊状混合物C中加入1.5mL浓度为1.25%的京尼平和2.5mg肝素后,而后放置在真空干燥器中真空处理7min,去除微针模腔中的空气,待糊状混合物填满模腔后,用疏水性较好的材料再进行进一步的压实,之后移除模板表面多余的糊状混合物。
(4)室温下,在上述的模腔上方滴加10mL浓度为15%明胶和200μL浓度为1.5%戊二醛组成的混合溶液。
(5)待混合溶液完全覆盖模腔表面后,将微针模板置于通风处自然风干,脱模,脱模后的微针贴片置于低温密封保存备用。
Claims (7)
1.一种多孔羟基磷灰石/明胶复合微针阵列贴片的制备方法,其特征在于,所述制备方法具体步骤如下:1)室温下,在表面洁净的聚二甲基硅氧烷微针模板模腔上方滴加羟基磷灰石前驱体材料、明胶、交联稳定剂和蛋白质类大分子药物组成的糊状混合物,离心或真空处理5~10min,待糊状混合物填满模腔后,移除模板表面多余的糊状混合物;2)室温下,在上述含药后的模腔上方滴加明胶和交联稳定剂组成的混合溶液;3)待混合溶液完全覆盖模腔表面后,将微针模板置于通风处自然风干,脱模,脱模后的微针贴片置于低温密封保存备用;所述复合微针阵列贴片包括交联明胶柔性贴片和位于贴片上的多孔羟基磷灰石/明胶复合微针;所述交联明胶柔性贴片由明胶和交联稳定剂制成;所述多孔羟基磷灰石/明胶复合微针由羟基磷灰石、明胶和交联稳定剂组成,多孔羟基磷灰石/明胶复合微针集成阵列位于交联明胶柔性贴片;所述多孔羟基磷灰石/明胶复合微针内包埋固态蛋白质类大分子药物。
2.根据权利要求1所述的一种多孔羟基磷灰石/明胶复合微针阵列贴片的制备方法,其特征在于,所述多孔羟基磷灰石/明胶复合微针为圆锥形或类圆锥形,整体高度200~1000μm,微针顶部直径为5~20μm,微针底部直径为300~500μm,贴片厚度500~1000μm。
3.根据权利要求1所述的一种多孔羟基磷灰石/明胶复合微针阵列贴片的制备方法,其特征在于,所述羟基磷灰石的前驱体材料选自水溶性钙盐和水溶性磷酸;其中,水溶性钙盐选自葡萄糖酸钙、乳酸钙、氯化钙中的一种;水溶性磷酸盐选自磷酸钠、磷酸氢钠、磷酸氢二铵、磷酸氢钾中的一种。
4.根据权利要求1所述的一种多孔羟基磷灰石/明胶复合微针阵列贴片的制备方法,其特征在于,所述明胶选自动物胶原的水解产物。
5.根据权利要求1所述的一种多孔羟基磷灰石/明胶复合微针阵列贴片的制备方法,其特征在于,所述交联稳定剂为戊二醛、碳化二亚胺、京尼平中的一种或几种。
6.根据权利要求1所述的一种多孔羟基磷灰石/明胶复合微针阵列贴片的制备方法,其特征在于,所述多孔羟基磷灰石/明胶复合微针中羟基磷灰石、明胶和交联稳定剂的重量比例为10-60:15-45:0.01-0.5。
7.根据权利要求1所述的一种多孔羟基磷灰石/明胶复合微针阵列贴片的制备方法,其特征在于,所述固态蛋白质类大分子药物选自胰岛素、肝素或酶。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610109651.3A CN105641801B (zh) | 2016-02-27 | 2016-02-27 | 一种多孔羟基磷灰石/明胶复合微针阵列贴片及其制备方法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610109651.3A CN105641801B (zh) | 2016-02-27 | 2016-02-27 | 一种多孔羟基磷灰石/明胶复合微针阵列贴片及其制备方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN105641801A CN105641801A (zh) | 2016-06-08 |
CN105641801B true CN105641801B (zh) | 2019-01-01 |
Family
ID=56491879
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201610109651.3A Expired - Fee Related CN105641801B (zh) | 2016-02-27 | 2016-02-27 | 一种多孔羟基磷灰石/明胶复合微针阵列贴片及其制备方法 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN105641801B (zh) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107126620A (zh) * | 2017-06-27 | 2017-09-05 | 傅书华 | 一种隐形注射针 |
CN115501474A (zh) * | 2022-09-16 | 2022-12-23 | 深圳高性能医疗器械国家研究院有限公司 | 可溶性微针贴膜的制备方法 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104661695A (zh) * | 2012-09-13 | 2015-05-27 | 阿米尔·亚夫拉罕 | 用于皮肤改善的递送装置和方法 |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003092785A1 (en) * | 2002-04-30 | 2003-11-13 | Morteza Shirkhanzadeh | Arrays of microneedles comprising porous calcium phosphate coating and bioactive agents |
AU2003275311A1 (en) * | 2002-09-16 | 2004-04-30 | Sung-Yun Kwon | Solid micro-perforators and methods of use |
JP2011012050A (ja) * | 2009-06-03 | 2011-01-20 | Bioserentack Co Ltd | 多孔性基盤を用いたマイクロニードル・アレイとその製造方法 |
CN103041452A (zh) * | 2011-10-13 | 2013-04-17 | 中国科学院理化技术研究所 | 明胶/纳米骨磷灰石的多孔骨修复框架材料及其制备方法和应用 |
CN102552913B (zh) * | 2012-01-19 | 2013-06-19 | 中国科学院上海硅酸盐研究所 | 一种纳米结构磷酸钙双载药体系及其制备方法 |
CN104288093B (zh) * | 2013-05-31 | 2017-03-08 | 袁伟恩 | 纳米药物透皮制剂在肿瘤中的应用 |
CN103330680A (zh) * | 2013-05-31 | 2013-10-02 | 袁伟恩 | 纳米药物透皮制剂及其制备方法 |
JP2016528971A (ja) * | 2013-07-22 | 2016-09-23 | ジン, トゥオJin, Tuo | 相転移マイクロニードルパッチの調製過程 |
KR101605711B1 (ko) * | 2014-06-16 | 2016-03-23 | (주)비아바이오텍 | 한방 조성물이 코팅된 미세침 및 이의 제조방법 |
-
2016
- 2016-02-27 CN CN201610109651.3A patent/CN105641801B/zh not_active Expired - Fee Related
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104661695A (zh) * | 2012-09-13 | 2015-05-27 | 阿米尔·亚夫拉罕 | 用于皮肤改善的递送装置和方法 |
Also Published As
Publication number | Publication date |
---|---|
CN105641801A (zh) | 2016-06-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
DE69733889T2 (de) | Lösliche oxide für biologische anwendungen | |
KR100330657B1 (ko) | 다공성생체재료및이것의제조방법 | |
CN105879213B (zh) | 生物可降解硫酸钙/明胶复合微针阵列贴片及其制备方法 | |
CN102921038B (zh) | 制备具有形状记忆功能的多孔支架的方法 | |
CN102604146A (zh) | 无机生物活性材料与聚合物多孔复合材料的制备方法 | |
CN105641801B (zh) | 一种多孔羟基磷灰石/明胶复合微针阵列贴片及其制备方法 | |
JPH0341176B2 (zh) | ||
CN106178106A (zh) | 3d打印海藻酸钠/聚乙烯醇全物理交联双网络水凝胶支架的方法 | |
CN104591679B (zh) | 一种改性氯氧镁骨水泥及其制备方法和应用 | |
CN101193834A (zh) | 成形物品 | |
JP2004261456A (ja) | 貫通を有する多孔質リン酸カルシウム高分子ハイドロゲル複合体、その製造方法及びそれを用いた人工骨または薬剤徐放体 | |
CN105380732B (zh) | 具有多维通道结构的骨修复材料 | |
CN105816918A (zh) | 一种脂肪族聚酯-纳米羟基磷灰石复合材料及制备方法 | |
CN107032775A (zh) | 一种纳米羟基磷灰石、硅酸二钙复合生物陶瓷及其制备方法和应用 | |
CZ20012748A3 (cs) | Způsob výroby řízeně biodegradovatelných keramických vláken z hydrosolu kysličníku křemičitého | |
CN102167843B (zh) | 胶原改性的聚己内酯/生物活性玻璃复合材料的制备方法 | |
CN113633829B (zh) | 一种多功能复合多孔支架及其制备方法与应用 | |
CN110882419A (zh) | 一种自固化磷酸钙骨水泥支架及其制备方法和应用 | |
CN101843920A (zh) | 自成孔磷酸钙骨水泥支架的制备方法 | |
CN1562389A (zh) | 矿化丝蛋白/高分子复合多孔材料及其制备方法 | |
CN102580157A (zh) | β-磷酸三钙/聚乙烯醇复合水凝胶人工角膜多孔支架材料及其制备方法 | |
CN105536059B (zh) | 一种自修复可注射骨水泥及制备方法 | |
CN101905039B (zh) | 大孔径的多孔羟基磷灰石/壳聚糖/聚乙烯醇骨替代材料 | |
RU2554811C1 (ru) | Способ получения пористых хитозановых губок, содержащих фосфаты кальция, для заполнения костных дефектов | |
CN105411725B (zh) | 一种具有多维通道结构的骨修复材料制备方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20190101 Termination date: 20210227 |
|
CF01 | Termination of patent right due to non-payment of annual fee |