CN101313873B - Biology polypeptide medicament blood vessel bracket and preparation method thereof - Google Patents
Biology polypeptide medicament blood vessel bracket and preparation method thereof Download PDFInfo
- Publication number
- CN101313873B CN101313873B CN 200710105816 CN200710105816A CN101313873B CN 101313873 B CN101313873 B CN 101313873B CN 200710105816 CN200710105816 CN 200710105816 CN 200710105816 A CN200710105816 A CN 200710105816A CN 101313873 B CN101313873 B CN 101313873B
- Authority
- CN
- China
- Prior art keywords
- medicine
- rack body
- polypeptide
- glycine
- preparation
- 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.)
- Active
Links
- 239000003814 drug Substances 0.000 title claims abstract description 139
- 229920001184 polypeptide Polymers 0.000 title claims abstract description 79
- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 79
- 102000004196 processed proteins & peptides Human genes 0.000 title claims abstract description 79
- 238000002360 preparation method Methods 0.000 title claims abstract description 31
- 210000004204 blood vessel Anatomy 0.000 title abstract description 10
- 229940079593 drug Drugs 0.000 claims abstract description 32
- 230000004663 cell proliferation Effects 0.000 claims abstract description 30
- 238000001035 drying Methods 0.000 claims abstract description 27
- 238000000576 coating method Methods 0.000 claims abstract description 25
- 239000011248 coating agent Substances 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 8
- 229910001069 Ti alloy Inorganic materials 0.000 claims abstract description 5
- 229910045601 alloy Inorganic materials 0.000 claims abstract description 5
- 239000000956 alloy Substances 0.000 claims abstract description 5
- 239000012567 medical material Substances 0.000 claims abstract description 5
- 238000013508 migration Methods 0.000 claims abstract description 5
- 229910001000 nickel titanium Inorganic materials 0.000 claims abstract description 5
- 239000004626 polylactic acid Substances 0.000 claims abstract description 5
- 239000011148 porous material Substances 0.000 claims abstract description 5
- 210000004509 vascular smooth muscle cell Anatomy 0.000 claims abstract description 5
- 229920000747 poly(lactic acid) Polymers 0.000 claims abstract description 4
- IYMAXBFPHPZYIK-BQBZGAKWSA-N Arg-Gly-Asp Chemical compound NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O IYMAXBFPHPZYIK-BQBZGAKWSA-N 0.000 claims description 48
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 30
- 210000000663 muscle cell Anatomy 0.000 claims description 20
- 108010069514 Cyclic Peptides Proteins 0.000 claims description 19
- 102000001189 Cyclic Peptides Human genes 0.000 claims description 19
- 239000013590 bulk material Substances 0.000 claims description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 18
- 239000007788 liquid Substances 0.000 claims description 13
- 238000004140 cleaning Methods 0.000 claims description 12
- 230000003647 oxidation Effects 0.000 claims description 11
- 238000007254 oxidation reaction Methods 0.000 claims description 11
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 claims description 10
- 229960002930 sirolimus Drugs 0.000 claims description 10
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 claims description 10
- LJRDOKAZOAKLDU-UDXJMMFXSA-N (2s,3s,4r,5r,6r)-5-amino-2-(aminomethyl)-6-[(2r,3s,4r,5s)-5-[(1r,2r,3s,5r,6s)-3,5-diamino-2-[(2s,3r,4r,5s,6r)-3-amino-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-hydroxycyclohexyl]oxy-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl]oxyoxane-3,4-diol;sulfuric ac Chemical compound OS(O)(=O)=O.N[C@@H]1[C@@H](O)[C@H](O)[C@H](CN)O[C@@H]1O[C@H]1[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](N)C[C@@H](N)[C@@H]2O)O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)N)O[C@@H]1CO LJRDOKAZOAKLDU-UDXJMMFXSA-N 0.000 claims description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 9
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Chemical compound CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 claims description 9
- 229920002988 biodegradable polymer Polymers 0.000 claims description 9
- 239000004621 biodegradable polymer Substances 0.000 claims description 9
- 239000000463 material Substances 0.000 claims description 9
- 229960001639 penicillamine Drugs 0.000 claims description 9
- 238000012805 post-processing Methods 0.000 claims description 9
- 238000001291 vacuum drying Methods 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 7
- 239000004815 dispersion polymer Substances 0.000 claims description 7
- 238000005516 engineering process Methods 0.000 claims description 7
- 238000002474 experimental method Methods 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- 206010013786 Dry skin Diseases 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 241001597008 Nomeidae Species 0.000 claims description 6
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 claims description 6
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 claims description 6
- 239000012153 distilled water Substances 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 229920000642 polymer Polymers 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 229910000831 Steel Inorganic materials 0.000 claims description 5
- 238000003618 dip coating Methods 0.000 claims description 5
- 238000000338 in vitro Methods 0.000 claims description 5
- 239000010959 steel Substances 0.000 claims description 5
- 230000012292 cell migration Effects 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
- 238000011068 loading method Methods 0.000 claims description 4
- HLXZNVUGXRDIFK-UHFFFAOYSA-N nickel titanium Chemical compound [Ti].[Ti].[Ti].[Ti].[Ti].[Ti].[Ti].[Ti].[Ti].[Ti].[Ti].[Ni].[Ni].[Ni].[Ni].[Ni].[Ni].[Ni].[Ni].[Ni].[Ni].[Ni].[Ni].[Ni].[Ni] HLXZNVUGXRDIFK-UHFFFAOYSA-N 0.000 claims description 4
- 239000008363 phosphate buffer Substances 0.000 claims description 4
- 230000001681 protective effect Effects 0.000 claims description 4
- DWNBOPVKNPVNQG-LURJTMIESA-N (2s)-4-hydroxy-2-(propylamino)butanoic acid Chemical compound CCCN[C@H](C(O)=O)CCO DWNBOPVKNPVNQG-LURJTMIESA-N 0.000 claims description 3
- NNRFRJQMBSBXGO-CIUDSAMLSA-N (3s)-3-[[2-[[(2s)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]acetyl]amino]-4-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-oxobutanoic acid Chemical compound NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O NNRFRJQMBSBXGO-CIUDSAMLSA-N 0.000 claims description 3
- RKDVKSZUMVYZHH-UHFFFAOYSA-N 1,4-dioxane-2,5-dione Chemical compound O=C1COC(=O)CO1 RKDVKSZUMVYZHH-UHFFFAOYSA-N 0.000 claims description 3
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 3
- FQJMMELDZQJBDH-UDSFRJCUSA-N 2-aminoacetic acid (2S)-2-aminobutanedioic acid (2S)-2-amino-5-(diaminomethylideneamino)pentanoic acid Chemical compound NCC(O)=O.NCC(O)=O.OC(=O)[C@@H](N)CC(O)=O.OC(=O)[C@@H](N)CCCNC(N)=N FQJMMELDZQJBDH-UDSFRJCUSA-N 0.000 claims description 3
- 102000053642 Catalytic RNA Human genes 0.000 claims description 3
- 108090000994 Catalytic RNA Proteins 0.000 claims description 3
- 108010092160 Dactinomycin Proteins 0.000 claims description 3
- 229920000219 Ethylene vinyl alcohol Polymers 0.000 claims description 3
- 108010010803 Gelatin Proteins 0.000 claims description 3
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 claims description 3
- 101000829980 Homo sapiens Ral guanine nucleotide dissociation stimulator Proteins 0.000 claims description 3
- HZQDCMWJEBCWBR-UUOKFMHZSA-N Mizoribine Chemical compound OC1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 HZQDCMWJEBCWBR-UUOKFMHZSA-N 0.000 claims description 3
- CUIJDJLRRFWTOC-BWDXOUPSSA-N NCC(O)=O.NCC(O)=O.OC[C@H](N)C(O)=O.OC(=O)[C@@H](N)CC(O)=O.OC(=O)[C@@H](N)CCCNC(N)=N Chemical compound NCC(O)=O.NCC(O)=O.OC[C@H](N)C(O)=O.OC(=O)[C@@H](N)CC(O)=O.OC(=O)[C@@H](N)CCCNC(N)=N CUIJDJLRRFWTOC-BWDXOUPSSA-N 0.000 claims description 3
- DIUWVMBPZWARSF-UMFOICNISA-N NCC(O)=O.NCC(O)=O.OC[C@H](N)C(O)=O.SC[C@H](N)C(O)=O.OC(=O)[C@@H]1CCCN1.OC(=O)[C@@H](N)CC(O)=O.OC(=O)[C@@H](N)CCCNC(N)=N Chemical compound NCC(O)=O.NCC(O)=O.OC[C@H](N)C(O)=O.SC[C@H](N)C(O)=O.OC(=O)[C@@H]1CCCN1.OC(=O)[C@@H](N)CC(O)=O.OC(=O)[C@@H](N)CCCNC(N)=N DIUWVMBPZWARSF-UMFOICNISA-N 0.000 claims description 3
- NJUUTRGQFJSKKB-MTGRVJIISA-N N[C@@H](CC(=O)O)C(=O)O.NCC(=O)O.N[C@@H](CCCNC(N)=N)C(=O)O.N[C@@H](CCCCN)C(=O)O.N[C@@H](CC1=CC=CC=C1)C(=O)O.N[C@@H](CC(=O)O)C(=O)O Chemical compound N[C@@H](CC(=O)O)C(=O)O.NCC(=O)O.N[C@@H](CCCNC(N)=N)C(=O)O.N[C@@H](CCCCN)C(=O)O.N[C@@H](CC1=CC=CC=C1)C(=O)O.N[C@@H](CC(=O)O)C(=O)O NJUUTRGQFJSKKB-MTGRVJIISA-N 0.000 claims description 3
- 229930012538 Paclitaxel Natural products 0.000 claims description 3
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 3
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 claims description 3
- 102100023320 Ral guanine nucleotide dissociation stimulator Human genes 0.000 claims description 3
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 claims description 3
- 235000010489 acacia gum Nutrition 0.000 claims description 3
- 239000001785 acacia senegal l. willd gum Substances 0.000 claims description 3
- XFILPEOLDIKJHX-QYZOEREBSA-N batimastat Chemical compound C([C@@H](C(=O)NC)NC(=O)[C@H](CC(C)C)[C@H](CSC=1SC=CC=1)C(=O)NO)C1=CC=CC=C1 XFILPEOLDIKJHX-QYZOEREBSA-N 0.000 claims description 3
- 229950001858 batimastat Drugs 0.000 claims description 3
- 230000010261 cell growth Effects 0.000 claims description 3
- 239000001913 cellulose Substances 0.000 claims description 3
- 229920002678 cellulose Polymers 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 229920001577 copolymer Polymers 0.000 claims description 3
- 238000005260 corrosion Methods 0.000 claims description 3
- 230000007797 corrosion Effects 0.000 claims description 3
- 229960000640 dactinomycin Drugs 0.000 claims description 3
- 229960003957 dexamethasone Drugs 0.000 claims description 3
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 claims description 3
- -1 distilled water compound Chemical class 0.000 claims description 3
- 239000003792 electrolyte Substances 0.000 claims description 3
- 210000002889 endothelial cell Anatomy 0.000 claims description 3
- 150000002159 estradiols Chemical class 0.000 claims description 3
- 238000005530 etching Methods 0.000 claims description 3
- 239000005038 ethylene vinyl acetate Substances 0.000 claims description 3
- 238000009472 formulation Methods 0.000 claims description 3
- JBFHTYHTHYHCDJ-UHFFFAOYSA-N gamma-caprolactone Chemical compound CCC1CCC(=O)O1 JBFHTYHTHYHCDJ-UHFFFAOYSA-N 0.000 claims description 3
- 229920000159 gelatin Polymers 0.000 claims description 3
- 239000008273 gelatin Substances 0.000 claims description 3
- 235000019322 gelatine Nutrition 0.000 claims description 3
- 235000011852 gelatine desserts Nutrition 0.000 claims description 3
- LVASCWIMLIKXLA-LSDHHAIUSA-N halofuginone Chemical compound O[C@@H]1CCCN[C@H]1CC(=O)CN1C(=O)C2=CC(Cl)=C(Br)C=C2N=C1 LVASCWIMLIKXLA-LSDHHAIUSA-N 0.000 claims description 3
- 229950010152 halofuginone Drugs 0.000 claims description 3
- 229920001519 homopolymer Polymers 0.000 claims description 3
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 claims description 3
- 229960003444 immunosuppressant agent Drugs 0.000 claims description 3
- 230000001861 immunosuppressant effect Effects 0.000 claims description 3
- 239000003018 immunosuppressive agent Substances 0.000 claims description 3
- 239000012535 impurity Substances 0.000 claims description 3
- JJTUDXZGHPGLLC-UHFFFAOYSA-N lactide Chemical compound CC1OC(=O)C(C)OC1=O JJTUDXZGHPGLLC-UHFFFAOYSA-N 0.000 claims description 3
- 229950000844 mizoribine Drugs 0.000 claims description 3
- 229960001592 paclitaxel Drugs 0.000 claims description 3
- 239000000137 peptide hydrolase inhibitor Substances 0.000 claims description 3
- 229920001490 poly(butyl methacrylate) polymer Polymers 0.000 claims description 3
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 claims description 3
- 229920003229 poly(methyl methacrylate) Polymers 0.000 claims description 3
- 239000002861 polymer material Substances 0.000 claims description 3
- 239000004926 polymethyl methacrylate Substances 0.000 claims description 3
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 3
- 235000019422 polyvinyl alcohol Nutrition 0.000 claims description 3
- FYPMFJGVHOHGLL-UHFFFAOYSA-N probucol Chemical compound C=1C(C(C)(C)C)=C(O)C(C(C)(C)C)=CC=1SC(C)(C)SC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 FYPMFJGVHOHGLL-UHFFFAOYSA-N 0.000 claims description 3
- 229960003912 probucol Drugs 0.000 claims description 3
- 230000003252 repetitive effect Effects 0.000 claims description 3
- 108091092562 ribozyme Proteins 0.000 claims description 3
- 235000010413 sodium alginate Nutrition 0.000 claims description 3
- 239000000661 sodium alginate Substances 0.000 claims description 3
- 229940005550 sodium alginate Drugs 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 239000001117 sulphuric acid Substances 0.000 claims description 3
- 235000011149 sulphuric acid Nutrition 0.000 claims description 3
- 229960001967 tacrolimus Drugs 0.000 claims description 3
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 claims description 3
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 3
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 claims description 3
- 229960004528 vincristine Drugs 0.000 claims description 3
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 claims description 3
- 229950009819 zotarolimus Drugs 0.000 claims description 3
- CGTADGCBEXYWNE-JUKNQOCSSA-N zotarolimus Chemical compound N1([C@H]2CC[C@@H](C[C@@H](C)[C@H]3OC(=O)[C@@H]4CCCCN4C(=O)C(=O)[C@@]4(O)[C@H](C)CC[C@H](O4)C[C@@H](/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C3)OC)C[C@H]2OC)C=NN=N1 CGTADGCBEXYWNE-JUKNQOCSSA-N 0.000 claims description 3
- 238000001311 chemical methods and process Methods 0.000 claims description 2
- 238000000053 physical method Methods 0.000 claims description 2
- 210000000329 smooth muscle myocyte Anatomy 0.000 abstract description 11
- 208000037803 restenosis Diseases 0.000 abstract description 9
- 210000003038 endothelium Anatomy 0.000 abstract description 8
- 210000000130 stem cell Anatomy 0.000 abstract description 6
- 208000007536 Thrombosis Diseases 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 210000004027 cell Anatomy 0.000 abstract description 3
- 230000005764 inhibitory process Effects 0.000 abstract description 3
- 230000035755 proliferation Effects 0.000 abstract description 2
- 229920001222 biopolymer Polymers 0.000 abstract 1
- 239000012528 membrane Substances 0.000 abstract 1
- 230000005012 migration Effects 0.000 abstract 1
- 239000010935 stainless steel Substances 0.000 abstract 1
- 229910001220 stainless steel Inorganic materials 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 34
- 230000003511 endothelial effect Effects 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 210000001956 EPC Anatomy 0.000 description 3
- 238000013310 pig model Methods 0.000 description 3
- 108010047852 Integrin alphaVbeta3 Proteins 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 239000008366 buffered solution Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 206010025482 malaise Diseases 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 239000007769 metal material Substances 0.000 description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 description 2
- 238000013146 percutaneous coronary intervention Methods 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 210000003556 vascular endothelial cell Anatomy 0.000 description 2
- 102100031573 Hematopoietic progenitor cell antigen CD34 Human genes 0.000 description 1
- 101000777663 Homo sapiens Hematopoietic progenitor cell antigen CD34 Proteins 0.000 description 1
- 206010020880 Hypertrophy Diseases 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000002586 coronary angiography Methods 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 210000003725 endotheliocyte Anatomy 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 230000003463 hyperproliferative effect Effects 0.000 description 1
- 108010044426 integrins Proteins 0.000 description 1
- 102000006495 integrins Human genes 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 210000004026 tunica intima Anatomy 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Images
Landscapes
- Materials For Medical Uses (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention relates to a biologic polypeptide medicine blood vessel support and a preparation method thereof. The biologic polypeptide medicine blood vessel support comprises a support body and active medicines. The support body which is medical material with pores and good biocompatibility is made from stainless steel, cobalt-base alloy, titanium alloy, nickel-titanium alloy or polylactic acid biopolymer; the active medicines comprise a biologic polypeptide medicine and a smooth muscle cell proliferation inhibition medicine. The support is characterized in that: the support body with the pores has the biologic polypeptide medicine fixed on the internal surface of the body and the smooth muscle cell proliferation inhibition medicine coated on the external surface of the body. The preparation me(3) carrying out the after-treatment of the surface of the support body; (4) preparing the medicines; (5) coating the external surface; (6) fixing the medicine onto the internal surface; (7) carrying out the process step of low temperature drying. The support can selectively absorb endothelium progenitor cells which quickly differentiate into endothelium cells to promote the restoration of the endothelium after the support is built in; the support can also effectively inhibit the proliferation and migration of vascular smooth muscle cells, persistently and effectively reduce the formation of a new inner membrane, effectively prevent restenosis inside the support, and avoid the risk of potentially fatal late thrombosis.
Description
Technical field
The invention belongs to medical instruments field, relate to a kind of biological polypeptide medicament intravascular stent and preparation method thereof.
Background technology
From 1987, uncommon lattice water (Sigwart) etc. has been used for metal rack in the blood vessel since the coronary artery first, for treatment blood vessel blockage disease provides good approach, yet restenosis is the main cause that influences percutaneous coronary intervention (pci) (PCI) curative effect always in the intravascular stent.The main mechanism of restenosis is the delay of the hypertrophy and the blood vessel endotheliumization of tunica intima in the intravascular stent, and therefore, the control in-stent restenosis mainly is the quick reparation that promotes blood vessel endothelium, suppresses the hyper-proliferative of smooth muscle cell.
The extensive use of bracket for eluting medicament has significantly reduced the generation of restenosis in the intravascular stent, though bracket for eluting medicament can effectively suppress the propagation of smooth muscle cell, reduces and the prevention neointimal hyperplasia, has postponed the reparation of blood vessel endothelium; Though CD34 antibody engineering support can be according to Ag-Ab binding isotherm capturing endothelial ancestral cell in blood vessel, at the quick endothelialization in intravascular stent surface, the specificity of ignoring smooth muscle cell suppresses.Therefore, preparation is endothelialization and do not influence smooth muscle cell proliferation fast, even the drug stent that can suppress smooth muscle cell proliferation to a certain extent has great importance for the sickness rate of further reduction thrombosis and in-stent restenosis.
Summary of the invention
The objective of the invention is to address the above problem and a kind of biological polypeptide medicament intravascular stent and preparation method thereof is provided, adopt the intravascular stent inner surface fixed biologically polypeptide in hole with holes, this biological polypeptide can the more seizure endothelial progenitor cells of the bonded mode of receptors ligand (EPCs), can after inserting, support be divided into endotheliocyte fast, promote the reparation of endothelium, and increase the biocompatibility of support inner surface; Apply inhibition smooth muscle cell proliferation medicine at rack outer surface, can effectively reduce the formation of thrombosis and the sickness rate of in-stent restenosis by the propagation that suppresses smooth muscle cell.
The technical solution used in the present invention: a kind of biological polypeptide medicament intravascular stent, comprise rack body, active medicine, its rack body is the medical material with good biocompatibility in hole with holes, selects rustless steel, cobalt-base alloys, titanium alloy, Nitinol or polylactic acid bioabsorbable polymer material for use; Active medicine comprises biological polypeptide medicine, anti-smooth muscle cell proliferation medicine; The described rack body inner surface that has hole is fixed with the biological polypeptide medicine, and outer surface is coated with anti-smooth muscle cell proliferation medicine.
A kind of preparation method of biological polypeptide medicament intravascular stent, at first rack body is prepared a large amount of holes by chemistry or physical method, or form the coating in one deck hole with holes at rack surface, then at the rack body inner surface embedding in hole with holes, fixing and coating, dip-coating RGD biological polypeptide medicine, again in the outer surface embedding of rack body, fixing and be coated with the active medicine that one or more can suppress vascular smooth muscle cell proliferation and migration.
Described polypeptide drugs are dissolved in the phosphate buffer, directly are fixed in the hole of rack body inner surface; Described anti-smooth muscle cell proliferation medicine directly is dissolved in the organic solvent or is sprayed at the rack body outer surface by the polymer of biodegradable polymer, degradable biological macromolecular material not.
Described preparation method comprise the pretreatment on 1. rack body surface, 2. prepare hole, 3. the rack body surface post processing, 4. medicine preparation, 5. outer surface apply, 6. inner surface fix, 7. low temperature drying technology step, wherein:
1. the pretreatment on rack body surface: working concentration is 99.5% acetone analytical pure solution, or concentration is 75% medical ethanol solvent, utilizing frequency is 28～100khz ultrasonic waves for cleaning rack body material, clean 5～15min, remove the impurity on bulk material surface, bulk material after cleaning is placed in the drying machine, and temperature is set in 30～40 ℃, takes out standby behind dry 30～60min;
2. prepare hole: be to adopt acid solution corrosion pore, the rack body material is immersed in the corrosive liquid of 0～100 ℃ of temperature, described corrosive liquid preferred concentration is 1～38% hydrochloric acid, or containing the hydrochloric acid mixed acid solution of the sulphuric acid composition of 1～38% mixed in hydrochloric acid 1～98%, etching time forms single size nanoscale hole after being controlled at 1min～480h according to concentration, temperature difference; The method that adopts anodic oxidation or differential arc oxidation, differential of the arc nitrogenize to combine again, carry out the compound hole of nanoscale that anodic oxidation prepares many sizes by anodic pulse equipment, its electrolyte preferred concentration is that 1～38% hydrochloric acid solution or concentration are 1～98% sulfuric acid solution, time 1～20min, electric current 0.01～0.1A, 25～3000 hertz of frequencies;
3. the post processing on rack body surface: the bulk material elder generation working concentration of handling well above-mentioned is 99.5% acetone analytical pure solution, and utilizing frequency through distilled water again is 28～100khz ultrasonic waves for cleaning bulk material, 5～15min; Bulk material after will cleaning at last is placed in the drying machine, and temperature is set in 30～40 ℃, takes out standby behind dry 30～60min; Or be 1～38% hydrochloric acid solution with the distilled water compound concentration, bulk material is immersed in the solution for preparing, be placed in the vacuum drying oven, solidified in 0.5～72 hour 20～100 ℃ of dryings;
4. the preparation of medicine: the be weight percentage RGD biological polypeptide medicine of 0.01-10% of formulation content; The medicine of anti-smooth muscle cell proliferation is an organic solution, and organic solution can be selected 0.2～5% oxolane or acetone for use, this medicine directly is dissolved in the organic solvent, and fully dissolving; The percentage by weight of described active medicine and organic solution is 1: 10～1: 10000;
5. outer surface applies the medicine of anti-smooth muscle cell proliferation: rack body is installed on the flush coater, adopts sacculus protective cradle inner surface, then the above-mentioned active medicine for preparing or polymer dispersion liquid are coated in uniformly the outer surface of rack body; Rack body with coating is put in the vacuum drying oven again, solidifies in 0.5～72 hour 20～100 ℃ of dryings;
The pretreatment on above-mentioned 1. rack body surface, 3. the rack body surface post processing, 5. the outer surface coating step can repeatedly repeat, or only repeat 5. outer surface coating step, the polymer dispersion liquid of repetitive coatings active medicine or different component is until reaching drug loading;
6. the fixing RGD biological polypeptide medicine that promotes endothelial cell growth of inner surface: take off the protectiveness sacculus, with the rack body dip-coating of band coating in content is weight percentage the solution of RGD biological polypeptide medicine of 0.01-10% 0.5～2 hour;
7. cold drying: rack body is taken out low temperature-20～-60 ℃ drying from the RGD drug solution.
Described rack body inner surface fixed biological polypeptide pharmaceutical pack vinculum polypeptide and annular polypeptide, wherein linear polypeptide comprises arginine-glycine-aspartic acid (RGD), glycine-arginine-glycine-aspartic acid (GRGD), arginine-glycine-aspartic acid-serine (RGDS), glycine-arginine-glycine-aspartic acid-serine (GRGDS), glycine-arginine-glycine-aspartic acid-serine-network propylhomoserin (GRGDSY), glycine-arginine-glycine-aspartic acid-serine-proline-cysteine (GRGDSPC) can be selected wherein any for use or appoint several; Wherein annular polypeptide comprises ARG-GLY-ASP-PHE-D-VAL cyclic peptide (cyclo-RGDFV), aspartic acid-phenylalanine-lysine-arginine-glycine-aspartic acid cyclic peptide (cyclo-DFKRGD), arginine-glycine-aspartic acid-serine-Ala-Ala cyclic peptide (cyclo-RGD-SAA), penicillamine cyclic peptide (cyclo-GpenGRGDSPCA) can be selected wherein any for use or appoint several.
The anti-smooth muscle cell proliferation medicine that described rack body outer surface applies comprises sirolimus, tacrolimus, Ai Luomosi, immunosuppressant ABT-578, dexamethasone, mizoribine, rapamycin, paclitaxel and derivant thereof, D actinomycin D, vincristine and derivant thereof, statins, 2-chlorine Deoxyadenosine, ribozyme, batimastat, Halofuginone, C-protease inhibitor, probucol, VEGF (VEGF), the estradiol class can be selected wherein any for use or appoint several.
The described biodegradable polymer or the polymer of biodegradable polymer not comprise the homopolymer of lactide, Acetic acid, hydroxy-, bimol. cyclic ester, 6-caprolactone and between the two or in three's copolymer, cellulose family, polyvidon, polyvinyl alcohol, arabic gum, sodium alginate, gelatin, polymethyl methacrylate, polybutyl methacrylate, ethylene-vinyl alcohol copolymer or the ethylene-vinyl acetate copolymer one or more.
Carry out 8. the effectiveness experiment after the described 7. low temperature drying technology step, 9. release in vitro is measured.
The present invention has following actively useful effect:
1. adopt and prepare the nanoscale hole at rack body, by the control hole degree of depth and fixed size polypeptide drugs and the effectively release of the anti-smooth muscle proliferation medicine of control, this nanoscale hole is to the not influence of the mechanical performance of instrument body, proved by animal experiment that its safety and effectiveness all are not less than even a little more than existing polymeric medicine eluting instrument;
2. at fixing arginine-glycine-aspartic acid (RGD) polypeptide drugs of support inner surface, utilize the special capturing endothelial ancestral cell of the bonded mode of integrin receptor (EPCs) of arginine-glycine-aspartic acid (RGD) polypeptide and endothelial progenitor cells, promote quick differentiation and the propagation of endothelial progenitor cells at rack surface, integrin alpha v beta 3 receptor and α 5 β1Shou Tis had bigger affinity, especially arginine-glycine-aspartic acid (RGD) cyclic peptide and the trim penicillamine cyclic peptide (cyclo-GpenGRGDSPCA) thereof that the integrin alpha v beta 3 receptor are had bigger affinity than α 5 β1Shou Tis, not only can pass through the more seizure endothelial progenitor cells of the bonded mode of receptors ligand (EPCs), make it be divided into vascular endothelial cell fast at rack surface, promote the reparation of blood vessel endothelium, and the propagation of smooth muscle cell is not influenced;
3. arginine-glycine-aspartic acid (RGD) polypeptide drugs are fixed on the support inner surface that is formed with the metal hole, utilize effectively fixedly arginine-glycine-aspartic acid (RGD) polypeptide drugs of the size of hole and the degree of depth;
4. apply arginine-glycine-aspartic acid (RGD) polypeptide drugs at same support inner surface, the outer surface coating effectively suppresses one or more of smooth muscle cell proliferation active medicine, effectively suppresses vascular smooth muscle cell proliferation and migration; Animal experiment shows that the present invention optionally adsorbs endothelial progenitor cells and vascular endothelial cell, and support can be repaired endothelium fast in 1 day, and can continuous and effective reduces the formation of new intima, effectively prevents and treats in-stent restenosis, avoids the risk of tardy property thrombosis.
Description of drawings
Fig. 1 is the cross section view of biological polypeptide medicament intravascular stent structural representation of the present invention;
Fig. 2 is the rack body vertical view in hole with holes of the present invention.
The specific embodiment
Consult Fig. 1, shown in Figure 2, a kind of biological polypeptide medicament intravascular stent mainly comprises rack body 1, active medicine 2 etc.; Its rack body 1 can be selected metal materials such as rustless steel, cobalt-base alloys, titanium alloy, Nitinol for use by the medical material manufacturing with good biocompatibility, and described active medicine 2 comprises biological polypeptide medicine 201, anti-smooth muscle cell proliferation medicine 202.The present invention is at fixing arginine-glycine-aspartic acid (RGD) the biological polypeptide medicine 201 of rack body 1 inner surface in hole 101 with holes, is coated with anti-smooth muscle cell proliferation medicine 202 at the outer surface of rack body 1.
A kind of preparation method of biological polypeptide medicament intravascular stent, at first by chemistry or physics, as the combination of method such as burn into anodic oxidation, differential arc oxidation, differential of the arc nitrogenize or these methods to a large amount of hole 101 of rack body 1 preparation, or form the coating in one deck hole 101 with holes at rack surface, rack body is by the medical material manufacturing with good biocompatibility, can select metal materials such as rustless steel, cobalt-base alloys, titanium alloy, Nitinol for use, also can select the bioabsorbable polymer material of polylactic acid for use; Adopt special process protective cradle inner surface then, the hole that reserves the support inner surface is so that the fixed biologically polypeptide, while is in the outer surface embedding of rack body 1, fix and be coated with one or more active medicines that can suppress vascular smooth muscle cell proliferation and migration 202, as the mixture of arginine-glycine-aspartic acid (RGD) biological polypeptide medicine, described anti-smooth muscle cell proliferation medicine 202 can directly be dissolved in the organic solvent or by biodegradable polymer not, the polymer of degradable biological macromolecular material is sprayed at rack body 1 outer surface; Adopt different coating processes at the rack body 1 inner surface embedding in hole 101 with holes, fixing RGD biological polypeptide medicine 201 at last, as penicillamine cyclic peptide (cyclo-GpenGRGDSPCA), described polypeptide drugs 201 may be dissolved in the phosphate buffer, directly are coated in the hole 101 of rack body 1 inner surface; The fixed biological polypeptide medicine 201 of described rack body 1 inner surface comprises linear polypeptide and annular polypeptide, wherein linear polypeptide comprises arginine-glycine-aspartic acid (RGD), glycine-arginine-glycine-aspartic acid (GRGD), arginine-glycine-aspartic acid-serine (RGDS), glycine-arginine-glycine-aspartic acid-serine (GRGDS), glycine-arginine-glycine-aspartic acid-serine-network propylhomoserin (GRGDSY), glycine-arginine-glycine-aspartic acid-serine-proline-cysteine (GRGDSPC) isoreactivity medicine 2 can be selected wherein any for use or appoint several; Wherein annular polypeptide comprises ARG-GLY-ASP-PHE-D-VAL cyclic peptide (cyclo-RGDFV), aspartic acid-phenylalanine-lysine-arginine-glycine-aspartic acid cyclic peptide (cyclo-DFKRGD), arginine-glycine-aspartic acid-serine-Ala-Ala cyclic peptide (cyclo-RGD-SAA), penicillamine cyclic peptide (cyclo-GpenGRGDSPCA) isoreactivity medicine 2 can be selected wherein any for use or appoint several.
The anti-smooth muscle cell proliferation medicine 202 that described rack body 1 outer surface applies comprises sirolimus, tacrolimus, Ai Luomosi, immunosuppressant ABT-578, dexamethasone, mizoribine, rapamycin, paclitaxel and derivant thereof, D actinomycin D, vincristine and derivant thereof, statins, 2-chlorine Deoxyadenosine, ribozyme, batimastat, Halofuginone, C-protease inhibitor, probucol, VEGF (VEGF), estradiol class isoreactivity medicine 2 can be selected wherein any for use or appoint several.
The described biodegradable polymer or the polymer of biodegradable polymer not comprise the homopolymer of lactide, Acetic acid, hydroxy-, bimol. cyclic ester, 6-caprolactone and between the two or in three's copolymer, cellulose family, polyvidon, polyvinyl alcohol, arabic gum, sodium alginate, gelatin, polymethyl methacrylate, polybutyl methacrylate, ethylene-vinyl alcohol copolymer or the ethylene-vinyl acetate copolymer one or more.
Described preparation method mainly comprise the pretreatment on 1. rack body surface, 2. prepare hole, 3. the rack body surface post processing, 4. medicine preparation, 5. outer surface apply, 6. inner surface fix, 7. processing step such as cold drying, wherein:
1. the pretreatment on rack body surface: select the rustless steel bare bracket for use, working concentration is 99.5% acetone analytical pure solution, or concentration is 75% medical ethanol solvent, utilizing frequency is 28～100khz ultrasonic waves for cleaning rack body material, clean 5～15min, remove the impurity on bulk material surface, the bulk material after cleaning is placed in the drying machine, temperature is set in 30～40 ℃, takes out standby behind dry 30～60min;
2. prepare hole: adopting acid solution corrosion pore is that the rack body material is immersed in the corrosive liquid of 0～100 ℃ of temperature, described corrosive liquid preferred concentration is 1～38% hydrochloric acid, or containing the hydrochloric acid mixed acid solution of the sulphuric acid composition of 1～38% mixed in hydrochloric acid 1～98%, etching time forms single size nanoscale hole after being controlled at 1min～480h according to concentration, temperature difference; The method that adopts anodic oxidation or differential arc oxidation, differential of the arc nitrogenize to combine again, carry out the compound hole of nanoscale that anodic oxidation prepares many sizes by anodic pulse equipment, its electrolyte preferred concentration is that 1～38% hydrochloric acid solution or concentration are 1～98% sulfuric acid solution, time 1～20min, electric current 0.01～0.1A, 25～3000 hertz of frequencies;
3. the post processing on rack body surface: the bulk material elder generation working concentration of handling well above-mentioned is 99.5% acetone analytical pure solution, and utilizing frequency through distilled water again is 28～100khz ultrasonic waves for cleaning bulk material, 5～15min; Bulk material after will cleaning at last is placed in the drying machine, and temperature is set in 30～40 ℃, takes out standby behind dry 30～60min; Or be 1～38% hydrochloric acid solution with the distilled water compound concentration, bulk material is immersed in the solution for preparing, be placed in the vacuum drying oven, solidified in 0.5～72 hour 20～100 ℃ of dryings;
4. the preparation of medicine: the be weight percentage RGD biological polypeptide medicine 201 of 0.01-10% of formulation content; The medicine 202 of anti-smooth muscle cell proliferation is an organic solution, and organic solution can be selected 0.2～5% oxolane or acetone for use, this medicine directly is dissolved in the organic solvent, and fully dissolving; The percentage by weight of described active medicine and organic solution is 1: 10～1: 10000;
5. outer surface applies the medicine of anti-smooth muscle cell proliferation: bulk material is installed on the flush coater, adopts sacculus protective cradle inner surface, then the above-mentioned active medicine for preparing or polymer dispersion liquid are coated in uniformly the outer surface of rack body; Rack body with coating is put in the vacuum drying oven again, solidifies in 0.5～72 hour 20～100 ℃ of dryings;
The pretreatment on above-mentioned 1. rack body surface, 3. the rack body surface post processing, 5. the outer surface coating step can repeatedly repeat, or only repeat 5. outer surface coating step, the polymer dispersion liquid of repetitive coatings active medicine or different component is until reaching drug loading;
6. the fixing RGD biological polypeptide medicine that promotes endothelial cell growth of inner surface: carefully take off the protectiveness sacculus, with the rack body dip-coating of band coating in content is weight percentage the solution of RGD biological polypeptide medicine 201 of anti-smooth muscle cell proliferation of 0.01-10% 0.5～2 hour;
7. cold drying: rack body is taken out low temperature-20～-60 ℃ drying from the RGD drug solution.
Below provide preferred embodiment:
Present embodiment is coated with the anti-smooth muscle cell proliferation medicine 202 of rapamycin at fixing arginine-glycine-aspartic acid (RGD) polypeptide drugs 201 of rack body 1 inner surface that has hole 101 at rack body 1 outer surface;
1. the pretreatment on rack body surface, 2. prepare hole, 3. the aftertreatment technology step on rack body surface is ditto described;
4. the preparation of medicine: the 0.2g rapamycin is added in the 10ml tetrahydrofuran solution;
5. outer surface applies: with the pertusate rack body inner surface of sacculus boundary belt, and be uniformly dispersed under the medicine room temperature condition with above-mentioned preparation, be sprayed at rack outer surface, air set 60min then; Repeat 5. outer surface coating step, reach 2.2 μ g/mm up to drug loading
2To prop up and be placed on drying in the vacuum drying oven;
6. inner surface is fixed: described biological polypeptide medicine 201 is selected 0.5g penicillamine cyclic peptide (cyclo-GpenGRGDSPCA) for use, be dissolved in the phosphate buffered solution, its proportioning percentage by weight is: potassium dihydrogen phosphate 1.36g, add 0.1mol/L sodium hydroxide solution 79ml, all the other are diluted to 200ml promptly for water, and the support after applying is immersed in the described penicillamine cyclic peptide solution 5min～2 hour;
7. cold drying: rack body is taken out low temperature-20～-60 ℃ lyophilizing from above-mentioned RGD drug solution;
8. effectiveness experiment: safety and effectiveness experiment to RGD biological polypeptide drug stent of the present invention are to carry out in Chinese Xiao Xiong's pig model, and experimental result comprises the change of the new intima area that is recorded by endothelialization observation, coronary angiography quantitative analysis (QCA) and tectology; In pig model, compare with the support of no medication coat, RGD biological polypeptide drug stent is inserted back 30 days new intima areas at support and is obviously reduced, and this shows, RGD biological polypeptide drug stent can continue to reduce new intima formation in pig model, prevents restenosis and thrombosis;
9. release in vitro is measured: it is to be placed in the extracorporeal circulation apparatus propping up that RGD biological polypeptide drug stent release in vitro of the present invention is measured, add a certain amount of, as the 4% bSA phosphate buffer 0.1mol/L of 500ml, pH 7.4, and keeping temperature is 37 ± 0.5 ℃; Change release medium weekly one time, at 6h, 1 day, 2 days, 7 days, 14 days and 30 days taking-up drug stents, analyze the residual volume of medicine in RGD biological polypeptide drug stent respectively with efficient liquid-phase chromatography method (HPLC).
Embodiment 2
1. the pretreatment on rack body surface, 2. prepare hole, 3. the aftertreatment technology step on rack body surface is ditto described;
4. the preparation of medicine: 0.1g polylactic acid (PLA) is added in the 10ml tetrahydrofuran solution, preparation biological polypeptide medicine 201, add the 0.5g rapamycin again, the mixed proportion of rapamycin and arginine-glycine-aspartic acid (RGD) polypeptide drugs is 0.1～10;
5. outer surface applies: with pertusate rack body 1 inner surface of sacculus boundary belt, and the medicine room temperature condition of above-mentioned preparation mixed down be uniformly dispersed, the polymer dispersion liquid that will be enclosed with said medicine then is coated on the outer surface of support, air set 30min equably; Repeat aforesaid operations and reach 2.5 μ g/mm up to drug-loaded layer weight
2Support 1 with coating places vacuum drying oven dry again;
6. inner surface is fixed: take by weighing 0.5g penicillamine cyclic peptide (cyclo-GpenGRGDSPCA), be dissolved in the phosphate buffered solution, its proportioning percentage by weight is: potassium dihydrogen phosphate 1.36g, add 0.1mol/L sodium hydroxide solution 79ml, all the other are diluted to 200ml promptly for water, and the support of spraying is immersed in the described penicillamine cyclic peptide solution 5min～2 hour;
Described 7. cold drying, 8. effectiveness experiment, 9. release in vitro is measured with embodiment 1.
Claims (8)
1. biological polypeptide medicament intravascular stent, comprise rack body, active medicine, its rack body is the medical material with good biocompatibility in hole with holes, selects rustless steel, cobalt-base alloys, titanium alloy, Nitinol or polylactic acid bioabsorbable polymer material for use; Active medicine comprises biological polypeptide medicine, anti-smooth muscle cell proliferation medicine; It is characterized in that described rack body (1) inner surface that has hole (101) is fixed with biological polypeptide medicine (201), outer surface is coated with anti-smooth muscle cell proliferation medicine (202); Wherein said hole (101) is the compound hole of nanoscale of many sizes; Described biological polypeptide medicine (201) is for containing the linear polypeptide and the annular polypeptide of arginine-glycine-aspartic acid.
2. the preparation method of a biological polypeptide medicament intravascular stent, at first rack body (1) is prepared a large amount of holes (101) by chemistry or physical method, or form the coating in one deck hole with holes (101) at rack surface, it is characterized in that, in the outer surface embedding of rack body (1), fixing and be coated with one or more active medicines that can suppress vascular smooth muscle cell proliferation and migration (202), then in rack body (1) the inner surface embedding of hole with holes (101), fix and coating, dip-coating RGD biological polypeptide medicine (201).
3. the preparation method of a kind of biological polypeptide medicament intravascular stent according to claim 2 is characterized in that described polypeptide drugs (201) are dissolved in the phosphate buffer, directly is fixed in the hole (101) of rack body (1) inner surface; Described anti-smooth muscle cell proliferation medicine (202) directly is dissolved in the organic solvent or is sprayed at rack body (1) outer surface by the polymer of biodegradable polymer, degradable biological macromolecular material not.
4. the preparation method of a kind of biological polypeptide medicament intravascular stent according to claim 2, it is characterized in that described preparation method comprise the pretreatment on 1. rack body surface, 2. prepare hole, 3. the rack body surface post processing, 4. medicine preparation, 5. outer surface apply, 6. inner surface fix, 7. low temperature drying technology step, wherein:
1. the pretreatment on rack body surface: working concentration is 99.5% acetone analytical pure solution, or concentration is 75% medical ethanol solvent, utilizing frequency is 28～100khz ultrasonic waves for cleaning rack body material, clean 5～15min, remove the impurity on bulk material surface, bulk material after cleaning is placed in the drying machine, and temperature is set in 30～40 ℃, takes out standby behind dry 30～60min;
2. prepare hole: be to adopt acid solution corrosion pore, the rack body material is immersed in the corrosive liquid of 0～100 ℃ of temperature, described corrosive liquid preferred concentration is 1～38% hydrochloric acid, or containing the hydrochloric acid mixed acid solution of the sulphuric acid composition of 1～38% mixed in hydrochloric acid 1～98%, etching time forms single size nanoscale hole after being controlled at 1min～480h according to concentration, temperature difference; The method that adopts anodic oxidation or differential arc oxidation, differential of the arc nitrogenize to combine again, carry out the compound hole of nanoscale that anodic oxidation prepares many sizes by anodic pulse equipment, its electrolyte preferred concentration is that 1～38% hydrochloric acid solution or concentration are 1～98% sulfuric acid solution, time 1～20min, electric current 0.01～0.1A, 25～3000 hertz of frequencies;
3. the post processing on rack body surface: the bulk material elder generation working concentration of handling well above-mentioned is 99.5% acetone analytical pure solution, and utilizing frequency through distilled water again is 28～100khz ultrasonic waves for cleaning bulk material, 5～15min; Bulk material after will cleaning at last is placed in the drying machine, and temperature is set in 30～40 ℃, takes out standby behind dry 30～60min; Or be 1～38% hydrochloric acid solution with the distilled water compound concentration, bulk material is immersed in the solution for preparing, be placed in the vacuum drying oven, solidified in 0.5～72 hour 20～100 ℃ of dryings;
4. the preparation of medicine: the be weight percentage RGD biological polypeptide medicine (201) of 0.01-10% of formulation content; The medicine of anti-smooth muscle cell proliferation is an organic solution, and organic solution can be selected 0.2～5% oxolane or acetone for use, this medicine directly is dissolved in the organic solvent, and fully dissolving; The percentage by weight of described active medicine and organic solution is 1: 10～1: 10000;
5. outer surface applies the medicine of anti-smooth muscle cell proliferation: rack body (1) is installed on the flush coater, adopts sacculus protective cradle inner surface, then the above-mentioned active medicine for preparing or polymer dispersion liquid are coated in uniformly the outer surface of rack body; Rack body (1) with coating is put in the vacuum drying oven again, solidifies in 0.5～72 hour 20～100 ℃ of dryings;
The pretreatment on above-mentioned 1. rack body surface, 3. the rack body surface post processing, 5. the outer surface coating step can repeatedly repeat, or only repeat 5. outer surface coating step, the polymer dispersion liquid of repetitive coatings active medicine or different component is until reaching drug loading;
6. the fixing RGD biological polypeptide medicine that promotes endothelial cell growth of inner surface: take off the protectiveness sacculus, with rack body (1) dip-coating of band coating in content is weight percentage the solution of RGD biological polypeptide medicine (201) of 0.01-10% 0.5～2 hour;
7. cold drying: rack body (1) is taken out low temperature-20～-60 ℃ drying from the RGD drug solution.
5. the preparation method of a kind of biological polypeptide medicament intravascular stent according to claim 2, it is characterized in that described rack body (1) the fixed biological polypeptide medicine of inner surface (201) comprises linear polypeptide and annular polypeptide, wherein linear polypeptide comprises arginine-glycine-aspartic acid (RGD), glycine-arginine-glycine-aspartic acid (GRGD), arginine-glycine-aspartic acid-serine (RGDS), glycine-arginine-glycine-aspartic acid-serine (GRGDS), glycine-arginine-glycine-aspartic acid-serine-network propylhomoserin (GRGDSY), glycine-arginine-glycine-aspartic acid-serine-proline-cysteine (GRGDSPC) can be selected wherein any for use or appoint several; Wherein annular polypeptide comprises ARG-GLY-ASP-PHE-D-VAL cyclic peptide (cyclo-RGDFV), aspartic acid-phenylalanine-lysine-arginine-glycine-aspartic acid cyclic peptide (cyclo-DFKRGD), arginine-glycine-aspartic acid-serine-Ala-Ala cyclic peptide (cyclo-RGD-SAA), penicillamine cyclic peptide (cyclo-GpenGRGDSPCA) can be selected wherein any for use or appoint several.
6. the preparation method of a kind of biological polypeptide medicament intravascular stent according to claim 2 is characterized in that the anti-smooth muscle cell proliferation medicine (202) that described rack body (1) outer surface applies comprises sirolimus, tacrolimus, Ai Luomosi, immunosuppressant ABT-578, dexamethasone, mizoribine, rapamycin, paclitaxel and derivant thereof, D actinomycin D, vincristine and derivant thereof, statins, 2-chlorine Deoxyadenosine, ribozyme, batimastat, Halofuginone, the C-protease inhibitor, probucol, VEGF (VEGF), the estradiol class can be selected wherein any for use or appoint several.
7. the preparation method of a kind of biological polypeptide medicament intravascular stent according to claim 2, it is characterized in that the described biodegradable polymer or the polymer of biodegradable polymer not, comprise the homopolymer of lactide, Acetic acid, hydroxy-, bimol. cyclic ester, 6-caprolactone and between the two or in three's copolymer, cellulose family, polyvidon, polyvinyl alcohol, arabic gum, sodium alginate, gelatin, polymethyl methacrylate, polybutyl methacrylate, ethylene-vinyl alcohol copolymer or the ethylene-vinyl acetate copolymer one or more.
8. the preparation method of a kind of biological polypeptide medicament intravascular stent according to claim 4 is characterized in that carrying out after the described 7. low temperature drying technology step 8. effectiveness experiment, 9. release in vitro is measured.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200710105816 CN101313873B (en) | 2007-05-31 | 2007-05-31 | Biology polypeptide medicament blood vessel bracket and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200710105816 CN101313873B (en) | 2007-05-31 | 2007-05-31 | Biology polypeptide medicament blood vessel bracket and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101313873A CN101313873A (en) | 2008-12-03 |
| CN101313873B true CN101313873B (en) | 2011-03-23 |
Family
ID=40105119
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200710105816 Active CN101313873B (en) | 2007-05-31 | 2007-05-31 | Biology polypeptide medicament blood vessel bracket and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101313873B (en) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101785718A (en) * | 2009-01-23 | 2010-07-28 | 微创医疗器械(上海)有限公司 | Biological peptide blood vessel stent |
| CN101548916B (en) * | 2009-05-08 | 2012-10-10 | 乐普（北京）医疗器械股份有限公司 | A medical equipment carrying extracellular matrix and its production method |
| JP5871790B2 (en) * | 2010-03-30 | 2016-03-01 | テルモ株式会社 | Stent |
| CN102727991B (en) * | 2011-04-08 | 2014-10-01 | 乐普（北京）医疗器械股份有限公司 | Method for carrying out loading, drug fixing and controlled release on medical device surface |
| CN102425000A (en) * | 2011-11-29 | 2012-04-25 | 哈尔滨工业大学 | Method for preparing biologically active titanium dioxide film on NiTi alloy surface |
| CN102579172A (en) * | 2012-02-15 | 2012-07-18 | 北京航空航天大学 | Drug-coating stent |
| EP3426700B1 (en) * | 2016-03-11 | 2021-12-15 | The Regents of the University of California | Engineered scaffolds for vascularized tissue repair |
| CN105816921A (en) * | 2016-04-20 | 2016-08-03 | 山东百多安医用材料改性工程技术中心 | Bionic vascular stent and preparation method thereof |
| CN109096366B (en) * | 2017-06-21 | 2021-09-10 | 中南大学 | RGD cyclopeptide coupled lipophilic cation spinosad derivative and preparation method and application thereof |
| CN111714706B (en) * | 2020-05-08 | 2023-04-28 | 领博生物科技(杭州)有限公司 | Vascular stent capable of promoting vascular cell proliferation and secreting extracellular matrix, preparation method of vascular stent and active artificial blood vessel |
| CN112336496A (en) * | 2020-11-19 | 2021-02-09 | 杭州云普医疗器械有限公司 | Medicine vein filter and manufacturing method thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN2753308Y (en) * | 2004-10-19 | 2006-01-25 | 哈尔滨医科大学 | Potassium channel paralyser medicine-coated intravascular stent |
| CN1244314C (en) * | 2002-12-25 | 2006-03-08 | 中国科学院金属研究所 | Coating preparing method for medicine coating cardiovascular stand |
| CN1870948A (en) * | 2003-02-26 | 2006-11-29 | 梅迪沃什有限公司 | Bioactive stents and methods for use thereof |
| CN1919353A (en) * | 2006-08-14 | 2007-02-28 | 董何彦 | Preparation method of metal support surface micro blind hole drug-loaded layer |
-
2007
- 2007-05-31 CN CN 200710105816 patent/CN101313873B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1244314C (en) * | 2002-12-25 | 2006-03-08 | 中国科学院金属研究所 | Coating preparing method for medicine coating cardiovascular stand |
| CN1870948A (en) * | 2003-02-26 | 2006-11-29 | 梅迪沃什有限公司 | Bioactive stents and methods for use thereof |
| CN2753308Y (en) * | 2004-10-19 | 2006-01-25 | 哈尔滨医科大学 | Potassium channel paralyser medicine-coated intravascular stent |
| CN1919353A (en) * | 2006-08-14 | 2007-02-28 | 董何彦 | Preparation method of metal support surface micro blind hole drug-loaded layer |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101313873A (en) | 2008-12-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101313873B (en) | Biology polypeptide medicament blood vessel bracket and preparation method thereof | |
| CN101327343B (en) | Compound medicament intravascular stent and preparation method thereof | |
| Sousa et al. | New frontiers in cardiology: drug-eluting stents: Part I | |
| Wessely | New drug-eluting stent concepts | |
| Nazneen et al. | Surface chemical and physical modification in stent technology for the treatment of coronary artery disease | |
| CN102228721A (en) | Degradable coronary stent and manufacturing method thereof | |
| CN103889475B (en) | Comprise the bioabsorbable stent of magnesium alloy | |
| CN101199873B (en) | Medicament elution instrument nanometer class colon washer machineole drug releasing structure and preparing method thereof | |
| Gong et al. | Heparin-immobilized polymers as non-inflammatory and non-thrombogenic coating materials for arsenic trioxide eluting stents | |
| CN104056307B (en) | A kind of development degradable polymer support and preparation method thereof | |
| CN101346156B (en) | Drug eluting stent with a biodegradable release layer attached with an electro-grafted primer coating | |
| EP2532373A1 (en) | Biocompatible device | |
| EP2762111A1 (en) | Interventional medical device and manufacturing method thereof | |
| WO2010081393A1 (en) | Medicament eluting apparatus with micro-hole structure capable of storing and releasing multiple medicines and preparation method | |
| JP2014530058A (en) | Intervention medical device and manufacturing method thereof | |
| CN107213512B (en) | Multifunctional small-caliber artificial blood vessel with staggered-time release double slow-release coatings and preparation method thereof | |
| CN101502696B (en) | Medical apparatus carrying gene and/or medicament and preparation method thereof | |
| CN107913119A (en) | A kind of interventional medical device and preparation method thereof | |
| CN107496998B (en) | Peripheral drug eluting stent and preparation and application thereof | |
| CN201006052Y (en) | Biological polypeptide blood vessel bracket | |
| CN108014379B (en) | Surface modification method for improving corrosion resistance of magnesium alloy intravascular stent | |
| Lee et al. | Promoting vascular healing using nanofibrous ticagrelor-eluting stents | |
| Ng et al. | In Vitro Evaluation of Cenderitide‐Eluting Stent I—An Antirestenosis and Proendothelization Approach | |
| JP5422999B2 (en) | Implant having a coating layer | |
| CN101601610B (en) | Novel biological antibody medical device and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C41 | Transfer of patent application or patent right or utility model | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20161009 Address after: 518054 Guangdong city of Shenzhen province Nanshan District Guangdong streets Changhong Technology Park Building Room 503 Patentee after: Lepu (Shenzhen) International Development Center Co.,Ltd. Address before: 102200, Beijing Changping science and Technology Park, super Road, No. 37 Patentee before: LEPU MEDICAL TECHNOLOGY (BEIJING) Co.,Ltd. |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20240208 Address after: No. 37, Chaoqian Road, Changping District, Beijing 102200 Patentee after: LEPU MEDICAL TECHNOLOGY (BEIJING) Co.,Ltd. Country or region after: China Address before: Room 503, Changhong Building, Science and Technology Park, Yuehai Street, Nanshan District, Shenzhen City, Guangdong Province, 518054 Patentee before: Lepu (Shenzhen) International Development Center Co.,Ltd. Country or region before: China |