WO2017117922A1 - 植入式器械 - Google Patents
植入式器械 Download PDFInfo
- Publication number
- WO2017117922A1 WO2017117922A1 PCT/CN2016/087291 CN2016087291W WO2017117922A1 WO 2017117922 A1 WO2017117922 A1 WO 2017117922A1 CN 2016087291 W CN2016087291 W CN 2016087291W WO 2017117922 A1 WO2017117922 A1 WO 2017117922A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- acid
- group
- stent
- zinc
- drug
- Prior art date
Links
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims abstract description 66
- 239000011701 zinc Substances 0.000 claims abstract description 66
- 229910052725 zinc Inorganic materials 0.000 claims abstract description 66
- 229940079593 drug Drugs 0.000 claims abstract description 39
- 239000003814 drug Substances 0.000 claims abstract description 39
- 229910001297 Zn alloy Inorganic materials 0.000 claims abstract description 21
- 239000000043 antiallergic agent Substances 0.000 claims abstract description 19
- 239000007943 implant Substances 0.000 claims abstract description 19
- 239000000758 substrate Substances 0.000 claims description 32
- -1 carbacetin Chemical compound 0.000 claims description 27
- 239000011248 coating agent Substances 0.000 claims description 18
- 238000000576 coating method Methods 0.000 claims description 18
- 239000008139 complexing agent Substances 0.000 claims description 18
- 210000004204 blood vessel Anatomy 0.000 claims description 16
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 claims description 14
- 229920006237 degradable polymer Polymers 0.000 claims description 13
- 239000003446 ligand Substances 0.000 claims description 13
- 239000000203 mixture Substances 0.000 claims description 10
- 229920000747 poly(lactic acid) Polymers 0.000 claims description 10
- 239000004626 polylactic acid Substances 0.000 claims description 10
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 claims description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 9
- 229960003957 dexamethasone Drugs 0.000 claims description 9
- 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 9
- 230000000399 orthopedic effect Effects 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 239000011159 matrix material Substances 0.000 claims description 8
- 239000000178 monomer Substances 0.000 claims description 8
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 7
- 229960000890 hydrocortisone Drugs 0.000 claims description 7
- ZKLPARSLTMPFCP-OAQYLSRUSA-N 2-[2-[4-[(R)-(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]ethoxy]acetic acid Chemical compound C1CN(CCOCC(=O)O)CCN1[C@@H](C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-OAQYLSRUSA-N 0.000 claims description 6
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 6
- FQISKWAFAHGMGT-SGJOWKDISA-M Methylprednisolone sodium succinate Chemical compound [Na+].C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)COC(=O)CCC([O-])=O)CC[C@H]21 FQISKWAFAHGMGT-SGJOWKDISA-M 0.000 claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- 229920000954 Polyglycolide Polymers 0.000 claims description 6
- 239000004793 Polystyrene Substances 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 6
- 229910052791 calcium Inorganic materials 0.000 claims description 6
- 239000011575 calcium Substances 0.000 claims description 6
- 235000001465 calcium Nutrition 0.000 claims description 6
- 229960001508 levocetirizine Drugs 0.000 claims description 6
- 229960004584 methylprednisolone Drugs 0.000 claims description 6
- 229920000515 polycarbonate Polymers 0.000 claims description 6
- 239000004417 polycarbonate Substances 0.000 claims description 6
- 239000004633 polyglycolic acid Substances 0.000 claims description 6
- 229920000642 polymer Polymers 0.000 claims description 6
- 229920002223 polystyrene Polymers 0.000 claims description 6
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Natural products OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 claims description 5
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 5
- 210000000988 bone and bone Anatomy 0.000 claims description 5
- SOYKEARSMXGVTM-UHFFFAOYSA-N chlorphenamine Chemical compound C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 SOYKEARSMXGVTM-UHFFFAOYSA-N 0.000 claims description 5
- 229960003291 chlorphenamine Drugs 0.000 claims description 5
- VILCJCGEZXAXTO-UHFFFAOYSA-N 2,2,2-tetramine Chemical compound NCCNCCNCCN VILCJCGEZXAXTO-UHFFFAOYSA-N 0.000 claims description 4
- 239000005725 8-Hydroxyquinoline Substances 0.000 claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 4
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 claims description 4
- RPNUMPOLZDHAAY-UHFFFAOYSA-N Diethylenetriamine Chemical compound NCCNCCN RPNUMPOLZDHAAY-UHFFFAOYSA-N 0.000 claims description 4
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 4
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 claims description 4
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical group C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 claims description 4
- 229920001577 copolymer Polymers 0.000 claims description 4
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 4
- 239000000174 gluconic acid Substances 0.000 claims description 4
- 235000012208 gluconic acid Nutrition 0.000 claims description 4
- 229960003540 oxyquinoline Drugs 0.000 claims description 4
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 4
- 229920001490 poly(butyl methacrylate) polymer Polymers 0.000 claims description 4
- 229920001610 polycaprolactone Polymers 0.000 claims description 4
- 239000004632 polycaprolactone Substances 0.000 claims description 4
- 229920002635 polyurethane Polymers 0.000 claims description 4
- 239000004814 polyurethane Substances 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- MCJGNVYPOGVAJF-UHFFFAOYSA-N quinolin-8-ol Chemical compound C1=CN=C2C(O)=CC=CC2=C1 MCJGNVYPOGVAJF-UHFFFAOYSA-N 0.000 claims description 4
- CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical group OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 3
- 239000004053 dental implant Substances 0.000 claims description 3
- WQABCVAJNWAXTE-UHFFFAOYSA-N dimercaprol Chemical compound OCC(S)CS WQABCVAJNWAXTE-UHFFFAOYSA-N 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 230000000968 intestinal effect Effects 0.000 claims description 3
- 125000000018 nitroso group Chemical group N(=O)* 0.000 claims description 3
- 229920003229 poly(methyl methacrylate) Polymers 0.000 claims description 3
- 229920001748 polybutylene Polymers 0.000 claims description 3
- 229920000921 polyethylene adipate Polymers 0.000 claims description 3
- 239000004926 polymethyl methacrylate Substances 0.000 claims description 3
- 229920000137 polyphosphoric acid Polymers 0.000 claims description 3
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 3
- 239000001577 tetrasodium phosphonato phosphate Substances 0.000 claims description 3
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 claims description 3
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 2
- WFNAKBGANONZEQ-UHFFFAOYSA-N 1-[(4-chlorophenyl)-phenylmethyl]-4-methylpiperazine Chemical compound C1CN(C)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 WFNAKBGANONZEQ-UHFFFAOYSA-N 0.000 claims description 2
- YXAOOTNFFAQIPZ-UHFFFAOYSA-N 1-nitrosonaphthalen-2-ol Chemical compound C1=CC=CC2=C(N=O)C(O)=CC=C21 YXAOOTNFFAQIPZ-UHFFFAOYSA-N 0.000 claims description 2
- WJFKNYWRSNBZNX-UHFFFAOYSA-N 10H-phenothiazine Chemical compound C1=CC=C2NC3=CC=CC=C3SC2=C1 WJFKNYWRSNBZNX-UHFFFAOYSA-N 0.000 claims description 2
- NBYLBWHHTUWMER-UHFFFAOYSA-N 2-Methylquinolin-8-ol Chemical compound C1=CC=C(O)C2=NC(C)=CC=C21 NBYLBWHHTUWMER-UHFFFAOYSA-N 0.000 claims description 2
- URDCARMUOSMFFI-UHFFFAOYSA-N 2-[2-[bis(carboxymethyl)amino]ethyl-(2-hydroxyethyl)amino]acetic acid Chemical compound OCCN(CC(O)=O)CCN(CC(O)=O)CC(O)=O URDCARMUOSMFFI-UHFFFAOYSA-N 0.000 claims description 2
- WXHLLJAMBQLULT-UHFFFAOYSA-N 2-[[6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl]amino]-n-(2-methyl-6-sulfanylphenyl)-1,3-thiazole-5-carboxamide;hydrate Chemical compound O.C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1S WXHLLJAMBQLULT-UHFFFAOYSA-N 0.000 claims description 2
- SPCKHVPPRJWQRZ-UHFFFAOYSA-N 2-benzhydryloxy-n,n-dimethylethanamine;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 SPCKHVPPRJWQRZ-UHFFFAOYSA-N 0.000 claims description 2
- ZPSJGADGUYYRKE-UHFFFAOYSA-N 2H-pyran-2-one Chemical compound O=C1C=CC=CO1 ZPSJGADGUYYRKE-UHFFFAOYSA-N 0.000 claims description 2
- BSYNRYMUTXBXSQ-FOQJRBATSA-N 59096-14-9 Chemical compound CC(=O)OC1=CC=CC=C1[14C](O)=O BSYNRYMUTXBXSQ-FOQJRBATSA-N 0.000 claims description 2
- 239000004114 Ammonium polyphosphate Substances 0.000 claims description 2
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical compound N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 claims description 2
- ZKLPARSLTMPFCP-UHFFFAOYSA-N Cetirizine Chemical compound C1CN(CCOCC(=O)O)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-UHFFFAOYSA-N 0.000 claims description 2
- 108090000317 Chymotrypsin Proteins 0.000 claims description 2
- FCKYPQBAHLOOJQ-UHFFFAOYSA-N Cyclohexane-1,2-diaminetetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)C1CCCCC1N(CC(O)=O)CC(O)=O FCKYPQBAHLOOJQ-UHFFFAOYSA-N 0.000 claims description 2
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 2
- TZXKOCQBRNJULO-UHFFFAOYSA-N Ferriprox Chemical compound CC1=C(O)C(=O)C=CN1C TZXKOCQBRNJULO-UHFFFAOYSA-N 0.000 claims description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 2
- 102000001554 Hemoglobins Human genes 0.000 claims description 2
- 108010054147 Hemoglobins Proteins 0.000 claims description 2
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 2
- PWWVAXIEGOYWEE-UHFFFAOYSA-N Isophenergan Chemical compound C1=CC=C2N(CC(C)N(C)C)C3=CC=CC=C3SC2=C1 PWWVAXIEGOYWEE-UHFFFAOYSA-N 0.000 claims description 2
- ZCVMWBYGMWKGHF-UHFFFAOYSA-N Ketotifene Chemical compound C1CN(C)CCC1=C1C2=CC=CC=C2CC(=O)C2=C1C=CS2 ZCVMWBYGMWKGHF-UHFFFAOYSA-N 0.000 claims description 2
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 claims description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 2
- 239000004472 Lysine Substances 0.000 claims description 2
- OCJYIGYOJCODJL-UHFFFAOYSA-N Meclizine Chemical compound CC1=CC=CC(CN2CCN(CC2)C(C=2C=CC=CC=2)C=2C=CC(Cl)=CC=2)=C1 OCJYIGYOJCODJL-UHFFFAOYSA-N 0.000 claims description 2
- HOKDBMAJZXIPGC-UHFFFAOYSA-N Mequitazine Chemical compound C12=CC=CC=C2SC2=CC=CC=C2N1CC1C(CC2)CCN2C1 HOKDBMAJZXIPGC-UHFFFAOYSA-N 0.000 claims description 2
- VQENOYXMFIFHCY-UHFFFAOYSA-N Monoglyceride citrate Chemical compound OCC(O)COC(=O)CC(O)(C(O)=O)CC(O)=O VQENOYXMFIFHCY-UHFFFAOYSA-N 0.000 claims description 2
- UCHDWCPVSPXUMX-TZIWLTJVSA-N Montelukast Chemical compound CC(C)(O)C1=CC=CC=C1CC[C@H](C=1C=C(\C=C\C=2N=C3C=C(Cl)C=CC3=CC=2)C=CC=1)SCC1(CC(O)=O)CC1 UCHDWCPVSPXUMX-TZIWLTJVSA-N 0.000 claims description 2
- JAUOIFJMECXRGI-UHFFFAOYSA-N Neoclaritin Chemical compound C=1C(Cl)=CC=C2C=1CCC1=CC=CN=C1C2=C1CCNCC1 JAUOIFJMECXRGI-UHFFFAOYSA-N 0.000 claims description 2
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 claims description 2
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 claims description 2
- 229920002732 Polyanhydride Polymers 0.000 claims description 2
- 229920000805 Polyaspartic acid Polymers 0.000 claims description 2
- 108010020346 Polyglutamic Acid Proteins 0.000 claims description 2
- 108010039918 Polylysine Proteins 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 2
- VOLMSPGWNYJHQQ-UHFFFAOYSA-N Pyranone Natural products CC1=C(O)C(=O)C(O)CO1 VOLMSPGWNYJHQQ-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- 229930003268 Vitamin C Natural products 0.000 claims description 2
- YEEZWCHGZNKEEK-UHFFFAOYSA-N Zafirlukast Chemical compound COC1=CC(C(=O)NS(=O)(=O)C=2C(=CC=CC=2)C)=CC=C1CC(C1=C2)=CN(C)C1=CC=C2NC(=O)OC1CCCC1 YEEZWCHGZNKEEK-UHFFFAOYSA-N 0.000 claims description 2
- MNZHBXZOPHQGMD-UHFFFAOYSA-N acetic acid;azane Chemical compound N.CC(O)=O.CC(O)=O.CC(O)=O MNZHBXZOPHQGMD-UHFFFAOYSA-N 0.000 claims description 2
- 150000008065 acid anhydrides Chemical class 0.000 claims description 2
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 claims description 2
- 239000000783 alginic acid Substances 0.000 claims description 2
- 235000010443 alginic acid Nutrition 0.000 claims description 2
- 229920000615 alginic acid Polymers 0.000 claims description 2
- 229960001126 alginic acid Drugs 0.000 claims description 2
- 150000004781 alginic acids Chemical class 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- 229910021529 ammonia Inorganic materials 0.000 claims description 2
- 235000019826 ammonium polyphosphate Nutrition 0.000 claims description 2
- 229920001276 ammonium polyphosphate Polymers 0.000 claims description 2
- 230000001387 anti-histamine Effects 0.000 claims description 2
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 2
- 229940124599 anti-inflammatory drug Drugs 0.000 claims description 2
- 230000002590 anti-leukotriene effect Effects 0.000 claims description 2
- 230000001028 anti-proliverative effect Effects 0.000 claims description 2
- 239000000739 antihistaminic agent Substances 0.000 claims description 2
- 229940127218 antiplatelet drug Drugs 0.000 claims description 2
- 235000003704 aspartic acid Nutrition 0.000 claims description 2
- 229960005261 aspartic acid Drugs 0.000 claims description 2
- 229940120638 avastin Drugs 0.000 claims description 2
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 claims description 2
- 239000012965 benzophenone Substances 0.000 claims description 2
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims description 2
- 210000001124 body fluid Anatomy 0.000 claims description 2
- 239000010839 body fluid Substances 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 229960001803 cetirizine Drugs 0.000 claims description 2
- 229960004831 chlorcyclizine Drugs 0.000 claims description 2
- 229930002875 chlorophyll Natural products 0.000 claims description 2
- 235000019804 chlorophyll Nutrition 0.000 claims description 2
- ATNHDLDRLWWWCB-AENOIHSZSA-M chlorophyll a Chemical compound C1([C@@H](C(=O)OC)C(=O)C2=C3C)=C2N2C3=CC(C(CC)=C3C)=[N+]4C3=CC3=C(C=C)C(C)=C5N3[Mg-2]42[N+]2=C1[C@@H](CCC(=O)OC\C=C(/C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)[C@H](C)C2=C5 ATNHDLDRLWWWCB-AENOIHSZSA-M 0.000 claims description 2
- 229960002376 chymotrypsin Drugs 0.000 claims description 2
- 229960000265 cromoglicic acid Drugs 0.000 claims description 2
- IMZMKUWMOSJXDT-UHFFFAOYSA-N cromoglycic acid Chemical compound O1C(C(O)=O)=CC(=O)C2=C1C=CC=C2OCC(O)COC1=CC=CC2=C1C(=O)C=C(C(O)=O)O2 IMZMKUWMOSJXDT-UHFFFAOYSA-N 0.000 claims description 2
- 229960001140 cyproheptadine Drugs 0.000 claims description 2
- JJCFRYNCJDLXIK-UHFFFAOYSA-N cyproheptadine Chemical compound C1CN(C)CCC1=C1C2=CC=CC=C2C=CC2=CC=CC=C21 JJCFRYNCJDLXIK-UHFFFAOYSA-N 0.000 claims description 2
- 229960001271 desloratadine Drugs 0.000 claims description 2
- 229960000520 diphenhydramine Drugs 0.000 claims description 2
- XPPKVPWEQAFLFU-UHFFFAOYSA-N diphosphoric acid Chemical compound OP(O)(=O)OP(O)(O)=O XPPKVPWEQAFLFU-UHFFFAOYSA-N 0.000 claims description 2
- ODQWQRRAPPTVAG-GZTJUZNOSA-N doxepin Chemical compound C1OC2=CC=CC=C2C(=C/CCN(C)C)/C2=CC=CC=C21 ODQWQRRAPPTVAG-GZTJUZNOSA-N 0.000 claims description 2
- 229960005426 doxepin Drugs 0.000 claims description 2
- 229960001971 ebastine Drugs 0.000 claims description 2
- MJJALKDDGIKVBE-UHFFFAOYSA-N ebastine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(=O)CCCN1CCC(OC(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 MJJALKDDGIKVBE-UHFFFAOYSA-N 0.000 claims description 2
- 229960003592 fexofenadine Drugs 0.000 claims description 2
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 239000003862 glucocorticoid Substances 0.000 claims description 2
- 239000004220 glutamic acid Substances 0.000 claims description 2
- 235000013922 glutamic acid Nutrition 0.000 claims description 2
- 229960002989 glutamic acid Drugs 0.000 claims description 2
- 210000003630 histaminocyte Anatomy 0.000 claims description 2
- 229960004958 ketotifen Drugs 0.000 claims description 2
- 229960003088 loratadine Drugs 0.000 claims description 2
- JCCNYMKQOSZNPW-UHFFFAOYSA-N loratadine Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC(Cl)=CC=C21 JCCNYMKQOSZNPW-UHFFFAOYSA-N 0.000 claims description 2
- 229960003646 lysine Drugs 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 239000011976 maleic acid Substances 0.000 claims description 2
- 239000001630 malic acid Substances 0.000 claims description 2
- 235000011090 malic acid Nutrition 0.000 claims description 2
- 229960001474 meclozine Drugs 0.000 claims description 2
- 239000012528 membrane Substances 0.000 claims description 2
- 229960005042 mequitazine Drugs 0.000 claims description 2
- KNBBZGZVUYEUGI-UHFFFAOYSA-N methyl 5-methyl-2-sulfanylbenzoate Chemical compound COC(=O)C1=CC(C)=CC=C1S KNBBZGZVUYEUGI-UHFFFAOYSA-N 0.000 claims description 2
- 229960005127 montelukast Drugs 0.000 claims description 2
- 229960003104 ornithine Drugs 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- KHPXUQMNIQBQEV-UHFFFAOYSA-N oxaloacetic acid Chemical compound OC(=O)CC(=O)C(O)=O KHPXUQMNIQBQEV-UHFFFAOYSA-N 0.000 claims description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 2
- 229950000688 phenothiazine Drugs 0.000 claims description 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 2
- 229920000141 poly(maleic anhydride) Polymers 0.000 claims description 2
- 108010064470 polyaspartate Proteins 0.000 claims description 2
- 229920002643 polyglutamic acid Polymers 0.000 claims description 2
- 229920000656 polylysine Polymers 0.000 claims description 2
- 108010055896 polyornithine Proteins 0.000 claims description 2
- 229920002714 polyornithine Polymers 0.000 claims description 2
- 239000011148 porous material Substances 0.000 claims description 2
- RKCAIXNGYQCCAL-UHFFFAOYSA-N porphin Chemical compound N1C(C=C2N=C(C=C3NC(=C4)C=C3)C=C2)=CC=C1C=C1C=CC4=N1 RKCAIXNGYQCCAL-UHFFFAOYSA-N 0.000 claims description 2
- 150000004032 porphyrins Chemical class 0.000 claims description 2
- 239000001508 potassium citrate Substances 0.000 claims description 2
- 229960002635 potassium citrate Drugs 0.000 claims description 2
- QEEAPRPFLLJWCF-UHFFFAOYSA-K potassium citrate (anhydrous) Chemical compound [K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QEEAPRPFLLJWCF-UHFFFAOYSA-K 0.000 claims description 2
- 235000011082 potassium citrates Nutrition 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 229960003910 promethazine Drugs 0.000 claims description 2
- XXPDBLUZJRXNNZ-UHFFFAOYSA-N promethazine hydrochloride Chemical compound Cl.C1=CC=C2N(CC(C)N(C)C)C3=CC=CC=C3SC2=C1 XXPDBLUZJRXNNZ-UHFFFAOYSA-N 0.000 claims description 2
- 229960002244 promethazine hydrochloride Drugs 0.000 claims description 2
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 claims description 2
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 2
- 229940005657 pyrophosphoric acid Drugs 0.000 claims description 2
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 2
- MHTSJSRDFXZFHQ-UHFFFAOYSA-N quinoline-8-thiol Chemical compound C1=CN=C2C(S)=CC=CC2=C1 MHTSJSRDFXZFHQ-UHFFFAOYSA-N 0.000 claims description 2
- VMXUWOKSQNHOCA-LCYFTJDESA-N ranitidine Chemical compound [O-][N+](=O)/C=C(/NC)NCCSCC1=CC=C(CN(C)C)O1 VMXUWOKSQNHOCA-LCYFTJDESA-N 0.000 claims description 2
- 229960000620 ranitidine Drugs 0.000 claims description 2
- 208000037803 restenosis Diseases 0.000 claims description 2
- FQENQNTWSFEDLI-UHFFFAOYSA-J sodium diphosphate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]P([O-])(=O)OP([O-])([O-])=O FQENQNTWSFEDLI-UHFFFAOYSA-J 0.000 claims description 2
- NGSFWBMYFKHRBD-UHFFFAOYSA-M sodium lactate Chemical compound [Na+].CC(O)C([O-])=O NGSFWBMYFKHRBD-UHFFFAOYSA-M 0.000 claims description 2
- 229940048086 sodium pyrophosphate Drugs 0.000 claims description 2
- 239000003381 stabilizer Substances 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- 229960000351 terfenadine Drugs 0.000 claims description 2
- 235000019818 tetrasodium diphosphate Nutrition 0.000 claims description 2
- 125000000335 thiazolyl group Chemical group 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 2
- 150000003573 thiols Chemical class 0.000 claims description 2
- NZHGWWWHIYHZNX-CSKARUKUSA-N tranilast Chemical compound C1=C(OC)C(OC)=CC=C1\C=C\C(=O)NC1=CC=CC=C1C(O)=O NZHGWWWHIYHZNX-CSKARUKUSA-N 0.000 claims description 2
- 229960005342 tranilast Drugs 0.000 claims description 2
- 229960002117 triamcinolone acetonide Drugs 0.000 claims description 2
- YNDXUCZADRHECN-JNQJZLCISA-N triamcinolone acetonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O YNDXUCZADRHECN-JNQJZLCISA-N 0.000 claims description 2
- 125000001425 triazolyl group Chemical group 0.000 claims description 2
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 claims description 2
- 235000019154 vitamin C Nutrition 0.000 claims description 2
- 239000011718 vitamin C Substances 0.000 claims description 2
- 229960004764 zafirlukast Drugs 0.000 claims description 2
- MWLSOWXNZPKENC-SSDOTTSWSA-N zileuton Chemical compound C1=CC=C2SC([C@H](N(O)C(N)=O)C)=CC2=C1 MWLSOWXNZPKENC-SSDOTTSWSA-N 0.000 claims description 2
- 229960005332 zileuton Drugs 0.000 claims description 2
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 claims 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims 2
- BCHZICNRHXRCHY-UHFFFAOYSA-N 2h-oxazine Chemical compound N1OC=CC=C1 BCHZICNRHXRCHY-UHFFFAOYSA-N 0.000 claims 1
- LGDFHDKSYGVKDC-UHFFFAOYSA-N 8-hydroxyquinoline-5-sulfonic acid Chemical compound C1=CN=C2C(O)=CC=C(S(O)(=O)=O)C2=C1 LGDFHDKSYGVKDC-UHFFFAOYSA-N 0.000 claims 1
- MBUVEWMHONZEQD-UHFFFAOYSA-N Azeptin Chemical compound C1CN(C)CCCC1N1C(=O)C2=CC=CC=C2C(CC=2C=CC(Cl)=CC=2)=N1 MBUVEWMHONZEQD-UHFFFAOYSA-N 0.000 claims 1
- ACTIUHUUMQJHFO-UHFFFAOYSA-N Coenzym Q10 Natural products COC1=C(OC)C(=O)C(CC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UHFFFAOYSA-N 0.000 claims 1
- 206010013700 Drug hypersensitivity Diseases 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 1
- 229920000388 Polyphosphate Polymers 0.000 claims 1
- SKZKKFZAGNVIMN-UHFFFAOYSA-N Salicilamide Chemical compound NC(=O)C1=CC=CC=C1O SKZKKFZAGNVIMN-UHFFFAOYSA-N 0.000 claims 1
- ISWQCIVKKSOKNN-UHFFFAOYSA-L Tiron Chemical compound [Na+].[Na+].OC1=CC(S([O-])(=O)=O)=CC(S([O-])(=O)=O)=C1O ISWQCIVKKSOKNN-UHFFFAOYSA-L 0.000 claims 1
- HKOAEJZAELGZDN-UHFFFAOYSA-N [Na].N(=O)C1=C(C=CC2=CC=CC=C12)O Chemical compound [Na].N(=O)C1=C(C=CC2=CC=CC=C12)O HKOAEJZAELGZDN-UHFFFAOYSA-N 0.000 claims 1
- 239000003470 adrenal cortex hormone Substances 0.000 claims 1
- 150000001412 amines Chemical class 0.000 claims 1
- 229960000510 ammonia Drugs 0.000 claims 1
- GXDALQBWZGODGZ-UHFFFAOYSA-N astemizole Chemical compound C1=CC(OC)=CC=C1CCN1CCC(NC=2N(C3=CC=CC=C3N=2)CC=2C=CC(F)=CC=2)CC1 GXDALQBWZGODGZ-UHFFFAOYSA-N 0.000 claims 1
- 229960004574 azelastine Drugs 0.000 claims 1
- 229960005069 calcium Drugs 0.000 claims 1
- FNAQSUUGMSOBHW-UHFFFAOYSA-H calcium citrate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O FNAQSUUGMSOBHW-UHFFFAOYSA-H 0.000 claims 1
- 239000001354 calcium citrate Substances 0.000 claims 1
- 150000001735 carboxylic acids Chemical class 0.000 claims 1
- LLYOXZQVOKALCD-UHFFFAOYSA-N chembl1400298 Chemical compound OC1=CC=C2C=CC=CC2=C1N=NC1=CC=CC=N1 LLYOXZQVOKALCD-UHFFFAOYSA-N 0.000 claims 1
- 235000017471 coenzyme Q10 Nutrition 0.000 claims 1
- ACTIUHUUMQJHFO-UPTCCGCDSA-N coenzyme Q10 Chemical compound COC1=C(OC)C(=O)C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UPTCCGCDSA-N 0.000 claims 1
- 229940110767 coenzyme Q10 Drugs 0.000 claims 1
- RKHQGWMMUURILY-UHRZLXHJSA-N cortivazol Chemical compound C([C@H]1[C@@H]2C[C@H]([C@]([C@@]2(C)C[C@H](O)[C@@H]1[C@@]1(C)C2)(O)C(=O)COC(C)=O)C)=C(C)C1=CC1=C2C=NN1C1=CC=CC=C1 RKHQGWMMUURILY-UHRZLXHJSA-N 0.000 claims 1
- 229960002768 dipyridamole Drugs 0.000 claims 1
- IZEKFCXSFNUWAM-UHFFFAOYSA-N dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 claims 1
- 229960004679 doxorubicin Drugs 0.000 claims 1
- 201000005311 drug allergy Diseases 0.000 claims 1
- 235000019441 ethanol Nutrition 0.000 claims 1
- 125000002883 imidazolyl group Chemical group 0.000 claims 1
- 230000001900 immune effect Effects 0.000 claims 1
- 125000005956 isoquinolyl group Chemical group 0.000 claims 1
- 229920001083 polybutene Polymers 0.000 claims 1
- 125000005575 polycyclic aromatic hydrocarbon group Chemical group 0.000 claims 1
- 239000001205 polyphosphate Substances 0.000 claims 1
- 235000011176 polyphosphates Nutrition 0.000 claims 1
- 230000001105 regulatory effect Effects 0.000 claims 1
- 229960000581 salicylamide Drugs 0.000 claims 1
- 235000013337 tricalcium citrate Nutrition 0.000 claims 1
- 238000002513 implantation Methods 0.000 abstract description 7
- 238000006243 chemical reaction Methods 0.000 abstract description 3
- 210000000056 organ Anatomy 0.000 abstract description 3
- 206010020751 Hypersensitivity Diseases 0.000 abstract 1
- 230000002792 vascular Effects 0.000 description 102
- 210000001519 tissue Anatomy 0.000 description 74
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 description 23
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 22
- 230000001575 pathological effect Effects 0.000 description 22
- 210000004351 coronary vessel Anatomy 0.000 description 20
- 206010070834 Sensitisation Diseases 0.000 description 17
- 230000008313 sensitization Effects 0.000 description 17
- 210000003979 eosinophil Anatomy 0.000 description 11
- 229910052742 iron Inorganic materials 0.000 description 11
- 230000000052 comparative effect Effects 0.000 description 8
- 238000005260 corrosion Methods 0.000 description 8
- 230000007797 corrosion Effects 0.000 description 7
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 5
- KFZAUHNPPZCSCR-UHFFFAOYSA-N iron zinc Chemical compound [Fe].[Zn] KFZAUHNPPZCSCR-UHFFFAOYSA-N 0.000 description 5
- 239000011777 magnesium Substances 0.000 description 5
- 229910052749 magnesium Inorganic materials 0.000 description 5
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- 229950008885 polyglycolic acid Drugs 0.000 description 4
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 3
- PVLJETXTTWAYEW-UHFFFAOYSA-N Mizolastine Chemical compound N=1C=CC(=O)NC=1N(C)C(CC1)CCN1C1=NC2=CC=CC=C2N1CC1=CC=C(F)C=C1 PVLJETXTTWAYEW-UHFFFAOYSA-N 0.000 description 3
- 229960001138 acetylsalicylic acid Drugs 0.000 description 3
- 229910045601 alloy Inorganic materials 0.000 description 3
- 239000000956 alloy Substances 0.000 description 3
- 229910052802 copper Inorganic materials 0.000 description 3
- 239000010949 copper Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 229960001144 mizolastine Drugs 0.000 description 3
- 239000001509 sodium citrate Substances 0.000 description 3
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 3
- 229940038773 trisodium citrate Drugs 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 102000008186 Collagen Human genes 0.000 description 2
- 108010035532 Collagen Proteins 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 229920001436 collagen Polymers 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 230000001235 sensitizing effect Effects 0.000 description 2
- VUJRPZKTJSPGQY-UHFFFAOYSA-N 1,1-bis(sulfanyl)propan-1-ol Chemical class CCC(O)(S)S VUJRPZKTJSPGQY-UHFFFAOYSA-N 0.000 description 1
- SRQBBOGWWZWJCF-UHFFFAOYSA-N 10-ethylnonadecan-10-ol Chemical compound C(CCCCCCCC)C(CC)(O)CCCCCCCCC SRQBBOGWWZWJCF-UHFFFAOYSA-N 0.000 description 1
- KZQCCHPNAFUOAE-UHFFFAOYSA-N 3-carbamoyl-4-hydroxybenzenesulfonic acid Chemical compound NC(=O)C1=CC(S(O)(=O)=O)=CC=C1O KZQCCHPNAFUOAE-UHFFFAOYSA-N 0.000 description 1
- ISLHTVXEVCZNHS-UHFFFAOYSA-N 4,5-dihydroxybenzene-1,3-disulfonic acid;sodium Chemical compound [Na].OC1=CC(S(O)(=O)=O)=CC(S(O)(=O)=O)=C1O ISLHTVXEVCZNHS-UHFFFAOYSA-N 0.000 description 1
- 150000004325 8-hydroxyquinolines Chemical class 0.000 description 1
- 102000052866 Amino Acyl-tRNA Synthetases Human genes 0.000 description 1
- 108700028939 Amino Acyl-tRNA Synthetases Proteins 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- TWFZGCMQGLPBSX-UHFFFAOYSA-N Carbendazim Natural products C1=CC=C2NC(NC(=O)OC)=NC2=C1 TWFZGCMQGLPBSX-UHFFFAOYSA-N 0.000 description 1
- 102000055007 Cartilage Oligomeric Matrix Human genes 0.000 description 1
- 101710176668 Cartilage oligomeric matrix protein Proteins 0.000 description 1
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 1
- 229910000881 Cu alloy Inorganic materials 0.000 description 1
- 208000036828 Device occlusion Diseases 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- RKUNBYITZUJHSG-UHFFFAOYSA-N Hyosciamin-hydrochlorid Natural products CN1C(C2)CCC1CC2OC(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- 229910000861 Mg alloy Inorganic materials 0.000 description 1
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 1
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- XJIIVPNKKQIVGX-UHFFFAOYSA-N [Fe].[Cu].[Cu] Chemical compound [Fe].[Cu].[Cu] XJIIVPNKKQIVGX-UHFFFAOYSA-N 0.000 description 1
- HRZMCMIZSOGQJT-UHFFFAOYSA-N [Zn].[Mn].[Mg] Chemical compound [Zn].[Mn].[Mg] HRZMCMIZSOGQJT-UHFFFAOYSA-N 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000002009 allergenic effect Effects 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 229910052797 bismuth Inorganic materials 0.000 description 1
- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 description 1
- 230000008468 bone growth Effects 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- QXDHJHQRJCJRAU-UHFFFAOYSA-N calcium;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Ca].OC(=O)CC(O)(C(O)=O)CC(O)=O QXDHJHQRJCJRAU-UHFFFAOYSA-N 0.000 description 1
- JNPZQRQPIHJYNM-UHFFFAOYSA-N carbendazim Chemical compound C1=C[CH]C2=NC(NC(=O)OC)=NC2=C1 JNPZQRQPIHJYNM-UHFFFAOYSA-N 0.000 description 1
- 239000006013 carbendazim Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000000919 ceramic Substances 0.000 description 1
- XMLNCADGRIEXPK-KUMOIWDRSA-M chembl2146143 Chemical compound [Br-].O([C@H]1C[C@H]2CC[C@@H](C1)[N+]2(C)C)C(=O)C(CO)C1=CC=CC=C1 XMLNCADGRIEXPK-KUMOIWDRSA-M 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229910052804 chromium Inorganic materials 0.000 description 1
- 239000011651 chromium Substances 0.000 description 1
- 239000011247 coating layer Substances 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 239000005515 coenzyme Substances 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 229940115080 doxil Drugs 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 210000003038 endothelium Anatomy 0.000 description 1
- 229910052732 germanium Inorganic materials 0.000 description 1
- GNPVGFCGXDBREM-UHFFFAOYSA-N germanium atom Chemical compound [Ge] GNPVGFCGXDBREM-UHFFFAOYSA-N 0.000 description 1
- 229960004275 glycolic acid Drugs 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 description 1
- 239000007769 metal material Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 229910052750 molybdenum Inorganic materials 0.000 description 1
- 239000011733 molybdenum Substances 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 210000000963 osteoblast Anatomy 0.000 description 1
- 210000002997 osteoclast Anatomy 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000009038 pharmacological inhibition Effects 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229960003975 potassium Drugs 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 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 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 229960000329 ribavirin Drugs 0.000 description 1
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 1
- 229910052711 selenium Inorganic materials 0.000 description 1
- 239000011669 selenium Substances 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 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 description 1
- 229960002930 sirolimus Drugs 0.000 description 1
- GCLGEJMYGQKIIW-UHFFFAOYSA-H sodium hexametaphosphate Chemical compound [Na]OP1(=O)OP(=O)(O[Na])OP(=O)(O[Na])OP(=O)(O[Na])OP(=O)(O[Na])OP(=O)(O[Na])O1 GCLGEJMYGQKIIW-UHFFFAOYSA-H 0.000 description 1
- 235000019982 sodium hexametaphosphate Nutrition 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 231100000057 systemic toxicity Toxicity 0.000 description 1
- 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 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000701 toxic element Toxicity 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- LEONUFNNVUYDNQ-UHFFFAOYSA-N vanadium atom Chemical compound [V] LEONUFNNVUYDNQ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/02—Inorganic materials
- A61L27/04—Metals or alloys
- A61L27/047—Other specific metals or alloys not covered by A61L27/042 - A61L27/045 or A61L27/06
-
- 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
- A61L31/022—Metals or alloys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
- A61B17/56—Surgical instruments or methods for treatment of bones or joints; Devices specially adapted therefor
- A61B17/58—Surgical instruments or methods for treatment of bones or joints; Devices specially adapted therefor for osteosynthesis, e.g. bone plates, screws, setting implements or the like
- A61B17/68—Internal fixation devices, including fasteners and spinal fixators, even if a part thereof projects from the skin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K6/00—Preparations for dentistry
- A61K6/80—Preparations for artificial teeth, for filling teeth or for capping teeth
- A61K6/84—Preparations for artificial teeth, for filling teeth or for capping teeth comprising metals or alloys
-
- 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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
-
- 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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
- A61L27/42—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having an inorganic matrix
- A61L27/427—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having an inorganic matrix of other specific inorganic materials not covered by A61L27/422 or A61L27/425
-
- 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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/58—Materials at least partially resorbable by the body
-
- 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
- A61L31/148—Materials at least partially resorbable by the body
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
- C07F3/06—Zinc compounds
-
- C—CHEMISTRY; METALLURGY
- C22—METALLURGY; FERROUS OR NON-FERROUS ALLOYS; TREATMENT OF ALLOYS OR NON-FERROUS METALS
- C22C—ALLOYS
- C22C1/00—Making non-ferrous alloys
- C22C1/02—Making non-ferrous alloys by melting
-
- C—CHEMISTRY; METALLURGY
- C22—METALLURGY; FERROUS OR NON-FERROUS ALLOYS; TREATMENT OF ALLOYS OR NON-FERROUS METALS
- C22C—ALLOYS
- C22C18/00—Alloys based on zinc
-
- C—CHEMISTRY; METALLURGY
- C22—METALLURGY; FERROUS OR NON-FERROUS ALLOYS; TREATMENT OF ALLOYS OR NON-FERROUS METALS
- C22F—CHANGING THE PHYSICAL STRUCTURE OF NON-FERROUS METALS AND NON-FERROUS ALLOYS
- C22F1/00—Changing the physical structure of non-ferrous metals or alloys by heat treatment or by hot or cold working
- C22F1/16—Changing the physical structure of non-ferrous metals or alloys by heat treatment or by hot or cold working of other metals or alloys based thereon
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2002/823—Stents, different from stent-grafts, adapted to cover an aneurysm
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2220/00—Fixations or connections for prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
- A61F2220/0008—Fixation appliances for connecting prostheses to the body
- A61F2220/0016—Fixation appliances for connecting prostheses to the body with sharp anchoring protrusions, e.g. barbs, pins, spikes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2240/00—Manufacturing or designing of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
- A61F2240/001—Designing or manufacturing processes
-
- 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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/02—Inorganic materials
- A61L27/04—Metals or alloys
- A61L27/045—Cobalt or cobalt alloys
-
- 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
- A61L31/005—Ingredients of undetermined constitution or reaction products thereof
Definitions
- the invention belongs to the field of medical devices and relates to an implantable device.
- implantable medical devices are typically made from metals and their alloys, ceramics, polymers, and related composite materials. Among them, metal-based implantable medical devices are particularly favored for their superior mechanical properties such as high strength and high toughness.
- vascular stents are generally made of non-degradable metal.
- the disadvantage is that the metal is not degradable and cannot be removed, and it is easy to cause late thrombosis and other late adverse events. Therefore, implantable medical devices prepared by using corrosive and degradable metal materials such as zinc and iron have good application potential.
- the absorbable stent with zinc as the matrix material has good flexibility and biocompatibility, and the zinc ion also has the function of resisting oxidation and stabilizing the endothelium, and at the same time, since zinc ions are transported very rapidly in human tissues, zinc-based planting Zinc enrichment, cytotoxicity or necrosis does not occur near the instrument.
- Zinc can also be used in the field of orthopedic implantable devices. Since zinc ions can activate aminoacyl tRNA synthetase in osteoblasts and effectively inhibit the differentiation and growth of osteoclasts, the presence of zinc ions not only promotes the increase of bone calcium content, but also contributes to collagen content. The improvement indicates that zinc ions have a direct function of promoting bone growth. In addition, zinc ions can also promote the binding of cartilage oligomeric matrix proteins to collagen, which is a catalytic element for cartilage growth and regeneration. A zinc-based degradable bone nail releases about 0.2 to 0.3 mg of zinc per day, while an adult who consumes about 300 mg of zinc per day may have a certain toxic reaction. It can be seen that zinc ions released by zinc-based degradable orthopedic implantable devices do not cause systemic toxicity.
- Implantable devices not only need to have good biocompatibility and low toxicity or toxicity, but also need to meet clinical safety requirements.
- the industry has long hoped to reduce the early safety risks after zinc implantation, but has not successfully solved this problem.
- Zinc-containing implantable devices may cause localized sensitization in the early stage after implantation.
- zinc-containing vascular stents may induce sensitization of peripheral vascular tissue after implantation into blood vessels, which may lead to stent occlusion. A more or more serious risk of death, which may have serious safety concerns.
- This early allergenic reaction is caused by free zinc ions produced by corrosion of pure zinc or zinc alloy itself in the body. It is an object of the present invention to reduce the aforementioned safety risks of zinc-containing implantable devices.
- the implantable device of the present invention can be used to implant an in vivo support lumen (e.g., a vascular stent), or to fill a hollow organ tissue (such as an occluder), or as an orthopedic implant or the like.
- the invention provides an implantable device comprising an instrument base and an active drug, wherein the device base is pure zinc and/or zinc alloy, the zinc content of the instrument substrate is 0.1-100%, and the active drug comprises anti-allergy. drug.
- the zinc alloy is a medical zinc-based alloy composed of zinc and a nutrient element or a low-toxic element in the human body.
- the nutrient or low toxic element in the human body is selected from at least one of the following elements: iron, magnesium, calcium, sodium, copper, manganese, chromium, selenium, molybdenum, cobalt, nickel, vanadium, tin, silicon, germanium, Boron, bismuth, lithium, potassium.
- the implantable device further comprises a zinc complexing agent that forms a complex with the pure zinc or zinc alloy in the instrument matrix in body fluids.
- Complexing agents also known as ligands, are structurally containing a coordinating group that provides a lone pair of electrons or a ⁇ -electron.
- the zinc complexing agent can complex with the corrosive product divalent zinc ions in the process of corrosion of pure zinc and/or zinc alloy, reducing the amount of free zinc ions, so that the tissue around the implant does not cause obvious Sensitive reaction.
- the zinc complexing agent contains at least one coordinating group; the coordinating group is selected from the group consisting of a hydroxyl group, a mercapto group, an amine group, an aromatic heterocyclic group, and a nitros group on a fused aromatic hydrocarbon.
- the hydroxyl group on the fused ring aromatic hydrocarbon is selected from the group consisting of a phenolic hydroxyl group; and the aromatic heterocyclic group is selected from the group consisting of furyl, pyrrolyl, and imidazole , triazolyl, thienyl, thiazolyl, pyridyl, pyridinyl, pyranyl, pyranone, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, pyridazine At least one of a group, an acridinyl group, a fluorenyl group, a fluorenyl group or a phenanthroline group.
- the zinc complexing agent is selected from at least one of the following: a polydentate ligand comprising a hydroxyl group on a fused ring aromatic hydrocarbon, including 8-hydroxyquinoline, 8-hydroxyquinaldine, 4,5 -dihydroxybenzene-1,3-disulfonic acid sodium, 4-[3,5-di-hydroxyphenyl-1H-1,2,4-triazole]-benzoic acid, 1-(2-pyridylazo -2-naphthol; the thiol-containing complexing agent, including 8-mercaptoquinoline, thioglycolic acid, dinonylpropanol, 5-methyl-2-mercaptobenzoic acid methyl ester; amine group-containing complex Agents, including ethylenediamine, triethylenetetramine, ethylenediaminetetraacetic acid, tetrasodium ethylenediaminetetraacetate, triethylenetetramine, N-(2-hydroxyethyl)
- the anti-allergic drug is selected from at least one of an antihistamine antiallergic drug, an anti-leukotriene drug, a mast cell membrane stabilizer, a glucocorticoid antiallergic drug, or a modulating immune antiallergic drug.
- an antihistamine antiallergic drug an anti-leukotriene drug, a mast cell membrane stabilizer, a glucocorticoid antiallergic drug, or a modulating immune antiallergic drug.
- the anti-allergic drug is selected from the group consisting of chlorpheniramine, diphenhydramine, promethazine hydrochloride, cetirizine, loratadine, mizolastine, ebastine, and aspirin.
- Imidazole terfenadine, desloratadine, fexofenadine, cyproheptadine, ketotifen, levocetirizine, meclizine, ethflurazine, carbendazim, nitrogen Zhuo Sting, dechlorpromazine, chlorcycline, amlexidine, avastin, azastatin, mequitazine, carbastine, statin, sirnadine, pupp Tropin, phenothiazine, pyridamine, ranitidine, ezetine, epilisine, promethazine, montelukast, zafirlukast, tokasti, zileuton, ammonia Leros, (2004), pomester, doxepin, vilucan, doxil, sodium cromoglycate, sodium hydroxypropionate, nitocolomi sodium, tranilast, tiram Te, ribavirin, butyl
- the anti-allergic drug is present in the surface of the device substrate in an amount ranging from 10 to 500 ug/cm 2 , and further, from 100 to 300 ug/cm 2 .
- the active drug further comprises at least one of an anti-restenosis drug, an anti-proliferative drug, an anti-platelet drug, or an anti-inflammatory drug.
- the active drug is contacted with the device substrate in at least one of the following: the active drug at least partially covers the surface of the device substrate; or the device substrate has micropores, The active drug is disposed in the micropores of the instrument substrate; or the device substrate is provided with a slit, a pore or a groove, and the active drug is disposed in a slit, a hole or a groove of the instrument base; or The instrument base has an internal cavity in which the active drug is filled.
- the active drug is in the form of a coating.
- the thickness of the coating ranges from 2 to 50 ⁇ m, and further, from 5 to 25 ⁇ m.
- a polymeric carrier is also included in the coating.
- the polymer carrier is a degradable polymer composed of polylactic acid, polyglycolic acid, polysuccinate, poly( ⁇ -hydroxybutyrate), polycaprolactone, polyhexan One or several physical blends of ethylene glycol diester, polylactic acid-glycolic acid copolymer or polyvalerate, or polylactic acid, polyglycolic acid, polysuccinate, poly( ⁇ Copolymerized with one or more of -hydroxybutyrate), polycaprolactone, polyethylene adipate, polylactic acid-glycolic acid copolymer or polyvalerate, or the polymer carrier a non-degradable polymer consisting of one or more of polyurethane, polycarbonate, polymethyl methacrylate, polystyrene, polybutylene or polybutyl methacrylate Blended, or copolymerized from one or more of polyurethane, polycarbonate, polymethyl methacrylate,
- the mass ratio of the polymeric carrier to the active drug is from 50:1 to 1:20, and further, from 10:1 to 1:10.
- the implantable device is a stent, an occluder, an orthopedic implant, a dental implant, a suture or a bolt.
- the stent is a vascular stent, a tracheal stent, an esophageal stent, a urethral stent, an intestinal stent, or a biliary stent.
- the orthopedic implant is a fixation screw, a fixed rivet or a bone plate.
- the implantable device provided by the present invention includes a zinc complexing agent, but does not include an active drug
- the implantable device can still exhibit a low sensitization risk to surrounding tissues, indicating that the zinc complexing agent can also reduce zinc. Sensitization to tissues.
- the present invention has the following advantages and benefits:
- the implantable device of the invention belongs to the industry for the first time to find that pure zinc or zinc alloy is sensitized by self-corrosion, and belongs to the first use of anti-allergic drugs to inhibit implanted devices containing pure zinc or zinc alloy after implantation in human body.
- the sensitization caused by the corrosion of pure zinc or zinc alloy reduces the safety hazard of the implant and solves the tissue sensitization risk exhibited by zinc-containing implanted devices that the industry has long been eager to solve but has never been successful. A technical problem.
- Figure 1 is a sensitized pathological section of the tissue surrounding the stent after the vascular stent of Comparative Example 1 was implanted into the porcine coronary vessel for 6 months;
- Figure 2 is a sensitized pathological section of the tissue surrounding the stent after 6 months of implantation of the vascular stent of Comparative Example 2;
- Example 3 is a pathological section of the tissue surrounding the stent after the vascular stent of Example 1 is implanted into the porcine coronary artery for 6 months;
- Example 4 is a pathological section of the tissue surrounding the stent after the vascular stent of Example 2 is implanted into the porcine coronary artery for 6 months;
- Example 5 is a pathological section of the tissue surrounding the stent after the vascular stent of Example 3 is implanted into the porcine coronary artery for 1 month;
- Example 6 is a pathological section of the tissue surrounding the stent after the vascular stent of Example 4 is implanted into the porcine coronary artery for 3 months;
- Example 7 is a pathological section of the tissue surrounding the stent after the vascular stent of Example 5 is implanted into the porcine coronary artery for 6 months;
- Figure 8 is a pathological section of the tissue surrounding the stent after the vascular stent of Example 6 is implanted into the porcine coronary artery for 6 months;
- Figure 9 is a pathological section of the tissue surrounding the stent after the vascular stent of Example 7 is implanted into the porcine coronary vessel for 1 month;
- Figure 10 is a pathological section of the tissue surrounding the stent after implantation of the vascular stent of Example 8 for 3 months;
- Figure 11 is a pathological section of the tissue surrounding the stent after the vascular stent of Example 9 was implanted into the porcine coronary artery for 6 months.
- a vascular stent based on pure zinc has a zinc content of 100% in the instrument base and is implanted into the porcine coronary vessels. After 6 months, the stent and its vascular tissue were removed, and the vascular tissue was pathologically observed.
- a vascular stent based on iron-zinc alloy has a zinc content of 70%, an iron content of 25%, a magnesium content of 3.5%, a calcium content of 0.5%, a copper content of 0.2%, and the remainder of the vascular stent.
- Inclusion elements are implanted into the porcine coronary vessels. After 6 months, the stent and its vascular tissue were removed, and the vascular tissue was pathologically observed.
- a vascular stent based on an iron-zinc alloy has a zinc content of 95% in the instrument substrate, an iron content of 4.5%, and a total amount of inclusion elements other than zinc and iron of 0.5%.
- a mixture containing polylactic acid, dexamethasone and gluconic acid was dispensed onto the surface of the stent, and after drying, the stent of the vessel of Example 1 was obtained.
- the thickness of the stent surface coating was 2 ⁇ m, and the quality of the polylactic acid and dexamethasone in the coating was The ratio of 2:1, the content of dexamethasone drug on the surface of the instrument substrate was 100 ug/cm 2 .
- the vascular stent of the present embodiment is implanted into a porcine coronary artery. After 6 months, the stent and its vascular tissue were removed, and the vascular tissue was pathologically observed.
- the pathological section shows that the vascular tissue surrounding the blood vessel stent of the present embodiment does not produce eosinophils. That is, the blood vessel stent of the present embodiment is not sensitized to the implanted tissue.
- the vascular stent of the present embodiment contains the antiallergic drug dexamethasone and gluconic acid which can form a complex with zinc.
- dexamethasone When it is implanted into vascular tissue, the efficacy of dexamethasone inhibits the zinc alloy in the matrix of the vascular stent device. Sensitization to vascular tissue.
- gluconic acid complexes with the zinc ion of the corrosion product of iron-zinc alloy, which reduces the amount of free zinc ions and further reduces the risk of sensitization of the implant.
- a pure zinc-based scaffold has a zinc content of 99.95% in the instrument substrate, and the rest is an inclusion element, and the surface is dip coated with polyglycolic acid, methylprednisolone, ethylenediaminetetraacetic acid tetrasodium salt and In the mixture of rapamycin, the mass ratio of the three in the mixture is 50:1:1, and a coating having a thickness of 25 ⁇ m is obtained.
- the vascular stent of Example 2 can be obtained, and the methylprednisolone drug is The content of the surface of the instrument substrate was 200 ug/cm 2 .
- the vascular stent of the present embodiment is implanted into a porcine coronary artery. After 6 months, the stent and its vascular tissue were removed, and the vascular tissue was pathologically observed.
- the pathological section shows that the vascular tissue surrounding the blood vessel stent of the present embodiment does not produce eosinophils. That is, the blood vessel stent of the present embodiment is not sensitized to the implanted tissue.
- the vascular stent of the present embodiment contains an antiallergic drug methylprednisolone and ethylenediaminetetraacetic acid which can form a complex with zinc.
- methylprednisolone When it is implanted into vascular tissue, the pharmacological inhibition of methylprednisolone The sensitization of pure zinc to vascular tissue in the matrix of the vascular stent device.
- the tetrasodium salt of ethylenediaminetetraacetate complexes with the zinc ion of the corrosion product of the device matrix, which reduces the amount of free zinc ions and further reduces the risk of sensitization of the implant.
- a surface-galvanized iron-based stent has a zinc content of 1% in the instrument substrate, an iron content of 98%, and the balance being inclusion elements.
- a solution containing polylactic acid glycolic acid, hydrocortisone and acetylsalicylic acid is sprayed on the surface of the instrument substrate to obtain a coating having a thickness of 50 ⁇ m.
- the mass ratio of polylactic acid glycolic acid to hydrocortisone in the coating is 1: 5, then a polylactic acid coating having a thickness of 5 ⁇ m was applied again to the surface of the drug coating layer, that is, the blood vessel stent of Example 3 was obtained, and the content of the hydrocortisone drug on the surface of the instrument substrate was 300 ug/cm 2 .
- the vascular stent of the present embodiment is implanted into a porcine coronary artery. One month later, the stent and its vascular tissue were removed, and the vascular tissue was pathologically observed.
- the pathological section shows that the vascular tissue surrounding the blood vessel stent of the present embodiment does not produce eosinophils. That is, the blood vessel stent of the present embodiment is not sensitized to the implanted tissue.
- the vascular stent of the present embodiment contains an antiallergic drug hydrocortisone and acetylsalicylic acid which can form a complex with zinc.
- hydrocortisone When it is implanted into vascular tissue, the effect of hydrocortisone inhibits the vascular stent device matrix. Sensitization of vascular tissue by pure zinc.
- acetylsalicylic acid complexes with zinc ions, reducing the amount of free zinc ions, further reducing the risk of sensitization of the implant.
- a vascular stent with a groove on the surface, the instrument substrate is an alloy containing zinc, magnesium and iron.
- the zinc content of the instrument substrate is 40%, the iron content is 50%, the magnesium content is 9.5%, and the rest are inclusion elements.
- a mixture containing polystyrene, 8-hydroxyquinoline and levocetirizine was dispensed onto the outer surface of the stent and the groove to obtain a coating having a thickness of 25 ⁇ m, and the coating was made of polystyrene and leucitride.
- the mass ratio of the alimazine was 1:1, and the vascular stent of Example 4 was obtained.
- the average content of levocetirizine drug on the surface of the device substrate was 50 ug/cm 2 .
- the vascular stent of the present embodiment is implanted into a porcine coronary artery. Three months later, the stent and its vascular tissue were removed, and the vascular tissue was pathologically observed.
- the pathological section shows that the vascular tissue surrounding the blood vessel stent of the present embodiment does not produce eosinophils. That is, the blood vessel stent of the present embodiment is not sensitized to the implanted tissue.
- the vascular stent of the present embodiment contains the anti-allergic drug levocetirizine and 8-hydroxyquinoline which can form a complex with zinc.
- levocetirizine When it is implanted into vascular tissue, the efficacy of levocetirizine inhibits blood vessels. Sensitization of vascular tissue by zinc alloy in the matrix of the stent device.
- 8-hydroxyquinoline complexes with zinc ions, reducing the amount of free zinc ions, further reducing the risk of sensitization of the implant.
- a vascular stent of a zinc-manganese-magnesium alloy has a zinc content of 20%, a manganese content of 5%, and a magnesium content of 75%.
- the stent has a plurality of slits on the surface of the stent, and the dexamethasone is filled into the gap.
- the vascular stent of Example 5 was obtained, and the content of the dexamethasone drug on the surface of the instrument substrate was 500 ug/cm 2 .
- the vascular stent of the present embodiment is implanted into a porcine coronary artery. After 6 months, the stent and its vascular tissue were removed, and the vascular tissue was pathologically observed.
- pathological sections show that the vascular tissue surrounding the vascular stent of this example did not produce significant eosinophils. That is, the blood vessel stent of the present embodiment has no significant allergenicity to the implanted tissue.
- a surface galvanized iron-copper-copper alloy stent has an iron content of 97%, a copper content of 1%, a calcium content of 0.5%, a zinc content of 0.5%, and the remainder being inclusion elements.
- the surface of the stent is dip-coated in a mixture containing polycarbonate and chlorpheniramine to obtain a coating having a thickness of 5 ⁇ m.
- the mass ratio of polycarbonate to chlorpheniramine in the coating is 1:20.
- the vascular stent of Example 6 had a chlorpheniramine drug content of 150 ug/cm 2 on the surface of the instrument substrate.
- the vascular stent of the present embodiment is implanted into a porcine coronary artery. After 6 months, the stent and its vascular tissue were removed, and the vascular tissue was pathologically observed.
- the pathological section shows that the vascular tissue surrounding the vascular stent of the present embodiment produces only individual eosinophils. That is, the blood vessel stent of the present embodiment has no significant allergenicity to the implanted tissue.
- a pure zinc-based stent has a zinc content of 100% in the instrument substrate, and a mixture of polyglycolic acid, mizolastine and paclitaxel is applied to a part of the stent to obtain a coating having a thickness of 30 ⁇ m.
- the mass ratio of the three was 1:10:1, and the vascular stent of Example 7 was obtained.
- the content of the mizolastine drug on the surface of the device substrate was 10 ug/cm 2 .
- the vascular stent of the present embodiment is implanted into a porcine coronary artery. One month later, the stent and its vascular tissue were removed, and the vascular tissue was pathologically observed.
- the pathological section shows that the vascular tissue around the vascular stent of the present embodiment does not produce significant eosinophils, that is, the vascular stent of the present embodiment has no obvious sensitization to the implanted tissue.
- An iron-zinc alloy stent has an iron content of 99.9% and a zinc content of 0.1% in the instrument substrate.
- the vascular stent of Example 8 was obtained by coating the surface of the stent with dimercaptopropanol and drying.
- the vascular stent of the present embodiment is implanted into a porcine coronary artery. Three months later, the stent and its vascular tissue were removed, and the vascular tissue was pathologically observed.
- the pathological section shows that the vascular tissue surrounding the vascular stent of the present example did not produce significant eosinophils. That is, the blood vessel stent of the present embodiment has no significant allergenicity to the implanted tissue.
- the vascular stent of the present embodiment includes dimercaptopropanol which can form a complex with zinc ions.
- dimercaptopropanol When it is implanted into the vascular tissue, the dimercaptopropanol complexes with the zinc alloy, a corrosion product of the zinc alloy, reduces the freeness. The concentration of zinc ions did not produce a significant sensitizing response to the tissue surrounding the implant.
- a stent made of pure zinc has a zinc content of 100% in the instrument substrate.
- the outer surface of the stent was rolled in trisodium citrate to obtain a stent of the vascular stent of Example 9, which had a discontinuous citric acid coating with an average thickness of 10 ⁇ m.
- the vascular stent of the present embodiment is implanted into a porcine coronary artery. After 6 months, the stent and its vascular tissue were removed, and the vascular tissue was pathologically observed.
- the pathological section shows that the vascular tissue surrounding the vascular stent of the present example did not produce significant eosinophils. That is, the blood vessel stent of the present embodiment has no significant allergenicity to the implanted tissue.
- the vascular stent of the present embodiment comprises trisodium citrate which can form a complex with zinc ions.
- the trisodium citrate complex with the zinc alloy corrosion product, zinc ion reduces the freeness.
- the concentration of zinc ions did not produce a significant sensitizing response to the tissue surrounding the implant.
- the specific embodiment of the present invention is schematically illustrated only by the zinc-containing vascular stent, and the technical solution provided by the present invention can also be applied to other implantable devices, such as a stent, an occluder, Orthopedic implants, dental implants, sutures or bolts.
- the stent is a vascular stent, a tracheal stent, an esophageal stent, a urethral stent, an intestinal stent or a biliary stent.
- the orthopedic implant is a fixation screw, a fixed rivet or a bone plate.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Oral & Maxillofacial Surgery (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Heart & Thoracic Surgery (AREA)
- Transplantation (AREA)
- Surgery (AREA)
- Vascular Medicine (AREA)
- Materials Engineering (AREA)
- Biomedical Technology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Metallurgy (AREA)
- Mechanical Engineering (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Dermatology (AREA)
- Pharmacology & Pharmacy (AREA)
- Inorganic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Cardiology (AREA)
- Molecular Biology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Immunology (AREA)
- Pulmonology (AREA)
- Plastic & Reconstructive Surgery (AREA)
- Medical Informatics (AREA)
- Crystallography & Structural Chemistry (AREA)
- Neurology (AREA)
- Physics & Mathematics (AREA)
- Thermal Sciences (AREA)
Abstract
一种植入式器械,包括器械基体和活性药物,所述器械基体为纯锌和/或锌合金,器械基体中锌的含量为0.1~100%,所述活性药物包括抗过敏药物。植入式器械被植入人体后,由于抗过敏药物的存在,植入物周围组织不会产生明显致敏反应,所述植入式器械可以被用于植入体内支撑官腔,或填塞空腔器官组织,或作为骨科植入物等。
Description
【技术领域】
本发明属于医疗器械领域,涉及一种植入式器械。
【背景技术】
当前,植入式医疗器械通常采用金属及其合金、陶瓷、聚合物和相关复合材料制成。其中,金属材料基植入式医疗器械以其优越的力学性能,如高强度、高韧性等,尤为受到青睐。
目前,在心血管植入应用领域,血管支架一般采用不可降解的金属制成,其缺点是金属不可降解、无法取出,滞留在血管内容易引发晚期血栓等诸多晚期不良事件。因此,使用锌、铁等可腐蚀降解的金属材料制备的植入式医疗器械,具备良好的应用潜力。以锌作为基体材料的可吸收支架具有良好的柔顺性和生物相容性,且锌离子还有抗氧化、稳定内皮的作用,同时由于锌离子在人体组织中的运输非常迅速,因此锌基植入式器械附近不会出现锌富集、细胞毒性或坏死。
锌也可以应用于骨科植入式器械领域。由于锌离子可以激活成骨细胞中的氨酰tRNA合成酶,并可有效抑制破骨细胞的分化与生长,因此锌离子的存在不仅促进了骨钙盐含量的增加,还有利于骨胶原蛋白含量的提高,说明锌离子有直接的促成骨组织生长功能。另外,锌离子还可以促进软骨低聚基质蛋白与胶原的结合,是软骨成长与再生的催化元素。一枚锌基可降解骨钉每天释放的锌大约为0.2~0.3毫克,而成年人每天摄入大约300毫克锌才可能会有一定毒性反应。可见锌基可降解骨科植入式器械降解释放的锌离子不会引起全身毒性。
植入式器械不仅需要具有良好的生物相容性和低毒性或无毒性,还需要满足临床上的安全性要求。对于含锌植入式器械,业界长期以来一直希望能降低锌植入后早期的安全性风险,但一直均未能成功解决此问题。
【发明内容】
含锌植入式器械植入后在早期可能会导致局部组织的致敏性反应,例如,含锌的血管支架在植入血管后可能会引发周围血管组织的致敏性反应,进而导致支架阻塞甚或更严重的死亡风险,从而可能具有严重的安全隐患。我们认为,该早期致敏性反应由纯锌或锌合金自身在体内腐蚀产生的游离锌离子引起。本发明的目的在于降低含锌植入式器械的前述安全性风险。本发明的植入式器械可以被用于植入体内支撑管腔(例如血管支架),或填塞空腔器官组织(如封堵器),或作为骨科植入物等。
本发明的技术方案如下:
本发明提供一种植入式器械,包括器械基体和活性药物,所述器械基体为纯锌和/或锌合金,所述器械基体中锌的含量为0.1~100%,所述活性药物包括抗过敏药物。所述锌合金为医用锌基合金,其由锌与人体内营养元素或低毒元素组成。所述人体内营养元素或低毒元素选自以下元素中的至少一种:铁、镁、钙、钠、铜、锰、铬、硒、钼、钴、镍、钒、锡、硅、锶、硼、铈、锂、钾。
在其中一个实施例中,所述植入式器械还包括锌络合剂,所述锌络合剂与所述器械基体中的纯锌或锌合金在体液中形成络合物。络合剂又称为配体,结构上含有能提供孤对电子或π电子的配位基团。所述锌络合剂可以在纯锌和/或锌合金腐蚀的过程中与腐蚀产物二价锌离子发生络合反应,减少游离锌离子的数量,从而使植入物周围组织不发生明显的致敏反应。
在其中一个实施例中,所述锌络合剂含有至少1个配位基团;所述配位基团选自稠环芳烃上的羟基、巯基、胺基、芳杂环基团、亚硝基、羰基、磺基,磷酸基团或有机膦基团中的至少一种;所述稠环芳烃上的羟基选自酚羟基;所述芳杂环基团选自呋喃基、吡咯基、咪唑基、三唑基、噻吩基、噻唑基、吡啶基、吡啶酮基、吡喃基、吡喃酮基、嘧啶基、哒嗪基、吡嗪基、喹啉基、异喹啉基、酞嗪基、喋啶基、吲哚基、嘌呤基或菲咯啉基中的至少一种。
在其中一个实施例中,所述锌络合剂选自以下至少一种:含稠环芳烃上的羟基的多齿配体,包括8-羟基喹啉、8-羟基喹哪啶、4,5-二羟基苯-1,3-二磺酸钠、4-[3,5-二-羟苯基-1H-1,2,4-三唑]-苯甲酸、1-(2-吡啶偶氮)-2-萘酚;所述含巯基的络合剂,包括8-巯基喹啉、巯基乙酸、二巯基丙醇、5-甲基-2-巯基苯甲酸甲酯;含胺基的络合剂,包括乙二胺、三乙烯四胺、乙二胺四乙酸、乙二胺四乙酸四钠、三亚乙基四胺、N-(2-羟乙基)乙二胺-N,N’,N’-三乙酸或N'-[5-[[4-[[5-(乙酰羟胺基)戊基]氨]-1,4-二氧丁基]羟胺]戊基]-N-(5-氨基戊基)-N-羟基琥珀酰胺;含芳杂环基团的络合剂,包括邻菲罗啉、联吡啶、卟啉、卟吩、叶绿素、血红蛋白或1,2-二甲基-3-羟基-4-吡啶酮;含亚硝基的多齿配体,包括1-亚硝基-2-萘酚或1-亚硝基-2-萘酚-6-磺酸钠;含磺基的多齿配体,包括磺基水杨酸或8-羟基喹啉-5-磺酸;含磷酸基团的多齿配体,包括焦磷酸、三聚磷酸、六偏聚磷酸、多聚磷酸、焦磷酸钠、六偏聚磷酸钠或多聚磷酸铵;含有机膦的络合剂,包括二乙烯三胺五甲叉膦酸钾或乙二胺四甲叉膦酸钠;含羰基的配体,包括羧酸及其盐、酸酐、酯、酰胺、聚羧酸或聚酸酐;进一步地,所述含羰基的配体,包括葡萄糖酸、草酸、酒石酸、苹果酸、草酰乙酸、延胡索酸、马来酸、柠檬酸、氨三乙酸、二乙烯三胺五羧酸、海藻酸、谷氨酸、天冬氨酸、鸟氨酸、赖氨酸、1,2-二氨基环己烷-N,N,N’,N’-四乙酸、柠檬酸钾、柠檬酸钙、柠檬酸甘油酯、乙酰水杨酸、磺基水杨酰胺、聚天冬氨酸、聚谷氨酸、聚鸟氨酸、聚赖氨酸或聚马来酸酐。
在其中一个实施例中,所述抗过敏药物选自抗组胺类抗过敏药物、抗白三烯药物、肥大细胞膜稳定剂、糖皮质激素类抗过敏药物或调节免疫类抗过敏药物中的至少一种。
在其中一个实施例中,所述抗过敏药物选自氯苯吡胺、苯海拉明、盐酸异丙嗪、西替利嗪、氯雷他定、咪唑斯汀、依巴斯汀、阿司咪唑、特非那定、地氯雷他定、非索非那定、赛庚啶、酮替芬、左旋西替利嗪、氯苯甲嗪、乙氟利嗪、卡依巴斯丁、氮卓斯汀、去氯羟嗪、氯环利嗪、氨来仙司、阿伐斯丁、阿扎他丁、甲喹吩嗪、左卡斯汀、赛他斯丁、斯喹那定、地普托品、苯噻啶、吡拉明、雷尼替丁、依美斯汀、依匹斯汀、异丙嗪、孟鲁司特、扎鲁司特、托卡司特、齐留通、氨来洛斯、伊布拉特、泊米司特、多塞平、维鲁司特、多西苯醌、色甘酸钠、色羟丙钠、尼多考米钠、曲尼司特、噻拉米特、瑞吡司特、丁氮菲酸、苯氮嘌呤酮、塔赞司特、奥萨格雷、瑞吡司特、地塞米松、甲基强的松龙、氢化可的松、曲安奈德、皮质类固醇、维他命C、钙剂、辅酶Q10或糜胰蛋白酶中的至少一种。
在其中一个实施例中,所述抗过敏药物在所述器械基体表面的含量范围为10~500ug/cm2,进一步地,为100~300ug/cm2。
在其中一个实施例中,所述活性药物还包括抗再狭窄药物、抗增生药物、抗血小板药物或抗炎症反应药物中的至少一种。
在其中一个实施例中,所述活性药物与所述器械基体接触的方式选自以下至少一种:所述活性药物至少部分覆盖在所述器械基体的表面;或者所述器械基体具有微孔,所述活性药物设于所述器械基体的微孔中;或者所述器械基体设有缝隙、孔隙或凹槽,所述活性药物设于所述器械基体的缝隙、孔隙或凹槽中;或者所述器械基体具有内腔,所述活性药物填充在所述器械基体的所述内腔中。
在其中一个实施例中,所述活性药物以涂层的形式存在。所述涂层的厚度范围为2~50μm,进一步地,为5~25μm。
在其中一个实施例中,所述涂层中还包括聚合物载体。所述聚合物载体为可降解的聚合物,所述可降解的聚合物由聚乳酸、聚乙醇酸、聚丁二酸酯、聚(β-羟基丁酸酯)、聚已内酯、聚己二酸乙二醇酯、聚乳酸-乙醇酸共聚物或聚戊酸酯中的一种或者几种物理共混而成,或者由聚乳酸、聚乙醇酸、聚丁二酸酯、聚(β-羟基丁酸酯)、聚已内酯、聚己二酸乙二醇酯、聚乳酸-乙醇酸共聚物或聚戊酸酯中的一种或者几种共聚而成,或者所述聚合物载体为不可降解的聚合物,所述不可降解的聚合物由聚氨酯、聚碳酸酯、聚甲基丙烯酸甲酯、聚苯乙烯、聚丁烯或聚甲基丙烯酸丁酯中的一种或者几种物理共混而成,或者由聚氨酯、聚碳酸酯、聚甲基丙烯酸甲酯、聚苯乙烯、聚丁烯或聚甲基丙烯酸丁酯中的一种或者几种共聚而成,或者所述聚合物载体由所述可降解的聚合物的单体和所述不可降解的聚合物的单体中的一种或者几种物理共混而成,或者由所述可降解的聚合物的单体和所述不可降解的聚合物的单体中的一种或者几种共聚而成。
在其中一个实施例中,所述聚合物载体与所述活性药物的质量比为50:1~1:20,进一步地,为10:1~1:10。
在其中一个实施例中,所述植入式器械为支架、封堵器、骨科植入物、齿科植入物、缝合线或螺栓。
在其中一个实施例中,所述支架为血管支架、气管支架、食道支架、尿道支架、肠道支架或胆道支架。
在其中一个实施例中,所述骨科植入物为固定螺钉、固定铆钉或骨板。
当本发明提供的植入式器械中包括锌络合剂,但不包括活性药物时,该植入式器械仍可表现出对周围组织的低致敏风险,说明锌络合剂也可降低锌对组织的致敏作用。
本发明与现有技术相比,具有以下有点和有益效果:
本发明的植入式器械,属于业界首次发现纯锌或锌合金会因自身腐蚀致敏,并属于首次利用抗过敏药物来抑制含纯锌或锌合金的植入式器械在植入人体后因纯锌或锌合金自身腐蚀导致的致敏作用,降低了植入物的安全隐患,解决了业内长期以来渴望解决但始终一直未能成功的含锌植入器械表现出的组织致敏性风险这一技术难题。
【附图说明】
图1为对比例1的血管支架植入猪冠脉血管6个月后,支架周围组织的致敏性病理切片;
图2为对比例2的血管支架植入猪冠脉血管6个月后,支架周围组织的致敏性病理切片;
图3为实施例1的血管支架植入猪冠脉血管6个月后,支架周围组织的病理切片;
图4为实施例2的血管支架植入猪冠脉血管6个月后,支架周围组织的病理切片;
图5为实施例3的血管支架植入猪冠脉血管1个月后,支架周围组织的病理切片;
图6为实施例4的血管支架植入猪冠脉血管3个月后,支架周围组织的病理切片;
图7为实施例5的血管支架植入猪冠脉血管6个月后,支架周围组织的病理切片;
图8为实施例6的血管支架植入猪冠脉血管6个月后,支架周围组织的病理切片;
图9为实施例7的血管支架植入猪冠脉血管1个月后,支架周围组织的病理切片;
图10为实施例8的血管支架植入猪冠脉血管3个月后,支架周围组织的病理切片;
图11为实施例9的血管支架植入猪冠脉血管6个月后,支架周围组织的病理切片。
【具体实施方式】
为了使本发明的目的、技术方案及优点更加清楚明白,以下结合附图及实施例,对本发明进行进一步详细说明。应当理解,此处所描述的具体实施例仅仅用以解释本发明,并不用于限定本发明。
除非另有定义,本文所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本文在说明书中所使用的术语只是为了描述具体的实施例的目的,不是旨在于限制本发明。
对比例1
将一种以纯锌为基体的血管支架,其器械基体中锌的含量为100%,植入猪冠脉血管。6个月后,取出支架及其所在的血管组织,对血管组织进行病理观察。
请参阅图1,病理切片显示,对比例1的血管支架周围的血管组织生成大量嗜酸性粒细胞。即,本对比例的纯锌基血管支架对植入组织具有明显的致敏性。
对比例2
将一种以铁锌合金为基体的血管支架,其器械基体中锌的含量为70%,铁含量为25%,镁含量为3.5%,钙含量为0.5%,铜含量为0.2%,其余为夹杂元素,植入猪冠脉血管。6个月后,取出支架及其所在的血管组织,对血管组织进行病理观察。
请参阅图2,病理切片显示,对比例2的血管支架周围的血管组织生成大量嗜酸性粒细胞。即,本对比例的铁锌合金血管支架对植入组织具有明显的致敏性。
实施例1
一种以铁锌合金为基体的血管支架,其器械基体中锌含量为95%,铁含量为4.5%,除锌、铁以外的夹杂元素总量为0.5%。向所述支架的表面滴涂含有聚乳酸、地塞米松和葡萄糖酸的混合物,干燥后得到实施例1的血管支架,支架表面涂层厚度为2μm,涂层中聚乳酸和地塞米松的质量比为2:1,地塞米松药物在器械基体表面的含量为100ug/cm2。将本实施例的血管支架植入猪冠脉血管。6个月后,取出支架及其所在的血管组织,对血管组织进行病理观察。
请参阅图3,病理切片显示,本实施例的血管支架周围的血管组织没有产生嗜酸性粒细胞。即,本实施例的血管支架对植入组织没有致敏性。
本实施例的血管支架含有抗过敏药物地塞米松及可以与锌生成络合物的葡萄糖酸,当其被植入血管组织后,地塞米松的药效抑制了血管支架器械基体中的锌合金对血管组织的致敏作用。另外,葡萄糖酸与铁锌合金的腐蚀产物——锌离子络合,减少了游离锌离子的数量,进一步降低了植入物的致敏风险。
实施例2
将一种以纯锌为基体的支架,其器械基体中锌含量为99.95%,其余为夹杂元素,表面浸涂于含有聚乙醇酸、甲基强的松龙、乙二胺四乙酸四钠盐以及雷帕霉素的混合物中,混合物中三者的质量比为50:1:1,得到厚度为25μm的涂层,干燥后即可得到实施例2的血管支架,甲基强的松龙药物在器械基体表面的含量为200ug/cm2。将本实施例的血管支架植入猪冠脉血管。6个月后,取出支架及其所在的血管组织,对血管组织进行病理观察。
请参阅图4,病理切片显示,本实施例的血管支架周围的血管组织没有产生嗜酸性粒细胞。即,本实施例的血管支架对植入组织没有致敏性。
本实施例的血管支架含有抗过敏药物甲基强的松龙及可以与锌生成络合物的乙二胺四乙酸,当其被植入血管组织后,甲基强的松龙的药效抑制了血管支架器械基体中的纯锌对血管组织的致敏作用。另外,乙二胺四乙酸四钠盐与器械基体的腐蚀产物——锌离子络合,减少了游离锌离子的数量,进一步降低了植入物的致敏风险。
实施例3
一种表面镀锌的铁基支架,其器械基体中锌含量为1%,铁含量为98%,其余为夹杂元素。先在器械基体表面喷涂含有聚乳酸乙醇酸、氢化可的松和乙酰水杨酸的溶液,得到厚度为50μm的涂层,涂层中聚乳酸乙醇酸和氢化可的松的质量比为1:5,然后在药物涂层表面再次涂覆厚度为5μm的聚乳酸涂层,即得到实施例3的血管支架,氢化可的松药物在器械基体表面的含量为300ug/cm2。将本实施例的血管支架植入猪冠脉血管。1个月后,取出支架及其所在的血管组织,对血管组织进行病理观察。
请参阅图5,病理切片显示,本实施例的血管支架周围的血管组织没有产生嗜酸性粒细胞。即,本实施例的血管支架对植入组织没有致敏性。
本实施例的血管支架含有抗过敏药物氢化可的松及可以与锌生成络合物的乙酰水杨酸,当其被植入血管组织后,氢化可的松的药效抑制了血管支架器械基体中的纯锌对血管组织的致敏作用。另外,乙酰水杨酸与锌离子络合,减少了游离锌离子的数量,进一步降低了植入物的致敏风险。
实施例4
一种表面有凹槽的血管支架,其器械基体为含有锌、镁和铁的合金,器械基体中锌含量为40%,铁含量为50%,镁含量为9.5%,其余为夹杂元素。向所述支架的外表面及凹槽里滴涂含有聚苯乙烯、8-羟基喹啉和左西替利嗪的混合物,得到厚度为25μm的涂层,涂层中聚苯乙烯和左西替利嗪的质量比为1:1,即可得到实施例4的血管支架,左西替利嗪药物在器械基体表面的平均含量为50ug/cm2。将本实施例的血管支架植入猪冠脉血管。3个月后,取出支架及其所在的血管组织,对血管组织进行病理观察。
请参阅图6,病理切片显示,本实施例的血管支架周围的血管组织没有产生嗜酸性粒细胞。即,本实施例的血管支架对植入组织没有致敏性。
本实施例的血管支架含有抗过敏药物左西替利嗪及可以与锌生成络合物的8-羟基喹啉,当其被植入血管组织后,左西替利嗪的药效抑制了血管支架器械基体中的锌合金对血管组织的致敏作用。另外,8-羟基喹啉与锌离子络合,减少了游离锌离子的数量,进一步降低了植入物的致敏风险。
实施例5
一种锌锰镁合金的血管支架,其器械基体中锌含量为20%,锰含量为5%,镁含量为75%,该支架表面分布多个缝隙,向所述缝隙中填塞地塞米松,得到实施例5的血管支架,地塞米松药物在器械基体表面的含量为500ug/cm2。将本实施例的血管支架植入猪冠脉血管。6个月后,取出支架及其所在的血管组织,对血管组织进行病理观察。
请参阅图7,病理切片显示,本实施例的血管支架周围的血管组织没有产生明显的嗜酸性粒细胞。即,本实施例的血管支架对植入组织没有明显的致敏性。
实施例6
一种表面镀锌的铁铜钙合金支架,其器械基体中铁含量为97%,铜含量为1%,钙含量为0.5%,锌含量为0.5%,其余为夹杂元素。将该支架表面浸涂于含有聚碳酸酯和氯苯吡胺的混合物中,得到厚度为5μm的涂层,涂层中聚碳酸酯和氯苯吡胺的质量比为1:20,即可得到实施例6的血管支架,氯苯吡胺药物在器械基体表面的含量为150ug/cm2。将本实施例的血管支架植入猪冠脉血管。6个月后,取出支架及其所在的血管组织,对血管组织进行病理观察。
请参阅图8,病理切片显示,本实施例的血管支架周围的血管组织仅生成个别嗜酸性粒细胞。即,本实施例的血管支架对植入组织没有明显的致敏性。
实施例7
一种以纯锌为基体的支架,其器械基体中锌含量为100%,在支架的部分表面刷涂含有聚乙醇酸、咪唑斯汀以及紫杉醇的混合物,得到厚度为30μm的涂层,涂层中三者的质量比为1:10:1,即可得到实施例7的血管支架,咪唑斯汀药物在器械基体表面的含量为10ug/cm2。将本实施例的血管支架植入猪冠脉血管。1个月后,取出支架及其所在的血管组织,对血管组织进行病理观察。
请参阅图9,病理切片显示,本实施例的血管支架周围的血管组织没有生成明显的嗜酸性粒细胞,即,本实施例的血管支架对植入组织没有明显的致敏性。
实施例8
一种铁锌合金支架,其器械基体中铁含量为99.9%,锌含量为0.1%。向该支架的表面涂覆二巯基丙醇并干燥,即可得到实施例8的血管支架。将本实施例的血管支架植入猪冠脉血管。3个月后,取出支架及其所在的血管组织,对血管组织进行病理观察。
请参阅图10,病理切片显示,本实施例的血管支架周围的血管组织没有生成明显的嗜酸性粒细胞。即,本实施例的血管支架对植入组织没有明显的致敏性。
本实施例的血管支架包括可以与锌离子生成络合物的二巯基丙醇,当其被植入血管组织后,二巯基丙醇与锌合金的腐蚀产物——锌离子络合,降低了游离锌离子的浓度,植入物周围组织没有产生明显的致敏反应。
实施例9
一种以纯锌为基体的支架,其器械基体中锌含量为100%。将该支架的外表面在柠檬酸三钠中辊压,得到实施例9的血管支架,其表面为不连续的柠檬酸涂层,涂层平均厚度为10μm。将本实施例的血管支架植入猪冠脉血管。6个月后,取出支架及其所在的血管组织,对血管组织进行病理观察。
请参阅图11,病理切片显示,本实施例的血管支架周围的血管组织没有生成明显的嗜酸性粒细胞。即,本实施例的血管支架对植入组织没有明显的致敏性。
本实施例的血管支架包括可以与锌离子生成络合物的柠檬酸三钠,当其被植入血管组织后,柠檬酸三钠与锌合金的腐蚀产物——锌离子络合,降低了游离锌离子的浓度,植入物周围组织没有产生明显的致敏反应。
在实施例1至9中,仅以含锌的血管支架对本发明的具体实施方式作了示意性说明,本发明提供的技术方案也可以用于其它植入式器械,例如支架、封堵器、骨科植入物、齿科植入物、缝合线或螺栓。所述支架为血管支架、气管支架、食道支架、尿道支架、肠道支架或胆道支架。所述骨科植入物为固定螺钉、固定铆钉或骨板。
以上结合附图对本发明的实施例进行了描述,但是本发明并不局限于上述的具体实施方式,上述的具体实施方式仅仅是示意性的,而不是限制性的,本领域的普通技术人员在本发明的启示下,在不脱离本发明宗旨和权利要求所保护的范围情况下,还可做出很多形式,这些均属于本发明的保护之内。
Claims (13)
- 一种植入式器械,包括器械基体和活性药物,其特征在于,所述器械基体为纯锌和/或锌合金,所述器械基体中锌的含量为0.1~100%,所述活性药物包括抗过敏药物。
- 根据权利要求1所述的植入式器械,其特征在于,所述植入式器械还包括锌络合剂,所述锌络合剂与所述器械基体中的纯锌或锌合金在体液中形成络合物。
- 根据权利要求2所述的植入式器械,其特征在于,所述锌络合剂含有至少1个配位基团;所述配位基团选自稠环芳烃上的羟基、巯基、胺基、芳杂环基团、亚硝基、羰基、磺基,磷酸基团或有机膦基团中的至少一种;所述稠环芳烃上的羟基选自酚羟基;所述芳杂环基团选自呋喃基、吡咯基、咪唑基、三唑基、噻吩基、噻唑基、吡啶基、吡啶酮基、吡喃基、吡喃酮基、嘧啶基、哒嗪基、吡嗪基、喹啉基、异喹啉基、酞嗪基、喋啶基、吲哚基、嘌呤基或菲咯啉基中的至少一种。
- 根据权利要求3所述的植入式器械,其特征在于,所述锌络合剂选自以下至少一种:含稠环芳烃上的羟基的多齿配体,包括8-羟基喹啉、8-羟基喹哪啶、4,5-二羟基苯-1,3-二磺酸钠、4-[3,5-二-羟苯基-1H-1,2,4-三唑]-苯甲酸、1-(2-吡啶偶氮)-2-萘酚;所述含巯基的络合剂,包括8-巯基喹啉、巯基乙酸、二巯基丙醇、5-甲基-2-巯基苯甲酸甲酯;含胺基的络合剂,包括乙二胺、三乙烯四胺、乙二胺四乙酸、乙二胺四乙酸四钠、三亚乙基四胺、N-(2-羟乙基)乙二胺-N,N’,N’-三乙酸或N'-[5-[[4-[[5-(乙酰羟胺基)戊基]氨]-1,4-二氧丁基]羟胺]戊基]-N-(5-氨基戊基)-N-羟基琥珀酰胺;含芳杂环基团的络合剂,包括邻菲罗啉、联吡啶、卟啉、卟吩、叶绿素、血红蛋白或1,2-二甲基-3-羟基-4-吡啶酮;含亚硝基的多齿配体,包括1-亚硝基-2-萘酚或1-亚硝基-2-萘酚-6-磺酸钠;含磺基的多齿配体,包括磺基水杨酸或8-羟基喹啉-5-磺酸;含磷酸基团的多齿配体,包括焦磷酸、三聚磷酸、六偏聚磷酸、多聚磷酸、焦磷酸钠、六偏聚磷酸钠或多聚磷酸铵;含有机膦的络合剂,包括二乙烯三胺五甲叉膦酸钾或乙二胺四甲叉膦酸钠;含羰基的配体,包括羧酸及其盐、酸酐、酯、酰胺、聚羧酸或聚酸酐;进一步地,所述含羰基的配体,包括葡萄糖酸、草酸、酒石酸、苹果酸、草酰乙酸、延胡索酸、马来酸、柠檬酸、氨三乙酸、二乙烯三胺五羧酸、海藻酸、谷氨酸、天冬氨酸、鸟氨酸、赖氨酸、1,2-二氨基环己烷-N,N,N’,N’-四乙酸、柠檬酸钾、柠檬酸钙、柠檬酸甘油酯、乙酰水杨酸、磺基水杨酰胺、聚天冬氨酸、聚谷氨酸、聚鸟氨酸、聚赖氨酸或聚马来酸酐。
- 根据权利要求1所述的植入式器械,其特征在于,所述抗过敏药物选自抗组胺类抗过敏药物、抗白三烯药物、肥大细胞膜稳定剂、糖皮质激素类抗过敏药物或调节免疫类抗过敏药物中的至少一种。
- 根据权利要求5所述的植入式器械,其特征在于,所述抗过敏药物选自氯苯吡胺、苯海拉明、盐酸异丙嗪、西替利嗪、氯雷他定、咪唑斯汀、依巴斯汀、阿司咪唑、特非那定、地氯雷他定、非索非那定、赛庚啶、酮替芬、左旋西替利嗪、氯苯甲嗪、乙氟利嗪、卡依巴斯丁、氮卓斯汀、去氯羟嗪、氯环利嗪、氨来仙司、阿伐斯丁、阿扎他丁、甲喹吩嗪、左卡斯汀、赛他斯丁、斯喹那定、地普托品、苯噻啶、吡拉明、雷尼替丁、依美斯汀、依匹斯汀、异丙嗪、孟鲁司特、扎鲁司特、托卡司特、齐留通、氨来洛斯、伊布拉特、泊米司特、多塞平、维鲁司特、多西苯醌、色甘酸钠、色羟丙钠、尼多考米钠、曲尼司特、噻拉米特、瑞吡司特、丁氮菲酸、苯氮嘌呤酮、塔赞司特、奥萨格雷、瑞吡司特、地塞米松、甲基强的松龙、氢化可的松、曲安奈德、皮质类固醇、维他命C、钙剂、辅酶Q10或糜胰蛋白酶中的至少一种。
- 根据权利要求1所述的植入式器械,其特征在于,所述抗过敏药物在所述器械基体表面的含量范围为10~500ug/cm2,进一步地,为100~300ug/cm2。
- 根据权利要求1所述的植入式器械,其特征在于,所述活性药物还包括抗再狭窄药物、抗增生药物、抗血小板药物或抗炎症反应药物中的至少一种。
- 根据权利要求1所述的植入式器械,其特征在于,所述活性药物与所述器械基体接触的方式选自以下至少一种:所述活性药物至少部分覆盖在所述器械基体的表面;或者所述器械基体具有微孔,所述活性药物设于所述器械基体的微孔中;或者所述器械基体设有缝隙、孔隙或凹槽,所述活性药物设于所述器械基体的缝隙、孔隙或凹槽中;或者所述器械基体具有内腔,所述活性药物填充在所述器械基体的所述内腔中。
- 根据权利要求9所述的植入式器械,其特征在于,所述活性药物以涂层的形式存在,所述涂层的厚度范围为2~50μm,进一步地,为5~25μm。
- 根据权利要求10所述的植入式器械,其特征在于,所述涂层中还包括聚合物载体,所述聚合物载体为可降解的聚合物,所述可降解的聚合物由聚乳酸、聚乙醇酸、聚丁二酸酯、聚(β-羟基丁酸酯)、聚已内酯、聚己二酸乙二醇酯、聚乳酸-乙醇酸共聚物或聚戊酸酯中的一种或者几种物理共混而成,或者由聚乳酸、聚乙醇酸、聚丁二酸酯、聚(β-羟基丁酸酯)、聚已内酯、聚己二酸乙二醇酯、聚乳酸-乙醇酸共聚物或聚戊酸酯中的一种或者几种共聚而成,或者所述聚合物载体为不可降解的聚合物,所述不可降解的聚合物由聚氨酯、聚碳酸酯、聚甲基丙烯酸甲酯、聚苯乙烯、聚丁烯或聚甲基丙烯酸丁酯中的一种或者几种物理共混而成,或者由聚氨酯、聚碳酸酯、聚甲基丙烯酸甲酯、聚苯乙烯、聚丁烯或聚甲基丙烯酸丁酯中的一种或者几种共聚而成,或者所述聚合物载体由所述可降解的聚合物的单体和所述不可降解的聚合物的单体中的一种或者几种物理共混而成,或者由所述可降解的聚合物的单体和所述不可降解的聚合物的单体中的一种或者几种共聚而成。
- 根据权利要求10所述的植入式器械,其特征在于,所述聚合物载体与所述活性药物的质量比为50:1~1:20,进一步地,为10:1~1:10。
- 根据权利要求1所述的植入式器械,其特征在于,所述植入式器械为支架、封堵器、骨科植入物、齿科植入物、缝合线或螺栓,所述支架为血管支架、气管支架、食道支架、尿道支架、肠道支架或胆道支架,所述骨科植入物为固定螺钉、固定铆钉或骨板。
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP16883063.6A EP3400969B1 (en) | 2016-01-08 | 2016-06-27 | Implanted device |
US16/068,122 US10799612B2 (en) | 2016-01-08 | 2016-06-27 | Implanted device |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610016894.2A CN106955374B (zh) | 2016-01-08 | 2016-01-08 | 植入式器械 |
CN201610016894.2 | 2016-01-08 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2017117922A1 true WO2017117922A1 (zh) | 2017-07-13 |
Family
ID=59273140
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2016/087291 WO2017117922A1 (zh) | 2016-01-08 | 2016-06-27 | 植入式器械 |
Country Status (4)
Country | Link |
---|---|
US (1) | US10799612B2 (zh) |
EP (1) | EP3400969B1 (zh) |
CN (1) | CN106955374B (zh) |
WO (1) | WO2017117922A1 (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108273119A (zh) * | 2018-03-08 | 2018-07-13 | 戴庆涛 | 一种胃肠外科的手术缝合线及其制作方法 |
GB2575487B (en) * | 2018-07-12 | 2023-02-08 | Cook Medical Technologies Llc | Coated medical device and method of coating such a device |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109381751B (zh) * | 2017-08-08 | 2022-01-28 | 上海微创医疗器械(集团)有限公司 | 一种可降解金属支架及其制备方法 |
CN109589456B (zh) * | 2017-09-30 | 2024-03-19 | 元心科技(深圳)有限公司 | 植入式器械 |
CN109966563B (zh) * | 2017-12-28 | 2021-08-03 | 元心科技(深圳)有限公司 | 植入式载药器械 |
CN111359021A (zh) * | 2018-12-25 | 2020-07-03 | 先健科技(深圳)有限公司 | 含锌植入器械 |
CN111110414B (zh) * | 2019-12-06 | 2022-01-04 | 先健科技(深圳)有限公司 | 植入系统 |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101077862A (zh) * | 2006-05-26 | 2007-11-28 | 首都医科大学 | D-葡萄糖基-l-氨基酸、其制备方法和应用 |
CN101283922A (zh) * | 2008-05-21 | 2008-10-15 | 中国科学院金属研究所 | 生物活性可吸收骨内固定植入器械 |
WO2008122596A2 (en) * | 2007-04-05 | 2008-10-16 | Cinvention Ag | Curable therapeutic implant composition |
US20090187258A1 (en) * | 2008-01-17 | 2009-07-23 | Wing Yuk Ip | Implant for Tissue Engineering |
CN102596277A (zh) * | 2009-07-09 | 2012-07-18 | 麦德托尼克瓦斯科尔勒公司 | 空心管状药物洗脱医疗器械 |
CN104212998A (zh) * | 2014-08-21 | 2014-12-17 | 北京大学 | 一种Zn-Mg系锌合金及其制备方法与应用 |
CN105648272A (zh) * | 2016-02-01 | 2016-06-08 | 中国科学院宁波材料技术与工程研究所 | 一种可降解的锌合金材料及其制备方法和应用 |
Family Cites Families (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090093875A1 (en) * | 2007-05-01 | 2009-04-09 | Abbott Laboratories | Drug eluting stents with prolonged local elution profiles with high local concentrations and low systemic concentrations |
CA2502018A1 (en) * | 2004-04-16 | 2005-10-16 | Conor Medsystems, Inc. | Bioresorbable stent delivery system |
US8293261B2 (en) * | 2005-01-28 | 2012-10-23 | Terumo Kabushiki Kaisha | Intravascular implant |
CA2885981A1 (en) * | 2005-04-05 | 2006-10-12 | Elixir Medical Corporation | Degradable implantable medical devices |
US20070244548A1 (en) * | 2006-02-27 | 2007-10-18 | Cook Incorporated | Sugar-and drug-coated medical device |
AU2008206954A1 (en) * | 2007-01-19 | 2008-07-24 | Cinvention Ag | Partially bioabsorbable implant |
RU2452517C2 (ru) * | 2007-01-30 | 2012-06-10 | Хемотек Аг | Биоразрушаемое средство для поддержания просвета сосудов |
US8084077B2 (en) * | 2007-05-25 | 2011-12-27 | Abbott Laboratories | One-step phosphorylcholine-linked polymer coating and drug loading of stent |
CN101283992A (zh) | 2008-05-29 | 2008-10-15 | 胡传良 | 盐酸曲美他嗪分散片及其制备方法 |
CN102190591A (zh) * | 2010-03-12 | 2011-09-21 | 陈郁 | 一种金属配合物、其制备方法及其应用 |
EP2425866A1 (en) * | 2010-08-04 | 2012-03-07 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. | Multifunctional coating with antimicrobial activity and cell adhesion regulating surface characteristics as well as a method for preparing the same |
CN104587534A (zh) * | 2013-10-31 | 2015-05-06 | 先健科技(深圳)有限公司 | 可吸收铁基合金支架 |
CN103948458A (zh) * | 2014-05-05 | 2014-07-30 | 加奇生物科技(上海)有限公司 | 颅内药物洗脱支架 |
CN104689369B (zh) * | 2015-03-13 | 2017-06-30 | 西安爱德万思医疗科技有限公司 | 一种人体可降解的耐蚀高强韧Zn‐Fe 系锌合金及其应用 |
-
2016
- 2016-01-08 CN CN201610016894.2A patent/CN106955374B/zh active Active
- 2016-06-27 EP EP16883063.6A patent/EP3400969B1/en active Active
- 2016-06-27 WO PCT/CN2016/087291 patent/WO2017117922A1/zh active Application Filing
- 2016-06-27 US US16/068,122 patent/US10799612B2/en active Active
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101077862A (zh) * | 2006-05-26 | 2007-11-28 | 首都医科大学 | D-葡萄糖基-l-氨基酸、其制备方法和应用 |
WO2008122596A2 (en) * | 2007-04-05 | 2008-10-16 | Cinvention Ag | Curable therapeutic implant composition |
US20090187258A1 (en) * | 2008-01-17 | 2009-07-23 | Wing Yuk Ip | Implant for Tissue Engineering |
CN101283922A (zh) * | 2008-05-21 | 2008-10-15 | 中国科学院金属研究所 | 生物活性可吸收骨内固定植入器械 |
CN102596277A (zh) * | 2009-07-09 | 2012-07-18 | 麦德托尼克瓦斯科尔勒公司 | 空心管状药物洗脱医疗器械 |
CN104212998A (zh) * | 2014-08-21 | 2014-12-17 | 北京大学 | 一种Zn-Mg系锌合金及其制备方法与应用 |
CN105648272A (zh) * | 2016-02-01 | 2016-06-08 | 中国科学院宁波材料技术与工程研究所 | 一种可降解的锌合金材料及其制备方法和应用 |
Non-Patent Citations (1)
Title |
---|
WEN, LIPING ET AL.: "Hypersensitivity to Implanted Devices: a Double-bladed Sword of High-tech? -From the Allergy Point of View", CHINESE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, vol. 3, no. 1, 31 March 2009 (2009-03-31), pages 9 - 15, XP009512828, ISSN: 1673-8705, DOI: 10.3969/j.issn.1673-8705.2009.01.003 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108273119A (zh) * | 2018-03-08 | 2018-07-13 | 戴庆涛 | 一种胃肠外科的手术缝合线及其制作方法 |
GB2575487B (en) * | 2018-07-12 | 2023-02-08 | Cook Medical Technologies Llc | Coated medical device and method of coating such a device |
Also Published As
Publication number | Publication date |
---|---|
CN106955374B (zh) | 2019-11-08 |
US20190008996A1 (en) | 2019-01-10 |
EP3400969A1 (en) | 2018-11-14 |
CN106955374A (zh) | 2017-07-18 |
US10799612B2 (en) | 2020-10-13 |
EP3400969B1 (en) | 2021-05-19 |
EP3400969A4 (en) | 2019-08-28 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2017117922A1 (zh) | 植入式器械 | |
US9474637B2 (en) | Absorbable stent having a coating for controlling degradation of the stent and maintaining pH neutrality | |
US8772437B2 (en) | Biodegradable nitric oxide generating polymers and related biomedical devices | |
US7323189B2 (en) | Liquid and low melting coatings for stents | |
RU2360646C2 (ru) | Эндолюминальный протез, содержащий лечебное средство | |
WO2015062547A1 (zh) | 可吸收铁基合金支架 | |
JP2007152126A (ja) | 分解コントロールおよびpH中性維持のためのコーティングを含む吸収性ステント | |
US8591931B2 (en) | Coronary stent with asymmetric drug releasing controlled coating | |
CA2641457A1 (en) | Medical devices for therapeutic agent delivery | |
JP2004173770A (ja) | 体内埋込医療器具 | |
WO2017067181A1 (zh) | 可吸收铁基合金植入医疗器械 | |
WO2017113657A1 (zh) | 可吸收铁基合金内固定植入医疗器械 | |
WO2016167460A1 (ko) | 생체 내 생분해 속도가 조절된 생분해성 스텐트 및 이의 제조 방법 | |
US8486434B2 (en) | Medical implant containing an antioxidative substance | |
JP2008253707A (ja) | 薬剤溶出ステント | |
WO2019128453A1 (zh) | 可吸收铁基植入式器械 | |
CN107865868B (zh) | 氨来呫诺的新用途 | |
AU2004226350A1 (en) | Devices, methods, and compositions to prevent restenosis | |
CN106902395B (zh) | 可吸收铁基合金植入医疗器械 | |
Chen et al. | Parylene-encapsulated copolymeric membranes as localized and sustained drug delivery platforms | |
Bhat et al. | Magnesium-lithium thin films for neurological applications–an in vitro investigation of glial cytocompatibility and neuroinflammatory response | |
CN114699567B (zh) | 一种可促进内皮细胞粘附和分化的体内植入物 | |
CN111388154A (zh) | 可吸收植入医疗器械 | |
JP2002193838A (ja) | 体内埋め込み医療材料および体内埋め込み医療器具 | |
AU2015218518A1 (en) | Coating II |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 16883063 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2016883063 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 2016883063 Country of ref document: EP Effective date: 20180808 |