CN1669597A - Medicine eluted cardiovascular support - Google Patents
Medicine eluted cardiovascular support Download PDFInfo
- Publication number
- CN1669597A CN1669597A CNA2004100169764A CN200410016976A CN1669597A CN 1669597 A CN1669597 A CN 1669597A CN A2004100169764 A CNA2004100169764 A CN A2004100169764A CN 200410016976 A CN200410016976 A CN 200410016976A CN 1669597 A CN1669597 A CN 1669597A
- Authority
- CN
- China
- Prior art keywords
- medicine
- support
- frame
- heparin
- biodegradable
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000003814 drug Substances 0.000 title claims abstract description 52
- 230000002526 effect on cardiovascular system Effects 0.000 title claims abstract description 15
- 229940079593 drug Drugs 0.000 title abstract description 11
- 229920000669 heparin Polymers 0.000 claims abstract description 20
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 claims abstract description 17
- 229960002897 heparin Drugs 0.000 claims abstract description 17
- 239000000463 material Substances 0.000 claims abstract description 17
- RQNWIZPPADIBDY-UHFFFAOYSA-N arsenic atom Chemical compound [As] RQNWIZPPADIBDY-UHFFFAOYSA-N 0.000 claims abstract description 9
- RKDVKSZUMVYZHH-UHFFFAOYSA-N 1,4-dioxane-2,5-dione Chemical compound O=C1COC(=O)CO1 RKDVKSZUMVYZHH-UHFFFAOYSA-N 0.000 claims abstract description 7
- JJTUDXZGHPGLLC-IMJSIDKUSA-N 4511-42-6 Chemical compound C[C@@H]1OC(=O)[C@H](C)OC1=O JJTUDXZGHPGLLC-IMJSIDKUSA-N 0.000 claims abstract description 7
- 229920001577 copolymer Polymers 0.000 claims abstract description 6
- 229920001519 homopolymer Polymers 0.000 claims abstract description 5
- 229910000831 Steel Inorganic materials 0.000 claims abstract description 3
- 150000001413 amino acids Chemical class 0.000 claims abstract description 3
- 239000010959 steel Substances 0.000 claims abstract description 3
- 208000037803 restenosis Diseases 0.000 claims description 30
- 239000011248 coating agent Substances 0.000 claims description 9
- 238000000576 coating method Methods 0.000 claims description 9
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 claims description 6
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 claims description 6
- JBFHTYHTHYHCDJ-UHFFFAOYSA-N gamma-caprolactone Chemical compound CCC1CCC(=O)O1 JBFHTYHTHYHCDJ-UHFFFAOYSA-N 0.000 claims description 6
- 229930002330 retinoic acid Natural products 0.000 claims description 6
- 229960001727 tretinoin Drugs 0.000 claims description 6
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 4
- 108010092160 Dactinomycin Proteins 0.000 claims description 3
- 229930012538 Paclitaxel Natural products 0.000 claims description 3
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 claims description 3
- 229960000640 dactinomycin Drugs 0.000 claims description 3
- ZFGMDIBRIDKWMY-PASTXAENSA-N heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 claims description 3
- 229960001008 heparin sodium Drugs 0.000 claims description 3
- 229960001592 paclitaxel Drugs 0.000 claims description 3
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 claims description 3
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 claims description 3
- 229960002930 sirolimus Drugs 0.000 claims description 3
- VWDXGKUTGQJJHJ-UHFFFAOYSA-N Catenarin Natural products C1=C(O)C=C2C(=O)C3=C(O)C(C)=CC(O)=C3C(=O)C2=C1O VWDXGKUTGQJJHJ-UHFFFAOYSA-N 0.000 claims description 2
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 claims description 2
- 229930105110 Cyclosporin A Natural products 0.000 claims description 2
- 239000010282 Emodin Substances 0.000 claims description 2
- RBLJKYCRSCQLRP-UHFFFAOYSA-N Emodin-dianthron Natural products O=C1C2=CC(C)=CC(O)=C2C(=O)C2=C1CC(=O)C=C2O RBLJKYCRSCQLRP-UHFFFAOYSA-N 0.000 claims description 2
- YOOXNSPYGCZLAX-UHFFFAOYSA-N Helminthosporin Natural products C1=CC(O)=C2C(=O)C3=CC(C)=CC(O)=C3C(=O)C2=C1O YOOXNSPYGCZLAX-UHFFFAOYSA-N 0.000 claims description 2
- NTGIIKCGBNGQAR-UHFFFAOYSA-N Rheoemodin Natural products C1=C(O)C=C2C(=O)C3=CC(O)=CC(O)=C3C(=O)C2=C1O NTGIIKCGBNGQAR-UHFFFAOYSA-N 0.000 claims description 2
- DFBIRQPKNDILPW-CIVMWXNOSA-N Triptolide Chemical compound O=C1OCC([C@@H]2C3)=C1CC[C@]2(C)[C@]12O[C@H]1[C@@H]1O[C@]1(C(C)C)[C@@H](O)[C@]21[C@H]3O1 DFBIRQPKNDILPW-CIVMWXNOSA-N 0.000 claims description 2
- RHMXXJGYXNZAPX-UHFFFAOYSA-N emodin Chemical compound C1=C(O)C=C2C(=O)C3=CC(C)=CC(O)=C3C(=O)C2=C1O RHMXXJGYXNZAPX-UHFFFAOYSA-N 0.000 claims description 2
- VASFLQKDXBAWEL-UHFFFAOYSA-N emodin Natural products OC1=C(OC2=C(C=CC(=C2C1=O)O)O)C1=CC=C(C=C1)O VASFLQKDXBAWEL-UHFFFAOYSA-N 0.000 claims description 2
- 229930182470 glycoside Natural products 0.000 claims description 2
- 150000002338 glycosides Chemical class 0.000 claims description 2
- PKUBGLYEOAJPEG-UHFFFAOYSA-N physcion Natural products C1=C(C)C=C2C(=O)C3=CC(C)=CC(O)=C3C(=O)C2=C1O PKUBGLYEOAJPEG-UHFFFAOYSA-N 0.000 claims description 2
- YKUJZZHGTWVWHA-UHFFFAOYSA-N triptolide Natural products COC12CC3OC3(C(C)C)C(O)C14OC4CC5C6=C(CCC25C)C(=O)OC6 YKUJZZHGTWVWHA-UHFFFAOYSA-N 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 16
- 208000007536 Thrombosis Diseases 0.000 abstract description 15
- 230000035876 healing Effects 0.000 abstract description 8
- 230000001154 acute effect Effects 0.000 abstract description 7
- 239000000126 substance Substances 0.000 abstract description 7
- 208000027418 Wounds and injury Diseases 0.000 abstract description 6
- 229920002521 macromolecule Polymers 0.000 abstract description 2
- PAPBSGBWRJIAAV-UHFFFAOYSA-N ε-Caprolactone Chemical compound O=C1CCCCCO1 PAPBSGBWRJIAAV-UHFFFAOYSA-N 0.000 abstract description 2
- 230000015556 catabolic process Effects 0.000 abstract 5
- 238000006731 degradation reaction Methods 0.000 abstract 5
- 229910052785 arsenic Inorganic materials 0.000 abstract 1
- 230000006378 damage Effects 0.000 abstract 1
- 230000007547 defect Effects 0.000 abstract 1
- 238000010828 elution Methods 0.000 abstract 1
- 201000006828 endometrial hyperplasia Diseases 0.000 abstract 1
- 230000003628 erosive effect Effects 0.000 abstract 1
- 208000014674 injury Diseases 0.000 abstract 1
- 239000002574 poison Substances 0.000 abstract 1
- 231100000614 poison Toxicity 0.000 abstract 1
- 210000005077 saccule Anatomy 0.000 abstract 1
- GOLCXWYRSKYTSP-UHFFFAOYSA-N Arsenious Acid Chemical compound O1[As]2O[As]1O2 GOLCXWYRSKYTSP-UHFFFAOYSA-N 0.000 description 15
- 210000004204 blood vessel Anatomy 0.000 description 13
- HJTAZXHBEBIQQX-UHFFFAOYSA-N 1,5-bis(chloromethyl)naphthalene Chemical compound C1=CC=C2C(CCl)=CC=CC2=C1CCl HJTAZXHBEBIQQX-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- 239000010410 layer Substances 0.000 description 11
- 239000002904 solvent Substances 0.000 description 9
- 206010061218 Inflammation Diseases 0.000 description 7
- 229940024606 amino acid Drugs 0.000 description 7
- 230000006907 apoptotic process Effects 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 7
- 238000005516 engineering process Methods 0.000 description 7
- 230000004054 inflammatory process Effects 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 230000003110 anti-inflammatory effect Effects 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 206010020718 hyperplasia Diseases 0.000 description 5
- 229920000642 polymer Polymers 0.000 description 5
- 201000011510 cancer Diseases 0.000 description 4
- 210000004351 coronary vessel Anatomy 0.000 description 4
- 229910001220 stainless steel Inorganic materials 0.000 description 4
- 239000010935 stainless steel Substances 0.000 description 4
- 208000036762 Acute promyelocytic leukaemia Diseases 0.000 description 3
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000005530 etching Methods 0.000 description 3
- 238000005227 gel permeation chromatography Methods 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 229940086984 trisenox Drugs 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 description 2
- 208000033826 Promyelocytic Acute Leukemia Diseases 0.000 description 2
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 2
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 2
- 230000033115 angiogenesis Effects 0.000 description 2
- 238000002399 angioplasty Methods 0.000 description 2
- 238000003782 apoptosis assay Methods 0.000 description 2
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 2
- 230000023555 blood coagulation Effects 0.000 description 2
- 239000003431 cross linking reagent Substances 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- 210000003725 endotheliocyte Anatomy 0.000 description 2
- 238000012869 ethanol precipitation Methods 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- 238000006116 polymerization reaction Methods 0.000 description 2
- 230000005522 programmed cell death Effects 0.000 description 2
- KSBAEPSJVUENNK-UHFFFAOYSA-L tin(ii) 2-ethylhexanoate Chemical compound [Sn+2].CCCCC(CC)C([O-])=O.CCCCC(CC)C([O-])=O KSBAEPSJVUENNK-UHFFFAOYSA-L 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical class CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- 206010000830 Acute leukaemia Diseases 0.000 description 1
- 102100027211 Albumin Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 description 1
- 206010003162 Arterial injury Diseases 0.000 description 1
- 206010065553 Bone marrow failure Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 102000011727 Caspases Human genes 0.000 description 1
- 108010076667 Caspases Proteins 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 208000005189 Embolism Diseases 0.000 description 1
- 230000010190 G1 phase Effects 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 102000006587 Glutathione peroxidase Human genes 0.000 description 1
- 108700016172 Glutathione peroxidases Proteins 0.000 description 1
- 101000971171 Homo sapiens Apoptosis regulator Bcl-2 Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010020880 Hypertrophy Diseases 0.000 description 1
- 206010027336 Menstruation delayed Diseases 0.000 description 1
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Natural products C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 1
- 208000001435 Thromboembolism Diseases 0.000 description 1
- PSDYQSWHANEKRV-UHFFFAOYSA-N [S]N Chemical compound [S]N PSDYQSWHANEKRV-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- -1 amino, carboxyl Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 230000003143 atherosclerotic effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000032677 cell aging Effects 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 239000011247 coating layer Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000007887 coronary angioplasty Methods 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000008069 intimal proliferation Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 238000005297 material degradation process Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 230000001473 noxious effect Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 230000010287 polarization Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000008844 regulatory mechanism Effects 0.000 description 1
- 229920002379 silicone rubber Polymers 0.000 description 1
- 239000004945 silicone rubber Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 210000003606 umbilical vein Anatomy 0.000 description 1
Landscapes
- Materials For Medical Uses (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A kind of medicinal elution cardiovascular frame, comprises frame and biological degradation layer, which is made of biological degradation material that embeds the drug and covered in the frame. The saccule expansion is made of rustless steel or biological degradation material. Wherein, the biological degradation material includes glycolide, L-lactide, homopolymers or one of the copolymer and the copolymer with polyfunctional group amino acid of Epsilon-caprolactone. The biological degradation layer contains the drug is a kind of macromolecule graft heparin, the drug contains arsenic has the effect of opposing being more narrow. After the frame is implanted, the drug is deliveried to limit the endometrial hyperplasia sufficiently, and the heparin is exist continuously and steadily. It can prevent the occurrence of acute or subacute thrombus, and can promote the healing of the injury vessel wall, prevent the occurrence of late thrombus. Compare to the traditional heparin frame, it overcomes the defects like intolerance by the humor erosion and interceding poison substance in the progress of chemical binding.
Description
Technical field
The present invention relates to a kind of medicinal support, particularly a kind of being used for cardiovascularly can discharge medicine, promote the balloon expandable stent of injured blood vessel wall healing simultaneously.
Background technology
Dotter in 1964 and Judkings (Dotter CT, Jukines MP.Tranaluminal treatmantof arteriosclerotic obstruction, 1964,30:654) notion of percutaneous transluminal angio plasty has been proposed, and hypothesis uses silicone rubber or plastics to come support blood vessels, unobstructed with blood flow in the maintenance lumen of vessels, 1987, Sigwart (Sigwart U, et al.Intravascular stents to prevent occlusion andrestenosis after tranaluminal angioplasty.N Engl J Med, 1987; 316:701) grade is used for metal rack in the blood vessel coronary artery first, for treatment blood vessel blockage disease provides good approach.
Ideal support should possess following feature: (1) better biocompatibility: minimum blood coagulation enhancing effect, and implant the back and be difficult for blood coagulation reaction and thrombosis take place, be difficult for causing the inflammatory reaction and the neointimal hyperplasia of blood vessel wall; (2) easy polarization; (3) have pliability preferably, easily shift diseased region onto; (4) easily expansion, support force is strong and mechanical robustness arranged.
Coronary atherosclerotic heart disease is one of major reason of cardiovascular disease death, although emergency treatment reconstructing blood vessel technology [comprises thromboembolism treatment, coronary artery bypass grafting CCABG], percutaneous transluminal coronary angioplasty (PTCA)] saved a large amount of dying patients, but the vascular restenosis incidence rate behind CABG and the PTCA still very high (restenosis rate is 40% behind the PTCA), it mainly comes from inner membrance, middle film hypertrophy and the comprehensive function of blood vessel wall construction geometry reconstruct institute, the appearance of coronary artery bracket and application have obviously reduced the vascular restenosis incidence rate behind the PTCA, yet the clinical practice of support is limited by following Several Factors: 1) subacute stent thrombosis forms (3-10 days); 2) in-stent restenosis in late period (about half a year) (incidence rate about about 20%); 3) tardy property thrombosis.
Patent EP132060 discloses a kind of balloon expandable formula stainless steel stent, and at present, this balloon expandable stainless steel stent can satisfy above-mentioned back three's condition, but subacute stent thrombosis and in-stent restenosis at a specified future date are two big complication of balloon expandable stainless steel stent.For solving an above-mentioned difficult problem, people not broken hair meter release the biological characteristics that New-support improves support, and drug-eluting stent is exactly wherein a kind of.
Human body drug resistance dosage is too low, is difficult to reach valid density at target site, and this may be the reason that systemic administration does not prove effective.And active drug is transported to the arterial injury place by support, will help the treatment of complication.
United States Patent (USP) U.S.6,231,600 for preventing the in-stent restenosis after support is implanted and the generation of thrombosis, designed a kind of overbrushing layer support technology: ground floor is made up of polymer, anti-restenosis (paclitaxel) and cross-linking agent (aziridine), the second layer is anticoagulant medicine heparin, two-layer between by the cross-linking agent bonding.But the technology of preparing of this Patent publish is comparatively complicated, and has introduced harmful substance (aziridine), is unfavorable for promoting the use of.
Summary of the invention
The technical issues that need to address of the present invention are to disclose a kind of medicine eluted cardiovascular frame and preparation method thereof, comparatively complicated to overcome subacute stent thrombosis that prior art exists and restenosis at a specified future date and technology of preparing, and introduced harmful substance (aziridine), be unfavorable for the defective promoted the use of, satisfy people's demand.
Technical scheme of the present invention:
Medicine eluted cardiovascular frame of the present invention is by support, be coated in the biodegradable layers that the employing Biodegradable material that is coated with medicine on the support makes and constitute.
Said balloon expandable stent can be made by rustless steel or biodegradable material;
Biodegradable material comprise Acetic acid, hydroxy-, bimol. cyclic ester (glycolic acid, GA), the L-lactide (L-lactic acid, LLA) or 6-caprolactone (caprolactone, a kind of in homopolymer CL) or the copolymer and with the copolymer of multifunctional amino acid.This preparation methods is a prior art, and its preparation method can be consulted document (Makromol.Chem.1987,188:1809-1814) disclosed method.
The biodegradable layers of coating medicine is a kind of Biodegradable high-molecular grafting heparin, and its preparation method is a prior art, can consult the disclosed method of patent (application number 01132179.2).
Said medicine is a kind of medicine with anti-restenosis function, comprise arsenicum or retinoic acid, or one or more in glycoside or the paclitaxel in arsenicum or retinoic acid and emodin, rapamycin, dactinomycin, ciclosporin A, Radix Tripterygii Wilfordii, triptolide, the Radix Tripterygii Wilfordii.
According to optimized technical scheme of the present invention, be coated in the biodegradable layers on the support, the weight percent content with medicine of anti-restenosis function is 0.02～80%; Too high levels, that then generation is filmed breaks, low excessively, then causes restenosis to suppress the decline of ability, will increase coating layer thickness simultaneously, causes the decline of coating quality;
The weight percent content of heparin sodium is 0.002～50%; Too high levels then causes and the conflicting of material and drug compatibility, and is low excessively, then is difficult to suppress the inflammatory reaction that material degradation brings out.
As adopt the L-lactide: Acetic acid, hydroxy-, bimol. cyclic ester: during the homopolymer of 6-caprolactone, its preferred weight ratio is:
L-lactide: Acetic acid, hydroxy-, bimol. cyclic ester: 6-caprolactone=1: 10～90: 5～10.
In JIUYUE, 2000, U.S. FDA are in approval TRISENOX (arsenic trioxide) listing.European commission classifies TRISENOX as in October, 2000 " seldom used medicine ", on March 13rd, 2002, wholly-owned subsidiary Cell Therapeutics (CTI) the Britain company limited of Cell Therapeutics is announced: European commission has checked and approved this medicine goes on the market in Europe, and indication is the leukemia (APL) of growing up.European commission also ratifies the medicine of TRISENOX for treatment multiple myeloma and myelodysplastic syndrome.
Arsenic trioxide has multiple action mechanism, comprising: promote born of the same parents' apoptotic effect, angiogenesis inhibiting effect, anti-hyperplasia effect etc.:
1, promote the apoptosis effect: apoptosis (Apoptosis) is called programmed cell death (Programmed cell death), the normally phenomenon that just can take place after the normal cell aging again.Arsenic trioxide may suppress bcl-2 albumen or disturb other regulatory mechanism and start the path in mitochondrion stage before the apoptosis program, impels apoptosis.Arsenic trioxide also may further suppress the effect of the amino sulfur of peroxidating husband (Glutathione peroxidase) and increase the content of cell hydrogen peroxide, makes apoptosis.Also having a kind of may be the activity that arsenic trioxide has excited half Guang-asparagine acid albumin (Caspases), causes apoptosis.
2, anti-hyperplasia effect: the human myeloma cell through arsenic trioxide was handled, can be stuck in G1 phase or G2-M between the phase, can't carry out cell cycle, and stop its hyperplasia effect.
3, angiogenesis inhibiting effect:, studied the back and find that arsenic trioxide can activate endotheliocyte, regulates the generation of the effect of endotheliocyte adhesion molecule, the growth that prevents the capillary tubule, prevention collateral blood vessels and suppress VEGF (VEGF) through the human umbilical vein endothelial cell (HUVECs) that arsenic trioxide was handled.
China at first was used for the treatment of arsenic trioxide acute promyelocytic leukemia and obtained surprising curative effect and come into one's own the 1970's.Every day is with the arsenic trioxide of 10mg, intravenous administration 28 to 60 days, its complete remission rate reaches 65.6% to 84%, even the survival of 28.2% sufferer is arranged more than 10 years, wherein most sufferer does not have the bone marrow depression phenomenon, does not have serious side effect to take place yet.1997, Shen Z-X used arsenic trioxide treatment acute leukemia, had 9 to reach fully and alleviate among 10 patients, and the administration time that reaches alleviation does not fully wait from 28 days by 44 days, and the administration accumulated dose is from 280 to 440mg.
Studies show that further arsenic trioxide is for many dissimilar cancer cell, for example: HEL, K-562, K-562 (002), K-562 (01) and Jurkat etc. have the growth of inhibition effect, and as: NB-4, HL-60, U-937, CEM, HL-60, KG-1a, PBL-985, the cancer cell of ML-2 and MV-4-11 or the like has the effect of dying of the cell of promotion carving.The effect machine of wide effect changes so, and multiple blood malignant tumor and solid tumor for beyond the acute promyelocytic leukemia in the application in future, provide the feasibility and the theoretical basis of clinical efficacy.
The present invention adopts the arsenicum drug stent of embedding trace to prevent restenosis after support is implanted by multiaction mechanism on the mechanism and basis in clinical practice of above-mentioned effect.Can significantly suppress intimal proliferation after 2 months pig coronary artery bracket is inserted, effect surpasses rapamycin, but endothelialization is good again.
Adopt infrared spectrum analysis, compare with the result who implanted two months, the characteristic group of all not finding coating material of support top layer and support top layer conjunctive tissue concludes that thus coating material is degraded fully.
Above-mentioned medicine eluted cardiovascular frame is preparation like this:
(1) at first prepares the balloon expandable stainless steel stent, or prepare the Biodegradable material support according to the technology of United States Patent (USP) U.S.5670161 patent disclosure according to the disclosed technology of patent EP132060;
(2) support be impregnated in the mixed system of the biodegradable layer material of medicine with anti-restenosis function, coating medicine and solvent composition, or adopt and to have the medicine of anti-restenosis function, the biodegradable layer material of coating medicine and the mixed system of solvent composition and spray, said solvent is can dissolved substance and the biodegradable layer material of coating medicine, comprises a kind of and composition thereof in chloroform, ethanol, methanol, dichloroethanes, acetone or the DMC dimethyl carbonate;
(3) after the support drying, promptly obtain medicine eluted cardiovascular frame of the present invention.
According to the present invention, support is etching in advance, resurfacing, etching again after also can coating.
Term " etching " refers to the laser clean cut.
By above-mentioned disclosed technical scheme as seen, the present invention has applied the Biodegradable high-molecular grafting heparin that one deck has anti-restenosis function on this support, after support is implanted, anti-restenosis medicaments discharges, fully suppress neointimal hyperplasia, the continual and steady existence of heparin, can prevent generation acute, subacute stent thrombosis, can promote simultaneously the healing of injured blood vessel wall, prevent the generation of advanced thrombus, compare with traditional heparin support, overcome the not anti-body fluid of heparin and washed away (heparin is a water soluble drug), and the defective of introducing noxious substance in the chemical bond process.
The specific embodiment
Embodiment 1
The preparation of Biodegradable material:
Take by weighing 70 parts of L-LA, 5 parts of GA and 25 parts of ε-CL in exsiccant, as to have stirrer polymerization bottle, with N2 displacement 3 times, place 160 ℃ of oil baths, after waiting to melt, the 0.02g/ml stannous octoate chloroformic solution (catalytic amount is the 0.02wt% of monomer mass) that adds certain volume, chloroform is removed in decompression, stirs reaction 5h down, polymer dissolves with chloroform, ethanol precipitation.(gel permeation chromatography GPC) characterizes the molecular weight of resulting polymers, and molecular weight is greater than 100,000 with gel permeation chromatography.
Embodiment 2
The preparation of heparinization poly-(lactic-co-glycolic acid-aminoacid):
Take by weighing 0.1molL-lactide and 0.05mol and contain the morpholine diketone derivatives monomer of benzyloxy protection glutamic acid in exsiccant, as to have stirrer polymerization bottle; with N2 displacement 3 times; place 160 ℃ of oil baths; after waiting to melt; the 0.02g/ml stannous octoate chloroformic solution that adds certain volume, chloroform is removed in decompression, stirs reaction 5h down; polymer dissolves with chloroform, ethanol precipitation.Resulting polymers is with the Pd/C catalyst, and hydrogen bubbling 40 is sloughed benzyloxy, is promptly gathered (lactic-co-glycolic acid-glutamic acid).
Contain amino, carboxyl in the heparin, will gather in the mixed solvent that (lactic-co-glycolic acid-aspartic acid) be dissolved in oxolane and water, heparin sodium is dissolved in the low amounts of water, regulating pH with diluted acid is about 4.Both are mixed, Dcci (the dicyclohexylcarbodiimide that adds equivalent, DCC), stir 24h down at 4 ℃, removal of solvent under reduced pressure adds an amount of chloroform again, the elimination insoluble matter, gained solution petroleum ether precipitation, dry 24h under the room temperature promptly obtains heparinization macromolecule (heparinizedpolymer).
Embodiment 3
0.1 gram heparinization is gathered (lactic-co-glycolic acid-aminoacid) and the 0.1 anti-restenosis medicaments arsenicum of gram and 0.2 Cray handkerchief mycin (Rampamycin) to be dissolved in the 5ml solvent, balloon expandable stent that again will be as shown in Figure 1 is dipped in this solution about 30s, dries up standby after the taking-up.This support can overcome in-stent restenosis, and can prevent formation acute, subacute stent thrombosis, and heparin has anti-inflammatory effect simultaneously, can suppress the foreign body inflammatory reaction of support, promotes the healing of blood vessel wound.
Embodiment 4
0.1 gram heparinization is gathered (lactic-co-glycolic acid-aminoacid) and the 0.2 anti-restenosis medicaments retinoic acid of gram and 0.2 gram dactinomycin (Actonimycin) to be dissolved in the 5ml solvent, balloon expandable stent that again will be as shown in Figure 1 is dipped in this solution about 30s, dries up standby after the taking-up.This support can overcome in-stent restenosis, and can prevent formation acute, subacute stent thrombosis, and heparin has anti-inflammatory effect simultaneously, can suppress the foreign body inflammatory reaction of support, promotes the healing of blood vessel wound.
Embodiment 5
0.1 gram heparinization is gathered (lactic-co-glycolic acid-aminoacid) and the 0.1 anti-restenosis medicaments arsenicum of gram and 0.2 gram paclitaxel (Taxol) to be dissolved in the 5ml solvent, balloon expandable stent that again will be as shown in Figure 1 is dipped in this solution about 30s, dries up standby after the taking-up.This support can overcome in-stent restenosis, and can prevent formation acute, subacute stent thrombosis, and heparin has anti-inflammatory effect simultaneously, can suppress the foreign body inflammatory reaction of support, promotes the healing of blood vessel wound.
Embodiment 6
0.1 gram heparinization poly-(lactic-co-glycolic acid-aminoacid) and the anti-restenosis medicaments retinoic acid of 0.2 gram are dissolved in the 5ml solvent, again will balloon expandable stent as shown in Figure 1 be dipped in this solution about 30s, dry up standby after the taking-up.This support can overcome in-stent restenosis, and can prevent formation acute, subacute stent thrombosis, and heparin has anti-inflammatory effect simultaneously, can suppress the foreign body inflammatory reaction of support, promotes the healing of blood vessel wound.
Embodiment 7
0.1 gram heparinization poly-(lactic-co-glycolic acid-aminoacid) and the anti-restenosis medicaments arsenicum of 0.2 gram are dissolved in the 5ml solvent, again will balloon expandable stent as shown in Figure 1 be dipped in this solution about 30s, dry up standby after the taking-up.This support can overcome in-stent restenosis, and can prevent formation acute, subacute stent thrombosis, and heparin has anti-inflammatory effect simultaneously, can suppress the foreign body inflammatory reaction of support, promotes the healing of blood vessel wound.
Claims (8)
1. medicine eluted cardiovascular frame, by support, be coated in the biodegradable layers that the employing Biodegradable material that is coated with medicine on the support makes and constitute, it is characterized in that, Biodegradable material comprise a kind of in the homopolymer of Acetic acid, hydroxy-, bimol. cyclic ester, L-lactide or 6-caprolactone or the copolymer and with the copolymer of multifunctional amino acid, the biodegradable layers of coating medicine is a kind of Biodegradable high-molecular grafting heparin, and said medicine is a kind of medicine with anti-restenosis function.
2. medicine eluted cardiovascular frame according to claim 1 is characterized in that, said support is a balloon expandable stent.
3. medicine eluted cardiovascular frame according to claim 2 is characterized in that, said support is made by rustless steel or biodegradable material;
4. medicine eluted cardiovascular frame according to claim 1, it is characterized in that, medicine with anti-restenosis function comprises arsenicum or retinoic acid, or one or more in glycoside or the paclitaxel in arsenicum or retinoic acid and emodin, rapamycin, dactinomycin, ciclosporin A, Radix Tripterygii Wilfordii, triptolide, the Radix Tripterygii Wilfordii.
5. according to each described medicine eluted cardiovascular frame of claim 1～4, it is characterized in that be coated in the biodegradable layers on the support, the weight percent content with medicine of anti-restenosis function is 0.02～80%;
6. want 4 described medicine eluted cardiovascular frames according to right, it is characterized in that, be coated in the biodegradable layers on the support, the weight percent content with medicine of anti-restenosis function is 0.02～80%.
7. want 6 described medicine eluted cardiovascular frames according to right, it is characterized in that, the weight percent content of heparin sodium is 0.002～50%.
8. want 7 described medicine eluted cardiovascular frames according to right, it is characterized in that, as adopting the L-lactide: Acetic acid, hydroxy-, bimol. cyclic ester: during the homopolymer of 6-caprolactone, its preferred weight ratio is:
L-lactide: Acetic acid, hydroxy-, bimol. cyclic ester: 6-caprolactone=1: 10～90: 5～10.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2004100169764A CN1669597A (en) | 2004-03-16 | 2004-03-16 | Medicine eluted cardiovascular support |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2004100169764A CN1669597A (en) | 2004-03-16 | 2004-03-16 | Medicine eluted cardiovascular support |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1669597A true CN1669597A (en) | 2005-09-21 |
Family
ID=35041172
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2004100169764A Pending CN1669597A (en) | 2004-03-16 | 2004-03-16 | Medicine eluted cardiovascular support |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1669597A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101007187A (en) * | 2007-01-26 | 2007-08-01 | 复旦大学附属华山医院 | Preparation method of composite drug-eluting stent and its drug coated layer |
| CN100360094C (en) * | 2005-10-21 | 2008-01-09 | 哈尔滨工程大学 | Preparation method of vascular stent covered with arsenic oxide film |
| US8518429B2 (en) | 2007-11-27 | 2013-08-27 | Beijing Amsino Medical Co., Ltd. | Arsenic trioxide medical elution scaffold |
| CN110711056A (en) * | 2014-10-28 | 2020-01-21 | 株式会社Jimro | drug eluting stent |
-
2004
- 2004-03-16 CN CNA2004100169764A patent/CN1669597A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100360094C (en) * | 2005-10-21 | 2008-01-09 | 哈尔滨工程大学 | Preparation method of vascular stent covered with arsenic oxide film |
| CN101007187A (en) * | 2007-01-26 | 2007-08-01 | 复旦大学附属华山医院 | Preparation method of composite drug-eluting stent and its drug coated layer |
| CN101007187B (en) * | 2007-01-26 | 2014-01-01 | 复旦大学附属华山医院 | A kind of preparation method of composite drug-eluting stent and drug coating thereof |
| US8518429B2 (en) | 2007-11-27 | 2013-08-27 | Beijing Amsino Medical Co., Ltd. | Arsenic trioxide medical elution scaffold |
| CN110711056A (en) * | 2014-10-28 | 2020-01-21 | 株式会社Jimro | drug eluting stent |
| US11241322B2 (en) | 2014-10-28 | 2022-02-08 | Jimro Co., Ltd. | Drug-eluting stent |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1303947C (en) | Medicine eluted cardiovascular frame and its preparing process | |
| US8021678B2 (en) | Implantable medical device with polymer coating in a surface area to volume ratio providing surface erosion characteristics | |
| CN101264351B (en) | Composite coating cardiovascular medicaments elution stent and preparation thereof | |
| RU2363497C2 (en) | Pharmaceutical compositions | |
| Strecker et al. | Effect on intimal hyperplasia of dexamethasone released from coated metal stents compared with non-coated stents in canine femoral arteries | |
| JP5329435B2 (en) | Coronary stent with asymmetric drug release controlled coating | |
| Gong et al. | Heparin-immobilized polymers as non-inflammatory and non-thrombogenic coating materials for arsenic trioxide eluting stents | |
| AU2003205586A1 (en) | Drug delivery systems for the prevention and treatment of vascular diseases comprising rapamycin and derivatives thereof | |
| JP2005530561A (en) | Silicone mixtures and composites for drug delivery | |
| JP4861178B2 (en) | Medical article surface coating with biocompatibility and biological stability | |
| JP2004222953A (en) | Indwelling stent | |
| JP2008253707A (en) | Drug-eluting stent | |
| CN1669597A (en) | Medicine eluted cardiovascular support | |
| US8591571B2 (en) | Drug-eluting stent | |
| CN1669595A (en) | Medicine eluted cardiovascular support | |
| CN1669596A (en) | Medicine eluted cardiovascular support | |
| CN1429547A (en) | Coronary artery skeleton medicinal coating for preventing restenosis of blood vessel | |
| CN113289073A (en) | Degradable drug stent for preventing or treating intimal hyperplasia after interventional operation and preparation method thereof | |
| RU2775427C1 (en) | Drug-eluting stent and method for production thereof | |
| CN120815228A (en) | A multifunctional vascular stent for diabetic patients and preparation method thereof | |
| CN113289074A (en) | Novel drug-coated stent and preparation method thereof | |
| MXPA06007319A (en) | Parmaceutical compositions | |
| AU2007200756A1 (en) | Drug delivery systems for the prevention and treatment of vascular diseases comprising rapamycin and derivatives thereof | |
| AU2009201507A1 (en) | Drug delivery systems for the prevention and treatment of vascular diseases comprising rapamycin and derivatives thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |