CN104174074A - Medicine coating composition as well as preparation method thereof and an implanting or intervention medical apparatus made thereof - Google Patents
Medicine coating composition as well as preparation method thereof and an implanting or intervention medical apparatus made thereof Download PDFInfo
- Publication number
- CN104174074A CN104174074A CN201410456663.4A CN201410456663A CN104174074A CN 104174074 A CN104174074 A CN 104174074A CN 201410456663 A CN201410456663 A CN 201410456663A CN 104174074 A CN104174074 A CN 104174074A
- Authority
- CN
- China
- Prior art keywords
- component
- solution
- medicine
- paclitaxel
- medication coat
- 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.)
- Granted
Links
- 239000003814 drug Substances 0.000 title claims abstract description 200
- 238000002360 preparation method Methods 0.000 title claims abstract description 71
- 229940079593 drug Drugs 0.000 title claims description 111
- 239000008199 coating composition Substances 0.000 title abstract description 10
- 239000000203 mixture Substances 0.000 claims abstract description 58
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 53
- 239000002904 solvent Substances 0.000 claims abstract description 25
- 210000004204 blood vessel Anatomy 0.000 claims abstract description 22
- 239000012153 distilled water Substances 0.000 claims abstract description 20
- 210000004369 blood Anatomy 0.000 claims abstract description 11
- 239000008280 blood Substances 0.000 claims abstract description 11
- 239000000126 substance Substances 0.000 claims abstract description 7
- -1 small molecule compounds Chemical class 0.000 claims abstract description 5
- 229930012538 Paclitaxel Natural products 0.000 claims description 108
- 229960001592 paclitaxel Drugs 0.000 claims description 108
- 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 108
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 90
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 89
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 88
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 88
- 230000001476 alcoholic effect Effects 0.000 claims description 82
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 48
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 22
- 229910052740 iodine Inorganic materials 0.000 claims description 22
- 239000011630 iodine Substances 0.000 claims description 22
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical group [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 21
- 238000002513 implantation Methods 0.000 claims description 19
- 238000007789 sealing Methods 0.000 claims description 19
- 238000003756 stirring Methods 0.000 claims description 19
- 229940113116 polyethylene glycol 1000 Drugs 0.000 claims description 16
- 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 16
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 16
- 229920000642 polymer Polymers 0.000 claims description 15
- 230000001954 sterilising effect Effects 0.000 claims description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- 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 14
- 229960002930 sirolimus Drugs 0.000 claims description 14
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 13
- 239000002202 Polyethylene glycol Substances 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 11
- 229920001223 polyethylene glycol Polymers 0.000 claims description 9
- 206010020880 Hypertrophy Diseases 0.000 claims description 8
- QGBSISYHAICWAH-UHFFFAOYSA-N dicyandiamide Chemical group NC(N)=NC#N QGBSISYHAICWAH-UHFFFAOYSA-N 0.000 claims description 7
- 229910017053 inorganic salt Inorganic materials 0.000 claims description 7
- 235000009518 sodium iodide Nutrition 0.000 claims description 7
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 6
- 239000001110 calcium chloride Substances 0.000 claims description 6
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 6
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 6
- 239000000047 product Substances 0.000 claims description 6
- 239000003146 anticoagulant agent Substances 0.000 claims description 5
- 229940127219 anticoagulant drug Drugs 0.000 claims description 5
- 210000003708 urethra Anatomy 0.000 claims description 5
- HKVAMNSJSFKALM-GKUWKFKPSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[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 HKVAMNSJSFKALM-GKUWKFKPSA-N 0.000 claims description 4
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 claims description 4
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 claims description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- RRGUKTPIGVIEKM-UHFFFAOYSA-N cilostazol Chemical compound C=1C=C2NC(=O)CCC2=CC=1OCCCCC1=NN=NN1C1CCCCC1 RRGUKTPIGVIEKM-UHFFFAOYSA-N 0.000 claims description 4
- 229960004588 cilostazol Drugs 0.000 claims description 4
- 229960003668 docetaxel Drugs 0.000 claims description 4
- 229960005167 everolimus Drugs 0.000 claims description 4
- 229960002897 heparin Drugs 0.000 claims description 4
- 229920000669 heparin Polymers 0.000 claims description 4
- 238000007917 intracranial administration Methods 0.000 claims description 4
- 210000005259 peripheral blood Anatomy 0.000 claims description 4
- 239000011886 peripheral blood Substances 0.000 claims description 4
- UNMYWSMUMWPJLR-UHFFFAOYSA-L Calcium iodide Chemical compound [Ca+2].[I-].[I-] UNMYWSMUMWPJLR-UHFFFAOYSA-L 0.000 claims description 3
- 241001597008 Nomeidae Species 0.000 claims description 3
- 229940046413 calcium iodide Drugs 0.000 claims description 3
- 229910001640 calcium iodide Inorganic materials 0.000 claims description 3
- 210000003238 esophagus Anatomy 0.000 claims description 3
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- 206010011224 Cough Diseases 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 210000005077 saccule Anatomy 0.000 claims description 2
- 239000011265 semifinished product Substances 0.000 claims description 2
- 239000011780 sodium chloride Substances 0.000 claims description 2
- YYSFXUWWPNHNAZ-PKJQJFMNSA-N umirolimus Chemical compound C1[C@@H](OC)[C@H](OCCOCC)CC[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 YYSFXUWWPNHNAZ-PKJQJFMNSA-N 0.000 claims description 2
- CGTADGCBEXYWNE-JUKNQOCSSA-N zotarolimus Chemical compound N1([C@H]2CC[C@@H](C[C@@H](C)[C@H]3OC(=O)[C@@H]4CCCCN4C(=O)C(=O)[C@@]4(O)[C@H](C)CC[C@H](O4)C[C@@H](/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C3)OC)C[C@H]2OC)C=NN=N1 CGTADGCBEXYWNE-JUKNQOCSSA-N 0.000 claims description 2
- 229950009819 zotarolimus Drugs 0.000 claims description 2
- 238000000576 coating method Methods 0.000 abstract description 41
- 239000011248 coating agent Substances 0.000 abstract description 37
- 239000013078 crystal Substances 0.000 abstract description 22
- 239000002245 particle Substances 0.000 abstract description 6
- 208000007536 Thrombosis Diseases 0.000 abstract description 4
- 150000003839 salts Chemical class 0.000 abstract description 3
- 206010020718 hyperplasia Diseases 0.000 abstract description 2
- 229920001477 hydrophilic polymer Polymers 0.000 abstract 1
- 238000000034 method Methods 0.000 description 28
- 239000000872 buffer Substances 0.000 description 22
- 238000012360 testing method Methods 0.000 description 22
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 18
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 15
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 13
- 239000008187 granular material Substances 0.000 description 13
- 239000007788 liquid Substances 0.000 description 12
- 241001411320 Eriogonum inflatum Species 0.000 description 11
- 229920003081 Povidone K 30 Polymers 0.000 description 11
- 230000003139 buffering effect Effects 0.000 description 11
- 238000013329 compounding Methods 0.000 description 11
- 238000001035 drying Methods 0.000 description 11
- 238000012856 packing Methods 0.000 description 11
- 239000008200 pharmaceutical coating composition Substances 0.000 description 11
- 239000008363 phosphate buffer Substances 0.000 description 11
- 230000003068 static effect Effects 0.000 description 11
- 229960003966 nicotinamide Drugs 0.000 description 9
- 235000005152 nicotinamide Nutrition 0.000 description 9
- 239000011570 nicotinamide Substances 0.000 description 9
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 8
- 239000002671 adjuvant Substances 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- DGAIEPBNLOQYER-UHFFFAOYSA-N iopromide Chemical compound COCC(=O)NC1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)N(C)CC(O)CO)=C1I DGAIEPBNLOQYER-UHFFFAOYSA-N 0.000 description 6
- 230000002792 vascular Effects 0.000 description 6
- 238000005516 engineering process Methods 0.000 description 5
- 235000013877 carbamide Nutrition 0.000 description 4
- 239000004202 carbamide Substances 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- 229960002603 iopromide Drugs 0.000 description 4
- 208000037803 restenosis Diseases 0.000 description 4
- 210000003141 lower extremity Anatomy 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- CPKVUHPKYQGHMW-UHFFFAOYSA-N 1-ethenylpyrrolidin-2-one;molecular iodine Chemical compound II.C=CN1CCCC1=O CPKVUHPKYQGHMW-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000001028 anti-proliverative effect Effects 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000002872 contrast media Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000007599 discharging Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- DCTZJRUXIXPDJP-UHFFFAOYSA-N trihexyl 2-hydroxy-4-oxoheptane-1,2,3-tricarboxylate Chemical compound CCCCCCOC(=O)CC(O)(C(=O)OCCCCCC)C(C(=O)CCC)C(=O)OCCCCCC DCTZJRUXIXPDJP-UHFFFAOYSA-N 0.000 description 2
- 206010059245 Angiopathy Diseases 0.000 description 1
- 208000010975 Dystrophic epidermolysis bullosa Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 241000736199 Paeonia Species 0.000 description 1
- 235000006484 Paeonia officinalis Nutrition 0.000 description 1
- 229920000153 Povidone-iodine Polymers 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000004308 accommodation Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 208000004298 epidermolysis bullosa dystrophica Diseases 0.000 description 1
- 238000013467 fragmentation Methods 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
- 238000005213 imbibition Methods 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 1
- 229940006461 iodide ion Drugs 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 210000002464 muscle smooth vascular Anatomy 0.000 description 1
- LQEATNFJCMVKAC-UHFFFAOYSA-N n-[2-(1h-indol-3-yl)ethyl]-n-prop-2-enylprop-2-en-1-amine Chemical compound C1=CC=C2C(CCN(CC=C)CC=C)=CNC2=C1 LQEATNFJCMVKAC-UHFFFAOYSA-N 0.000 description 1
- HEDOODBJFVUQMS-UHFFFAOYSA-N n-[2-(5-methoxy-1h-indol-3-yl)ethyl]-n-methylpropan-2-amine Chemical group COC1=CC=C2NC=C(CCN(C)C(C)C)C2=C1 HEDOODBJFVUQMS-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 210000003101 oviduct Anatomy 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 229960001621 povidone-iodine Drugs 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 230000029547 smooth muscle hypertrophy Effects 0.000 description 1
- CMXPERZAMAQXSF-UHFFFAOYSA-M sodium;1,4-bis(2-ethylhexoxy)-1,4-dioxobutane-2-sulfonate;1,8-dihydroxyanthracene-9,10-dione Chemical compound [Na+].O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=CC=C2O.CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC CMXPERZAMAQXSF-UHFFFAOYSA-M 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 210000004509 vascular smooth muscle cell Anatomy 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M25/00—Catheters; Hollow probes
- A61M25/10—Balloon catheters
- A61M25/1027—Making of balloon catheters
- A61M25/1029—Production methods of the balloon members, e.g. blow-moulding, extruding, deposition or by wrapping a plurality of layers of balloon material around a mandril
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M25/00—Catheters; Hollow probes
- A61M25/10—Balloon catheters
- A61M25/1027—Making of balloon catheters
- A61M25/1029—Production methods of the balloon members, e.g. blow-moulding, extruding, deposition or by wrapping a plurality of layers of balloon material around a mandril
- A61M2025/1031—Surface processing of balloon members, e.g. coating or deposition; Mounting additional parts onto the balloon member's surface
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M25/00—Catheters; Hollow probes
- A61M25/10—Balloon catheters
- A61M2025/1043—Balloon catheters with special features or adapted for special applications
- A61M2025/105—Balloon catheters with special features or adapted for special applications having a balloon suitable for drug delivery, e.g. by using holes for delivery, drug coating or membranes
Landscapes
- Health & Medical Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Anesthesiology (AREA)
- Animal Behavior & Ethology (AREA)
- Biophysics (AREA)
- Pulmonology (AREA)
- Manufacturing & Machinery (AREA)
- Biomedical Technology (AREA)
- Hematology (AREA)
- Child & Adolescent Psychology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Media Introduction/Drainage Providing Device (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of medical appliances, and particularly relates to a medicine coating composition as well as a preparation method thereof and an implanting or intervention medical apparatus made thereof. The medicine coating composition for being coated on the surface of an implanting or intervention medical apparatus comprises the following components: a hydrophilic polymer as the first component, a medicine for treating blood vessel hyperplasia as the second component, an inorganic substance as the third component which is one or more than two compositions selected from inorganic simple substances, water soluble inorganic salts or amphiphilic small molecule compounds, and a solvent system as the fourth component, and the solvent system comprises corresponding solvents for the first component, the second component and the third component. The medicine balloon coating made of the medicine coating composition has good compatibility with balloons and little coating falling rate when folded, and does not form large medicine crystal particles while quickly disintegrating after immersing blood or distilled water, thereby avoiding the occurrence of thrombosis and angiemphraxis.
Description
Technical field
The invention belongs to technical field of medical instruments, particularly a kind of medication coat compositions, its preparation method and utilize its implantation of making or interventional medical device.
Background technology
Medicine-coated balloon and bracket for eluting medicament (DES) all come from essence take conduit as this concept of basic local drug delivery devices, by carrying medicine, suppresses neointimal hyperplasia, and mode and the topical remedy of just carrying medicine are different action time; Think traditionally, local vascular is pharmaceutically-active to be maintained is the basis of its anti-proliferative effect of performance, yet along with the carrying out of isolated cells, zoopery and human research, it is found that true really not so.Initial people carry medicine by contrast agent to be made it to contact with blood vessel wall is of short duration, inquire into the probability that this method suppresses restenosis, research is found, to add the contrast agent of lipotropy paclitaxel---the vascular smooth muscle cell of Ultravist and cultivation is hatched altogether, even if of short duration 3min cultivates, can suppress vascular smooth muscle hypertrophy completely, and the time can reach 2 weeks; Cultivate after 15min, fat-soluble paclitaxel enters 20 times that the dosage of local intra-arterial wall can DALT.Zoopery subsequently is also found, in art, use the Ultravist and the coated sacculus of paclitaxel (expansion 1min) that add paclitaxel, can make the concentration of paclitaxel in blood vessel wall reach the concentration (entering blood flow even if surpass 90% medicine) of cell proliferation, thereby significantly reduce the generation of restenosis, this effect is even better than DES, this may be that struts due to support itself can cause blood vessel injury reaction, and the smooth damage of both having avoided operation itself to bring of balloon surface has guaranteed that again medicine steadily evenly discharges and contacts.The appearance of medicine-coated balloon is just based on two theories: (1) fat-soluble paclitaxel or sirolimus can be absorbed by vascular tissue rapidly, and the sustained release of anti-proliferative drugs is also inessential concerning the inflammatory reaction process of inhibition restenosis; (2) medicine short-term exposes and can obviously block the early stage hypertrophy startup factor.
Drug stent, through development for many years, has obtained extraordinary effect in arteria coronaria angiopathy, but the application in periphery lower limb vascular support has existed certain limitation.This be mainly due to, be different from arteria coronaria blood vessel, the arterial blood pipe range of shank and straight, is not the position of persistent movement.After blood vessel blockage dredging, the restenosis probability of periphery lower limb vascular is high more a lot of than arteria coronaria blood vessel.The advantage of medicament elution sacculus is that it can adapt to the blood vessel that diameter range is very large, owing to there is no in vivo residual of metal, the fragmentation that does not also just exist support to exist, the risk of hamartoplasia or even artery-clogging.In Europe, in intervene operation, adopt DEB treatment periphery lower limb vascular to be blocked in and external be proved to be a kind of effectively means in clinical, but there is launch in Europe You Shuo company not yet enters Chinese market, domestic producer is in development, temporarily also there is no Related product listing.Domestic market sales only have a not periphery foley's tube of medicine carrying, relevant enterprise mainly contains: Johnson & Johnson's medical treatment, happy general medical treatment, Boston science and technology, Cook, the Ahmedabad world etc.Medicine-coated balloon conduit exists great advantage in late result with respect to medicine carrying foley's tube not.
External main periphery medicinal balloon company is as following table:
Key prepared by medicinal balloon is the coating of medicine, the product of different company has different design concepts, if the medicine of the Sequent Please balloon system of B.Braun company is paclitaxel, employing Iopromide is carrier, reaches the quick release of paclitaxel by the water solublity of Iopromide.Dior I is used the technology of nanoporous directly paclitaxel to be incorporated into balloon surface for balloon system, by pressurization, medicine is discharged from hole to intravasation tissue.At clinical effectiveness, absorbtivity in hole absorption Hou Zai vascular tissue is less, therefore Dior II has changed technique, employing Lac is carrier, Lac after imbibition, arrives lesion locations in blood, energy rapid delivery of pharmaceuticals after extruding, from public data, show, after change, the diseased region drug absorption of technique is greatly improved.
The technological difficulties of medication coat are:
1. the selection of formula, under different formula conditions, the release profiles of medicine is different.For medicinal balloon, need medicine to discharge fast, in the time of release, reduce the size of release particles as far as possible, in course of conveying, can reduce the loss simultaneously as far as possible.And because medicinal balloon belongs to cardiovascular Interventional material, just more limited the selection of material.
2. the selection of coating processes, choose after formula, need suitable technique that medicine carrying solution is coated to balloon surface, the technique of this coating can directly have influence on medicine at the distribution uniformity of balloon surface, medicine, in the form of balloon surface, finally can have influence on the release of medicine, the granule of drug release, even if therefore had tested recipe in the situation that there is no suitable coating processes, also cannot obtain the medication coat of expectation.
3. the selection of folding technology, after the coating of sacculus is dried completely, sacculus need to be folded, now, the medicinal balloon of looking ahead can pass through smoothly in blood vessel, by process Chinese medicine, can not lose in a large number, coating can not come off by sheet in transmitting procedure, the folding release profiles that can not have influence on medicine.Sometimes use three foldings, sometimes use five foldings.
Existing medicinal balloon and technology of preparing mainly contain following several:
It is adjuvant that the formula of the CVIngenuity of u s company (US Patent No. 8491925B2, US8257722B2, US8128951B2, US8114429B2) adopts betadin (polynylpyrrol idone or PVP-I), the medication coat effect obtaining is pretty good, coating is even, after water breakthrough, rate of release is fast, also can not form large taxol drug crystal.But the shortcoming of this formula is betadin, be by chemosynthesis (United States Patent (USP) 2,739,922, European patent EP 19790100966) polyvidon obtaining and the stable coordination compound (stable complex is shown in http://en.wikipedia.org/wiki/Povidone-iodine) of iodine.Betadin contains the very elementoid iodine of high-load (brown or peony, 9-12%, the dry weight ratio of PVP) conventionally.It is normally used as the sterilization of spectrum, sterilization antiseptical medicament.In the environment that the iodine of element state can discharge gradually, go.Cause like this stimulation and irritated patient's ratio also can improve.
The Sequent please medicine carrying sacculus of German company B.Braun be take paclitaxel as function medicament, and Iopromide is carrier material (US Patent No. 8439868B2; US8389043B2; US8257305B2; US7750041B2).By the fast feature of Iopromide rate of dissolution in water, reach the quick release of paclitaxel.This is the representative of first generation medicament elution sacculus, occupies no small market on market.But in using widely, the coating affinity of issuing this class sacculus is very poor, and strength of coating is bad, in arriving release place future, lose serious.After discharging, the taxol drug insoluble matter of bulk produces, easily artery-clogging.
It is pharmaceutical carrier (US Patent No. 20110295200A1 that the product I n.Pact of u s company's Medtronic (Medtronic/Invatec) has used carbamide; US20100233228A1).But due to carbamide and paclitaxel, nature difference is very large, dissolubility and Crystallization Characteristics in same solvent are different, so coating phase-splitting is obvious, homogeneity is undesirable.Carbamide can not increase the affinity between paclitaxel and balloon surface yet.Their dissolution velocities in water are widely different in addition, cause the formation compared with large medicament particles, increase the obstruction of thrombosis or blood vessel.That similarly, the Passeo-18Lux of German company Biotronik uses is butyryl citric acid tri-n-hexyl ester (n-Butyryl tri-n-hexyl-citrate).Than carbamide height a bit better with being separated of paclitaxel, but be micromolecule adjuvant after all, the affinity of coating formula and sacculus is poor for this adjuvant fat-soluble, and coating stripping is serious, arrive lose in discharging place future serious.
Formula (the US Patent No. 8425459B2 of Lutonix Moxy; US8414526B2; US8241249B2) used surfactant, paclitaxel is pretty good at the coating uniformity of balloon surface, also good with the cohesive of sacculus, but due to the use of surfactant, it is obvious that balloon surface absorbs moisture, and medication coat easily comes off.Medicine is too even in addition, slow release well after intravasation wall.Drug effect is not good enough.
The sacculus coating of German company Aachen-Resonance and the COOK Medical of u s company adopts pure paclitaxel, relies on the crystallization of medicine self to form single coating.Intravasation wall under the mechanical pressure producing when balloon expandable, has certain slow-release period.But owing to there is no carrier, cohesive is bad, sacculus is folding be lose not little.Form oarse-grained chance a lot.Safety is under suspicion.
German company Eurocor Freeway (US Patent No. 20120143132A1; US20100076542A1; European patent EP 2125060B1;
EP2421572A2; EP2243501A1) used Lac, cohesive is good, and coating is transparent, evenly.But it is very crisp that shortcoming is Lac, after being combined with water-fast paclitaxel, the stability of whole medication coat is bad.Simultaneously because Lac is natural product, still unavoidable through purification rear impurity.The danger of biocompatibility and thermal source increases many.
In sum, medicament elution sacculus is to get involved a new effective treatment blood vessel of medical profession and the method for the interior official jargon of other bodies, has obtained doctor's generally approval in clinical use.The product of selling on market now and researching and developing has certain curative effect, also all has shortcoming in varying degrees.
Summary of the invention
The present invention aims to provide a kind of medication coat compositions that is applicable to be coated in implantation or interventional medical device surface, this medication coat compositions can make implantation or interventional medical device as disintegrate fast in the immersion blood such as medicine-coated balloon and bracket for eluting medicament (DES) or distilled water after using, can not form large medicine crystal granule, avoid the situation of thrombosis and blood vessel blockage simultaneously.
The present invention also provides a kind of preparation method of described medication coat compositions.
The present invention also provides a kind of implantation of making or interventional medical device that utilizes described medication coat compositions, and described implantation or interventional medical device comprise medicament elution sacculus, bracket for eluting medicament etc.
The technical solution adopted for the present invention to solve the technical problems is:
A medication coat compositions that is applicable to be coated in implantation or interventional medical device surface, comprises following component:
The first component is hydrophilic high polymer;
Second component is for treating the blood vessel medicine of hypertrophy again;
The 3rd component is inorganic matter, is selected from one or more the compositions in inorganic simple substance, water-soluble inorganic salt or amphipathic small molecules compound;
In each component, hydrophilic high polymer and treatment the blood vessel again weight ratio of the medicine of hypertrophy are 0.3-3: 1, the three component accounts for the 0.005-5.0% of the first component, second component and the 3rd component gross weight;
The 4th component is dicyandiamide solution, and dicyandiamide solution comprises the solvent that the first component, second component and the 3rd component are dissolved separately.The therapentic part of this implantation or interventional medical device comprises: other pipelines of blood vessel and human body are as trachea, esophagus, urethra, vagina and fallopian tube.
Further, hydrophilic high polymer and treatment blood vessel be the medicine of hypertrophy again, and the weight ratio of the first component and second component is 1.8-2.2: 1, the three component accounts for the 0.005-2.0% of the first component, second component and the 3rd component gross weight.
As preferably, described hydrophilic high polymer is selected from polyvidon (PVP), the polyvidon that contains the iodine that is coupled, polyvinyl alcohol (PVA), polyethylene glycol oxide (PEO) or Polyethylene Glycol (PEG); The described treatment blood vessel again medicine of hypertrophy is selected from paclitaxel or derivatives thereof, rapamycin or derivatives thereof, anticoagulant medicine; Described inorganic simple substance is selected from iodine, bromine or nicotiamide; Water-soluble inorganic salt is selected from sodium iodide, calcium iodide, and sodium chloride or calcium chloride, amphipathic small molecules compound is D-ALPHA-tocopheryl polyethylene glycol 1000 succinate.Here it is to be noted, due to polyvidon (PVP), the polyvidon that contains the iodine that is coupled, polyvinyl alcohol (PVA), polyethylene glycol oxide (PEO) or these several high polymers of Polyethylene Glycol (PEG) are at water or ethanol, and the dissolubility in methanol is basic identical, therefore can replace mutually, in use, make the medication coat good hydrophilic property that finally obtains, disintegration rate is fast; And inorganic salt separates medicine in whole component, therefore can not form bulky grain medicine crystal.
As preferably, the derivant of described paclitaxel comprises that the derivant of described paclitaxel comprises Docetaxel (docetaxel); Rapamycin derivative comprises everolimus (everolimus), if he coughs up Li Mosi (Zotarolimus), and Baeyer Li Mosi (Biolimus); Anticoagulant medicated bag is drawn together cilostazol (Cilostazol), heparin (heparin).
As preferably, described implantation or interventional medical device comprise: coronary blood pipe holder, arteria coronaria blood saccule, peripheral blood vessel support, peripheral blood vessel sacculus, intracranial vessel support, intracranial vessel sacculus, urethra rack, urethra sacculus, esophageal stents appear or esophagus sacculus.
As preferably, in described dicyandiamide solution, the solvent of the first components dissolved is selected to water, ethanol, the compositions of one or more in methanol or oxolane; The solvent that second component is dissolved is ethanol, methanol, the compositions of one or more in oxolane or acetone; By the solvent of the 3rd components dissolved, be water, the compositions of one or more in ethanol or methanol.The first component and second component dissolving and the mixed process in different solvents is very important.Different solvents can preferentially dissolve no component, as medicine or high polymer, also has inorganic component etc., to obtain evenly firmly coating.
As preferably, with ethanol, the first component solution will be obtained after the first components dissolved, in the first component solution, add the 3rd component and suitable quantity of water to be fully mixed to get the 3rd component solution, after second component being dissolved with ethanol, obtain second component solution, the volume ratio between second component solution, the 3rd component solution and water three is 1-2: 1-2: 0.1-1.Further, the volume ratio between second component solution, the 3rd component solution and water three is for being preferably 1: 1-2: 0.25-0.28.
A kind of preparation method of described medication coat compositions, comprise the steps: the preparation of a, the 3rd component solution: the first component is fully mixed with solvent, configuration concentration is the first component solution of 0.1-1g/ml, and preserve the first component is all dissolved at 40-50 ℃ of temperature, in the first component solution, add the 3rd component fully to mix again, obtain the 3rd component solution, the concentration that makes the 3rd component in the 3rd component solution is 0.001-0.1g/ml; The preparation of b, second component solution: second component is fully mixed with solvent, the second component solution that configuration concentration is 0.05-0.5g/ml, and at 40-50 ℃ of temperature, be incubated until second component dissolves completely; The preparation of c, medication coat compositions: add described the 3rd component solution and water in described second component solution, volume ratio between second component solution, the 3rd component solution and water three is 1-2: 1-2: 0.1-1, sealing, stir, obtain for being coated in the medication coat compositions on implantation or interventional medical device surface.
Further, the preparation method of said medicine coating composition comprises a kind of following method, the preparation of a, iodine solution: polyvinylpyrrolidone (PVP) is fully mixed with ethanol, configuration concentration is polyvinylpyrrolidone (PVP) alcoholic solution of 0.1-0.3g/ml, and preserve PVP is all dissolved at 40-50 ℃ of temperature, in PVP alcoholic solution, add I fully to mix again, obtain iodine solution, concentration is 0.001-0.01g/ml; The preparation of b, paclitaxel alcoholic solution: paclitaxel is fully mixed with ethanol, the paclitaxel alcoholic solution that configuration concentration is 0.1-0.3g/ml, and at 40-50 ℃ of temperature, be incubated until paclitaxel dissolves completely; The preparation of c, medication coat compositions: add described iodine solution and distilled water in described paclitaxel alcoholic solution, volume ratio between paclitaxel alcoholic solution, iodine solution and water three is 1: 1-2: 0.25-0.28, sealing, stirs, and obtains medication coat compositions.
Further, the preparation method of said medicine coating composition comprises a kind of following method, the preparation of a, IodineSodium Solution: polyvinylpyrrolidone (PVP) is fully mixed with ethanol, configuration concentration is polyvinylpyrrolidone (PVP) alcoholic solution of 0.1-0.3g/ml, and preserve PVP is all dissolved at 40-50 ℃ of temperature, in PVP alcoholic solution, add NaI fully to mix again, obtain IodineSodium Solution, making NaI concentration in IodineSodium Solution is 0.05-0.5g/ml; The preparation of b, paclitaxel alcoholic solution: paclitaxel is fully mixed with ethanol, the paclitaxel alcoholic solution that configuration concentration is 0.1-0.3g/ml, and at 40-50 ℃ of temperature, be incubated until paclitaxel dissolves completely; The preparation of c, medication coat compositions: add described IodineSodium Solution and distilled water in described paclitaxel alcoholic solution, volume ratio between paclitaxel alcoholic solution, IodineSodium Solution and water three is 1: 1-2: 0.25-0.28, sealing, stirs, and obtains medication coat compositions.
Further, the preparation method of said medicine coating composition comprises a kind of following method, the preparation of a, nicotinamide soln: polyvinylpyrrolidone (PVP) is fully mixed with ethanol, configuration concentration is polyvinylpyrrolidone (PVP) alcoholic solution of 0.1-0.3g/ml, and preserve PVP is all dissolved at 40-50 ℃ of temperature, in PVP alcoholic solution, add nicotiamide fully to mix again, obtain nicotinamide soln, making concentration for nicotinamide in nicotinamide soln is 0.02-0.2g/ml; The preparation of b, paclitaxel alcoholic solution: paclitaxel is fully mixed with ethanol, the paclitaxel alcoholic solution that configuration concentration is 0.1-0.3g/ml, and at 40-50 ℃ of temperature, be incubated until paclitaxel dissolves completely; The preparation of c, medication coat compositions: add described nicotinamide soln and distilled water in described paclitaxel alcoholic solution, volume ratio between paclitaxel alcoholic solution, nicotinamide soln and water three is 1: 1-2: 0.25-0.28, sealing, stirs, and obtains medication coat compositions.
Further, the preparation method of said medicine coating composition comprises a kind of following method, a, the preparation of nicotiamide calcium chloride solution: polyvinylpyrrolidone (PVP) is fully mixed with ethanol, configuration concentration is polyvinylpyrrolidone (PVP) alcoholic solution of 0.1-0.3g/ml, and preserve PVP is all dissolved at 40-50 ℃ of temperature, in PVP alcoholic solution, add nicotiamide and calcium chloride fully to mix again, obtain nicotiamide calcium chloride solution, making concentration for nicotinamide in nicotiamide calcium chloride solution is 0.01-0.05g/ml, calcium chloride concentration is 0.002-0.0lg/ml, the preparation of b, paclitaxel alcoholic solution: paclitaxel is fully mixed with ethanol, the paclitaxel alcoholic solution that configuration concentration is 0.1-0.3g/ml, and at 40-50 ℃ of temperature, be incubated until paclitaxel dissolves completely, the preparation of c, medication coat compositions: add described nicotiamide calcium chloride solution and distilled water in described paclitaxel alcoholic solution, volume ratio between paclitaxel alcoholic solution, nicotiamide calcium chloride solution and water three is 1: 1-2: 0.25-0.28, sealing, stir, obtain medication coat compositions.
Further, the preparation method of said medicine coating composition comprises a kind of following method, the preparation of a, BHT solution: polyvinylpyrrolidone (PVP) is fully mixed with ethanol, configuration concentration is polyvinylpyrrolidone (PVP) alcoholic solution of 0.1-0.3g/ml, and preserve PVP is all dissolved at 40-50 ℃ of temperature, in PVP alcoholic solution, add BHT fully to mix again, obtain BHT solution, concentration is 0.00025-0.01g/ml; The preparation of b, paclitaxel alcoholic solution: paclitaxel is fully mixed with ethanol, the paclitaxel alcoholic solution that configuration concentration is 0.1-0.3g/ml, and at 40-50 ℃ of temperature, be incubated until paclitaxel dissolves completely; The preparation of c, medication coat compositions: add described BHT solution and distilled water in described paclitaxel alcoholic solution, volume ratio between paclitaxel alcoholic solution, BHT solution and water three is 1: 1-2: 0.25-0.28, sealing, stirs, and obtains medication coat compositions.
In the preparation method of the above-mentioned various preferred medication coat compositions providing, the drug taxol adopting can be replaced by medicines such as paclitaxel or derivatives thereof, rapamycin or derivatives thereof, anticoagulant medicines, when medicine is rapamycin, the compound method of rapamycin alcoholic solution and concentration are controlled with paclitaxel alcoholic solution.Further, when medicine is rapamycin, system solvent be take methanol can make the dissolubility of rapamycin better as master.
The implantation or the interventional medical device that utilize described medication coat compositions to prepare, its process is: the implantation or the interventional medical device semi-finished product that through medicine, do not apply are immersed in medication coat compositions of the present invention, keep 5-60 to take out after second; Dry under room temperature, folding, sterilizing, obtains product.
As preferably, implantation or interventional medical device prepared by described medication coat compositions, the density of its face coat is 0.5-10 μ g/mm
2, the density of medicine net content on medicament eluting instrument surface is 0.2-8 μ g/mm
2.
Specifically, the present invention adopts water soluble polymer as the carrier of polyvidon as medication coat.Due to the hydrophilic high polymer having as polyvidon, medication coat can rapid disintegrate after contact blood vessel (at 60-120 in second), allows the complete intravasation wall of medicine in coating.Simultaneously because polyvidon is amphipathic compound (polarity and non-polar solven and compound are had to affinity), so can not form and be separated with paclitaxel.After having used this class high polymer, medication coat is very even, bonding also very good with balloon surface.But be immersed in the water, coating disintegrate, forms gr water-fast big particle.May artery-clogging.
Another key component of the present invention is the additive that has the mineral-type of special efficacy, as iodine, and calcium iodide, sodium iodide, calcium chloride or other water miscible micromolecule, as nicotiamide etc.These water miscible salts or inorganic elements (not being to stablize the iodide ion etc. of coupling or coordination with high polymer) exist with medication coat in, cut off medicine (as paclitaxel and rapamycin) and hydrophilic high polymer (as polyvidon).Formed again evenly, after the good sacculus coating of cohesive, immersed after water or blood, played the effect of regulating drug granularity.Through evidence, the formula that ratio is suitable and coating, after sacculus coating is immersed in the water, reached quick disintegrate and drug particles degree little (naked eyes range estimation is emulsion form, rather than bulky grain).The ratio of these inorganic molecules additives is very crucial, and consumption is too high, can affect coating and become thin performance (too crisp or too sticky), too low, can not play again the effect that forms small drug particles.
The 3rd key point of the present invention is the formula of solvent, and simple solvent does not have has similar dissolubility to medicine (paclitaxel or rapamycin) with high polymer.So double solvents effect can be better, such as ethanol, methanol, acetone, water, oxolane philosophy dissolved substance, high polymer, then mixes two solution, forms homogeneous phase masking liquid.The dicyandiamide solution of using in the present invention, the preferred solvent of the first component is ethanol, water, or the mixed system of two kinds; The preferred solvent of second component is ethanol, acetone, oxolane, or the mixed system of two kinds wherein; The preferred solvent of the 3rd component is ethanol, methanol, or the mixed system of two kinds.
Formula of the present invention and coating process have certain scope of application, such as well several inorganic salts and neutral micromolecule can both play adjusting coating uniformity, affinity, and in water, speed and the medication coat of (blood) middle disintegrate is residual, also has the formation of medicine crystal granule.
By formula of the present invention and coating process, the medicinal balloon coating finally forming, evenly, good with the affinity of sacculus, when folding, coating shedding is little, can quick disintegrate after immersing in blood or distilled water, and most medication coat all can depart from balloon surface within very short time, (to be shorter than 1 minute), do not form large medicine crystal granule, avoid the situation of thrombosis and blood vessel blockage simultaneously.
The specific embodiment
Below by specific embodiment, technical scheme of the present invention is described in further detail.Should be appreciated that enforcement of the present invention is not limited to the following examples, any pro forma accommodation that the present invention is made and/or change all will fall into protection domain of the present invention.
In the present invention, if not refer in particular to, all part, percentage ratios are unit of weight, and the equipment adopting and raw material etc. all can be buied from market or this area is conventional.Method in following embodiment, if no special instructions, is the conventional method of this area.
Embodiment 1A: containing the preparation method of inorganic salt medicinal balloon
The configuration of polyvinylpyrrolidone (PVP) alcoholic solution: weigh 4g PVP (Povidone K30) with the balance of 0.0001g precision, add in 25ml sample bottle, the ethanol of drawing 20ml with liquid-transfering gun joins in sample bottle.Screw bottle stopper, after vibration is stirred, be put into 45 ℃ of baking ovens and preserve until PVP all dissolves.
The preparation of paclitaxel alcoholic solution: weigh about 0.15g paclitaxel, add 25ml vial; The ethanol that adds 1ml in vial; At 45 ℃ of baking ovens, be incubated until paclitaxel dissolves completely.
Preparation IodineSodium Solution: about 0.4g NaI is added in 25ml sample bottle; With liquid-transfering gun, drawing PVP alcoholic solution 8ml joins in sample bottle;
Compounding pharmaceutical coating composition: add the IodineSodium Solution of about 1-2ml and the distilled water of a small amount of (0.262ml) in paclitaxel alcoholic solution, sealing, stirs.
Sacculus coating: sacculus is immersed in above-mentioned medication coat compositions (solution); Keep 5-60 second, rear taking-up; Drying at room temperature 6 hours; Folding, sterilizing, packing.
The test of drug releasing rate and granularity: the inflated to 2 that said method an is made atmospheric pressure, be then put in the phosphate buffer bottle of 0.1M of 20ml, static 1 minute, then take out sacculus, dry, weigh.Observe the residual condition of balloon surface medication coat and the state of the medicine crystal in buffer bottle, result of the test is in Table 1 simultaneously.Result: the medication coat over 80% is successfully discharged in buffer, simultaneous buffering liquid bottle is not observed bulky grain (without 10 microns of above granules of diameter).
Table 1
Embodiment 1B: containing the preparation method of inorganic salt medicinal balloon
The configuration of polyvinylpyrrolidone (PVP) methanol solution: weigh 4g PVP (Povidone K30) with the balance of 0.0001g precision, add in 25ml sample bottle, the methanol of drawing 20ml with liquid-transfering gun joins in sample bottle.Screw bottle stopper, after vibration is stirred, be put into 45 ℃ of baking ovens and preserve until PVP all dissolves.
The preparation of paclitaxel methanol solution: weigh about 0.15g paclitaxel, add 25ml vial; The methanol that adds 1ml in vial; At 45 ℃ of baking ovens, be incubated until paclitaxel dissolves completely.
Preparation IodineSodium Solution: about 0.4g NaI is added in 25ml sample bottle; With liquid-transfering gun, drawing PVP methanol solution 8ml joins in sample bottle;
Compounding pharmaceutical coating composition: add the IodineSodium Solution of about 1-2ml and the distilled water of a small amount of (0.262ml) in paclitaxel methanol solution, sealing, stirs.
Sacculus coating: sacculus is immersed in above-mentioned medication coat compositions; Keep 5-60 second, rear taking-up; Drying at room temperature 6 hours; Folding, sterilizing, packing.
The test of drug releasing rate and granularity: the inflated to 2 that said method an is made atmospheric pressure, be then put in the phosphate buffer bottle of 0.1M of 20ml, static 1 minute, then take out sacculus, dry, weigh.Observe the residual condition of balloon surface medication coat and the state of the medicine crystal in buffer bottle, result of the test is in Table 2 simultaneously.Result: the medication coat over 72% is successfully discharged in buffer, simultaneous buffering liquid bottle is not observed bulky grain (without 10 microns of above granules of diameter, lower same).
Table 2
Embodiment 2: the medicinal balloon preparation method that contains micromolecule adjuvant:
The configuration of PVP alcoholic solution: weigh 4g PVP (Povidone K30) with the balance of 0.0001g precision, add in 25ml sample bottle; The ethanol of drawing 20ml with liquid-transfering gun joins in sample bottle.Screw bottle stopper, after vibration is stirred, be put into 45 ℃ of baking ovens and preserve until PVP all dissolves.
The preparation of paclitaxel alcoholic solution: weigh about 0.15g paclitaxel, add 25ml vial; The ethanol that adds 1ml in vial; At 45 ℃ of baking ovens, be incubated until paclitaxel dissolves completely.
Preparation nicotinamide soln: about 0.2g nicotiamide is added in 25ml sample bottle; With liquid-transfering gun, drawing PVP alcoholic solution 8ml joins in sample bottle;
Compounding pharmaceutical coating composition: add the nicotinamide soln of about 1-2ml and the distilled water of a small amount of (0.262ml) in paclitaxel alcoholic solution, sealing, stirs.
Sacculus coating: sacculus is immersed in above-mentioned medication coat compositions; Keep 5-60 second, rear taking-up; Drying at room temperature 6 hours; Folding, sterilizing, packing.
The test of drug releasing rate and granularity: the inflated to 2 that said method an is made atmospheric pressure, be then put in the phosphate buffer bottle of 0.1M of 20ml, static 1 minute, then take out sacculus, dry, weigh.Observe the residual condition of balloon surface medication coat and the state of the medicine crystal in buffer bottle, result of the test is in Table 3 simultaneously.Result: the medication coat over 73% is successfully discharged in buffer, simultaneous buffering liquid bottle is observed the bulky grain (10 microns of above granules of diameter) of minute quantity.
Table 3
Embodiment 3: the medicinal balloon preparation method that contains two kinds of micromolecule adjuvant:
The configuration of PVP alcoholic solution: weigh 4g PVP (Povidone K30) with the balance of 0.0001g precision, add in 25ml sample bottle; The ethanol of drawing 20ml with liquid-transfering gun joins in sample bottle.Screw bottle stopper, after vibration is stirred, be put into 45 ℃ of baking ovens and preserve until PVP all dissolves.
The preparation of paclitaxel alcoholic solution: weigh about 0.15g paclitaxel, add 25ml vial; The ethanol that adds 1ml in vial; At 45 ℃ of baking ovens, be incubated until paclitaxel dissolves completely.
Preparation nicotiamide calcium chloride solution: about 0.1g nicotiamide and about 0.02g calcium chloride are added in 25ml sample bottle; With liquid-transfering gun, drawing PVP alcoholic solution 8ml joins in sample bottle;
Compounding pharmaceutical coating composition: add the nicotiamide calcium chloride solution of about 1-2ml and the distilled water of a small amount of (0.262ml) in paclitaxel alcoholic solution, sealing, stirs.
Sacculus coating: sacculus is immersed in above-mentioned medication coat compositions; Keep 5-60 second, rear taking-up; Drying at room temperature 6 hours; Folding, sterilizing, packing.
The test of drug releasing rate and granularity: the inflated to 2 that said method an is made atmospheric pressure, be then put in the phosphate buffer bottle of 0.1M of 20ml, static 1 minute, then take out sacculus, dry, weigh.Observe the residual condition of balloon surface medication coat and the state of the medicine crystal in buffer bottle, result of the test is in Table 4 simultaneously.Result: the medication coat over 76% is successfully discharged in buffer, simultaneous buffering liquid bottle is observed a certain amount of bulky grain (10 microns of above granules of diameter).
Table 4
Embodiment 4A: containing the medicinal balloon preparation method 1 of inorganic iodine (PTX: PVP: I=1.0: 1.33: 0.007, gram/gram/gram):
The configuration of PVP alcoholic solution: weigh 4g PVP (Povidone K30) with the balance of 0.0001g precision, add in 25ml sample bottle; The ethanol of drawing 20ml with liquid-transfering gun joins in sample bottle.Screw bottle stopper, after vibration is stirred, be put into 45 ℃ of baking ovens and preserve until PVP all dissolves.
The preparation of paclitaxel alcoholic solution: weigh about 0.15g paclitaxel, add 25ml vial; The ethanol that adds 1ml in vial; At 45 ℃ of baking ovens, be incubated until paclitaxel dissolves completely.
The alcoholic solution of preparation iodine: about 0.008g iodine is added in 25ml sample bottle; With liquid-transfering gun, drawing PVP alcoholic solution 8ml joins in sample bottle;
Compounding pharmaceutical coating composition: add the element state iodine solution of about 1ml and the distilled water of a small amount of (0.262ml) in paclitaxel alcoholic solution, sealing, stirs.
Sacculus coating: sacculus is immersed in above-mentioned medication coat compositions; Keep 5-60 second, rear taking-up; Drying at room temperature 6 hours; Folding, sterilizing, packing.
The test of drug releasing rate and granularity: the inflated to 2 that said method an is made atmospheric pressure, be then put in the phosphate buffer bottle of 0.1M of 20ml, static 1 minute, then take out sacculus, dry, weigh.Observe the residual condition of balloon surface medication coat and the state of the medicine crystal in buffer bottle, result of the test is in Table 5 simultaneously.Result: the medication coat over 90% is successfully discharged in buffer, simultaneous buffering liquid bottle is not observed bulky grain medicine (10 microns of above granules of diameter).
Table 5
Embodiment 4B: containing the medicinal balloon preparation method 2 of inorganic iodine (PTX: PVP: I=1.5: 1: 0.005, gram/gram/gram)
The configuration of PVP alcoholic solution: weigh 4g PVP (Povidone K30) with the balance of 0.0001g precision, add in 25ml sample bottle; The ethanol of drawing 20ml with liquid-transfering gun joins in sample bottle.Screw bottle stopper, after vibration is stirred, be put into 45 ℃ of baking ovens and preserve until PVP all dissolves.
The preparation of paclitaxel (PTX) alcoholic solution: weigh about 0.30g paclitaxel, add 25ml vial; The ethanol that adds 1ml in vial; At 45 ℃ of baking ovens, be incubated until paclitaxel dissolves completely.
The alcoholic solution of preparation iodine: about 0.008g iodine is added in 25ml sample bottle; With liquid-transfering gun, drawing PVP alcoholic solution 8ml joins in sample bottle;
Compounding pharmaceutical coating composition: add the element state iodine solution of about 1ml and the distilled water of a small amount of (0.262ml) in paclitaxel alcoholic solution, sealing, stirs.
Sacculus coating: sacculus is immersed in above-mentioned medication coat compositions; Keep 5-60 second, rear taking-up; Drying at room temperature 6 hours; Folding, sterilizing, packing.
The test of drug releasing rate and granularity: the inflated to 2 that said method an is made atmospheric pressure, be then put in the phosphate buffer bottle of 0.1M of 20ml, static 1 minute, then take out sacculus, dry, weigh.Observe the residual condition of balloon surface medication coat and the state of the medicine crystal in buffer bottle, result of the test is in Table 6 simultaneously.Result: the medication coat over 90% is successfully discharged in buffer, simultaneous buffering liquid bottle is not observed bulky grain medicine (10 microns of above granules of diameter).
Table 6
Embodiment 5A contains the medicinal balloon preparation method of micromolecule adjuvant D-ALPHA-tocopheryl polyethylene glycol 1000 succinate:
The configuration of PVP alcoholic solution: weigh 4g PVP (Povidone K30) with the balance of 0.0001g precision, add in 25ml sample bottle; The ethanol of drawing 20ml with liquid-transfering gun joins in sample bottle.Screw bottle stopper, after vibration is stirred, be put into 45 ℃ of baking ovens and preserve until PVP all dissolves.
The preparation of paclitaxel alcoholic solution: weigh about 0.15g paclitaxel, add 25ml vial; The ethanol that adds 1ml in vial; At 45 ℃ of baking ovens, be incubated until paclitaxel dissolves completely.
The alcoholic solution of preparation D-ALPHA-tocopheryl polyethylene glycol 1000 succinate: about 0.002g D-ALPHA-tocopheryl polyethylene glycol 1000 succinate is added in 25ml sample bottle; With liquid-transfering gun, drawing PVP alcoholic solution 8ml joins in sample bottle;
Compounding pharmaceutical coating composition: add the D-ALPHA-tocopheryl polyethylene glycol 1000 succinate solution of about 1-2ml and the distilled water of a small amount of (0.262ml) in paclitaxel alcoholic solution, sealing, stirs.
Sacculus coating: sacculus is immersed in above-mentioned medication coat compositions; Keep 5-60 second, rear taking-up; Drying at room temperature 6 hours; Folding, sterilizing, packing.
The test of drug releasing rate and granularity: the inflated to 2 that said method an is made atmospheric pressure, be then put in the phosphate buffer bottle of 0.1M of 20ml, static 1 minute, then take out sacculus, dry, weigh.Observe the residual condition of balloon surface medication coat and the state of the medicine crystal in buffer bottle, result of the test is in Table 7 simultaneously.Result: the medication coat over 75% is successfully discharged in buffer, simultaneous buffering liquid bottle is observed the bulky grain medicine crystal (10 microns of above granules of diameter) of some.
Table 7
Embodiment 5B contains the medicinal balloon preparation method of micromolecule adjuvant D-ALPHA-tocopheryl polyethylene glycol 1000 succinate:
The configuration of PVP alcoholic solution: weigh 4g PVP (Povidone K30) with the balance of 0.0001g precision, add in 25ml sample bottle; The ethanol of drawing 20ml with liquid-transfering gun joins in sample bottle.Screw bottle stopper, after vibration is stirred, be put into 45 ℃ of baking ovens and preserve until PVP all dissolves.
The preparation of paclitaxel acetone soln: weigh about 0.15g paclitaxel, add 25ml vial; The acetone that adds 1ml in vial; At 45 ℃ of baking ovens, be incubated until paclitaxel dissolves completely.
The alcoholic solution of preparation D-ALPHA-tocopheryl polyethylene glycol 1000 succinate: about 0.002g D-ALPHA-tocopheryl polyethylene glycol 1000 succinate is added in 25ml sample bottle; With liquid-transfering gun, drawing PVP alcoholic solution 8ml joins in sample bottle;
Compounding pharmaceutical coating composition: add the D-ALPHA-tocopheryl polyethylene glycol 1000 succinate solution of about 1-2ml and the distilled water of a small amount of (0.262ml) in paclitaxel acetone soln, sealing, stirs.
Sacculus coating: sacculus is immersed in above-mentioned medication coat compositions; Keep 5-60 second, rear taking-up; Drying at room temperature 6 hours; Folding, sterilizing, packing.
The test of drug releasing rate and granularity: the inflated to 2 that said method an is made atmospheric pressure, be then put in the phosphate buffer bottle of 0.1M of 20ml, static 1 minute, then take out sacculus, dry, weigh.Observe the residual condition of balloon surface medication coat and the state of the medicine crystal in buffer bottle, result of the test is in Table 8 simultaneously.Result: the medication coat over 60% is successfully discharged in buffer, simultaneous buffering liquid bottle is observed the bulky grain medicine crystal (10 microns of above granules of diameter) of some.
Table 8
Embodiment 5C contains the medicinal balloon preparation method of micromolecule adjuvant D-ALPHA-tocopheryl polyethylene glycol 1000 succinate:
The configuration of PVP alcoholic solution: weigh 4g PVP (Povidone K30) with the balance of 0.0001g precision, add in 25ml sample bottle; The ethanol of drawing 20ml with liquid-transfering gun joins in sample bottle.Screw bottle stopper, after vibration is stirred, be put into 45 ℃ of baking ovens and preserve until PVP all dissolves.
The preparation of paclitaxel tetrahydrofuran solution: weigh about 0.15g paclitaxel, add 25ml vial; The oxolane that adds 1ml in vial; At 45 ℃ of baking ovens, be incubated until paclitaxel dissolves completely.
The alcoholic solution of preparation D-ALPHA-tocopheryl polyethylene glycol 1000 succinate: about 0.002g D-ALPHA-tocopheryl polyethylene glycol 1000 succinate is added in 25ml sample bottle; With liquid-transfering gun, drawing PVP alcoholic solution 8ml joins in sample bottle;
Compounding pharmaceutical coating composition: add the D-ALPHA-tocopheryl polyethylene glycol 1000 succinate solution of about 1-2ml and the distilled water of a small amount of (0.262ml) in paclitaxel tetrahydrofuran solution, sealing, stirs.
Sacculus coating: sacculus is immersed in above-mentioned medication coat compositions; Keep 5-60 second, rear taking-up; Drying at room temperature 6 hours; Folding, sterilizing, packing.
The test of drug releasing rate and granularity: the inflated to 2 that said method an is made atmospheric pressure, be then put in the phosphate buffer bottle of 0.1M of 20ml, static 1 minute, then take out sacculus, dry, weigh.Observe the residual condition of balloon surface medication coat and the state of the medicine crystal in buffer bottle, result of the test is in Table 9 simultaneously.Result: the medication coat over 80% is successfully discharged in buffer, simultaneous buffering liquid bottle is observed the bulky grain medicine crystal (10 microns of above granules of diameter) of some.
Table 9
Embodiment 6A contains the medicinal balloon preparation method of small molecule antioxidant 2,6 ditertiary butyl p cresol (3,5-di-tert-butyl-4-hydroxytoluene, BHT):
The configuration of PVP alcoholic solution: weigh 4g PVP (Povidone K30) with the balance of 0.0001g precision, add in 25ml sample bottle; The ethanol of drawing 20ml with liquid-transfering gun joins in sample bottle.Screw bottle stopper, after vibration is stirred, be put into 45 ℃ of baking ovens and preserve until PVP all dissolves.
The preparation of paclitaxel alcoholic solution: weigh about 0.15g paclitaxel, add 25ml vial; The ethanol that adds 1ml in vial; At 45 ℃ of baking ovens, be incubated until paclitaxel dissolves completely.
The alcoholic solution of preparation BHT: about 0.002g BHT is added in 25ml sample bottle; With liquid-transfering gun, drawing PVP alcoholic solution 8ml joins in sample bottle;
Compounding pharmaceutical coating composition: add the D-ALPHA-tocopheryl polyethylene glycol 1000 succinate solution of about 1-2ml and the distilled water of a small amount of (0.262m1) in paclitaxel alcoholic solution, sealing, stirs.
Sacculus coating: sacculus is immersed in above-mentioned medication coat compositions; Keep 5-60 second, rear taking-up; Drying at room temperature 6 hours; Folding, sterilizing, packing.
The test of drug releasing rate and granularity: the inflated to 2 that said method an is made atmospheric pressure, be then put in the phosphate buffer bottle of 0.1M of 20ml, static 1 minute, then take out sacculus, dry, weigh.Observe the residual condition of balloon surface medication coat and the state of the medicine crystal in buffer bottle, result of the test is in Table 10 simultaneously.Result: the medication coat over 80% is successfully discharged in buffer, and simultaneous buffering liquid bottle is observed the bulky grain medicine crystal of minute quantity.
Table 10
Embodiment 6B contains the medicinal balloon preparation method of small molecule antioxidant 2,6 ditertiary butyl p cresol (3,5-di-tert-butyl-4-hydroxytoluene, BHT):
The configuration of PVP alcoholic solution: weigh 4g PVP (Povidone K30) with the balance of 0.0001g precision, add in 25ml sample bottle; The ethanol of drawing 20ml with liquid-transfering gun joins in sample bottle.Screw bottle stopper, after vibration is stirred, be put into 45 ℃ of baking ovens and preserve until PVP all dissolves.
The preparation of rapamycin alcoholic solution: weigh about 0.15g rapamycin, add 25ml vial; The ethanol that adds 1ml in vial; At 45 ℃ of baking ovens, be incubated until rapamycin dissolves completely.
The alcoholic solution of preparation BHT: about 0.002g BHT is added in 25ml sample bottle; With liquid-transfering gun, drawing PVP alcoholic solution 8ml joins in sample bottle;
Compounding pharmaceutical coating composition: add the D-ALPHA-tocopheryl polyethylene glycol 1000 succinate solution of about 1-2ml and the distilled water of a small amount of (0.262m1) in rapamycin alcoholic solution, sealing, stirs.
Sacculus coating: sacculus is immersed in above-mentioned medication coat compositions; Keep 5-60 second, rear taking-up; Drying at room temperature 6 hours; Folding, sterilizing, packing.
The test of drug releasing rate and granularity: the inflated to 2 that said method an is made atmospheric pressure, be then put in the phosphate buffer bottle of 0.1M of 20ml, static 1 minute, then take out sacculus, dry, weigh.Observe the residual condition of balloon surface medication coat and the state of the medicine crystal in buffer bottle, result of the test is in Table 11 simultaneously.Result: 58% medication coat is successfully discharged in buffer, simultaneous buffering liquid bottle is observed the bulky grain medicine crystal of minute quantity.
Table 11
In above each embodiment of the present invention, adopt the first component solution---PVP alcoholic solution concentration is 0.2g/ml, the 0.2g/ml is here optium concentration, from integrated artistic angle, its concentration is relevant with the medication coat density finally obtaining, can suitably increase under a proportional relationship or reduce, thus the density of adjusting coating.
Above-described embodiment is preferably scheme more of the present invention, not the present invention is done to any pro forma restriction, also has other variant and remodeling under the prerequisite that does not exceed the technical scheme that claim records.
Claims (10)
1. a medication coat compositions that is applicable to be coated in implantation or interventional medical device surface, is characterized in that comprising following component:
The first component is hydrophilic high polymer;
Second component is for treating the blood vessel medicine of hypertrophy again;
The 3rd component is inorganic matter, is selected from one or more the compositions in inorganic simple substance, water-soluble inorganic salt or amphipathic small molecules compound;
In each component, hydrophilic high polymer and treatment the blood vessel again weight ratio of the medicine of hypertrophy are 0.3-3: 1, the three component accounts for the 0.005-5.0% of the first component, second component and the 3rd component gross weight;
The 4th component is dicyandiamide solution, and dicyandiamide solution comprises the solvent that the first component, second component and the 3rd component are dissolved separately.
2. medication coat compositions according to claim 1, it is characterized in that: described hydrophilic high polymer is selected from polyvidon (PVP), the polyvidon that contains the iodine that is coupled, polyvinyl alcohol (PVA), polyethylene glycol oxide (PEO) or Polyethylene Glycol (PEG); The described treatment blood vessel again medicine of hypertrophy is selected from paclitaxel or derivatives thereof, rapamycin or derivatives thereof, anticoagulant medicine; Described inorganic simple substance is selected from iodine, bromine or nicotiamide; Water-soluble inorganic salt is selected from sodium iodide, calcium iodide, and sodium chloride or calcium chloride, amphipathic small molecules compound is D-ALPHA-tocopheryl polyethylene glycol 1000 succinate.
3. medication coat compositions according to claim 1, is characterized in that: the derivant of described paclitaxel comprises Docetaxel (docetaxel); Rapamycin derivative comprises everolimus (everolimus), if he coughs up Li Mosi (Zotarolimus), and Baeyer Li Mosi (Biolimus); Anticoagulant medicated bag is drawn together cilostazol (Cilostazol), heparin (heparin).
4. medication coat compositions according to claim 1, it is characterized in that: described implantation or interventional medical device comprise: coronary blood pipe holder, arteria coronaria blood saccule, peripheral blood vessel support, peripheral blood vessel sacculus, intracranial vessel support, intracranial vessel sacculus, urethra rack, urethra sacculus, esophageal stents appear or esophagus sacculus.
5. medication coat compositions according to claim 1, is characterized in that: in described dicyandiamide solution, the solvent of the first components dissolved is selected to water, ethanol, the compositions of one or more in methanol or oxolane; The solvent that second component is dissolved is ethanol, methanol, the compositions of one or more in oxolane or acetone; By the solvent of the 3rd components dissolved, be water, the compositions of one or more in ethanol or methanol.
6. medication coat compositions according to claim 5, it is characterized in that: with ethanol, will after the first components dissolved, obtain the first component solution, in the first component solution, add the 3rd component and suitable quantity of water to be fully mixed to get the 3rd component solution, after second component being dissolved with ethanol, obtain second component solution, the volume ratio between second component solution, the 3rd component solution and water three is 1-2: 1-2: 0.1-1.
7. a preparation method for described medication coat compositions, is characterized in that comprising the steps:
The preparation of a, the 3rd component solution: the first component is fully mixed with solvent, configuration concentration is the first component solution of 0.1-1g/ml, and preserve the first component is all dissolved at 40-50 ℃ of temperature, in the first component solution, add the 3rd component fully to mix again, obtain the 3rd component solution, the concentration that makes the 3rd component in the 3rd component solution is 0.001-0.1g/ml;
The preparation of b, second component solution: second component is fully mixed with solvent, the second component solution that configuration concentration is 0.05-0.5g/ml, and at 40-50 ℃ of temperature, be incubated until second component dissolves completely;
The preparation of c, medication coat compositions: add described the 3rd component solution and water in described second component solution, volume ratio between second component solution, the 3rd component solution and water three is 1-2: 1-2: 0.1-1, sealing, stir, obtain for being coated in the medication coat compositions on implantation or interventional medical device surface.
8. the preparation method of medication coat compositions according to claim 7, is characterized in that comprising the steps:
The preparation of a, iodine solution: polyvinylpyrrolidone (PVP) is fully mixed with ethanol, configuration concentration is polyvinylpyrrolidone (PVP) alcoholic solution of 0.1-0.3g/ml, and preserve PVP is all dissolved at 40-50 ℃ of temperature, in PVP alcoholic solution, add I fully to mix again, obtain iodine solution, concentration is 0.001-0.01g/ml;
The preparation of b, paclitaxel alcoholic solution: paclitaxel is fully mixed with ethanol, the paclitaxel alcoholic solution that configuration concentration is 0.1-0.3g/ml, and at 40-50 ℃ of temperature, be incubated until paclitaxel dissolves completely;
The preparation of c, medication coat compositions: add described iodine solution and distilled water in described paclitaxel alcoholic solution, volume ratio between paclitaxel alcoholic solution, iodine solution and water three is 1: 1-2: 0.25-0.28, sealing, stirs, and obtains medication coat compositions.
9. implantation or an interventional medical device that utilizes described medication coat compositions to prepare, it is characterized in that: the implantation not applying through medicine or interventional medical device semi-finished product are immersed in the medication coat compositions described in claim 1 or 7, keep 5-60 to take out after second; Dry under room temperature, folding, sterilizing, obtains product.
10. implantation according to claim 9 or interventional medical device, is characterized in that: the density of its face coat is 0.5-10 μ g/mm
2, the density of medicine net content on medicament eluting instrument surface is 0.2-8 μ g/mm
2.
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| PCT/CN2014/091205 WO2016037413A1 (en) | 2014-09-09 | 2014-11-14 | Drug coating composition, manufacturing method therefor and implantable or interventional medical device made therefrom |
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| CN108042112A (en) * | 2018-01-12 | 2018-05-18 | 郑州大学第附属医院 | A kind of tubal occlusion apparatus for diagnosis and therapy |
| CN108042112B (en) * | 2018-01-12 | 2024-02-23 | 郑州大学第一附属医院 | Oviduct blockage diagnosis and treatment device |
| CN109966561A (en) * | 2018-04-02 | 2019-07-05 | 首都医科大学附属北京安贞医院 | Medical instrument for being coated in the medication coat composition of the medical apparatus surface of guiding device and being prepared using it |
| CN111671982A (en) * | 2020-05-08 | 2020-09-18 | 北京永益润成科技有限公司 | Medicinal coating composition and preparation method thereof |
| CN113476669A (en) * | 2021-06-17 | 2021-10-08 | 北京永益润成科技有限公司 | Medicine coating composition and coating process thereof |
| WO2023179082A1 (en) * | 2022-03-21 | 2023-09-28 | 上海以心医疗器械有限公司 | Drug coating medical instrument, preparation method therefor and use thereof, and drug coating and use thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104324421A (en) | 2015-02-04 |
| CN104324421B (en) | 2017-02-08 |
| CN104174074B (en) | 2016-05-18 |
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