CN1303947C - Medicine eluted cardiovascular frame and its preparing process - Google Patents
Medicine eluted cardiovascular frame and its preparing process Download PDFInfo
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- CN1303947C CN1303947C CNB011426411A CN01142641A CN1303947C CN 1303947 C CN1303947 C CN 1303947C CN B011426411 A CNB011426411 A CN B011426411A CN 01142641 A CN01142641 A CN 01142641A CN 1303947 C CN1303947 C CN 1303947C
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- Media Introduction/Drainage Providing Device (AREA)
Abstract
本发明公开了一种药物洗脱性心血管支架及其制备方法。该支架由球囊扩张支架和涂覆在支架上的包覆药物的可生物降解层构成。可生物降解材料包括乙交酯、L-丙交酯或ε-己内酯的均聚物或共聚物中的一种及其与多官能团氨基酸的共聚物，包覆药物的可生物降解层材料为一种可生物降解高分子接枝肝素，药物为一种具有抗再狭窄功能的药物。该支架是这样制备的，先制备球囊扩张架，再将支架浸渍于具有抗再狭窄功能的药物、包覆药物的可生物降解层材料及溶剂组成的混合体系中，取出支架，干燥后，即获得本发明的药物洗脱性心血管支架。本发明的药物洗脱性心血管支架，能防止急性、亚急性血栓的发生，同时能促进损伤血管壁的愈合，防止晚期血栓的发生。The invention discloses a drug-eluting cardiovascular stent and a preparation method thereof. The stent is composed of a balloon-expandable stent and a drug-coated biodegradable layer coated on the stent. Biodegradable materials include one of the homopolymers or copolymers of glycolide, L-lactide or ε-caprolactone and their copolymers with multifunctional amino acids, biodegradable layer materials for coating drugs It is a kind of biodegradable macromolecule grafted heparin, and the drug is a drug with anti-restenosis function. The stent is prepared in the following way. First, the balloon expansion stent is prepared, and then the stent is immersed in a mixed system composed of drugs with anti-restenosis function, biodegradable layer materials coated with drugs, and solvents. The stent is taken out and dried. That is, the drug-eluting cardiovascular stent of the present invention is obtained. The drug-eluting cardiovascular stent of the invention can prevent the occurrence of acute and subacute thrombus, and at the same time, can promote the healing of damaged blood vessel walls and prevent the occurrence of late thrombus.
Description
Technical field
The present invention relates to a kind of medicinal support, particularly a kind ofly be used for cardiovascular balloon expandable stent that can discharge medicine.
Background technology
Dotter in 1964 and Judkings (Dotter CT, Jukines MP.Tranaluminal treatmant ofarteriosclerotic 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, etal.Intravascular stents to prevent occlusion and restenosis after tranaluminal angioplasty.N Engl JMed, 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 constantly design and 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, on this support, applied the Biodegradable high-molecular grafting heparin that one deck has anti-restenosis function, after support is implanted soon, anti-restenosis medicaments discharges in a large number, fully suppress neointimal hyperplasia, the continual and steady release of heparin, can prevent acute, the generation of subacute stent thrombosis, can promote simultaneously the healing of injured blood vessel wall, prevent the generation of advanced thrombus, 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 made of balloon expandable stent and the biodegradable layers that is coated in the coating medicine on the support.
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.Concrete preparation method can be referring to embodiment 1.
The biodegradable layer material 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).Concrete preparation method can referring to
Embodiment 2.
Said medicine is a kind of medicine with anti-restenosis function, comprises in rapamycin, dactinomycin, ciclosporin A or the paclitaxel one or more.
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, generally speaking, dip time is 10～60s; Said solvent be for dissolving the biodegradable layer material of coating medicine, comprises a kind of and composition thereof in chloroform, acetone or the DMC dimethyl carbonate;
(3) take out support, after the 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 in stent surface coated one Biodegradable high-molecular grafting heparin with anti-restenosis function, the continual and steady release 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, the not anti-body fluid that has overcome physical blending washes away (heparin is a water soluble drug), and the defective of introducing noxious substance in the chemical bond process.
Description of drawings
Fig. 1 is the structural representation of balloon expandable stent.
Fig. 2 is the structural representation after the balloon expandable stent expansion.
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, use N
2Replace 3 times, place 160 ℃ of oil baths, after waiting to melt, add the 0.02g/ml stannous octoate chloroformic solution (catalytic amount is the 0.02wt% of monomer mass) of certain volume, chloroform is removed in decompression, stirs reaction 5h down, and polymer dissolves with chloroform, ethanol precipitation.(gel permeationchromatography 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 morpholine diketone derivatives monomer that 0.1molL-lactide and 0.05mol contain benzyloxy protection glutamic acid in exsiccant, as to have stirrer polymerization bottle, use N
2Replace 3 times, place 160 ℃ of oil baths, after waiting to melt, add the 0.02g/ml stannous octoate chloroformic solution of certain volume, chloroform is removed in decompression, stirs reaction 5h down, and 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, to gather in the mixed solvent that (lactic-co-glycolic acid-aspartic acid) be dissolved in oxolane and water, other takes by weighing a certain amount of (according to the Gel Permeation Chromatography of polymer, be called for short GPC molecular weight and amino acid content) heparin sodium be 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 (heparinized polymer).
Embodiment 3
0.1 gram heparinization poly-(lactic-co-glycolic acid-aminoacid) and the 0.1 anti-restenosis medicaments rapamycin of gram (Rampamycin) are dissolved in the 5ml chloroform, 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 4
0.1 gram heparinization poly-(lactic-co-glycolic acid-aminoacid) and the 0.2 anti-restenosis medicaments dactinomycin of gram (Actonimycin) are dissolved in the 5ml chloroform, 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 5
0.1 gram heparinization poly-(lactic-co-glycolic acid-aminoacid) and the 0.4 anti-restenosis medicaments paclitaxel of gram (Taxol) are dissolved in the 5ml chloroform, 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 6
Get a medical stainless steel tubing, coat heparinization poly-(lactic-co-glycolic acid-aminoacid) at internal layer, outer is that coating material coats paclitaxel with heparinization poly-(lactic-co-glycolic acid-aminoacid), again pipe is become balloon expandable stent with laser ablation.This rack inner wall contacts with blood, owing to there is heparin coating to have the anticoagulation function, can prevent the formation of tampon; Skin slowly releases paclitaxel, and paclitaxel can suppress neointimal hyperplasia, thereby alleviates in-stent restenosis, and heparinization poly-(lactic-co-glycolic acid-aminoacid) can promote the healing of blood vessel wound simultaneously.
Embodiment 7
Get a medical tubing, coat heparinization poly-(lactic-co-glycolic acid-aminoacid) at internal layer, outer is that coating material coats dactinomycin with heparinization poly-(lactic-co-glycolic acid-aminoacid), again pipe is become balloon expandable stent with laser ablation.This rack inner wall contacts with blood, owing to there is heparin coating to have the anticoagulation function, can prevent the formation of tampon; Skin slowly releases dactinomycin, and dactinomycin can suppress neointimal hyperplasia, thereby alleviates in-stent restenosis, and heparinization poly-(lactic-co-glycolic acid-aminoacid) can promote the healing of blood vessel wound simultaneously.
Embodiment 8
Get a medical tubing, coat heparinization poly-(lactic-co-glycolic acid-aminoacid) at internal layer, outer is that coating material coats rapamycin with heparinization poly-(lactic-co-glycolic acid-aminoacid), again pipe is become balloon expandable stent with laser ablation.This rack inner wall contacts with blood, owing to there is heparin coating to have the anticoagulation function, can prevent the formation of tampon; Skin slowly releases rapamycin, and rapamycin can suppress neointimal hyperplasia, thereby alleviates in-stent restenosis, and heparinization poly-(lactic-co-glycolic acid-aminoacid) can promote the healing of blood vessel wound simultaneously.
Claims (7)
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| CNB011426411A CN1303947C (en) | 2001-12-13 | 2001-12-13 | Medicine eluted cardiovascular frame and its preparing process |
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| CNB011426411A CN1303947C (en) | 2001-12-13 | 2001-12-13 | Medicine eluted cardiovascular frame and its preparing process |
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| CN1303947C true CN1303947C (en) | 2007-03-14 |
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Cited By (1)
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| CN110711056A (en) * | 2014-10-28 | 2020-01-21 | 株式会社Jimro | drug eluting stent |
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| CN101467921B (en) * | 2001-11-05 | 2012-08-15 | 生物传感器国际集团有限公司 | Method for producing bracket for eluting medicament |
| JP2005531391A (en) * | 2002-06-27 | 2005-10-20 | 微創医療器械（上海）有限公司 | Drug release stent |
| CN1306917C (en) * | 2002-12-17 | 2007-03-28 | 微创医疗器械(上海)有限公司 | A stent for preventing/treating intravascular restenosis through a composite mechanism of action |
| CN100346850C (en) * | 2003-05-28 | 2007-11-07 | 微创医疗器械(上海)有限公司 | Medicine coating rack |
| LT1585548T (en) * | 2002-12-09 | 2018-09-25 | Abraxis Bioscience, Llc | Compositions and methods of delivery of pharmacological agents |
| CN100371032C (en) * | 2004-01-16 | 2008-02-27 | 东南大学 | Anti-restenosis drug slow-release vascular stent and preparation method thereof |
| US7875282B2 (en) * | 2004-03-22 | 2011-01-25 | Cordis Corporation | Coated medical device for local vascular delivery of Panzem® in combination with rapamycin to prevent restenosis following vascular injury |
| WO2005097186A2 (en) * | 2004-04-05 | 2005-10-20 | Medivas, Llc | Bioactive stents for type ii diabetics and methods for use thereof |
| CN100450557C (en) * | 2004-08-13 | 2009-01-14 | 重庆大学 | Medication eluting type blood vessel bracket |
| CN1799650B (en) * | 2005-12-30 | 2010-07-14 | 李文涛 | Preparation method of biodegradable drug-loaded polymer material scaffold |
| EP2085057B1 (en) * | 2006-11-20 | 2016-10-12 | Lepu Medical Technology (Beijing) CO., LTD. | Vessel stent with multi drug-coatings |
| CN101199873B (en) * | 2006-12-14 | 2013-06-19 | 乐普（北京）医疗器械股份有限公司 | Nanometer-level hole drug release structure for drug eluting instrument and preparation method thereof |
| CN101641059B (en) * | 2007-02-14 | 2011-10-19 | 山东瑞安泰医疗技术有限公司 | Intracoronary stent with asymmetric drug releasing controlled coating |
| CN101161300B (en) | 2007-11-27 | 2011-03-16 | 北京美中双和医疗器械有限公司 | Arsenic trioxide medicament elution bracket and its preparation method |
| CN102711674A (en) * | 2009-08-26 | 2012-10-03 | 大塚医疗器械有限公司 | Medical device for placement into a lumen and manufacturing method thereof |
| CN102784418B (en) * | 2012-08-10 | 2014-04-16 | 中国医学科学院生物医学工程研究所 | Procedurally-released biological drug nanoporous intravascular stent, preparation method and application thereof |
| CN102860890B (en) * | 2012-10-14 | 2014-12-17 | 梁春永 | Composite medicine carrying vessel stent and preparation method thereof |
| CN105797220B (en) * | 2014-12-31 | 2020-07-31 | 先健科技(深圳)有限公司 | Degradable iron-based alloy stent |
| CN106883451A (en) * | 2016-12-29 | 2017-06-23 | 高州市兆翔新材料有限公司 | A kind of nano kaoline |
| CN113967112A (en) * | 2021-10-15 | 2022-01-25 | 东华大学 | Preparation method of 3D-printed intravascular absorbable stent with anticoagulation function |
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