CN107158486A - 小檗碱洗脱支架 - Google Patents
小檗碱洗脱支架 Download PDFInfo
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- CN107158486A CN107158486A CN201710181676.9A CN201710181676A CN107158486A CN 107158486 A CN107158486 A CN 107158486A CN 201710181676 A CN201710181676 A CN 201710181676A CN 107158486 A CN107158486 A CN 107158486A
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- jamaicin
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Classifications
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/16—Biologically active materials, e.g. therapeutic substances
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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- A—HUMAN NECESSITIES
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
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- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
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Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Surgery (AREA)
- Heart & Thoracic Surgery (AREA)
- Vascular Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Biomedical Technology (AREA)
- Engineering & Computer Science (AREA)
- Inorganic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
一种小檗碱洗脱支架,包括医用金属骨架,骨架上包覆有控释膜,所述金属骨架上载有小檗碱。本发明提供的小檗碱抗去甲肾上腺素刺激肺动脉平滑肌细胞的作用突出,能够有效改善心室功能,同时可以显著降低肺动脉平均压;还具备防治支架内再狭窄及支架内血栓的作用;小檗碱具有防治心肌梗死的独特作用,还能够有效防治缺血性心肌病及其导致的心力衰竭。本发明提供的小蘖碱洗脱支架包括医用金属骨架,骨架上包覆有控释膜,所述金属骨架上载有小檗碱。小蘖碱洗脱支架具有显著抑制平滑肌细胞增生的作用,可以显著改善血管狭窄所引起的心肌缺血,并且能够抑制再狭窄病变及支架内血栓的发生发展。
Description
技术领域
本发明属于药物洗脱支架技术领域,具体涉及小檗碱洗脱支架。
背景技术
药物洗脱支架(DES)也称之为药物释放支架,通过包被于金属支架表面的聚合物携带药物,当支架置入血管内病变部位后,药物自聚合物涂层中通过洗脱方式有控制地释放至血管壁组织而发挥生物学效应。其中,药物缓释支架对于实现药物在体内的缓慢可控释放具有重要的意义。可降解的药物缓释支架材料由于在体内不会滞留残留物而不需要二次手术,从而减少了患者的痛苦。在动物实验与临床前期试验的药物洗脱支架种类繁多,上市的DES只有雷帕霉素洗脱支架和紫杉醇洗脱支架。CYPHER支架携带药物雷帕霉素,剂量为148μg/cm2,雷帕霉素释放周期为28天。雷帕霉素为天然大环内酯类抗生素,具有较强的抗细胞增殖与免疫抑制作用,主要作用于血管平滑肌有丝***的G1期,使细胞有丝***停止于静止期G0期。TAXUS支架则是携带药物紫杉醇,剂量为1.0μg/mm2,缓慢释放。紫杉醇可作用于血管平滑肌细胞有丝***G2-M期,抑制血管平滑肌细胞增殖。小檗碱又称黄连素。一种常见的异喹啉生物碱,分子式C20H18NO4。它存在于小檗科等四个科十个属的许多植物中。1826年M.-E.夏瓦利埃和G.佩尔坦从Xanthoxylonclava树皮中首次获得。小檗碱为一种季铵生物碱。从***中可析出黄色针状晶体;熔点85-86℃;溶于水,难溶于苯、***和氯仿。其盐类在水中的溶解度都比较小,例如盐酸盐为1:500,硫酸盐为1:30。小檗碱对溶血性链球菌,金黄色葡萄球菌,***和弗氏、志贺氏痢疾杆菌等均有抗菌作用,并有增强白血球吞噬作用,对结核杆菌、鼠疫菌也有不同程度的抑制作用,对大鼠的阿米巴菌也有抑制效用。小檗碱在动物身上有抗箭毒作用,并具有末梢性的降压及解热作用。小檗碱的盐酸盐(俗称盐酸黄连素)已广泛用于治疗胃肠炎、细菌性痢疾等,对肺结核、猩红热、急性扁桃腺炎和呼吸道感染也有一定疗效。小檗碱尚具有降低血脂及调节血糖的作用。
发明内容
解决的技术问题:本发明提供一种小檗碱洗脱支架,该支架应用于临床可有效改善右心室功能,同时可以显著降低肺动脉平均压,防治支架内再狭窄及支架内血栓的作用,同时可以防治心肌梗死,还可以防治缺血性心肌病及其导致的心力衰竭。
技术方案:小檗碱洗脱支架,包括医用金属骨架,骨架上包覆有控释膜,所述金属骨架或控释膜上载有小檗碱。
优选的,金属骨架为钴铬合金,骨架厚度80~100μm。金属骨架上的载药剂量70-180μg/mm2。
上述控释膜为可降解膜,可降解膜为聚乙丙交酯(PGLA)或聚乳酸(PLA);可降解膜植入体内3天释放总药剂量25wt.%、7天后释放总药剂量的50wt.%、28天后释放总药剂量的85wt.%;该可降解膜60天内完全降解。
有益结果:本发明提供的洗脱支架上含有可缓释的小檗碱,利用小檗碱抗去甲肾上腺素刺激肺动脉平滑肌细胞的作用突出,能够有效改善右心室功能,同时可以显著降低肺动脉平均压;还具备防治支架内再狭窄及支架内血栓的作用;小檗碱具有防治心肌梗死的独特作用,还能够有效防治缺血性心肌病及其导致的心力衰竭。
附图说明
图1为小檗碱抗去甲肾上腺素示意图;肺动脉平滑肌细胞经过去甲肾上腺素(NE)刺激2小时后,随机分为小檗碱组(Ctl组,小檗碱作用4小时)及对照组。对照组分别于分组后不同时间点(30分钟-4小时)收集细胞,测定肝脏激酶B1(LKB1)和G蛋白偶联受体激酶2(Grk2)的蛋白磷酸化活性。GAPDH是内参蛋白;
图2为小檗碱抑制肺动脉重构对比实验镜像图;肺动脉高压动物随机分为正常对照组、小檗碱组和未治疗的空白组。组织化学染色(HE)及血管内皮vWF染色、平滑肌细胞染色(SMA)。14周时结果显示小檗碱组肺血管病理重构显著减轻;
图3为小檗碱显著升高右心室收缩位移幅度(TAPSE)柱状图;小檗碱治疗组右心室功能显著改善;
图4为小檗碱降低肺动脉平均压对比实验数据柱状图;小檗碱治疗组肺动脉平均压显著降低,图中每三个数据柱为一组,自左往右依次为正常组、空白组和小檗碱组;
图5为小檗碱防治支架内再狭窄实验对照图;女性79岁心绞痛患者,支架术前冠状动脉造影显示左主干末端严重下肢,支架术后即刻显示狭窄基本消失;术后第4个月有余再发心绞痛,冠状动脉造影显示前降支开口及回旋支近端严重支架内狭窄,并累计左主干末端;持续使用小檗碱治疗6个月后冠状动脉造影显示支架内再狭窄基本消失;
图6为小檗碱防治缺血性心肌病的实验结果图;荧光染色(左)及电子显微镜(右A-C)显示小檗碱治疗组心肌细胞凋亡显著减轻;
图7为小檗碱显著改善缺血性心肌病导致的心力衰竭研究结果图;一例缺血性心肌病患者于心肌梗死后第22天心脏超声心动图显示心室功能严重减退,连续使用小檗碱3个月后左心室射血分数明显增高、心肌收缩功能得到改善。
图8为小檗碱洗脱支架的使用状态成像照片;
图9为小檗碱洗脱支架的缓释规律示意图。
图10为小蘖碱与GRK2信号通路和平滑肌细胞作用关系示意图。上行,与对照组相比(左),去加肾上腺素(NE)刺激后动脉平滑肌细胞迁移明显增多(中),而同时使用小蘖碱(BB)后平滑肌细胞的迁移显著减少(右);中行,NE刺激持续24小时后,G-蛋白偶联受体酶2(GRK2)显著增多,而小蘖碱(BB)可以显著降低GRK2的蛋白磷酸化水平;下行,平滑肌细胞经NE刺激1小时后,分离细胞膜并提取膜蛋白,结果小蘖碱(BB)降低α1-肾上腺素能受体(α1-AR)的作用显著强于GRK2的特异性抑制剂(G),提示小蘖碱能够有效抑制GRK2信号通路和平滑肌细胞收缩。
具体实施方式
以下实施例进一步说明本发明的内容,但不应理解为对本发明的限制。在不背离本发明精神和实质的情况下,对本发明方法、步骤或条件所作的修改和替换,均属于本发明的范围。若未特别指明,实施例中所用的技术手段为本领域技术人员所熟知的常规手段。
实施例1
防治肺动脉高压及右心衰的作用
细胞实验:
选用正常动物肺动脉平滑肌细胞,经去甲肾上腺素刺激不同时间后右心衰时最常见高表达的Grk2和LKB1显著升高,而同时加入小檗碱30分钟后(CTL)组显著降低。结果表明小檗碱抗去甲肾上腺素刺激肺动脉平滑肌细胞的作用突出(图1)
动物实验:
选取20只比格犬,测定肺动脉血流动力学后,随机分为小檗碱(灌胃饲养,0.1g/d,共计14天)和对照组(灌胃小檗碱糖衣层,其中无小檗碱,共计14天)。第14天时右心房内注射去氢野百合碱(60mg/kg),观察8周,复测肺动脉学血流动力学。结果:小檗碱组仅1只动物肺动脉平均压达28mmHg,其余9只动物的平均肺动脉压均<25mmHg(19±3.0mmHg);相反,对照组8只动物平均肺动脉压均>26mmHg(28.4±2.1mmHg),1只动物为24.6mmHg,另外1只为24.8mmHg。结果表明,小檗碱具有抑制去氢野百合碱诱导肺动脉高压的作用。继之,给于对照组平均肺动脉压力>25mmHg的8只动物灌胃小檗碱(0.1g/d,共计42天)后,肺动脉平滑肌增生程度显著降低(图2)。
临床实验:
6例特发性肺动脉高压患者,分为两组(每组各3例):对照组(按原来剂量服用靶向药物),小檗碱组(在原来靶向药物基础上,加服小檗碱0.3g/d,共计3个月)。治疗3月后,小檗碱组右心室功能显著改善(图3),而且肺动脉平均压显著降低(图4)
实施例2
防治支架内再狭窄及支架内血栓的作用
100例药物洗脱支架植入术后的患者,随机分为两组:对照组(不加服小檗碱)和小檗碱组(自术后第3个月时加服小檗碱0.3/d,共计6个月),术后第12个月时复查冠状动脉造影。结果:对照组支架内再狭窄的比例为14%(N=7),小檗碱组仅2例出现再狭窄(4%,p=0.035)且狭窄程度明显低于对照组(58±4%对76.3±9%,p=0.029)。对于对照组中7例再狭窄的患者口服小檗碱(0.3/d,共计6个月),继续随访9个月,结果6例患者狭窄程度显著减轻(图5)。
实施例3
防治心肌梗死的作用
30只心肌梗死模型动物,随机分为对照组及小檗碱灌胃饲养组,结果显示小檗碱(0.3g,每日3次,3个月后)心肌细胞凋亡显著减轻(图6左图),电子显微镜证实凋亡小体减少(图6右图A-C)。小檗碱治疗组心肌细胞排列较为完整。
实施例4
防治缺血性心肌病导致的心力衰竭
40例急性心肌梗死后患者随机分为对照组及小檗碱组(0.3g,每日3次,3个月后),对照组平均左心室射血分数为41%,而小檗碱组增减到53%(p=0.037)。图7显示一例急性前壁心肌梗死患者梗死后第22天左心室显著扩大、射血分数降低、心肌收缩平坦(上行),经过3个月的小檗碱治疗后心腔缩小、射血分数显著增加、心肌收缩力明显增强(下行)。
实施例5
小檗碱洗脱支架,包括医用钴铬合金骨架,骨架厚度80~100μm,骨架上包覆有聚乙丙交酯(PGLA)或聚乳酸(PLA)可降解膜,所述金属骨架上载有小檗碱。将小檗碱及可降解膜在乙醇中溶解,得到药物涂层溶液;将药物涂层溶液涂覆到支架表面;将带有涂层的支架真空干燥固化,即得到药物洗脱支架,载药剂量70-180μg/mm2。使用及效果参见图8~图10。
不同剂量小蘖碱植入医用小型猪冠状动脉6个月时平滑肌细胞增生及并发症结果,见下表所示:
<70μg/mm2 | 70-170μg/mm2 | 171-180μg/mm2 | >180μg/mm2 | |
动物数量,只 | 11 | 26 | 14 | 12 |
支架长度,mm | 23±5 | 24±6 | 23±6 | 23±5 |
支架直径,mm | 2.52±0.3 | 2.50±0.3 | 2.50±0.3 | 2.50±0.3 |
晚期管腔丢失,mm | 0.20±0.09 | 0.13±0.05 | 0.13±0.06 | 0.13±0.07 |
支架内血栓,% | 0 | 0 | 0 | 4 |
死亡,% | 0 | 0 | 0 | 2 |
载药剂量介于70-180μg/mm2的小蘖碱洗脱支架同时具有显著降低管腔直径丢失、支架内血栓及死亡的作用。载药剂量<70μg/mm2时,晚期管腔丢失显著增大(p<0.05)。
Claims (7)
1.小檗碱洗脱支架,包括医用金属骨架,骨架上包覆有控释膜,其特征在于所述金属骨架或控释膜上载有小檗碱。
2.根据权利要求1所述的小檗碱洗脱支架,其特征在于所述金属骨架为钴铬合金,骨架厚度80~100μm。
3.根据权利要求1所述的小檗碱洗脱支架,其特征在于所述洗脱支架上的小檗碱载药剂量 70-180 μg/mm2。
4.根据权利要求1所述的小檗碱洗脱支架,其特征在于所述控释膜为可降解膜。
5.根据权利要求4所述的小檗碱洗脱支架,其特征在于所述可降解膜为聚乙丙交酯(PGLA)或聚乳酸(PLA)。
6.根据权利要求4所述的小檗碱洗脱支架,其特征在于所述可降解膜植入体内3天释放总药剂量25wt.%、7天后释放总药剂量的50wt.%、28天后释放总药剂量的85wt.%。
7.根据权利要求4所述的小檗碱洗脱支架,其特征在于所述可降解膜60天内完全降解。
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