CN116747219A - 维替泊芬在制备预防/治疗血管再狭窄的药物中的应用 - Google Patents
维替泊芬在制备预防/治疗血管再狭窄的药物中的应用 Download PDFInfo
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- CN116747219A CN116747219A CN202310721115.9A CN202310721115A CN116747219A CN 116747219 A CN116747219 A CN 116747219A CN 202310721115 A CN202310721115 A CN 202310721115A CN 116747219 A CN116747219 A CN 116747219A
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Classifications
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- A—HUMAN NECESSITIES
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Abstract
本发明涉及生物医药领域，具体涉及维替泊芬在制备预防/治疗血管再狭窄的药物中的应用。外伤或涉及血管的医疗干预手段如血管穿刺、血管夹闭、血管吻合、经皮穿刺血管介入手术等均会引起血管内膜损伤和局部血管平滑肌细胞增殖，进一步导致正常血管再狭窄的发生。本发明提出的药物维替泊芬能够有效抑制内膜损伤后血管再狭窄的发生，在制备外伤/医源性操作损伤所致血管再狭窄性疾病方面的药物、体内植入材料及手术器械上存在广阔的应用前景。
Description
技术领域
本发明涉及生物医药领域，具体涉及维替泊芬在制备预防/治疗血管再狭窄的药物中的应用。
背景技术
血液循环是人体各个组织器官保持生理活性的基础。血管狭窄引起远心端供血区域血供缺乏或血流淤滞，进而产生一系列具有部位特异性的相关临床症状。如心脏冠状动脉狭窄引起心绞痛、下肢动脉闭塞导致足缺血坏疽。暴力伤害或涉及血管的医疗干预手段如血管穿刺、血管夹闭、血管吻合、血管介入等均会引起血管内膜损伤和局部血管平滑肌细胞增殖，进一步导致血管管腔狭窄的发生。
然而，血管损伤后管腔再狭窄的发生率居高不下。心脏冠状动脉支架植入术后血管管腔再狭窄的发生率为5-15％(Jukema,J.W.,et al.,Restenosis after PCI.Part 1:pathophysiology and risk factors.Nature Reviews Cardiology,2012.9(1):p.53-62.)，下肢动脉粥样硬化闭塞征球囊扩张术后1年内血管再次狭窄的发生率为40-80％(Zeller,T.,et al.,Drug-coated balloons in the lower limb.Journal ofCardiovascular Surgery,2011.52(2):p.235.)。血管再狭窄严重影响手术治疗的远期效果。现有研究证实，血管损伤所致的内膜平滑肌细胞过度增殖是导致血管狭窄的主要因素。暴力或血管手术操作引起血管内膜损伤/破坏，血管壁中层的血管平滑肌细胞由静止的收缩型转变为分泌型，从动脉中膜迁移入内膜，发生局部增殖，并分泌大量细胞外基质，从而导致血管管腔再狭窄发生(Buccheri,D.,et al.,Understanding and managing in-stentrestenosis:a review of clinical data,from pathogenesis to treatment.J ThoracDis,2016.8(10):p.E1150-e1162.)。
因此，亟需开发一种能够预防或治疗血管狭窄的特效药物。
发明内容
维替泊芬，英文名Verteporfin，是一种卟啉类小分子化合物，临床上常用作光动力疗法的光敏剂。本申请的发明人通过实验首次发现并证实了非光照条件下的维替泊芬对血管介入操作损伤术后血管再狭窄有抑制作用，从而提供一种能够预防或治疗血管再狭窄的特效药物。
为此，本发明第一方面提供维替泊芬在制备药物中的用途，所述药物用于预防或治疗血管损伤后再狭窄。
本申请的发明人通过实验首次发现并证实了非光照条件下的维替泊芬对血管介入操作损伤术后血管再狭窄有抑制作用，从而提供一种能够预防或治疗血管再狭窄的特效药物。维替泊芬能够抑制Hippo信号通路下游的YAP蛋白与转录因子TEAD相互作用，发明人发现药物维替泊芬能够抑制血管介入术后局部平滑肌细胞的迁移、增殖，从而抑制介入术后局部血管再狭窄的发生。
本发明提出的药物维替泊芬能够有效抑制内膜损伤后血管再狭窄的发生，在制备外伤/医源性操作损伤所致血管再狭窄性疾病方面的药物、体内植入材料及手术器械上存在广阔的应用前景。
根据本发明的具体实施方案，所述血管损伤包括选自外伤所致的血管挤压、撕裂、血管离断或涉及血管的医疗干预手段导致的血管损伤。
根据本发明的具体实施方案，所述涉及血管的医疗干预手段包括选自血管穿刺、血管夹闭手术、血管吻合手术、经皮穿刺血管介入手术中的至少之一。
根据本发明的具体实施方案，所述药物进一步含有药学上可接受的赋形剂或载体。
根据本发明的具体实施方案，所述赋形剂包括选自粘合剂、崩解剂、润滑剂、助流剂、稳定剂、填充剂、稀释剂、缓释剂中的至少之一。
根据本发明的具体实施方案，所述载体包括选自糖类、淀粉类、纤维素及其衍生物、磷酸钙类、硬脂酸碱土金属盐、植物油类、表面活性剂、脂肪醇类、谷物水解固形物中的至少之一。
根据本发明的具体实施方案，所述药物的剂型包括选自注射剂、散剂、颗粒剂、乳剂、中的至少之一。
根据本发明的具体实施方案，所述药物的给药方式包括选自注射给药、局部给药、浸泡给药中的至少之一。
根据本发明的具体实施方案，所述注射给药包括选自血管内注射、经皮肤或自然体腔穿刺血管周围注射、血管壁内注射、肌肉注射、皮下注射中的至少一种。
根据本发明的具体实施方案，所述局部给药包括将所述药物负载于手术器械或体内植入材料表面。
根据本发明的具体实施方案，所述手术器械包括选自血管扩张球囊、介入用血管导丝、介入用血管内导管、血管穿刺针、血管内留置输液针、血管内留置输液导管中的至少一种。
根据本发明的具体实施方案，所述体内植入材料包括选自血管内血栓滤网、血管支架、植入式血管内留置输液装置中的至少一种。
本发明第二方面提供一种手术器械，所述手术器械表面负载有维替泊芬。
在一些具体实施方式中，所述手术器械用于预防/治疗血管再狭窄，所述手术器械包括选自血管扩张球囊、介入用血管导丝、介入用血管内导管、血管穿刺针、血管内留置输液针、血管内留置输液导管中的至少一种。
本发明第三方面提供一种医用材料，所述医用材料表面负载有维替泊芬。
在一些具体实施方式中，所述医用材料用于预防/治疗血管再狭窄，所述医用材料包括血管内血栓滤网、血管支架、植入式血管内留置输液装置中的至少一种。
本发明的附加方面和优点将在下面的描述中部分给出，部分将从下面的描述中变得明显，或通过本发明的实践了解到。
附图说明
本发明的上述和/或附加的方面和优点从结合下面附图对实施例的描述中将变得明显和容易理解，其中：
图1显示了本发明实施例1中维替泊芬局部灌注对球囊损伤术后大鼠颈动脉再狭窄的抑制作用效果图，其中，图1中A图为各组颈动脉横断面HE染色图，B图为各组颈动脉血管管腔直径统计图，C图为血管内膜面积统计图，其中，“NC”代表球囊损伤对照组，“10”代表10μg/ml维替泊芬治疗组，“50”代表50μg/ml维替泊芬治疗组；
图2显示了本发明实施例2中维替泊芬载药球囊抑制球囊损伤术后大鼠颈动脉再狭窄效果图，其中，图2中A图为各组颈动脉横断面HE染色图，B图为各组颈动脉血管管腔直径统计图，C图为血管内膜面积统计图，其中，“NC”代表球囊损伤对照组，“VP”代表维替泊芬载药球囊组。
具体实施方式
下面详细描述本发明的实施例。下面描述的实施例是示例性的，仅用于解释本发明，而不能理解为对本发明的限制。
需要说明的是，术语“第一”、“第二”仅用于描述目的，而不能理解为指示或暗示相对重要性或者隐含指明所指示的技术特征的数量。由此，限定有“第一”、“第二”的特征可以明示或者隐含地包括一个或者更多个该特征。进一步地，在本发明的描述中，除非另有说明，“多个”的含义是两个或两个以上。
在本文中所披露的范围的端点和任何值都不限于该精确的范围或值，这些范围或值应当理解为包含接近这些范围或值的值。对于数值范围来说，各个范围的端点值之间、各个范围的端点值和单独的点值之间，以及单独的点值之间可以彼此组合而得到一个或多个新的数值范围，这些数值范围应被视为在本文中具体公开。
为了更容易理解本发明，以下具体定义了某些技术和科学术语。除显而易见在本文件中的它处另有明确定义，否则本文中使用的所有其它技术和科学术语都具有本发明所属领域的一般技术人员通常理解的含义。
在本文中，术语“包含”或“包括”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。
在本文中，术语“任选地”、“任选的”或“任选”通常是指随后所述的事件或状况可以但未必发生，并且该描述包括其中发生该事件或状况的情况，以及其中未发生该事件或状况的情况。
在本文中，术语“赋形剂”在药物制剂中除主药以外的附加物，也可称为辅料。如片剂中的黏合剂、填充剂、崩解剂、润滑剂；中药丸剂中的酒、醋、药汁等；半固体制剂软膏剂、霜剂中的基质部分；液体制剂中的防腐剂、抗氧剂、矫味剂、芳香剂、助溶剂、乳化剂、增溶剂、渗透压调节剂、着色剂等均可称为赋形剂。
在本文中，术语“局部给药”指应用于局部，并在应用部位发挥作用的药物的给药方式。
在本文中，再狭窄(restenosis)是血管外科的领域中一个专门的疾病/研究方向。血管狭窄性疾病往往是动脉粥样硬化引起的。通过对狭窄的动脉粥样硬化斑块形成部位进行球囊扩张/植入支架来恢复狭窄部位管腔直径。但是手术后动脉粥样硬化斑块部位很快会再次狭窄(Restenosis)。
根据本发明的具体实施方案，本发明提供一种维替泊芬在抑制血管损伤后再狭窄中的应用，所述维替泊芬的化学式如式一或式二所示：
根据本发明的具体实施方案，所述维替泊芬可以作为唯一活性成分，也可以作为多种活性成分之一。
根据本发明的具体实施方案，本发明提出维替泊芬在制备治疗或抑制血管损伤后再狭窄的药物中的应用，所述药物包含有药学上可接受的赋形剂或载体。
根据本发明的具体实施方案，赋形剂能增强药物制剂的操作特性，即通过增加流动性和/或粘着性使制剂更适于直接压缩。适用于上述制剂的典型的“药学上可接受的载体”的实例为：糖类，例如乳糖、蔗糖、甘露醇和山梨醇；淀粉类，例如玉米淀粉、木薯淀粉和土豆淀粉；纤维素及其衍生物，例如羧甲基纤维素钠，乙基纤维素和甲基纤维素；磷酸钙类，例如磷酸二钙和磷酸三钙；硫酸钠；硫酸钙；聚乙烯吡咯烷酮；聚乙烯醇；硬脂酸；硬脂酸碱土金属盐，例如硬脂酸镁和硬脂酸钙；硬脂酸；植物油类，例如花生油、棉籽油、芝麻油、橄榄油和玉米油；非离子、阳离子和负离子表面活性剂；乙二醇聚合物；脂肪醇类；和谷物水解固形物以及其它无毒的可相容的填充剂、粘合剂、崩解剂、缓冲剂、防腐剂、抗氧剂、润滑剂、着色剂等在药物制剂中常用到的辅料。
根据本发明的具体实施方案，所述维替泊芬包裹于本领域已知的任何能运转化学药物有效成分的载体中，例如脂质体。
根据本发明的具体实施方案，所述药物的作用方式包括直接结合生物大分子YAP蛋白干扰细胞信号传导途径。
根据本发明的具体实施方案，所述药物的形式包括溶液/悬混液状态，或负载于手术器械、体内植入物表面。
根据本发明的具体实施方案，所述溶液/悬混液给药途径包括注射给药、局部给药、浸泡给药中的至少之一。
根据本发明的具体实施方案，所述局部给药包括将所述药物负载于手术器械、体内植入材料表面。
根据本发明的具体实施方案，所述手术器械包括选自血管扩张球囊、介入用血管导丝、介入用血管内导管、血管穿刺针、血管内留置输液针、血管内留置输液导管中的至少一种。
根据本发明的具体实施方案，所述体内植入材料包括选自血管内血栓滤网、血管支架、植入式血管内留置输液装置中的至少一种。
根据本发明的具体实施方案，维替泊芬所治疗的血管损伤包括但不限于外伤所致的血管挤压、撕裂、离断、涉及血管的医疗干预手段。
血管穿刺、血管夹闭手术、血管吻合手术、动静脉造瘘手术、经皮穿刺血管介入手术等。
根据本发明的具体实施方案，所述涉及血管的医疗干预手段包括选自血管穿刺、血管夹闭手术、血管吻合手术、经皮穿刺血管介入手术中的至少之一。
根据本发明的具体实施方案，所述经皮穿刺血管介入手术是指通过血管穿刺技术将导丝、导管或各种腔内操作器械置入血管内施加干预措施。包括但不限于：经皮穿刺血管造影术、经皮穿刺血管球囊扩张成形术、经皮穿刺血管支架植入术、经皮穿刺血管内置管溶栓术、经皮穿刺血管内血栓抽吸术、经皮穿刺血管内机械旋切减容术、经皮穿刺血管内激光消融术。
根据本发明的具体实施方案，本发明中，能被维替泊芬治疗的再狭窄血管包括但不限于：心脏冠状动/静脉，肝动/静脉、门静脉、胸主动脉、腹主动脉、下腔静脉、肠系膜上动/静脉、肠系膜下动/静脉、颅内动/静脉、颈动/静脉、椎动/静脉、锁骨下动/静脉、肱动/静脉、桡动/静脉、尺动/静脉、手部动/静脉、腹主动/静脉、肾动/静脉、髂动/静脉、股总动/静脉、股浅动/静脉、股深动/静脉、腘动/静脉、腘动/静脉、胫前动/静脉、胫后动/静脉动脉、足部动/静脉、透析用动静脉内瘘通路血管等。
根据本发明的具体实施方案，在非光照条件下，使用局部灌注维替泊芬时，所述维替泊芬的单次应用剂量在0.1-100μg之间，进一步优选为2-10μg之间，能够有效的抑制球囊损伤术后大鼠颈动脉再狭窄。
根据本发明的具体实施方案，在非光照条件下，当维替泊芬负载于手术器械或体内植入材料表面时，操作一般为将所述手术器械或体内植入材料浸泡在维替泊芬溶液中，浸泡时的维替泊芬浓度及浸泡时长依据手术器械或体内植入材料的不同而不同，只需满足最终负载于手术器械或体内植入材料表面的维替泊芬剂量/载量在0.1-200μg之间，进一步优选为1-50μg之间即可有效的抑制球囊损伤术后大鼠颈动脉再狭窄。
下面将结合实施例对本公开的方案进行解释。本领域技术人员将会理解，下面的实施例仅用于说明本公开，而不应视为限定本公开的范围。实施例中未注明具体技术或条件的，按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
实施例1维替泊芬局部灌注对球囊损伤术后大鼠颈动脉再狭窄的抑制作用
将9只SPF级12周龄雄性SD实验大鼠，饲养至体重大于500g，随机分为药物溶剂(20％DMSO水溶液(v/v)，“NC”组)、10μg/ml维替泊芬(溶于20％DMSO水溶液(v/v))治疗组(“10”组)、50μg/ml维替泊芬(溶于20％DMSO水溶液(v/v))治疗组(“50”组)。
按50mg/kg剂量腹腔注射20mg/ml戊巴比妥水溶液麻醉大鼠后，按100U/kg剂量尾静脉注射肝素钠预防血栓形成。修剪颈部毛发并消毒铺巾，沿颈前正中线切开皮肤，在左侧颈前三角区暴露颈总动脉及颈内、颈外动脉，分离1.5-2cm长度。用血管夹临时夹闭颈总动脉近心端及颈内动脉，于颈外动脉处作一“V”形切口，盐水冲洗后向近心端插入2.0FEdwards Lifesciences球囊导管至颈总动脉起始部，用压力泵注射生理盐水至球囊中维持压力为1.5atm扩充球囊，来回拉动球囊至颈外动脉分叉处剥脱内膜，反复3次，损伤完成后结扎颈外动脉。
用胰岛素针向颈外动脉结扎处近心端管腔内分别注入200μl药物溶剂、10μg/ml维替泊芬、50μg/ml维替泊芬，于损伤部位停留两分钟后抽出，去除颈总动脉处血管夹，恢复血流，缝合伤口。
术后对实验大鼠肌注青霉素20万单位/天/只，共3天，预防感染。常规饲养至术后4周处死大鼠取颈总动脉标本。将取得的颈总动脉标本立即浸入多聚甲醛组织固定液24小时进行组织固定，然后将标本脱水，石蜡包埋，行切片和HE染色。观察颈总动脉的组织学形态，并使用Image J软件对HE染色图像进行定量分析，计算有效血管管腔直径、有效内膜面积并绘制直方图。其中，管腔面积及有效内膜面积可以由ImageJ软件直接计算得出。有效管腔直径＝2*管腔面积1/2/Π。如图1所示，显示血管周围局部灌注维替泊芬能够剂量依赖性增加球囊损伤模型的血管管腔直径，抑制内膜增厚。
实施例2维替泊芬载药球囊对球囊损伤术后大鼠颈动脉再狭窄的抑制作用
将6只SPF级12周龄雄性SD实验大鼠，饲养至体重大于500g。随机分为动物模型对照组(NC组)、维替泊芬载药球囊组(VP组)。
将2.0F Edwards Lifesciences球囊导管浸泡于5mg/ml维替泊芬药物溶液(维替泊芬溶解于20％DMSO水溶液(v/v))中5分钟，避光在无菌通风橱中晾干，制备得到维替泊芬载药球囊。
按50mg/kg剂量腹腔注射20mg/ml戊巴比妥溶液麻醉大鼠后，按100U/kg剂量尾静脉注射肝素钠预防血栓形成。修剪颈部毛发并消毒铺巾，沿颈前正中线切开皮肤，在左侧颈前三角区暴露颈总动脉及颈内、颈外动脉，分离1.5-2cm长度。用血管夹临时夹闭颈总动脉近心端及颈内动脉，于颈外动脉处作一“V”形切口，盐水冲洗后向近心端插入2.0FEdwardsLifesciences球囊导管(NC组)或前述制备所得维替泊芬载药球囊(VP组)至颈总动脉起始部，用压力泵注射生理盐水至球囊中维持压力为1.5atm扩充球囊，来回拉动球囊至颈外动脉分叉处剥脱内膜，反复3次，损伤完成后结扎颈外动脉。去除颈总动脉处血管夹，恢复血流，缝合伤口。
术后对实验大鼠肌注青霉素20万单位/天/只，共3天，预防感染。常规饲养至术后4周处死大鼠取颈总动脉标本。将取得的颈总动脉标本立即浸入多聚甲醛组织固定液24小时进行组织固定，然后将标本脱水，石蜡包埋，行切片和HE染色。观察颈总动脉的组织学形态，并使用Image J软件对HE染色图像进行定量分析，计算效血管管腔直径、有效内膜面积并绘制直方图。其中，管腔面积及有效内膜面积可以由ImageJ软件直接计算得出。有效管腔直径＝2*管腔面积1/2/Π。如图2所示，显示维替泊芬载药球囊能够增加球囊损伤模型的血管管腔直径，抑制内膜增厚。
发明人通过实验性大鼠颈动脉损伤后再狭窄模型研究证明了维替泊芬对血管介入操作损伤术后血管再狭窄的抑制作用，发明人发现药物维替泊芬能够抑制血管介入术后局部平滑肌细胞的迁移、增殖，从而抑制介入术后局部血管再狭窄的发生，从而提供一种能够治疗和预防血管再狭窄的特效药物。
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、“一些实施方案”或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。
Claims (9)
1.维替泊芬在制备药物中的用途，所述药物用于预防或治疗血管损伤后再狭窄。
2.根据权利要求1所述的用途，其特征在于，所述血管损伤包括选自外伤所致的血管挤压、撕裂、离断或涉及血管的医疗干预手段所致的血管损伤。
3.根据权利要求2所述的用途，其特征在于，所述涉及血管的医疗干预手段包括选自血管穿刺、血管夹闭手术、血管吻合手术、动静脉造瘘手术、经皮穿刺血管介入手术中的至少之一。
4.根据权利要求3所述的用途，其特征在于，所述经皮穿刺血管介入手术包括选自经皮穿刺血管造影术、经皮穿刺血管球囊扩张成形术、经皮穿刺血管支架植入术、经皮穿刺血管内置管溶栓术、经皮穿刺血管内血栓抽吸术、经皮穿刺血管内机械旋切减容术、经皮穿刺血管内激光消融术中的至少一种。
5.根据权利要求1所述的用途，其特征在于，所述药物进一步含有药学上可接受的赋形剂或载体；
任选地，所述赋形剂包括选自粘合剂、崩解剂、润滑剂、助流剂、稳定剂、填充剂、稀释剂、缓释剂中的至少之一；
任选地，所述载体包括选自糖类、淀粉类、纤维素及其衍生物、磷酸钙类、硬脂酸碱土金属盐、植物油类、表面活性剂、脂肪醇类、谷物水解固形物中的至少之一；
任选地，所述药物的剂型包括选自注射剂、散剂、颗粒剂、乳剂中的至少之一。
6.根据权利要求1所述的用途，其特征在于，所述药物的给药方式包括选自注射给药、局部给药、浸泡给药中的至少之一；
任选地，所述注射给药包括选自血管内注射、经皮肤或自然体腔穿刺血管周围注射、血管壁内注射、肌肉注射、皮下注射中的至少一种。
7.根据权利要求6所述的用途，其特征在于，所述局部给药包括将所述药物负载于手术器械或体内植入材料表面；
任选地，所述手术器械包括选自血管扩张球囊、介入用血管导丝、介入用血管内导管、血管穿刺针、血管内留置输液针、血管内留置输液导管中的至少一种；
任选地，所述体内植入材料包括选自血管内血栓滤网、血管支架、植入式血管内留置输液装置中的至少一种。
8.一种手术器械，其特征在于，所述器械表面负载有维替泊芬。
9.一种医用材料，其特征在于，所述材料表面负载有维替泊芬。
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