技术领域Technical Field
本发明涉及医用材料技术领域，更具体地说，是涉及一种药物球囊导管。The present invention relates to the technical field of medical materials, and more specifically to a drug balloon catheter.
背景技术Background Art
外周动脉疾病(PAD)是指由于动脉粥样硬化，导致外周动脉狭窄或阻塞，血流受阻，从而出现缺血的症状和体征。外周动脉泛指除心脑动脉以外的血管，但本病下肢病变占绝大多数，因此通常外周动脉疾病特指下肢动脉的动脉硬化性闭塞症。下肢动脉硬化闭塞症(ASO)指由于动脉硬化造成的下肢供血动脉内膜增厚、管腔狭窄或闭塞，病变肢体血液供应不足，引起下肢间歇性跛行、皮温降低、疼痛、甚至发生溃疡或坏死等临床表现的慢性进展性疾病，常为全身性动脉硬化血管病变在下肢动脉的表现。ASO的主要病因是动脉粥样硬化。在我国，ASO的发病率约10％，随年龄增长而上升，70岁以上人群的发病率为15％～20％；约15％～30％患者会由间歇性跛行发展为严重下肢缺血(CLI)，CLI患者一年内死亡率大约为25％，一年内截肢为33％。Peripheral arterial disease (PAD) refers to the narrowing or obstruction of peripheral arteries and obstruction of blood flow due to atherosclerosis, resulting in symptoms and signs of ischemia. Peripheral arteries refer to blood vessels other than cardiovascular and cerebral arteries, but the majority of this disease occurs in the lower limbs, so peripheral arterial disease usually refers specifically to arteriosclerotic occlusive disease of the lower limb arteries. Lower limb arteriosclerosis obliterans (ASO) refers to a chronic progressive disease caused by arteriosclerosis that causes thickening of the intima, stenosis or occlusion of the lumen of the lower limb blood supply arteries, insufficient blood supply to the affected limbs, and clinical manifestations such as intermittent claudication, decreased skin temperature, pain, and even ulcers or necrosis of the lower limbs. It is often a manifestation of systemic arteriosclerotic vascular lesions in the lower limb arteries. The main cause of ASO is atherosclerosis. In my country, the incidence of ASO is about 10%, which increases with age. The incidence in people over 70 years old is 15% to 20%. About 15% to 30% of patients will develop intermittent claudication into severe lower limb ischemia (CLI). The mortality rate of CLI patients within one year is about 25%, and the amputation rate within one year is 33%.
随着介入手术和器械的发展，许多中心选择腔内治疗作为首选的血运重建方法，因为相对手术而言，腔内治疗并发症发生率和死亡率均较低，而且如果治疗失败还可以改用开放手术治疗。当间歇性跛行影响生活质量，运动或药物治疗效果不佳，而临床特点提示采用腔内治疗可以改善患者症状并且具有良好的风险获益比时，腔内治疗是首选治疗方案。治疗ASO的血管腔内技术较多，例如经皮球囊扩张成形术(PTA)、支架植入、斑块切除术、激光成形术、切割球囊、药物球囊、冷冻球囊以及用药物溶栓治疗或血栓切除等。With the development of interventional surgery and devices, many centers choose endovascular treatment as the preferred revascularization method because the morbidity and mortality of endovascular treatment are lower than those of surgery, and if the treatment fails, it can be replaced by open surgery. When intermittent claudication affects the quality of life, exercise or drug treatment is ineffective, and clinical characteristics suggest that endovascular treatment can improve patient symptoms and has a good risk-benefit ratio, endovascular treatment is the preferred treatment option. There are many endovascular technologies for the treatment of ASO, such as percutaneous balloon angioplasty (PTA), stent implantation, plaque resection, laser angioplasty, cutting balloon, drug balloon, cryoballoon, and thrombolytic therapy or thrombectomy.
近年来，药物涂层球囊(drugcoatedballoon，DCB)作为一种新的介入治疗技术在欧洲逐渐广泛应用于冠状动脉及外周介入领域，在国内也有多个DCB产品已经或即将投入临床使用。DCB的出现为我国外周动脉疾病的治疗提供了新的选择。In recent years, drug-coated balloon (DCB) has been widely used in the field of coronary artery and peripheral intervention in Europe as a new interventional treatment technology. In China, many DCB products have been or will be put into clinical use. The emergence of DCB provides a new option for the treatment of peripheral arterial disease in China.
目前，在国内以及国外上市的几款药物球囊，均采用药物与赋形剂共同涂覆在球囊上，通过赋形剂来控制药物涂层的牢固性能。然而，这种药物涂层会引入除了有效药物以外的另外一种或几种物质，有一定概率在人体内部产生过敏或者不良刺激反应等安全问题。药物涂层快速释放的同时，输送过程也会被血液冲刷掉较多药物，作用于局部的药物非常少。通过增大球囊涂层的载药量能够在局部增加药物吸收量，但大量多余药物流向血管远端，影响患者健康。此外，由于普通药物球囊扩张导管扩张时间短，药物并不好被释放，且血管在普通球囊撤出后，由于失去支撑会快速的回弹成原状，所以目前普通药物球囊扩张导管所面临诸多问题和难点。At present, several drug balloons launched in China and abroad all use drugs and excipients to coat the balloons together, and the excipients are used to control the firmness of the drug coating. However, this drug coating will introduce one or more substances in addition to the effective drugs, and there is a certain probability that it will cause safety problems such as allergies or adverse irritation reactions in the human body. While the drug coating is released quickly, a lot of drugs will be washed away by the blood during the delivery process, and very few drugs will act locally. By increasing the drug loading of the balloon coating, the amount of drug absorption can be increased locally, but a large amount of excess drug flows to the distal end of the blood vessel, affecting the health of the patient. In addition, because the expansion time of ordinary drug balloon dilatation catheters is short, the drug is not easy to be released, and the blood vessels will quickly rebound to their original state after the ordinary balloon is withdrawn due to the loss of support, so the current ordinary drug balloon dilatation catheters face many problems and difficulties.
综上，为了更好处理下肢动脉硬化闭塞症，临床上急需一款能够提高药物在血管壁内的持续释放的周期并且能够极大降低球囊介入过程中药物流失的产品。In summary, in order to better treat lower limb arteriosclerosis obliterans, there is an urgent need in clinical practice for a product that can increase the sustained release period of drugs within the blood vessel wall and greatly reduce drug loss during balloon intervention.
发明内容Summary of the invention
有鉴于此，本发明的目的在于提供一种药物球囊导管，能够将药物尽可能牢固的贴附到球囊的外表面，同时球囊外表面的载药物在通过导管将球囊送入病变部位的过程中降低药物被血管中的血液冲洗损失，从而解决药物球囊在送达到病变部位后药物转移效率低以及持续释放药效周期短的问题。In view of this, the object of the present invention is to provide a drug balloon catheter, which can attach the drug to the outer surface of the balloon as firmly as possible, and at the same time reduce the loss of the drug by blood washing in the blood vessels during the process of delivering the balloon to the lesion site through the catheter, thereby solving the problems of low drug transfer efficiency and short sustained release drug efficacy period of the drug balloon after it is delivered to the lesion site.
本发明提供了一种药物球囊导管，包括：The present invention provides a drug balloon catheter, comprising:
依次连接的球囊、推送杆和导管底座；The balloon, the push rod and the catheter base are connected in sequence;
所述球囊包括球囊头部、球囊体和标记带；所述球囊体表面覆盖有药物涂层，所述标记带设置在药物涂层两侧；The balloon comprises a balloon head, a balloon body and a marking band; the surface of the balloon body is covered with a drug coating, and the marking bands are arranged on both sides of the drug coating;
所述推送杆为中空结构，全长设有可以通过导丝的内腔，球囊沿导丝滑行；The push rod is a hollow structure, with an inner cavity through which a guide wire can pass, and the balloon slides along the guide wire;
所述导管底座通过Y型接口与所述推送杆相连，设有导丝端口和压力泵端口。The catheter base is connected to the push rod through a Y-shaped interface and is provided with a guide wire port and a pressure pump port.
优选的，所述药物涂层由载药微球、增塑剂和两亲性脂质体赋形剂制备而成；所述载药微球由抑制内膜增生的药物和可降解聚合物制备而成。Preferably, the drug coating is prepared from drug-loaded microspheres, a plasticizer and an amphiphilic liposome excipient; and the drug-loaded microspheres are prepared from drugs that inhibit intimal hyperplasia and a degradable polymer.
优选的，所述药物涂层的厚度为10μm～20μm；所述载药微球的粒径为0.5μm～10μm；所述药物涂层中抑制内膜增生的药物的浓度为2μg/mm2～5μg/mm2。Preferably, the thickness of the drug coating is 10 μm to 20 μm; the particle size of the drug-loaded microspheres is 0.5 μm to 10 μm; and the concentration of the drug for inhibiting intimal hyperplasia in the drug coating is 2 μg/mm2 to 5 μg/mm2 .
优选的，所述增塑剂选自甘油、乙醇、二甲基亚砜、乳酸乙酯、苄醇、苯甲酸苄基酯、聚氧乙烯、维生素E、生育酚、液体PEG、柠檬酸三乙酯、柠檬酸三丁酯、柠檬酸乙酰基三丁酯、柠檬酸乙酰基三乙酯、邻苯二甲酸二丁酯、癸二酸二丁酯、邻苯二甲酸二甲酯、三醋精、丙二醇中的一种或多种；Preferably, the plasticizer is selected from one or more of glycerol, ethanol, dimethyl sulfoxide, ethyl lactate, benzyl alcohol, benzyl benzoate, polyethylene oxide, vitamin E, tocopherol, liquid PEG, triethyl citrate, tributyl citrate, acetyl tributyl citrate, acetyl triethyl citrate, dibutyl phthalate, dibutyl sebacate, dimethyl phthalate, triacetin, and propylene glycol;
所述两亲性脂质体赋形剂选自葡聚糖、聚山梨酯、山梨糖醇、紫胶铵盐中的一种或多种；The amphiphilic liposome excipient is selected from one or more of dextran, polysorbate, sorbitol, and lac ammonium salt;
所述抑制内膜增生的药物选自尼莫司汀、卡莫司汀、氟尿嘧啶、氟鸟苷、吉西他滨、柔红霉素、多柔比星、雷帕霉素、紫杉醇、长春碱、拓扑替康、氨鲁米特、西罗莫司、依维莫司、佐他莫司中的一种或多种；The drug for inhibiting intimal hyperplasia is selected from one or more of nimustine, carmustine, fluorouracil, fluguanidine, gemcitabine, daunorubicin, doxorubicin, rapamycin, paclitaxel, vinblastine, topotecan, aminoglutethimide, sirolimus, everolimus, and zotarolimus;
所述可降解聚合物选自聚乳酸、聚乙醇酸、聚偏氟乙烯-六氟丙烯、聚二噁烷酮、聚己内酯、聚磷腈、胶原、明胶、壳聚糖、糖胺聚糖、聚消旋丙交酯-乙交酯、聚丙交酯-己内酯、单甲氧基聚乙二醇聚消旋乳酸乙醇酸共聚物、聚乙二醇聚消旋乳酸乙醇酸共聚物、聚三亚甲基碳酸酯中的一种或多种。The degradable polymer is selected from one or more of polylactic acid, polyglycolic acid, polyvinylidene fluoride-hexafluoropropylene, polydioxanone, polycaprolactone, polyphosphazene, collagen, gelatin, chitosan, glycosaminoglycan, polyracemic lactide-glycolide, polylactide-caprolactone, monomethoxy polyethylene glycol polyracemic lactic acid-glycolic acid copolymer, polyethylene glycol polyracemic lactic acid-glycolic acid copolymer, and polytrimethylene carbonate.
优选的，所述药物涂层的制备方法具体为：Preferably, the preparation method of the drug coating is specifically as follows:
将载药微球、增塑剂和两亲性脂质体赋形剂混合，超声震荡0.5h～1.5h后过滤，得到喷涂溶液；The drug-loaded microspheres, plasticizer and amphiphilic liposome excipient are mixed, ultrasonically shaken for 0.5 h to 1.5 h, and then filtered to obtain a spray solution;
将上述喷涂溶液雾化成液滴后，通过载气喷涂到球囊体表面，干燥后，得到药物涂层。The spray solution is atomized into droplets, which are then sprayed onto the surface of the balloon through a carrier gas, and dried to obtain a drug coating.
优选的，所述喷涂的喷涂室温度为15℃～30℃，喷涂室湿度≤70％，气压为1psi～2psi，流速为0.01mL/min～0.1mL/min，喷涂温度为30℃～50℃，喷涂高度为10mm～80mm。Preferably, the spraying chamber temperature is 15°C to 30°C, the spraying chamber humidity is ≤70%, the air pressure is 1psi to 2psi, the flow rate is 0.01mL/min to 0.1mL/min, the spraying temperature is 30°C to 50°C, and the spraying height is 10mm to 80mm.
优选的，所述干燥的温度为40℃～60℃，时间为20min～40min。Preferably, the drying temperature is 40° C. to 60° C., and the drying time is 20 min to 40 min.
优选的，所述载药微球的制备方法具体为：Preferably, the preparation method of the drug-loaded microspheres is specifically as follows:
将抑制内膜增生的药物和可降解聚合物溶于溶剂中，得到药物溶液；dissolving a drug for inhibiting intimal hyperplasia and a degradable polymer in a solvent to obtain a drug solution;
将上述药物溶液进行超临界干燥，得到载药微球。The drug solution is subjected to supercritical drying to obtain drug-loaded microspheres.
优选的，所述抑制内膜增生的药物、可降解聚合物和溶剂的用量比为(1mg～2mg)：1mg：(20ml～30ml)；Preferably, the dosage ratio of the drug for inhibiting intimal hyperplasia, the degradable polymer and the solvent is (1 mg to 2 mg): 1 mg: (20 ml to 30 ml);
所述溶剂选自甲醇、丙酮、异丙醇、甲基乙烯基酮、二甲基亚砜、乙酸乙酯、乙腈、四氢呋喃、二氯甲烷、三氯甲烷、正庚烷、乙酸甲酯、乙酸丁酯中的一种或多种。The solvent is selected from one or more of methanol, acetone, isopropanol, methyl vinyl ketone, dimethyl sulfoxide, ethyl acetate, acetonitrile, tetrahydrofuran, dichloromethane, chloroform, n-heptane, methyl acetate, and butyl acetate.
优选的，所述超临界干燥的温度为35℃～40℃，压力为5MPa～15MPa，采用CO2液体，充液流量为14LPM～16LPM，排液流量为8LPM～12LPM。Preferably, the supercritical drying temperature is 35°C to 40°C, the pressure is 5MPa to 15MPa,CO2 liquid is used, the filling flow rate is 14LPM to 16LPM, and the discharge flow rate is 8LPM to 12LPM.
本发明提供了一种药物球囊导管，包括：依次连接的球囊、推送杆和导管底座；所述球囊包括球囊头部、球囊体和标记带；所述球囊体表面覆盖有药物涂层，所述标记带设置在药物涂层两侧；所述推送杆为中空结构，全长设有可以通过导丝的内腔，球囊沿导丝滑行；所述导管底座通过Y型接口与所述推送杆相连，设有导丝端口和压力泵端口。与现有技术相比，本发明提供的药物球囊导管采用特定结构及连接关系，配合特定药物涂层，实现整体较好的相互作用，能够将药物尽可能牢固的贴附到球囊的外表面，同时球囊外表面的载药物在通过导管将球囊送入病变部位的过程中降低药物被血管中的血液冲洗损失，从而解决药物球囊在送达到病变部位后药物转移效率低以及持续释放药效周期短的问题。The present invention provides a drug balloon catheter, comprising: a balloon, a push rod and a catheter base connected in sequence; the balloon comprises a balloon head, a balloon body and a marking band; the surface of the balloon body is covered with a drug coating, and the marking bands are arranged on both sides of the drug coating; the push rod is a hollow structure, and an inner cavity through which a guide wire can pass is provided throughout the entire length, and the balloon slides along the guide wire; the catheter base is connected to the push rod through a Y-shaped interface, and is provided with a guide wire port and a pressure pump port. Compared with the prior art, the drug balloon catheter provided by the present invention adopts a specific structure and connection relationship, and cooperates with a specific drug coating to achieve overall better interaction, and can attach the drug to the outer surface of the balloon as firmly as possible. At the same time, the drug-loaded drug on the outer surface of the balloon reduces the loss of the drug being washed by the blood in the blood vessels during the process of delivering the balloon to the lesion site through the catheter, thereby solving the problems of low drug transfer efficiency and short sustained release drug efficacy period of the drug balloon after it is delivered to the lesion site.
附图说明BRIEF DESCRIPTION OF THE DRAWINGS
图1为本发明实施例中药物球囊导管的结构示意图；FIG1 is a schematic structural diagram of a drug balloon catheter according to an embodiment of the present invention;
图2为本发明实施例中药物球囊导管的药物涂层的示意图；FIG2 is a schematic diagram of a drug coating of a drug balloon catheter according to an embodiment of the present invention;
图3为本发明实施例中药物和生物降解的聚合物结合状态(SEM)；FIG3 is a SEM diagram of the combination of a drug and a biodegradable polymer in an embodiment of the present invention;
图4为本发明实施例中载药微球和两亲性脂质体赋形剂结合状态(SEM)；FIG4 is a diagram showing the combination state of drug-loaded microspheres and amphiphilic liposome excipients in an embodiment of the present invention (SEM);
图5为本发明实施例中超临界点干燥仪的操作流程图；FIG5 is an operation flow chart of a supercritical point dryer according to an embodiment of the present invention;
图6为对比例中Passeo-18 Lux药物球囊药物释放曲线；FIG6 is a drug release curve of Passeo-18 Lux drug balloon in a comparative example;
图7为本发明实施例的药物释放曲线。FIG. 7 is a drug release curve of an embodiment of the present invention.
具体实施方式DETAILED DESCRIPTION
下面将结合本发明实施例，对本发明的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.
本发明提供了一种药物球囊导管，包括：The present invention provides a drug balloon catheter, comprising:
依次连接的球囊、推送杆和导管底座；The balloon, the push rod and the catheter base are connected in sequence;
所述球囊包括球囊头部、球囊体和标记带；所述球囊体表面覆盖有药物涂层，所述标记带设置在药物涂层两侧；The balloon comprises a balloon head, a balloon body and a marking band; the surface of the balloon body is covered with a drug coating, and the marking bands are arranged on both sides of the drug coating;
所述推送杆为中空结构，全长设有可以通过导丝的内腔，球囊沿导丝滑行；The push rod is a hollow structure, with an inner cavity through which a guide wire can pass, and the balloon slides along the guide wire;
所述导管底座通过Y型接口与所述推送杆相连，设有导丝端口和压力泵端口。The catheter base is connected to the push rod through a Y-shaped interface and is provided with a guide wire port and a pressure pump port.
在本发明中，所述药物球囊导管由一个远端头端固定有药物涂层球囊的同轴整体交换式(OTW)导管组成，球囊上涂有药物涂层，药物涂层均匀地分布在球囊的整个工作长度上，药物涂层配方的主要功能特性是在扩张过程中使药物释放到血管壁的组织中。In the present invention, the drug balloon catheter is composed of a coaxial integral exchange (OTW) catheter with a drug-coated balloon fixed at the distal tip, the balloon is coated with a drug coating, and the drug coating is evenly distributed over the entire working length of the balloon. The main functional characteristic of the drug coating formula is to release the drug into the tissue of the blood vessel wall during the expansion process.
在本发明中，所述药物球囊导管采用OTW球囊，多用于CTO病变；所述药物球囊导管包括依次连接的球囊、推送杆和导管底座。In the present invention, the drug balloon catheter adopts an OTW balloon, which is mostly used for CTO lesions; the drug balloon catheter comprises a balloon, a push rod and a catheter base which are connected in sequence.
在本发明中，所述球囊包括球囊头部、球囊体和标记带；所述球囊体表面覆盖有药物涂层，所述标记带设置在药物涂层两侧。In the present invention, the balloon comprises a balloon head, a balloon body and a marking band; the surface of the balloon body is covered with a drug coating, and the marking bands are arranged on both sides of the drug coating.
在本发明中，所述推送杆为中空结构，全长设有可以通过导丝的内腔，球囊沿导丝滑行。In the present invention, the push rod is a hollow structure, and an inner cavity through which a guide wire can pass is provided throughout the entire length, and the balloon slides along the guide wire.
在本发明中，所述导管底座通过Y型接口与所述推送杆相连，设有导丝端口和压力泵端口。In the present invention, the catheter base is connected to the push rod through a Y-shaped interface and is provided with a guide wire port and a pressure pump port.
在本发明中，所述药物涂层优选由载药微球、增塑剂和两亲性脂质体赋形剂制备而成；所述载药微球能够提高药物持续释放周期，优选由抑制内膜增生的药物和可降解聚合物制备而成。In the present invention, the drug coating is preferably prepared from drug-loaded microspheres, plasticizers and amphiphilic liposome excipients; the drug-loaded microspheres can increase the sustained release period of the drug, and are preferably prepared from drugs that inhibit intimal hyperplasia and degradable polymers.
在本发明中，所述药物涂层的厚度优选为10μm～20μm，更优选为14μm～16μm；所述载药微球的粒径优选为0.5μm～10μm，更优选为1μm～5μm；所述药物涂层中抑制内膜增生的药物的浓度优选为2μg/mm2～5μg/mm2，更优选为3μg/mm2～4μg/mm2。In the present invention, the thickness of the drug coating is preferably 10 μm to 20 μm, more preferably 14 μm to 16 μm; the particle size of the drug-loaded microspheres is preferably 0.5 μm to 10 μm, more preferably 1 μm to 5 μm; the concentration of the drug inhibiting intimal hyperplasia in the drug coating is preferably 2 μg/mm2 to 5 μg/mm2 , more preferably 3 μg/mm2 to 4 μg/mm2 .
在本发明中，所述增塑剂的加入可以防止在充气期间涂层裂纹或脆性，优选选自甘油、乙醇、二甲基亚砜、乳酸乙酯、苄醇、苯甲酸苄基酯、聚氧乙烯、维生素E、生育酚、液体PEG、柠檬酸三乙酯、柠檬酸三丁酯、柠檬酸乙酰基三丁酯、柠檬酸乙酰基三乙酯、邻苯二甲酸二丁酯、癸二酸二丁酯、邻苯二甲酸二甲酯、三醋精、丙二醇中的一种或多种，更优选为乙醇。本发明对所述增塑剂的来源没有特殊限制，采用本领域技术人员熟知的市售商品即可。In the present invention, the addition of the plasticizer can prevent cracks or brittleness of the coating during inflation, and is preferably selected from one or more of glycerol, ethanol, dimethyl sulfoxide, ethyl lactate, benzyl alcohol, benzyl benzoate, polyethylene oxide, vitamin E, tocopherol, liquid PEG, triethyl citrate, tributyl citrate, acetyl tributyl citrate, acetyl triethyl citrate, dibutyl phthalate, dibutyl sebacate, dimethyl phthalate, triacetin, and propylene glycol, and more preferably ethanol. The present invention has no particular restrictions on the source of the plasticizer, and commercially available products well known to those skilled in the art can be used.
在本发明中，所述两亲性脂质体赋形剂将载药微球均匀地吸附在球囊表面并在球囊插入以及膨胀过程中起到保护作用，优选选自葡聚糖、聚山梨酯、山梨糖醇、紫胶铵盐中的一种或多种，更优选为聚山梨酯。本发明对所述两亲性脂质体赋形剂的来源没有特殊限制，采用本领域技术人员熟知的市售商品即可。在本发明中，所述两亲性脂质体赋形剂能够提高药物转移效率，减少药物流失。In the present invention, the amphiphilic liposome excipient uniformly adsorbs the drug-loaded microspheres on the balloon surface and plays a protective role during the balloon insertion and expansion process, and is preferably selected from one or more of dextran, polysorbate, sorbitol, and lac ammonium salt, and more preferably polysorbate. The present invention has no special restrictions on the source of the amphiphilic liposome excipient, and commercially available products well known to those skilled in the art can be used. In the present invention, the amphiphilic liposome excipient can improve the drug transfer efficiency and reduce drug loss.
在本发明中，所述抑制内膜增生的药物优选选自尼莫司汀、卡莫司汀、氟尿嘧啶、氟鸟苷、吉西他滨、柔红霉素、多柔比星、雷帕霉素、紫杉醇、长春碱、拓扑替康、氨鲁米特、西罗莫司、依维莫司、佐他莫司中的一种或多种，更优选为雷帕霉素和/或紫杉醇，更更优选为雷帕霉素。本发明对所述抑制内膜增生的药物的来源没有特殊限制，采用本领域技术人员熟知的市售商品即可。In the present invention, the drug for inhibiting intimal hyperplasia is preferably selected from one or more of nimustine, carmustine, fluorouracil, fluguanidine, gemcitabine, daunorubicin, doxorubicin, rapamycin, paclitaxel, vinblastine, topotecan, aminoglutethimide, sirolimus, everolimus, and zotarolimus, more preferably rapamycin and/or paclitaxel, and even more preferably rapamycin. The present invention has no particular restrictions on the source of the drug for inhibiting intimal hyperplasia, and commercially available products well known to those skilled in the art can be used.
在本发明中，所述可降解聚合物优选选自聚乳酸、聚乙醇酸、聚偏氟乙烯-六氟丙烯、聚二噁烷酮、聚己内酯、聚磷腈、胶原、明胶、壳聚糖、糖胺聚糖、聚消旋丙交酯-乙交酯、聚丙交酯-己内酯、单甲氧基聚乙二醇聚消旋乳酸乙醇酸共聚物、聚乙二醇聚消旋乳酸乙醇酸共聚物、聚三亚甲基碳酸酯中的一种或多种，更优选为聚偏氟乙烯-六氟丙烯。本发明对所述可降解聚合物的来源没有特殊限制，采用本领域技术人员熟知的市售商品即可。In the present invention, the degradable polymer is preferably selected from one or more of polylactic acid, polyglycolic acid, polyvinylidene fluoride-hexafluoropropylene, polydioxanone, polycaprolactone, polyphosphazene, collagen, gelatin, chitosan, glycosaminoglycan, polyracemic lactide-glycolide, polylactide-caprolactone, monomethoxy polyethylene glycol polyracemic lactic acid-glycolic acid copolymer, polyethylene glycol polyracemic lactic acid-glycolic acid copolymer, and polytrimethylene carbonate, and more preferably polyvinylidene fluoride-hexafluoropropylene. The present invention has no particular restrictions on the source of the degradable polymer, and commercially available products well known to those skilled in the art can be used.
在本发明中，所述药物涂层的制备方法优选具体为：In the present invention, the preparation method of the drug coating is preferably as follows:
将载药微球、增塑剂和两亲性脂质体赋形剂混合，超声震荡0.5h～1.5h后过滤，得到喷涂溶液；The drug-loaded microspheres, plasticizer and amphiphilic liposome excipient are mixed, ultrasonically shaken for 0.5 h to 1.5 h, and then filtered to obtain a spray solution;
将上述喷涂溶液雾化成液滴后，通过载气喷涂到球囊体表面，干燥后，得到药物涂层。The spray solution is atomized into droplets, which are then sprayed onto the surface of the balloon through a carrier gas, and dried to obtain a drug coating.
在本发明中，所述喷涂的过程优选在喷涂室中进行，所述喷涂的喷涂室温度优选为15℃～30℃，更优选为20℃～29℃，喷涂室湿度优选≤70％，更优选≤60％，气压优选为1psi～2psi，更优选为1.3psi～1.5psi，流速优选为0.01mL/min～0.1mL/min，更优选为0.04mL/min～0.06mL/min，喷涂温度优选为30℃～50℃，喷涂高度优选为10mm～80mm。In the present invention, the spraying process is preferably carried out in a spraying room, the temperature of the spraying room is preferably 15°C to 30°C, more preferably 20°C to 29°C, the humidity of the spraying room is preferably ≤70%, more preferably ≤60%, the air pressure is preferably 1psi to 2psi, more preferably 1.3psi to 1.5psi, the flow rate is preferably 0.01mL/min to 0.1mL/min, more preferably 0.04mL/min to 0.06mL/min, the spraying temperature is preferably 30°C to 50°C, and the spraying height is preferably 10mm to 80mm.
在本发明中，所述干燥的温度优选为40℃～60℃，更优选为50℃，时间优选为20min～40min，更优选为30min。In the present invention, the drying temperature is preferably 40° C. to 60° C., more preferably 50° C., and the drying time is preferably 20 min to 40 min, more preferably 30 min.
在本发明中，所述载药微球的制备方法优选具体为：In the present invention, the method for preparing the drug-loaded microspheres is preferably as follows:
将抑制内膜增生的药物和可降解聚合物溶于溶剂中，得到药物溶液；dissolving a drug for inhibiting intimal hyperplasia and a degradable polymer in a solvent to obtain a drug solution;
将上述药物溶液进行超临界干燥，得到载药微球。The drug solution is subjected to supercritical drying to obtain drug-loaded microspheres.
在本发明中，所述抑制内膜增生的药物、可降解聚合物和溶剂的用量比优选为(1mg～2mg)：1mg：(20ml～30ml)。In the present invention, the dosage ratio of the drug for inhibiting intimal hyperplasia, the degradable polymer and the solvent is preferably (1 mg to 2 mg): 1 mg: (20 ml to 30 ml).
在本发明中，所述溶剂优选选自甲醇、丙酮、异丙醇、甲基乙烯基酮、二甲基亚砜、乙酸乙酯、乙腈、四氢呋喃、二氯甲烷、三氯甲烷、正庚烷、乙酸甲酯、乙酸丁酯中的一种或多种，更优选为四氢呋喃。本发明对所述溶剂的来源没有特殊限制，采用本领域技术人员熟知的市售商品即可。In the present invention, the solvent is preferably selected from one or more of methanol, acetone, isopropanol, methyl vinyl ketone, dimethyl sulfoxide, ethyl acetate, acetonitrile, tetrahydrofuran, dichloromethane, chloroform, n-heptane, methyl acetate, and butyl acetate, and is more preferably tetrahydrofuran. The present invention has no particular restrictions on the source of the solvent, and commercially available products known to those skilled in the art can be used.
在本发明中，所述超临界干燥的温度优选为35℃～40℃，压力优选为5MPa～15MPa，更优选为9MPa～11MPa，采用CO2液体，充液流量优选为14LPM～16LPM，排液流量优选为8LPM～12LPM。In the present invention, the temperature of supercritical drying is preferably 35°C to 40°C, the pressure is preferably 5MPa to 15MPa, more preferably 9MPa to 11MPa,CO2 liquid is used, the filling flow rate is preferably 14LPM to 16LPM, and the discharge flow rate is preferably 8LPM to 12LPM.
在此基础上，本发明首先将药物与可降解聚合物溶于溶剂中，得到药物溶液，再通过超临界干燥技术收集符合要求粒径的载药微球，将其混合到含有赋形剂的溶液中，并加入增塑剂得到药物喷涂溶液；最后通过药物喷涂装置的超声喷头将药物喷涂溶液喷涂到球囊表层，干燥后获取药物涂层球囊。On this basis, the present invention first dissolves the drug and the degradable polymer in a solvent to obtain a drug solution, then collects drug-loaded microspheres with a required particle size through supercritical drying technology, mixes them into a solution containing an excipient, and adds a plasticizer to obtain a drug spray solution; finally, the drug spray solution is sprayed onto the surface of the balloon through an ultrasonic nozzle of a drug spray device, and the drug-coated balloon is obtained after drying.
本发明具有如下有益效果：The present invention has the following beneficial effects:
目前，球囊成形术是治疗外周动脉疾病的主流方式；本发明提供的药物球囊导管的药物球囊对比药物洗脱支架(DES)，药物球囊为短期接触不存在金属异物覆盖，因此很大程度降低内膜增生、血栓形成的风险；本发明通过雷帕霉素与生物可降解聚合物结合，形成数以万计的载药微球，实现一致性和可预测的药物释放；具有与DES技术相当的药物持续释放的能力以及药物在血管壁内的滞留时间。At present, balloon angioplasty is the mainstream method for treating peripheral arterial disease. Compared with drug-eluting stents (DES), the drug balloon of the drug balloon catheter provided by the present invention is for short-term contact and is not covered by metal foreign matter, thereby greatly reducing the risks of intimal hyperplasia and thrombosis. The present invention combines rapamycin with a biodegradable polymer to form tens of thousands of drug-loaded microspheres, thereby achieving consistent and predictable drug release. It has the ability of sustained drug release and the retention time of drugs in the blood vessel wall comparable to DES technology.
同时，本发明提供的药物球囊对比同类产品，国内同类产品采用药物与赋形剂共同涂覆在球囊上，通过赋形剂来控制药物涂层的牢固性能；然而，这种药物涂层会引入除了有效药物以外的另外一种或几种物质，有一定概率在人体内部产生过敏或者不良刺激反应等安全问题；而且药物涂层快速释放的同时，输送过程也会被血液冲刷掉较多药物，作用于局部的药物非常少；本发明采用专有的两亲性赋形剂作为载体，它将载药微球结合到球囊表面，在球囊插入和膨胀时起到保护作用；在提高药物转移效率的同时减少球囊介入过程中的药物流失，最大限度地使血管壁的细胞摄取药物。At the same time, the drug balloon provided by the present invention is compared with similar products. Domestic similar products use drugs and excipients to coat the balloon together, and the excipients are used to control the firmness of the drug coating; however, this drug coating will introduce one or more substances other than the effective drug, and there is a certain probability of causing safety problems such as allergic or adverse irritation reactions in the human body; and while the drug coating is released quickly, a lot of drugs will be washed away by the blood during the delivery process, and very little drug will act locally; the present invention uses a proprietary amphiphilic excipient as a carrier, which combines the drug-loaded microspheres to the balloon surface, playing a protective role during balloon insertion and expansion; while improving the drug transfer efficiency, it reduces drug loss during balloon intervention, and maximizes the drug uptake by cells in the vascular wall.
本发明提供了一种药物球囊导管，包括：依次连接的球囊、推送杆和导管底座；所述球囊包括球囊头部、球囊体和标记带；所述球囊体表面覆盖有药物涂层，所述标记带设置在药物涂层两侧；所述推送杆为中空结构，全长设有可以通过导丝的内腔，球囊沿导丝滑行；所述导管底座通过Y型接口与所述推送杆相连，设有导丝端口和压力泵端口。与现有技术相比，本发明提供的药物球囊导管采用特定结构及连接关系，配合特定药物涂层，实现整体较好的相互作用，能够将药物尽可能牢固的贴附到球囊的外表面，同时球囊外表面的载药物在通过导管将球囊送入病变部位的过程中降低药物被血管中的血液冲洗损失，从而解决药物球囊在送达到病变部位后药物转移效率低以及持续释放药效周期短的问题。The present invention provides a drug balloon catheter, comprising: a balloon, a push rod and a catheter base connected in sequence; the balloon comprises a balloon head, a balloon body and a marking band; the surface of the balloon body is covered with a drug coating, and the marking bands are arranged on both sides of the drug coating; the push rod is a hollow structure, and an inner cavity through which a guide wire can pass is provided throughout the entire length, and the balloon slides along the guide wire; the catheter base is connected to the push rod through a Y-shaped interface, and is provided with a guide wire port and a pressure pump port. Compared with the prior art, the drug balloon catheter provided by the present invention adopts a specific structure and connection relationship, and cooperates with a specific drug coating to achieve overall better interaction, and can attach the drug to the outer surface of the balloon as firmly as possible. At the same time, the drug-loaded drug on the outer surface of the balloon reduces the loss of the drug being washed by the blood in the blood vessels during the process of delivering the balloon to the lesion site through the catheter, thereby solving the problems of low drug transfer efficiency and short sustained release drug efficacy period of the drug balloon after it is delivered to the lesion site.
为了进一步说明本发明，下面通过以下实施例进行详细说明。In order to further illustrate the present invention, the following examples are provided for detailed description.
实施例Example
请参阅图1，图1为本发明实施例中药物球囊导管的结构示意图；该药物球囊导管由一个远端头端固定有药物涂层球囊的同轴整体交换式(OTW)导管组成，包括球囊头部、球囊体、标记带、推送杆、导管座组成；导管座通过Y型接口与推送杆相连，设有导丝端口和压力泵端口；推送杆为中空结构，不带有金属内核，全长有可以通过导丝的内腔，球囊沿导丝滑行；药物涂层覆盖在球囊体表面，标记带设置在药物涂层两侧；使用时，通过压力泵向药物球囊导管内注水或注气使球囊扩张，球囊持续作用于狭窄部位的血管壁，使血管产生全周的外张力，从而使狭窄的管腔迅速扩大。Please refer to Figure 1, which is a schematic diagram of the structure of a drug balloon catheter in an embodiment of the present invention; the drug balloon catheter is composed of a coaxial integral exchange (OTW) catheter with a drug-coated balloon fixed at the distal head end, including a balloon head, a balloon body, a marking band, a push rod, and a catheter seat; the catheter seat is connected to the push rod through a Y-shaped interface, and is provided with a guide wire port and a pressure pump port; the push rod is a hollow structure without a metal core, and has an inner cavity through the entire length that can pass the guide wire, and the balloon slides along the guide wire; the drug coating covers the surface of the balloon body, and the marking bands are set on both sides of the drug coating; when in use, water or air is injected into the drug balloon catheter through a pressure pump to expand the balloon, and the balloon continuously acts on the blood vessel wall at the narrow part, so that the blood vessel generates external tension around the whole circumference, thereby rapidly expanding the narrow lumen.
请参阅图2，图2为本发明实施例中药物球囊导管的药物涂层的示意图；药物涂层中，药物总浓度为3μg/mm2～4μg/mm2。Please refer to FIG. 2 , which is a schematic diagram of the drug coating of the drug balloon catheter in an embodiment of the present invention; in the drug coating, the total drug concentration is 3 μg/mm2 -4 μg/mm2 .
制备方法如下：The preparation method is as follows:
(1)将150mg雷帕霉素与100mg可降解聚合物聚偏氟乙烯-六氟丙烯溶于25ml四氢呋喃溶剂中，得到药物溶液；然后将充分溶解后的溶液注入台式超临界点干燥仪中，进行超临界干燥(操作流程参见图5)，相应工艺参数如表1所示，收集干燥后的、符合要求粒径的载药微球(图3)；将收集好的载药微球与1wt％聚山梨酯水溶液相混合溶于10ml乙醇中，超声震荡1h，过滤得到喷涂溶液。(1) 150 mg of rapamycin and 100 mg of a biodegradable polymer polyvinylidene fluoride-hexafluoropropylene were dissolved in 25 ml of tetrahydrofuran solvent to obtain a drug solution; the fully dissolved solution was then injected into a desktop supercritical point dryer for supercritical drying (see FIG5 for the operation flow), and the corresponding process parameters are shown in Table 1. The dried drug-loaded microspheres with the required particle size were collected ( FIG3 ); the collected drug-loaded microspheres were mixed with a 1 wt % polysorbate aqueous solution and dissolved in 10 ml of ethanol, ultrasonically shaken for 1 h, and filtered to obtain a spray solution.
表1超临界干燥工艺参数Table 1 Supercritical drying process parameters
(2)将喷涂溶液放置于喷涂设备供药装置中，通过超声发生装置将供药系统供给的药液雾化成均匀液滴，然后通过载气将液雾喷涂到球囊上以得到结晶细小、均匀、牢固的药物涂层(图4)；相应的喷涂工艺参数如表2所示，喷涂结束后，将球囊放置于专用的干燥箱进行干燥处理，干燥温度50℃，干燥时间为30min，得到药物涂层。(2) The spray solution is placed in the drug supply device of the spray equipment, and the drug solution supplied by the drug supply system is atomized into uniform droplets by an ultrasonic generator. Then, the liquid mist is sprayed onto the balloon by a carrier gas to obtain a fine, uniform, and firm drug coating (Figure 4); the corresponding spray process parameters are shown in Table 2. After the spraying is completed, the balloon is placed in a special drying oven for drying at a drying temperature of 50°C and a drying time of 30 min to obtain a drug coating.
表2药物球囊喷涂工艺参数Table 2 Drug balloon spraying process parameters
本发明实施例中制备药物涂层的信息参见下表3。The information on the preparation of the drug coating in the examples of the present invention is shown in Table 3 below.
表3制备药物涂层的信息Table 3 Information on preparation of drug coating
经检测，本发明提供的药物涂层球囊导管的药物释放率参见下表4，与传统药物涂层球囊药物释放周期对比参见图6～7。After testing, the drug release rate of the drug-coated balloon catheter provided by the present invention is shown in Table 4 below, and the drug release cycle compared with that of the traditional drug-coated balloon is shown in Figures 6 to 7.
表4药物涂层球囊导管的药物释放率Table 4 Drug release rate of drug-coated balloon catheter
实验结果表明，百多力推出的用于下肢动脉疾病治疗的紫杉醇药物涂层球囊Passeo-18 Lux经验证，紫杉醇药物在血管中的浓度在一周内得到快速释放，药物释放持续近1个月(图6)。而本发明的涂层技术提供了最佳的递送机制，确保在产品输送过程及球囊扩张过程中药物损失最小，经实验表明，本发明制备的应用于外周血管的血管夹层的药物球囊扩张导管，药物释放时间可提高至3个月(图7)，大大的提升了持续治疗的效果。The experimental results show that the paclitaxel drug-coated balloon Passeo-18 Lux launched by Biotronik for the treatment of lower extremity arterial disease has been verified to have a rapid release of paclitaxel drug concentration in the blood vessels within one week, and the drug release lasts for nearly 1 month (Figure 6). The coating technology of the present invention provides the best delivery mechanism to ensure that the drug loss is minimized during the product delivery process and the balloon dilation process. Experiments have shown that the drug balloon dilation catheter prepared by the present invention for peripheral vascular dissection can increase the drug release time to 3 months (Figure 7), greatly improving the effect of continuous treatment.
所公开的实施例的上述说明，使本领域专业技术人员能够实现或使用本发明。对这些实施例的多种修改对本领域的专业技术人员来说将是显而易见的，本文中所定义的一般原理可以在不脱离本发明的精神或范围的情况下，在其它实施例中实现。因此，本发明将不会被限制于本文所示的这些实施例，而是要符合与本文所公开的原理和新颖特点相一致的最宽的范围。The above description of the disclosed embodiments enables those skilled in the art to implement or use the present invention. Various modifications to these embodiments will be apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention will not be limited to the embodiments shown herein, but rather to the widest scope consistent with the principles and novel features disclosed herein.
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| CN202410605717.2ACN118512703B (en) | 2024-05-15 | 2024-05-15 | Medicine sacculus pipe |
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| CN202410605717.2ACN118512703B (en) | 2024-05-15 | 2024-05-15 | Medicine sacculus pipe |
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