WO2015096614A1 - 药物涂层球囊导管 - Google Patents

药物涂层球囊导管 Download PDF

Info

Publication number
WO2015096614A1
WO2015096614A1 PCT/CN2014/093305 CN2014093305W WO2015096614A1 WO 2015096614 A1 WO2015096614 A1 WO 2015096614A1 CN 2014093305 W CN2014093305 W CN 2014093305W WO 2015096614 A1 WO2015096614 A1 WO 2015096614A1
Authority
WO
WIPO (PCT)
Prior art keywords
drug
balloon
balloon catheter
carrier
coating
Prior art date
Application number
PCT/CN2014/093305
Other languages
English (en)
French (fr)
Inventor
谢琦宗
张永木
卢金华
宋精忠
Original Assignee
先健科技(深圳)有限公司
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by 先健科技(深圳)有限公司 filed Critical 先健科技(深圳)有限公司
Priority to EP14875412.0A priority Critical patent/EP3088013B1/en
Priority to US15/107,806 priority patent/US10058636B2/en
Publication of WO2015096614A1 publication Critical patent/WO2015096614A1/zh

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A61L29/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/04—Macromolecular materials
    • A61L29/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
    • 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

Definitions

  • the invention belongs to the field of interventional medical devices, in particular to drug coated balloon catheters.
  • the field of cardiovascular interventional therapy has experienced three milestones since the 1970s. This was the first milestone in 1977 when humans first used balloon to dilate coronary artery stenosis. Although balloon dilatation can eliminate coronary stenosis, it can promote restenosis due to elastic retraction of the vessel wall, excessive intimal hyperplasia and endometrial tear of the wall, and restenosis 3 to 6 months after target vessel operation. The rate is as high as 30 ⁇ 50%. In 1986, bare metal stents were introduced, which not only eliminated immediate vascular stenosis, but also greatly reduced the incidence of acute reocclusion. It became the second milestone in interventional therapy, but the incidence of target vessel restenosis was still as high as 30%. The advent of drug-eluting stents in 2001, which reduced the rate of target vessel restenosis to less than 3%, is called the third milestone.
  • the stent can treat atherosclerosis and intravascular stenosis, but there is a risk of restenosis in the blood vessels and in the stent, and the stent is not ideal for the treatment of small blood vessels, bifurcated vessels and in situ lesions.
  • Current methods for treating restenosis include: re-expansion of a simple balloon, directional atherectomy, atherectomy, intravascular radiotherapy, and repeated stent implantation.
  • Existing bare balloons and drug stents have certain limitations. The rate of restenosis of the bare balloon is high, and the drug stent is not effective for the treatment of small vessels and bifurcation vessels, neither of which shows its ideal effectiveness or safety.
  • the existing drug-expanded balloon catheter has been coated with a contrast agent iopromide as a carrier and a paclitaxel as a drug coating on a balloon catheter for treating coronary vascular restenosis, which can improve the drug transfer rate, but the contrast agent
  • a contrast agent iopromide as a carrier
  • a paclitaxel as a drug coating on a balloon catheter for treating coronary vascular restenosis
  • the key technical point of the drug balloon is how to achieve a bond balance between the drug coating and the balloon surface. If the adhesion between the drug coating and the balloon surface is small, the drug tends to fall off during balloon folding, or during transport during placement in the lesion, or during expansion prior to contact with the target tissue. The rupture falls off and is washed away by the blood flowing at a high speed. If the adhesion between the drug coating and the balloon surface is large, the drug is not easily transferred to the tissue during contact of the balloon with the target lesion.
  • the absorption rate in the diseased tissue can solve the rapid transfer of the drug to the target lesion after the drug loss during the clinical use and the balloon expansion.
  • a drug-coated balloon catheter comprising a balloon and a drug coating covering the outer surface of the balloon, the drug coating comprising an active drug and a carrier; the active drug being paclitaxel, rapamycin, paclitaxel derivative Or a rapamycin derivative;
  • the carrier comprises an organic acid salt and a polyol, wherein the mass ratio of the active drug to the carrier in the drug coating is 0.2 to 100, and the mass ratio of the organic acid salt to the polyol is (0.2 ⁇ 5): 1.
  • the organic acid salt is acetate, benzoate, maleate, succinate, ascorbate, citrate, tartrate, lactate, oxalate, aspartate, nicotinic acid
  • a salt a gluconate, a glutamate, a vanillate or a lactobionate
  • the polyol is polyethylene glycol, tromethamine, xylitol, sorbitol, mannose One or more of an alcohol or an amino alcohol.
  • the content of the active drug on the outer surface of the balloon catheter is 0.5-20 ⁇ g/mm 2 .
  • the material of the balloon catheter is nylon, nylon elastomer, PET or polyethylene.
  • the balloon catheter is used to deliver an active drug to a target site of a blood vessel or a lumen, to treat a stenosis in a blood vessel or lumen, and to prevent intimal or epithelial hyperplasia;
  • the blood vessel is a coronary artery, a peripheral artery or a brain An arterial vessel;
  • the lumen is the esophagus, airway, intestine, biliary tract, urinary tract, prostate or cerebral access.
  • the carrier is composed of a hydrophilic substance and a hydrophilic lipophilic substance, and the two synergistically accelerate the release and absorption of the drug.
  • the hydrophilic lipophilic substance of the carrier first binds to a lipophilic drug such as rapamycin or paclitaxel, preventing the hydrophobic drug molecules from aggregating or accumulating on the device, increasing the solubility of the drug in the intercellular space, and accelerating the drug reaching the target tissue cell membrane.
  • the lipid bilayer after the medical device is in contact with the tissue, the hydrophilic substance of the carrier is rapidly released, facilitating the faster release of the drug during placement of the balloon catheter into the target site, thereby accelerating the drug into the tissue.
  • the spread and increase the penetration of the drug into the tissue, the drug is more easily absorbed by the tissue.
  • the present invention has the following advantages and benefits:
  • the drug coating of the present invention contains an organic acid salt and a polyhydric alcohol, both of which function together during the insertion of the balloon catheter to promote rapid release of the drug from the balloon surface and absorption by the target tissue, while preventing The drug balloon catheter is released prematurely before being placed in the target site, so the drug balloon catheter can produce better drug transfer effects while reducing drug loss during delivery;
  • the raw materials used in the balloon catheter of the present invention can be used for intravenous injection, and have good safety and biocompatibility.
  • FIG. 1 is a histopathological section of a blood vessel after expansion of a balloon catheter according to a third embodiment of the present invention.
  • paclitaxel 120 mg
  • 1.0 mg of citrate 1.0 mg
  • amino alcohol 10 ml of ethanol, and 4 ml of purified water
  • the coating solution is applied to the surface of the polyester balloon after the flap by a precision syringe (accurate to 2 ⁇ l) in a 100-stage clean environment, and then the balloon is dried.
  • the coating was repeated until the drug concentration on the surface of the balloon reached 20 ⁇ g/mm 2 , and after drying for 24 hours, the package was sterilized by ethylene oxide.
  • paclitaxel 120 mg
  • paclitaxel 36 mg
  • sodium benzoate 36 mg
  • polyethylene glycol 2000 10 ml of ethanol
  • 4 ml of purified water purified water
  • the coating solution is sprayed onto the surface of the polyester balloon after the flap in a 100-level clean environment, so that the drug concentration on the surface of the balloon reaches 3 ⁇ g/mm 2 . Dry, package, and sterilize ethylene oxide.
  • paclitaxel 100 mg of paclitaxel, 50 mg of sodium benzoate, 50 mg of polyethylene glycol 2000, 10 ml of ethanol, and 4 ml of purified water were mixed to prepare a solution, wherein the mass ratio of the active drug to the carrier was 1.00; and the PTCA balloon catheter (diameter 3 mm, length 20 mm) was used in 10,000 After the flaps are tri-folded in the clean environment, the coating solution is sprayed on the surface of the polyester balloon after the flaps in a 100-level clean environment, so that the drug concentration on the surface of the balloon reaches 3 ⁇ g/mm 2 and is dried. Packaging, ethylene oxide sterilization.
  • paclitaxel 120 mg of paclitaxel, 20 mg of sodium benzoate, 20 mg of polyethylene glycol 2000, 10 ml of ethanol, and 4 ml of purified water were mixed to prepare a solution, wherein the mass ratio of the active drug to the carrier was 3.00; and the PTCA balloon catheter (diameter 3 mm, length 20 mm) was used in 10,000 After the flaps are tri-folded in the clean environment, the coating solution is sprayed on the surface of the polyester balloon after the flaps in a 100-level clean environment, so that the drug concentration on the surface of the balloon reaches 3 ⁇ g/mm 2 and is dried. Packaging, ethylene oxide sterilization.
  • the coating solution was sprayed to the fold in a 100-level clean environment.
  • the drug concentration in the coating was 3 ⁇ g/mm 2 , naturally dried for 24 hours, packaged, and sterilized with ethylene oxide.
  • a porcine coronary vessel was used to simulate the target vessel of the coronary system for a delivery process loss simulation test to test for loss of dose prior to balloon filling, ie, during insertion of the balloon catheter and movement to the target site.
  • the balloon catheters prepared in Examples 1 to 6 and Comparative Example 1 were inserted into an in vitro simulated blood vessel model, respectively.
  • the floating time in the simulated vasculature was 90 seconds and the catheter was then removed.
  • the residual drug on the balloon catheter was analyzed by HPLC.
  • the PTCA balloon catheters prepared in Examples 1 to 6 and Comparative Example 1 were inserted into the simulated target blood vessels, respectively, and the balloon fluid was charged to about 12 atm.
  • the transition rate ie, the ratio of the diameter of the balloon to the diameter of the blood vessel
  • the drug is delivered to the target tissue during a liquid filling time of 30 to 60 seconds, and then the balloon catheter is deflated and removed from the in vitro simulation test system to collect target vascular tissue.
  • the drug content in the molecular target tissue and the residual drug amount retained on the balloon were analyzed by tissue extraction and HPLC.
  • the test conditions were the same as above, and the results are shown in Table 2.
  • the balloon catheter of the present invention has an increased absorption rate of the vascular tissue during the catheter expansion process, and the absorption rate and the active drug and the carrier are compared with the drug-coated balloon catheter without the carrier.
  • the quality ratio is related.
  • the balloon catheters prepared in Examples 1 to 6 and Comparative Example 1 were filled in a PBS solution at 37 ° C for 2 minutes to 12 atm, and the residual drug on the balloon catheter was analyzed by HPLC.
  • the test conditions were the same as above.
  • the balloon catheter prepared in Example 3 and the balloon catheter prepared in Comparative Example 1 were respectively used on the left anterior descending coronary artery (LAD) and the left circumflex artery (LCX) of the mini-pigs for 1:(1.1 ⁇ 1.2) vasodilation, 28 days after the removal of the corresponding coronary artery, paraffin section preparation (RM2235 paraffin slicer, Leica, Germany), applied optical microscope (DM2500 microscopic measurement system, Leica, Germany) and image analysis software for images 1 is a histopathological section of the vascular tissue after expansion of the balloon catheter of Comparative Example 1, and FIG. 2 is a histopathological section of the vascular tissue after expansion of the balloon catheter of Example 3.
  • LAD left anterior descending coronary artery
  • LCX left circumflex artery
  • the balloon stenosis rate after expansion of the balloon catheter prepared in Example 3 averaged 9.19%, and the vascular stenosis rate after expansion of the balloon catheter of Comparative Example 1 averaged 20.46%.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Molecular Biology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Biophysics (AREA)
  • Pulmonology (AREA)
  • Anesthesiology (AREA)
  • Hematology (AREA)
  • Materials For Medical Uses (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Polymers & Plastics (AREA)
  • Organic Chemistry (AREA)

Abstract

一种药物涂层球囊导管，包括球囊和覆盖在球囊表面的药物涂层，所述药物涂层包括活性药物和载体，所述活性药物为紫杉醇、雷帕霉素、紫杉醇衍生物或雷帕霉素衍生物；所述载体包括有机酸盐和多元醇，所述药物涂层中的活性药物与载体的质量比为0.2-100，所述有机酸与多元醇的质量比为(0.2-5):1。药物涂层中的有机酸盐和多元醇共同发挥作用，防止在球囊导管被置入到靶位点前药物过早释放，促进药物从球囊表面快速释放并被靶组织吸收，既能减少输送过程中药物损失又具有较好药物转载效果。

Description

药物涂层球囊导管
【技术领域】
本发明属于介入型医疗器械领域，具体涉及药物涂层球囊导管。
【背景技术】
心血管介入治疗领域从上个世纪70年代到现在，经历了三个里程碑式的飞跃。1977年人类第一次使用球囊扩张冠状动脉狭窄病变，此为第一个里程碑。虽然球囊扩张可以消除冠脉狭窄，但由于血管管壁的弹性回缩、内膜过度增生及管壁内膜撕裂等可促发血管再狭窄，靶血管术后3~6个月再狭窄率高达30~50％。1986年裸金属支架问世，它不仅可以消除即刻血管狭窄，同时大大降低了急性再闭塞的发生率，它成为介入治疗的第二个里程碑，但靶血管再狭窄的发生率仍高达30％。2001年药物洗脱支架问世，使靶血管再狭窄率降至3％以下，称为第三个里程碑。
支架可以治疗动脉粥样硬化和血管内狭窄，但血管内和支架内会有再狭窄风险，且支架对于小血管、分叉血管及原位病变等的治疗效果并不理想。目前治疗再狭窄的方法包括：单纯球囊的再次扩张、定向斑块旋切术、旋磨术、血管内放射治疗及重复支架植入等。现有的裸球囊和药物支架都存在一定的局限性。裸球囊的再狭窄率偏高，而药物支架对于小血管和分叉血管的治疗效果也不佳，二者均未能显示其理想的有效性或安全性。
药物洗脱球囊的出现为解决再狭窄带来了新的希望。现有的已上市药物扩张球囊导管，利用造影剂碘普罗胺作为载体与紫杉醇一起作为药物涂层涂覆在球囊导管上治疗冠脉血管再狭窄，可以提高药物转载率，但该造影剂在诊断过程中，存在一定的并发症发生率，且由于碘普罗胺是大的亲水性分子，并不能有效地携带亲脂性的紫杉醇穿过膜脂双层进入细胞。
药物球囊的关键技术点在于如何实现药物涂层与球囊表面之间的粘结平衡。如果药物涂层与球囊表面之间的粘结力较小，则药物在球囊折叠过程中易脱落，或在置入病变处的输送过程中损失，或在与靶组织接触之前的膨胀过程中破裂脱落并被高速流动的血液冲走。如果药物涂层与球囊表面之间的粘结力较大，则在球囊与靶病变组织接触过程中，药物不容易转载到组织上。
【发明内容】
针对上述现有技术的不足，需要开发用于医疗器械的高针对性的涂层，可以在临床过程中或之后将活性药物快速直接输送到局部组织区域，球囊导管应当在所需的靶位置以有效且高效的方式快速地释放活性药物，使之可以快速地渗入靶组织以治疗疾病，例如减轻血管内腔狭窄以及预防身体内腔的再狭窄或晚期管腔丢失。
本发明的目的在于提供具有快速药物释放涂层的球囊导管，用于将活性药物输送到血管或管腔的靶位点，药物涂层覆盖在球囊导管的外表面上，药物涂层中含有活性药物和载体，载体加快了活性药物从球囊上的释放速度，药物在非常短的时期内释放并快速渗透进入患病部位处的组织，从而提高药物在血管系统或其他身体管腔的患病组织中的吸收率，可以解决在临床使用输送过程中的药物损失和球囊扩张之后药物向靶病变部位的快速转载。
为了达到上述目的，本发明采用了以下技术方案：
一种药物涂层球囊导管，包括球囊和覆盖在球囊外表面的药物涂层，所述药物涂层包括活性药物和载体；所述活性药物为紫杉醇、雷帕霉素、紫杉醇衍生物或雷帕霉素衍生物；所述载体包括有机酸盐和多元醇，所述药物涂层中的活性药物与载体的质量比为0.2~100，所述有机酸盐与多元醇的质量比为（0.2~5）：1。
所述有机酸盐为乙酸盐、苯甲酸盐、马来酸盐、琥珀酸盐、抗坏血酸盐、柠檬酸盐、酒石酸盐、乳酸盐、草酸盐、天冬氨酸盐、烟酸盐、葡萄糖酸盐、谷氨酸盐、香草酸盐或乳糖酸盐中的一种或两种以上；所述多元醇为聚乙二醇、氨丁三醇、木糖醇、山梨醇、甘露醇或氨基醇中的一种或两种以上。
所述活性药物在球囊导管外表面的含量为0.5~20μg/mm2。
所述球囊导管的材料为尼龙、尼龙弹性体、PET或聚乙烯。
所述球囊导管用于将活性药物输送到血管或管腔的靶位点，治疗血管或管腔内的狭窄、防止内膜或上皮增生；所述血管为冠状动脉血管、外周动脉血管或脑动脉血管；所述管腔为食道、气道、肠道、胆道、泌尿道、前列腺或脑通道。
本发明的球囊导管表面的药物涂层中，载体由亲水性物质和亲水亲脂性物质组成，两者产生协同作用加快药物的释放和吸收。载体的亲水亲脂物质首先会与雷帕霉素或紫杉醇等亲脂性药物结合，防止疏水的药物分子相互聚集或聚集到器械上，增加药物在细胞间隙中的溶解度，加速药物到达靶组织细胞膜的脂双层；而在医疗器械与组织接触之后，载体的亲水物质被快速地释放，促进药物在球囊导管置入靶位点的过程中更为快速地释放，从而加速药物向组织中的扩散并且增加药物向组织中的穿透，药物更易被组织吸收。
本发明与现有技术相比，具有以下优点和有益效果：
（1）本发明的药物涂层中含有有机酸盐和多元醇，二者在球囊导管的置入过程中共同发挥作用，促进药物从球囊表面快速释放并且被靶组织吸收，同时防止在药物球囊导管被置入到靶位点之前过早释放，因此药物球囊导管可以产生比较好的药物转载效果，同时减少输送过程中的药物损失；
（2）本发明的球囊导管使用的原材料均可用于静脉注射，安全性和生物相容性较好。
【附图说明】
图1为经过本发明实施例3的球囊导管扩张后的血管组织病理切片。
图2为经过对比例1的球囊导管扩张后的血管组织病理切片。
【具体实施方式】
以下结合附图和实施例对本发明的具体实施方式作进一步详细说明，但是本发明要求保护的内容并不局限于此。
实施例1
将120mg紫杉醇，1.0mg柠檬酸盐，0.1mg氨基醇，10ml乙醇，4ml纯化水混合配制涂层溶液，其中活性药物和载体的质量比为100；将PTCA球囊导管（直径3mm，长20mm）在万级洁净环境中折翼三折后，在百级洁净环境下将涂层溶液用精密注射器（精确到2μl）滴涂到折翼后的聚酯球囊表面，然后使所述球囊干燥，重复滴涂直至所述球囊表面药物浓度达到20μg/mm2，干燥24小时后，包装，环氧乙烷灭菌。
实施例2
将20mg雷帕霉素，17mg乳酸盐，83mg甘露醇，7ml乙醇，3ml纯化水混合配制溶液，其中活性药物和载体的质量比为0.2；将PTCA球囊导管（直径3mm，长20mm）在万级洁净环境中折翼三折后，在百级洁净环境下，将涂层溶液用精密注射器（精确到2μl）滴涂到聚酯球囊的表面上，然后使所述球囊干燥，重复滴涂直至所述球囊表面药物浓度达到1μg/mm2，干燥24小时后，包装，环氧乙烷灭菌。
实施例3
将120mg紫杉醇，36mg苯甲酸钠，36mg聚乙二醇2000，10ml乙醇，4ml纯化水混合配制涂层溶液，其中活性药物和载体的质量比为1.67；将PTCA球囊导管（直径3mm，长20mm）在万级洁净环境中折翼三折后，在百级洁净环境下将涂层溶液用喷涂设备喷涂到折翼后的聚酯球囊表面上，使球囊表面药物浓度达到3μg/mm2，干燥，包装，环氧乙烷灭菌。
实施例4
将100mg紫杉醇，50mg苯甲酸钠，50mg聚乙二醇2000，10ml乙醇，4ml纯化水混合配制溶液，其中活性药物和载体的质量比为1.00；将PTCA球囊导管（直径3mm，长20mm）在万级洁净环境中折翼三折后，在百级洁净环境下将涂层溶液用喷涂设备喷涂到折翼后的聚酯球囊表面上，使球囊表面药物浓度达到3μg/mm2，干燥，包装，环氧乙烷灭菌。
实施例5
将120mg紫杉醇，20mg苯甲酸钠，20mg聚乙二醇2000，10ml乙醇，4ml纯化水混合配制溶液，其中活性药物和载体的质量比为3.00；将PTCA球囊导管（直径3mm，长20mm）在万级洁净环境中折翼三折后，在百级洁净环境下将涂层溶液用喷涂设备喷涂到折翼后的聚酯球囊表面上，使球囊表面药物浓度达到3μg/mm2，干燥，包装，环氧乙烷灭菌。
实施例6
将120mg紫杉醇，10mg苯甲酸钠，10mg聚乙二醇2000，10ml乙醇，4ml纯化水混合配制溶液，其中活性药物和载体的质量比为5.00；将PTCA球囊导管（直径3mm，长20mm）在万级洁净环境中折翼三折后，在百级洁净环境下将涂层溶液用喷涂设备喷涂到折翼后的聚酯球囊表面上，使球囊表面药物浓度达到3μg/mm2，干燥，包装，环氧乙烷灭菌。
对比例1
将50mg紫杉醇，1ml乙醇混合配制溶液；将PTCA球囊导管（直径3mm，长20mm）在万级洁净环境中折翼三折后，在百级洁净环境下将涂层溶液用喷涂设备喷涂到折翼后的聚酯球囊表面上，使涂层中药物浓度为3μg/mm2，自然晾干24小时，包装，环氧乙烷灭菌。
输送过程损失模拟测试
用猪冠脉血管模拟冠状动脉系统的靶血管进行输送过程损失模拟测试，测试在球囊充盈之前，即球囊导管插入并且移动到靶位点的过程中的药量损失。
分别将实施例1~6和对比例1制备的球囊导管插入体外模拟血管模型中。在模拟血管系统中漂浮时间为90秒，然后取出导管。利用HPLC分析球囊导管上残余的药物，HPLC测试条件为：日本岛津LC-20A高效液相色谱仪，色谱柱：Aglilent ZOBAX SB-C18 4.6×250mm，5um，流动相：甲醇:乙腈:水＝230:360:410，柱温：30℃，紫外检测器，检测波长227nm，流速：1.0 ml/min。
HPLC测定结果如表1所示：
表 1 输送过程损失模拟测试结果
编号 初始药物含量
（ μg/mm2 ）		 球囊表面残留药物 / 初始药物
%
实施例 1 20.0 57.2
实施例 2 1.0 62.5
实施例 3 3.0 83.0
实施例 4 3.08 78.3
实施例 5 2.81 80.7
实施例 6 2.71 74.3
对比例 1 3.22 51.0
表1结果表明：与没有载体的药物涂层球囊导管相比，本发明的球囊导管在移动到治疗性介入位点的过程中，减少了药物在血管系统中的损失，说明本发明的球囊导管与药物涂层之间的粘结力较大。
体外模拟测试
用猪冠脉血管模拟冠状动脉系统的靶血管进行体外模拟测试。
分别将实施例1~6和对比例1制备的PTCA球囊导管插入模拟靶血管中，对球囊液充至约12atm。过渡伸展率（即：球囊直径与血管直径的比例）约为1.10~1.20。药物在30~60秒的液充时间内被输送到靶组织中，然后将球囊导管放气并从体外模拟测试系统中取出，收集靶血管组织。通过组织提取和HPLC，分析分子靶组织中的药物含量以及球囊上保留的残余药量，测试条件同上，结果如表2所示。
表 2 体外模拟测试结果
编号 初始药物含量
（ μg/mm2 ）		 球囊表面残留药物 / 初始药物
%		 组织中的药物 / 初始药物
%
实施例 1 20.0 10.2 2.0
实施例 2 1.0 4.5 2.2
实施例 3 3.0 2.3 4.2
实施例 4 3.08 11.4 4.0
实施例 5 2.81 14.7 3.9
实施例 6 2.71 6.3 3.0
对比例 1 3.22 15.6 1.8
由表2可知：与没有载体的药物涂层球囊导管相比，本发明的球囊导管在导管扩张过程中，血管组织对药物的吸收率有所提高，并且吸收率和活性药物与载体的质量比有关。
药物释放试验
测试在球囊充盈过程中药物的损失量。
将实施例1~6和对比例1制备的球囊导管于37℃，在PBS溶液中，液充2分钟至12atm，利用HPLC分析球囊导管上残余的药物，测试条件同上。
经HPLC测定，结果如表3所示：
表 3 药物释放试验结果
编号 初始药物含量
（ μg/mm2 ）		 球囊表面残留药物 / 初始药物
%
实施例 1 20.0 39.2
实施例 2 1.0 41.5
实施例 3 3.0 42.0
实施例 4 3.08 41.4
实施例 5 2.81 44.7
实施例 6 2.71 46.3
对比例 1 3.22 35.0
表3结果表明：与没有载体的药物涂层球囊导管相比，本发明的球囊导管在液充过程中，药物损失量减少。
组织病理切片试验
测试血管在球囊导管充盈后的组织变化。
在小型猪的左前降支冠状动脉（简称：LAD）、左回旋支动脉（简称：LCX）上分别使用实施例3制备的球囊导管和对比例1制备的球囊导管进行1:(1.1~1.2)的血管扩张，28天后取出相应的冠状动脉，石蜡切片制备（RM2235型石蜡切片机，德国Leica公司），应用光学显微镜（DM2500型显微测量系统，德国Leica公司）和图像分析软件进行图像分析，图1为经过对比例1的球囊导管扩张后的血管组织病理切片，图2为经过实施例3的球囊导管扩张后的血管组织病理切片。
经过实施例3制备的的球囊导管扩张后的血管狭窄率平均为9.19%，而经过对比例1的球囊导管扩张后的血管狭窄率平均为20.46%。
结果表明：与没有载体的药物涂层球囊导管相比，经过本发明的球囊导管扩张后的血管，其狭窄率明显下降。
以上测试结果表明，本发明的药物涂层球囊导管，在输送过程中减少了药物损失，同时在扩张过程中药物可以相对更快速地释放到组织上并被组织吸收。

Claims (5)

  1. 一种药物涂层球囊导管，包括球囊和覆盖在球囊外表面的药物涂层，其特征在于，所述药物涂层包括活性药物和载体；所述活性药物为紫杉醇、雷帕霉素、紫杉醇衍生物或雷帕霉素衍生物；所述载体包括有机酸盐和多元醇，所述药物涂层中的活性药物与载体的质量比为0.2~100，所述有机酸盐与多元醇的质量比为（0.2~5）：1。
  2. 根据权利要求1所述的药物涂层球囊导管，其特征在于，所述有机酸盐为乙酸盐、苯甲酸盐、马来酸盐、琥珀酸盐、抗坏血酸盐、柠檬酸盐、酒石酸盐、乳酸盐、草酸盐、天冬氨酸盐、烟酸盐、葡萄糖酸盐、谷氨酸盐、香草酸盐、乳糖酸盐中的至少一种；所述多元醇为聚乙二醇、氨丁三醇、木糖醇、山梨醇、甘露醇、氨基醇中的至少一种。
  3. 根据权利要求1所述的药物涂层球囊导管，其特征在于，所述有机酸盐为苯甲酸盐；所述多元醇为聚乙二醇。
  4. 根据权利要求1所述的药物涂层球囊导管，其特征在于，所述活性药物在球囊外表面的含量为0.5~20μg/mm2。
  5. 根据权利要求1~4之任一项所述的药物涂层球囊导管，其特征在于，所述球囊导管的材料为尼龙、尼龙弹性体、PET或聚乙烯。
PCT/CN2014/093305 2013-12-26 2014-12-08 药物涂层球囊导管 WO2015096614A1 (zh)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP14875412.0A EP3088013B1 (en) 2013-12-26 2014-12-08 Drug coated balloon catheter
US15/107,806 US10058636B2 (en) 2013-12-26 2014-12-08 Drug coated balloon catheter

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201310732989.0 2013-12-26
CN201310732989.0A CN103736154B (zh) 2013-12-26 2013-12-26 药物涂层球囊导管

Publications (1)

Publication Number Publication Date
WO2015096614A1 true WO2015096614A1 (zh) 2015-07-02

Family

ID=50493266

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2014/093305 WO2015096614A1 (zh) 2013-12-26 2014-12-08 药物涂层球囊导管

Country Status (4)

Country Link
US (1) US10058636B2 (zh)
EP (1) EP3088013B1 (zh)
CN (1) CN103736154B (zh)
WO (1) WO2015096614A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11045589B2 (en) 2017-09-22 2021-06-29 Becton, Dickinson And Company 4% trisodium citrate solution for use as a catheter lock solution

Families Citing this family (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103736154B (zh) * 2013-12-26 2015-06-17 先健科技(深圳)有限公司 药物涂层球囊导管
CN103949003B (zh) * 2014-05-12 2019-09-20 辽宁生物医学材料研发中心有限公司 扩张不断流球囊导管及其制备方法
CN106267377A (zh) * 2015-05-26 2017-01-04 先健科技(深圳)有限公司 药物涂层球囊导管
CN107865982B (zh) * 2016-09-28 2020-09-25 先健科技(深圳)有限公司 药物涂层球囊
CN109414571B (zh) * 2016-11-17 2021-10-08 脉科私人有限公司 一种药物洗脱球囊
CN108211094B (zh) * 2016-12-19 2023-12-05 先健科技(深圳)有限公司 药物涂层球囊
US11207505B2 (en) * 2017-01-06 2021-12-28 Cardiofocus, Inc. Balloon catheter and fluid management system thereof
EP3459469A1 (en) 2017-09-23 2019-03-27 Universität Zürich Medical occluder device
CN109954198B (zh) * 2017-12-25 2021-10-12 先健科技(深圳)有限公司 药物球囊及其制备方法
CN109966564B (zh) * 2017-12-28 2022-11-18 先健科技(深圳)有限公司 载药球囊及其制备方法
CN108904892B (zh) * 2018-06-27 2021-09-28 南京师范大学 一种药物涂层球囊及其制备方法和应用
CN108744233A (zh) * 2018-06-28 2018-11-06 山东吉威医疗制品有限公司 一种药物球囊扩张导管及其工艺
CN109260526A (zh) * 2018-08-21 2019-01-25 陈绍良 小檗碱洗脱球囊赋形液及其应用
CN109481827A (zh) * 2018-11-05 2019-03-19 南京友德邦医疗科技有限公司 一种药物洗脱球囊导管及其制备方法
US11944315B2 (en) 2019-09-26 2024-04-02 Universität Zürich Left atrial appendage occlusion devices
CN111701081B (zh) * 2020-06-23 2021-11-16 首都医科大学 一种药物涂层球囊用药物涂覆液、药物涂层球囊
CN112704686B (zh) * 2020-12-28 2022-03-22 浙江大学 磷酸钙-雷帕霉素复合药物制备方法、药物涂层球囊制作方法及药物涂层球囊

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001078626A1 (en) * 2000-04-13 2001-10-25 Sts Biopolymers, Inc. Targeted therapeutic agent release devices and methods of making and using the same
CN101610798A (zh) * 2007-10-19 2009-12-23 美国乐通公司 医疗器械的药物释放涂层
CN101808676A (zh) * 2007-08-03 2010-08-18 因瓦泰克技术中心有限公司 改良的涂覆药物的医药产品及其制造和应用
CN103736154A (zh) * 2013-12-26 2014-04-23 先健科技(深圳)有限公司 药物涂层球囊导管

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5071429A (en) * 1990-08-24 1991-12-10 Medical Engineering Corporation Method for inserting a balloon catheter through an endoscope
DE10244847A1 (de) * 2002-09-20 2004-04-01 Ulrich Prof. Dr. Speck Medizinische Vorrichtung zur Arzneimittelabgabe
US9192697B2 (en) * 2007-07-03 2015-11-24 Hemoteq Ag Balloon catheter for treating stenosis of body passages and for preventing threatening restenosis
EP3378506B1 (en) * 2010-03-25 2023-06-07 Lutonix, Inc. Drug releasing coatings for medical devices
EP2968687A1 (en) * 2013-03-15 2016-01-20 Abbott Cardiovascular Systems Inc. Tissue adhesive coatings for drug balloon
CN103611212B (zh) * 2013-11-21 2015-10-28 先健科技(深圳)有限公司 药物球囊的制备方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001078626A1 (en) * 2000-04-13 2001-10-25 Sts Biopolymers, Inc. Targeted therapeutic agent release devices and methods of making and using the same
CN101808676A (zh) * 2007-08-03 2010-08-18 因瓦泰克技术中心有限公司 改良的涂覆药物的医药产品及其制造和应用
CN101610798A (zh) * 2007-10-19 2009-12-23 美国乐通公司 医疗器械的药物释放涂层
CN103736154A (zh) * 2013-12-26 2014-04-23 先健科技(深圳)有限公司 药物涂层球囊导管

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11045589B2 (en) 2017-09-22 2021-06-29 Becton, Dickinson And Company 4% trisodium citrate solution for use as a catheter lock solution

Also Published As

Publication number Publication date
CN103736154B (zh) 2015-06-17
US10058636B2 (en) 2018-08-28
EP3088013A1 (en) 2016-11-02
EP3088013B1 (en) 2020-03-04
EP3088013A4 (en) 2017-09-13
CN103736154A (zh) 2014-04-23
US20160331870A1 (en) 2016-11-17

Similar Documents

Publication Publication Date Title
WO2015096614A1 (zh) 药物涂层球囊导管
JP6309988B2 (ja) 薬剤を分散させるための医療器具
US10583225B2 (en) Method of coating scoring or cutting balloon catheters
WO2016188303A1 (zh) 药物涂层球囊导管
KR101476900B1 (ko) 개선된 약물-코팅된 메디컬 디바이스용 제제
CN111166942A (zh) 用于非血管狭窄的药物涂层球囊导管
WO2018059167A1 (zh) 药物涂层球囊
US20230285639A1 (en) Medical devices having an immediately detachable, permanently proliferation-inhibiting coating comprising at least one limus substance and method of production

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 14875412

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 15107806

Country of ref document: US

NENP Non-entry into the national phase

Ref country code: DE

REEP Request for entry into the european phase

Ref document number: 2014875412

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2014875412

Country of ref document: EP