WO2016188303A1 - 药物涂层球囊导管 - Google Patents

药物涂层球囊导管 Download PDF

Info

Publication number
WO2016188303A1
WO2016188303A1 PCT/CN2016/080746 CN2016080746W WO2016188303A1 WO 2016188303 A1 WO2016188303 A1 WO 2016188303A1 CN 2016080746 W CN2016080746 W CN 2016080746W WO 2016188303 A1 WO2016188303 A1 WO 2016188303A1
Authority
WO
WIPO (PCT)
Prior art keywords
drug
balloon
balloon catheter
carrier
coating layer
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/CN2016/080746
Other languages
English (en)
French (fr)
Inventor
谢琦宗
卢金华
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Lifetech Scientific Shenzhen Co Ltd
Original Assignee
Lifetech Scientific Shenzhen Co Ltd
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 Lifetech Scientific Shenzhen Co Ltd filed Critical Lifetech Scientific Shenzhen Co Ltd
Publication of WO2016188303A1 publication Critical patent/WO2016188303A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

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
    • 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
    • A61L31/08—Materials for coatings
    • 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
    • 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

Definitions

  • the invention belongs to the field of interventional medical devices, in particular to drug coated balloon catheters.
  • the invention of the stent provides a better solution for the treatment of atherosclerosis and intravascular stenosis, which greatly improves the treatment efficiency, but at the same time, intravascular and in-stent restenosis, for small blood vessels, bifurcation vessels and in situ
  • the treatment effect of lesions and the like is not ideal, and the number of patients undergoing PCI is increasing year by year, and the absolute number of patients with stent restenosis is considerable.
  • Current methods for restenosis include: re-expansion of simple balloon, directional atherectomy, atherectomy, intravascular radiotherapy, and repeated stent implantation.
  • Existing bare balloons and drug stents exist. Due to 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.
  • Drug-eluting balloons similar to DES, essentially stem from the concept of a catheter-based topical drug delivery device, through the ball
  • the drug carried by the capsule inhibits intimal hyperplasia, but the way the drug is carried and the time of action of the local drug are different.
  • the drug coated balloon is a combination of an anti-proliferative drug, such as paclitaxel or a combination of rapamycin and an additive, on the surface of the balloon.
  • an anti-proliferative drug such as paclitaxel or a combination of rapamycin and an additive
  • the drug is released into the local vessel wall by tearing the intima of the vessel wall and applying pressure to rapidly release.
  • the drug acts as a local anti-vascular intimal hyperplasia, thereby preventing vascular restenosis after vascular intervention.
  • the core of the drug balloon and the therapeutic effect is the drug coating.
  • the active anti-proliferative drug is a lipophilic drug, it is hardly soluble in water, and is easily agglomerated and agglomerated to form large particles, which are easily washed away by blood during transportation. If the number of exfoliated particles is large, it is easy to cause complications such as distal vascular occlusion and thrombosis, and severe cases may lead to amputation.
  • the active drug can be rapidly and directly delivered to the local tissue region during or after the clinical process; 2. Effective at the desired target site and The active drug is rapidly released in an efficient manner so that it can rapidly penetrate into the target tissue to treat the disease; 3.
  • the drug coating has a small particle size, and during the delivery to the target site and at the target site, the drug particles are Less blood is washed away.
  • the present invention provides a drug-coated balloon catheter having a rapid drug release coating and having a small drug particle size in a drug coating.
  • the drug-coated balloon catheter has a drug coating containing an active drug and a carrier for speeding up the release of the active drug from the balloon, enabling the drug to be released in a very short period of time and rapidly infiltrating into the affected site.
  • the organization of the tissue enhances the absorption rate of the drug in the diseased tissue of the vascular system or other body lumens, thereby realizing the rapid retransmission of the drug to the target lesion after the drug loss during the clinical use and the balloon expansion.
  • it is achieved that the particle size of the drug particles is small, and the drug particles are less washed away by the blood during delivery to the target site and at the target site.
  • the drug-coated balloon catheter comprises 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 is paclitaxel, rapamycin, paclitaxel derived Or a rapamycin derivative;
  • the carrier comprises an organic acid salt and a polyol, and the mass ratio of the active drug to the carrier in the drug coating is from 0.5 to 49, and the mass ratio of the organic acid salt to the polyol It is (3 to 50):1.
  • the organic acid salt is acetate, benzoate, maleate, succinate, ascorbate, citrate, tartrate, lactate, oxalate, aspartate, nicotinic acid
  • a salt a gluconate, a stearate, a glutamate, a vanillate or a lactobionate
  • the polyol is polyethylene glycol, tromethamine, xylitol At least one of sorbitol, mannitol or amino alcohol.
  • the content of the active drug on the outer surface of the balloon catheter is 0.5 to 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 lipophilic substance organic acid salt and a hydrophilic substance polyol, and both of them have synergistic effects in both the drug delivery and the transfer process to accelerate the drug.
  • the elution releases and absorbs and greatly reduces the shedding of transport particles, reducing the safety of the coating.
  • the carrier used has the following effects:
  • the hydrophilic lipophilic substance of the carrier firstly combines with a lipophilic drug such as rapamycin or paclitaxel, thereby lowering the surface tension of the coating, facilitating the increase of the hydrophilicity of the coating, and further facilitating the transfer of the drug to the tissue;
  • a lipophilic drug such as rapamycin or paclitaxel
  • the lipophilic anti-proliferative drugs are easy to aggregate with each other, and the hydrophilic lipophilic carrier can be quickly combined with the lipophilic carrier, thereby causing a separation between the molecules of the drug, thereby greatly reducing the probability of agglomeration between the drugs and preventing the drug molecules.
  • the hydrophilic lipophilic carrier binds to the lipophilic drug molecule, because of its hydrophilicity, and because of the spacing, the specific surface area of the coating is increased, thereby increasing the solubility of the drug in the intercellular space and accelerating the drug reaching the target tissue membrane.
  • 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 effect, while reducing the size and number of drug particles, further reducing the size of particle shedding. And the quantity greatly improves the safety of the coating.
  • 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 graph showing drug release profiles of Examples 1 to 6 and Comparative Examples 1 to 4.
  • FIG. 2 is a 28-day pathological section of the distal skeletal muscle of the drug balloon catheter prepared in Example 1.
  • Example 3 is a 28-day pathological section of the distal skeletal muscle of the drug balloon catheter prepared in Example 2.
  • Example 4 is a 28-day pathological section of the distal skeletal muscle of the drug balloon catheter prepared in Example 3.
  • Figure 5 is a 28-day pathological section of the distal skeletal muscle of the drug balloon catheter prepared in Example 4.
  • Figure 6 is a 28-day pathological section of the distal skeletal muscle of the drug balloon catheter prepared in Example 5.
  • Figure 7 is a 28-day pathological section of the distal skeletal muscle of the drug balloon catheter prepared in Example 6.
  • Figure 8 is a 28-day pathological section of the distal skeletal muscle of the drug balloon catheter prepared in Comparative Example 1.
  • Figure 9 is a 28-day pathological section of the distal skeletal muscle of the drug balloon catheter prepared in Comparative Example 2.
  • Figure 10 is a 28-day pathological section of the distal skeletal muscle of the drug balloon catheter prepared in Comparative Example 3.
  • Figure 11 is a 28-day pathological section of the distal skeletal muscle of the drug balloon catheter prepared in Comparative Example 4.
  • paclitaxel 250 mg
  • citrate 5.0 mg
  • amino alcohol 10 ml of ethanol, 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, 12 mg polyethylene glycol 2000, 10 ml ethanol, 4 ml purified water were mixed to prepare a coating solution, wherein the mass ratio of active drug to carrier was 2.5; PTA balloon catheter (diameter 4 mm, length 40 mm) After being folded in a 10,000-degree clean environment, 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, 5 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 1.82; and the PTA balloon catheter (diameter 4 mm, length 40 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 40 mg of sodium stearate, 10 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 1.92; and the PTA balloon catheter (diameter 4 mm, length 40 mm)
  • 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, 0.5 mg of sodium benzoate, 0.5 mg of sorbitol, 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 100; and the PTA balloon catheter (diameter 4 mm, length 40 mm) was at 10,000 After the flap is tri-folded in a clean environment, the coating solution is sprayed on the surface of the polyester balloon after the flap by spraying equipment in a 100-level clean environment, so that the drug concentration on the surface of the balloon reaches 3 ⁇ g/mm 2 , dry, and packaged. , ethylene oxide sterilization.
  • 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 . , drying, packaging, and ethylene oxide sterilization.
  • rapamycin 3.7 mg sodium acetate, 18.3 mg mannitol, 8 ml ethanol, 3 ml purified water were mixed to prepare a solution, wherein the mass ratio of active drug to carrier was 0.2; PTA balloon catheter (diameter 4 mm, length 40 mm)
  • the coating solution is applied to the surface of the polyester balloon by a precision syringe (accurate to 2 ⁇ l) in a clean environment of 100 grades, and then the balloon is dried.
  • the coating was repeated until the drug concentration on the surface of the balloon reached 3 ⁇ g/mm 2 , and after drying for 24 hours, the package was sterilized by 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 Examples 1 to 4 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 PTA balloon catheters prepared in Examples 1 to 6 and Comparative Examples 1 to 4 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 charging time of 30 to 60 seconds, and then the balloon catheter is deflated and removed from the in vitro analog 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 drug balloon of the present invention has an increased absorption rate of the drug in the process of catheter expansion, and Comparative Example 2 to 4
  • the absorption rate of vascular tissue to drugs is also increased, and the absorption rate and the active drug are related to the mass ratio of the carrier.
  • the drug balloon of the present invention has a much higher level of particle shedding during the expansion of the catheter simulation path than the comparative examples 1 to 4 (maximum The particle size is smaller than this, and the number of particles in each size range is smaller than that).
  • the size and number of particle shedding are also significantly related to the mass ratio of the active drug to the carrier, and the mass ratio between the carriers, and a smaller drug particle size and less particle shedding can be obtained within the scope of the embodiment of the present invention. Quantity.
  • the balloon catheters prepared in Examples 1 to 6 and Comparative Examples 1 to 4 were implanted in healthy minipigs, and the peripheral arterial vessels were dilated, and were followed up for 30 minutes, 24 hours, 7 days, and 28 days, respectively, and the blood vessels were expanded and cleaned.
  • the drug content was measured by HPLC: the drug release profile is shown in Figure 1.
  • Fig. 1 show that the drug balloon catheter drug reversal effect and bioavailability of the present invention are significantly better than those of the drug-coated balloon catheter without the carrier (Comparative Examples 1-4). It is further explained that the drug release effect of the drug balloon catheter prepared by the invention is obviously better than that of the comparative example.
  • the drug balloon catheter prepared in Examples 1 to 6 and the drug balloon catheter prepared in Comparative Examples 1 to 4 were used for vascular dilatation of 1: (1.1 to 1.2), and taken out after 28 days.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Surgery (AREA)
  • Vascular Medicine (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Materials For Medical Uses (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。活性药物与载体的质量比为（0.5-49）：1，有机酸盐与多元醇的质量比为（3-50）：1。药物涂层中的有机酸盐和多元醇能够防止球囊导管置入靶位前的药物过早释放，促进药物从球囊表面快速释放并快速释放进入靶组织。药物涂层中的小粒径药物能够减少在输送过程中血液冲脱的药物颗粒的量。

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(简称：BMS)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(简称DES)问世，使靶血管再狭窄率降至3％以下，称为第三个里程碑。
支架的发明对于解决动脉粥样硬化和血管内狭窄提供了比较好的解决方案，使治疗效率大为提高，但同时出现了血管内和支架内再狭窄，对于小血管，分叉血管及原位病变等的治疗效果并不理想等缺点，由于接受PCI治疗的患者数量逐年上升，发生支架再狭窄的患者的绝对数量相当可观。目前针对再狭窄而采用的方法包括：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(简称DEB)的出现为解决再狭窄带来了新的希望。药物洗脱球囊与DES类似，本质上源于以导管为基础的局部药物输送装置理念，通过球 囊携带的药物抑制内膜增生，只是携带药物的方式以及局部药物作用时间不同。
药物涂层球囊是将抗增生性的药物，如紫杉醇或雷帕霉素和添加剂的组合物，涂层于球囊表面。当球囊输送到病变血管壁并被撑开、扩张、与血管壁内膜接触时，通过撕裂血管壁内膜并加压快速释放、转移药物至局部血管壁内。药物在局部起到抗血管内膜增生的作用，从而预防血管介入术后的血管再狭窄。
药物球囊的核心并起治疗作用的是药物涂层。由于起作用的抗增生性药物为亲脂性药物，难溶于水，且容易团聚结块，形成大的微粒，在输送过程中这些大的药物微粒容易被血液冲脱。若脱落的微粒数量多，很容易引起远端血管闭塞、血栓等并发症，严重者会导致截肢。
发明内容
针对上述现有技术的不足，需要开发满足以下条件药物涂层球囊：1.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；2.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；3.药物涂层中药物粒径小，在输送至靶位置的过程中以及在靶位置治疗时，药物颗粒被血液冲脱少。
本发明提供一种具有快速药物释放涂层、且药物涂层中药物粒径小的药物涂层球囊导管。该药物涂层球囊导管的药物涂层中含有活性药物和载体，该载体用于加快活性药物从球囊上的释放速度，能使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，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，从而实现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。另外，通过配方设计，达成药物颗粒粒径较小，且在输送至靶位置的过程中以及在靶位置治疗时，药物颗粒被血液冲脱少。
该药物涂层球囊导管，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0.5～49，所述有机酸盐与多元醇的质量比为(3～50)∶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、硬脂酸盐、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至少一种。
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。
本发明球囊导管表面的药物涂层中，载体由亲水亲脂性物质有机酸盐和亲水性物质多元醇组成，两者在药物输送以及转载这两个过程中皆产生协同作用加快了药物的洗脱释放和吸收并大大减少输送微粒脱落，降低涂层安全性。具体地，所用载体具有以下作用：
1、作表面活性剂；
载体的亲水亲脂性物质首先会与雷帕霉素或紫杉醇等亲脂性药物结合，从而降低了涂层表面张力，有利于增加涂层的亲水性，进一步地有利于药物向组织转载；
2、作分散剂间隔药物晶体颗粒，有助于药物洗脱和转载；
亲脂性的抗增生性药物容易相互聚集，亲水亲脂载体由于具有亲脂性可快速与之结合后，使得药物分子间产生间隔作用，从而大大降低了药物分子间团聚的几率，防止了药物分子间大面积的团聚，以及聚集在器械上。也因此减小了药物颗粒的尺寸和数量，更进一步的减少了微粒脱落的尺寸和数量，大大的 提高了涂层的安全性。
3、作助溶剂具有细胞渗透作用，有利于药物吸收。
亲水亲脂性载体与亲脂性药物分子结合后，因其具有亲水性，同时因为间隔作用，增加了涂层的比表面积从而增加了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，同时减小了药物颗粒的尺寸和数量，更进一步的减少了微粒脱落的尺寸和数量，大大的提高了涂层的安全性。
(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为实施例1～6及对比例1～4的药物释放曲线图。
图2为实施例1制备的药物球囊导管远端骨骼肌28天病理切片图。
图3为实施例2制备的药物球囊导管远端骨骼肌28天病理切片图。
图4为实施例3制备的药物球囊导管远端骨骼肌28天病理切片图。
图5为实施例4制备的药物球囊导管远端骨骼肌28天病理切片图。
图6为实施例5制备的药物球囊导管远端骨骼肌28天病理切片图。
图7为实施例6制备的药物球囊导管远端骨骼肌28天病理切片图。
图8为经过对比实施例1制备的药物球囊导管远端骨骼肌28天病理切片图。
图9为经过对比实施例2制备的药物球囊导管远端骨骼肌28天病理切片图。
图10为经过对比实施例3制备的药物球囊导管远端骨骼肌28天病理切片图。
图11为经过对比实施例4制备的药物球囊导管远端骨骼肌28天病理切片图。
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250mg紫杉醇，5.0mg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49；将PTA球囊导管(直径4mm，长40mm)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11mg雷帕霉素，17mg乳酸盐，5mg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0.5；将PTA球囊导管(直径4mm，长40mm)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3μg/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，12mg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2.5；将PTA球囊导管(直径4mm，长40mm)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，5mg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1.82；将PTA球囊导管(直径4mm，长40mm)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12mg紫杉醇，20mg硬脂酸镁，4mg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0.5；将PTA球囊导管(直径4mm，长40mm)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96mg紫杉醇，40mg硬脂酸钠，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1.92；将PTA球囊导管(直径4mm，长40mm)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，20mg碘普罗胺，5ml乙醇混合配制溶液；将PTA球囊导管(直径4mm，长40mm)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。
对比例2
将100mg紫杉醇，0.5mg苯甲酸钠，0.5mg山梨醇，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100；将PTA球囊导管(直径4mm，长40mm)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3
将75mg紫杉醇，0.74mg柠檬酸钠，0.26mg聚乙二醇1000，10ml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75；将PTA球囊导管(直径4mm，长40mm)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4
将4.4mg雷帕霉素，3.7mg乙酸钠，18.3mg甘露醇，8ml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PTA球囊导管(直径4mm，长40mm)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3μg/mm2，干燥24小时后，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1～4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：1.0ml/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
Figure PCTCN2016080746-appb-000001
表1结果表明：与对比例1未添加载体的药物涂层球囊相比，本发明的药物球囊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。而与对比例2～4相比药物损失量则基本相当。
体外模拟测试
用猪冠脉血管作靶血管在体外模拟设备进行体外模拟测试。
分别将实施例1～6和对比例1～4制备的PTA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
Figure PCTCN2016080746-appb-000002
Figure PCTCN2016080746-appb-000003
由表2可知：与对比例1未添加载体的药物涂层球囊相比，本发明的药物球囊在导管扩张过程中，血管组织对药物的吸收率有所提高，与对比例2～4相比，血管组织对药物的吸收率也有所提高，吸收率和活性药物与载体的质量比有关。
微粒脱落测试
在体外模拟测试(纯化水，37℃，300ml/min)环境下，模拟输送，扩张球囊，洗脱球囊表面，检测药物涂层脱落的微粒，通过微粒检测仪检测脱落的微粒大小和数量。并通过显微镜法观察测定大尺寸微粒(＞100μm)的具体大小及形貌。
表3 体外模拟微粒脱落测试结果
Figure PCTCN2016080746-appb-000004
由表3可知：与对比例1～4的药物涂层球囊相比，本发明的药物球囊在导管模拟路径扩张过程中，微粒脱落水平相比于对比例1～4远远要好(最大粒径尺寸比其小，各尺寸范围微粒数量比其少)。从而可知，微粒脱落的尺寸和数量跟活性药物与载体的质量比，以及载体之间的质量比也有重大关系,在本发明实施例范围内能获得更小的药物颗粒尺寸和更少的微粒脱落数量。
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1～4制备的球囊导管于健康小型猪体内，外周动脉血管扩张，分别在30min，24h，7天，28天后随访，取球扩段血管，清洗干净，于HPLC测量药物含量：药物释放曲线如图1所示。
图1结果表明：与没有载体的药物涂层球囊导管(对比实施例1～4)相比，本发明的药物球囊导管药物转载效果以及生物可利用度明显要好。更进一步说明，本发明制备药物球囊导管药物释放效果较对比例明显要好。
安全性研究试验
在健康小型猪左右股浅动脉上，分别使用实施例1～6制备的药物球囊导管和对比例1～4制备的药物球囊导管进行1:(1.1～1.2)的血管扩张，28天后取出远端骨骼肌组织，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，观察骨骼肌内血管血栓，闭塞情况以及局部缺血，骨骼肌细胞坏死等并发症。
结果表明：经过本发明的药物球囊导管经过血管扩张后，其远端骨骼肌组织没发现任何变化(图2～图7)，也没有发现血栓、局部缺血以及细胞坏死等并发症；对比例2～4的药物球囊导管经过血管扩张后，球扩段血管，远端骨骼肌组织没发现任何变化(图9～11)，也未发现血栓、局部缺血以及细胞坏死等并发症；而经过对比例1的药物球囊导管经过血管扩张后发现了局部梗塞(图8)，以及梗塞周围组织细胞坏死现象。进一步地说明，本发明制备药物球囊导管微粒脱落较少，更安全。

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0.5～49，所述有机酸盐与多元醇的质量比为(3～50)∶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、硬脂酸盐、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/CN2016/080746 2015-05-26 2016-04-29 药物涂层球囊导管 Ceased WO2016188303A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201510276542.6A CN106267377A (zh) 2015-05-26 2015-05-26 药物涂层球囊导管
CN201510276542.6 2015-05-26

Publications (1)

Publication Number Publication Date
WO2016188303A1 true WO2016188303A1 (zh) 2016-12-01

Family

ID=57393806

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2016/080746 Ceased WO2016188303A1 (zh) 2015-05-26 2016-04-29 药物涂层球囊导管

Country Status (2)

Country Link
CN (1) CN106267377A (zh)
WO (1) WO2016188303A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112933301A (zh) * 2019-11-26 2021-06-11 上海微创医疗器械（集团）有限公司 载药植入医疗器械及其制备方法

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108261569B (zh) * 2016-12-31 2021-01-22 先健科技(深圳)有限公司 药物球囊的制备方法
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
CN110292701B (zh) * 2019-06-27 2021-11-16 山东瑞安泰医疗技术有限公司 一种药物洗脱球囊导管及其制备方法
CN110201243B (zh) * 2019-07-09 2021-10-26 科睿驰（深圳）医疗科技发展有限公司 一种复合药物涂层球囊导管及其制备方法
CN111249536A (zh) * 2020-01-15 2020-06-09 山东瑞安泰医疗技术有限公司 一种新型药物洗脱球囊导管及其制备方法
CN113117220B (zh) * 2021-04-14 2023-03-21 深圳市赛禾医疗技术有限公司 一种药物球囊导管、药物球囊导管系统及其控制方法
CN116350859B (zh) * 2023-06-01 2023-09-12 北京久事神康医疗科技有限公司 一种药物涂层球囊导管及其制备方法

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008087488A2 (en) * 2006-10-22 2008-07-24 Ophir Perelson Expandable medical device for the treatment and prevention of cardiovascular diseases
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
CN101808646A (zh) * 2007-11-30 2010-08-18 阿斯比奥制药株式会社 用于改善帕金森氏病的运动并发症或精神症状的药剂
CN103611212A (zh) * 2013-11-21 2014-03-05 先健科技(深圳)有限公司 药物球囊的制备方法
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
CN104353132A (zh) * 2014-11-21 2015-02-18 浙江归创医疗器械有限公司 一种植入或介入医疗器械上药物涂层的涂覆工艺

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102512747A (zh) * 2011-12-27 2012-06-27 微创医疗器械(上海)有限公司 药物洗脱球囊导管

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008087488A2 (en) * 2006-10-22 2008-07-24 Ophir Perelson Expandable medical device for the treatment and prevention of cardiovascular diseases
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
CN101808646A (zh) * 2007-11-30 2010-08-18 阿斯比奥制药株式会社 用于改善帕金森氏病的运动并发症或精神症状的药剂
CN103611212A (zh) * 2013-11-21 2014-03-05 先健科技(深圳)有限公司 药物球囊的制备方法
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
CN104353132A (zh) * 2014-11-21 2015-02-18 浙江归创医疗器械有限公司 一种植入或介入医疗器械上药物涂层的涂覆工艺

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112933301A (zh) * 2019-11-26 2021-06-11 上海微创医疗器械（集团）有限公司 载药植入医疗器械及其制备方法
CN112933301B (zh) * 2019-11-26 2023-01-24 上海微创医疗器械（集团）有限公司 载药植入医疗器械及其制备方法

Also Published As

Publication number Publication date
CN106267377A (zh) 2017-01-04

Similar Documents

Publication Publication Date Title
CN103736154B (zh) 药物涂层球囊导管
JP7821734B2 (ja) ポリマー封入薬物粒子
JP6756664B2 (ja) 薬剤を分散させるための医療器具
WO2016188303A1 (zh) 药物涂层球囊导管
JP5989064B2 (ja) スコアリングまたはカッティングバルーンカテーテルのための改善されたコーティング調合物
EP3174567B1 (en) Paclitaxel-eluting balloon and method for manufacturing the same
CN111166942A (zh) 用于非血管狭窄的药物涂层球囊导管
CN107865982B (zh) 药物涂层球囊
WO2016101771A1 (zh) 药物球囊扩张导管的制备方法及折翼卷绕球囊
WO2018019055A1 (zh) 用于动脉血管病变扩张载药球囊的复配药物及载药球囊
CN107995869B (zh) 一种表面液化药物涂层球囊
JP2023541523A (ja) 少なくとも１種のリムス物質を有する即時移動可能で永久的に増殖を阻害するコーティングを有する医療器具および調製方法
CN114126678A (zh) 具有可立即移除涂层的支架
JP2023520837A (ja) 増強された効果を有する薬剤の送達のための医薬製品
HK40063666A (zh) 具有可立即移除涂层的支架
HK1146910A (zh) 用於配药的医用设备
HK1147216A (zh) 用於配药的医用设备
HK1116100B (zh) 用於递送药物的气囊导管及其制备方法和应用
HK1114798B (zh) 用於递送药物的气囊导管及其制备方法和应用

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: 16799192

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 18/04/2018)

122 Ep: pct application non-entry in european phase

Ref document number: 16799192

Country of ref document: EP

Kind code of ref document: A1