WO2018059167A1 - 药物涂层球囊 - Google Patents

药物涂层球囊 Download PDF

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Publication number
WO2018059167A1
WO2018059167A1 PCT/CN2017/099022 CN2017099022W WO2018059167A1 WO 2018059167 A1 WO2018059167 A1 WO 2018059167A1 CN 2017099022 W CN2017099022 W CN 2017099022W WO 2018059167 A1 WO2018059167 A1 WO 2018059167A1
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drug
acid
balloon
coated balloon
alcohol
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PCT/CN2017/099022
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English (en)
French (fr)
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宋精忠
谢琦宗
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先健科技(深圳)有限公司
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Publication of WO2018059167A1 publication Critical patent/WO2018059167A1/zh

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    • 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
    • A61L29/08—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
    • 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
    • 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
    • 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
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/606—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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/80—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special chemical form
    • A61L2300/802—Additives, excipients, e.g. cyclodextrins, fatty acids, surfactants
    • 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
    • A61L2420/00—Materials or methods for coatings medical devices
    • A61L2420/06—Coatings containing a mixture of two or more compounds

Definitions

  • the present invention relates to interventional medical devices, and in particular to drug coated balloons.
  • the drug-coated balloon belongs to the interventional device.
  • the principle is that the active drug is loaded on the surface of the common balloon, and after being transported to the target lesion of the blood vessel, the balloon is inflated and inflated, so that the drug is in full contact with the blood vessel wall, thereby eliminating the target lesion.
  • the long-term stenosis of the site is a very short, very long-term stenosis of the site.
  • the vessel wall is generally divided into the intima, media, and adventitia from the lumen facing outward.
  • the inner membrane is the innermost layer of the vessel wall and consists of the endothelium and the subendothelial layer.
  • the endothelial cells and the substrate constitute a permeability tight barrier through which liquid, gas and macromolecular substances can selectively enter the middle membrane.
  • the thickness and composition of the middle membrane vary depending on the type of blood vessel.
  • the aorta is mainly composed of elastic membrane with a few smooth muscles.
  • the middle artery is mainly composed of smooth muscle.
  • the drug coating on the surface of the balloon is eluted from the surface of the balloon and released to the blood vessel of the lesion after reaching the target lesion, and in fact, the drug effect cannot be fully exerted.
  • drugs that are absorbed by the intima and enter the vascular smooth muscle cell layer can exert therapeutic effects, inhibit malignant proliferation of smooth muscle cells, and reduce the rate of restenosis. Since vascular restenosis is a chronic process, the more drug is absorbed by the intima and enters the vascular membrane, the longer the drug stays in the vascular tissue of the target lesion, and the better the effect of inhibiting vascular restenosis.
  • Existing drug-coated balloons incorporate carriers and additives into the drug coating to increase the solubility of the drug and increase the immediate drug release rate (ie, turnover rate) of the drug.
  • these carriers and additives usually only ensure that the active drug is released to the blood vessel wall of the lesion as quickly as possible in a short period of time when the balloon is in contact with the target vessel of the lesion, and the drug released to the inner wall of the blood vessel cannot be quickly absorbed by the vascular tissue. It is not lost by blood scouring; in addition, because there is not enough active drug to enter the vascular membrane through the endometrium, there must be no sufficient amount of drug to remain in the vascular layer for a long time to continue to exert its efficacy and inhibit long-term vascular restenosis.
  • the absorption process of anti-restenosis drugs or anti-proliferative drugs from the surface of the endothelium into the middle membrane is mainly due to the difference in the concentration of the drug on the surface of the endothelium and the concentration of the drug in the vascular membrane.
  • the drug penetrates the intima through the intima and enters the middle membrane.
  • the smooth muscle cell layer acts at the target site.
  • a penetration enhancer as a drug carrier can reduce the resistance of the drug through the endothelium, assisting the drug to rapidly cross the endothelium, diffuse, and reach the media through the substrate.
  • a penetration enhancer to a drug coating of a drug-loading device such as a drug eluting balloon or a drug-eluting stent, so that the drug penetrates into the endothelium and the substrate more rapidly, reaches the vascular membrane and inhibits smooth muscle cell proliferation.
  • a drug-loading device such as a drug eluting balloon or a drug-eluting stent
  • the present invention provides a drug coated balloon comprising a balloon body and a drug coating overlying the surface of the balloon body.
  • the drug coating contains an active drug and a carrier.
  • the active drug includes an anti-restenosis drug or an anti-proliferative drug.
  • the carrier includes a penetration enhancer.
  • the penetration enhancer carrier in the drug coating acts on the vascular endothelial cells, changes the structure of the endothelial cells, affects the permeability of the endothelial cells, accelerates the penetration of the drug into the intima of the lesion and diffuses into the media, thereby making the drug more It is quickly absorbed by the tissue and increases the total dose absorbed by the tissue, which is beneficial for the drug to remain in the middle layer of the blood vessel for a long time.
  • the mass ratio of the active drug to the carrier ranges from (0.5 to 49):1.
  • the carrier further comprises a dispersing agent. Since lipophilic anti-restenosis drugs or anti-proliferative drugs are easy to aggregate with each other, hydrophilic lipophilic dispersing agents can quickly bind with lipophilic drugs, separating drug particles, thereby reducing the probability of agglomeration between drugs and improving coating. Layer uniformity. Secondly, after the dispersant is added, the fineness of the drug-coated particles can be increased, the size of the drug particles can be reduced, and the small-sized drug can be more easily absorbed.
  • the drug molecule bound to the dispersing agent has an increased specific surface area, improved solubility, and improved adsorption capacity after contact with the vascular lipophilic structure, contributing to the transfer of the drug coating from the balloon surface to the blood vessel wall.
  • the lipophilic drug is formed during the balloon transportation process, which is beneficial to the adhesion of the drug coating to the surface of the balloon body, and reduces the loss of the drug coating during the transportation process, thereby ensuring the loss of the drug coating during the transportation process. Before the expansion of the adherent balloon, there is sufficient drug to be transferred to the tissue.
  • the dispersing agent and the penetration enhancer synergistically not only can accelerate the release process of the drug and promote the permeation and absorption of the drug on the endothelium surface, but also reduce the particle shedding and process loss of the drug coating on the surface of the balloon during the delivery process, thereby obtaining Better treatment results.
  • the mass ratio of the dispersant to the penetration enhancer ranges from (0.01 to 50):1.
  • the anti-proliferative drug is selected from at least one of paclitaxel, paclitaxel derivatives, rapamycin or rapamycin derivatives.
  • the penetration enhancer is selected from at least one of an alcohol compound and a derivative thereof, a fatty acid and a derivative thereof, an aromatic acid, and a derivative thereof.
  • an alcohol compound and a derivative thereof Different from conventional transdermal patches or other agents for transdermal administration Because the composition of the blood vessel wall is different from that of the skin, the physiological environment inside the blood vessel is also different from the environment for transdermal administration.
  • the penetration enhancer suitable for drug coating of vascular implanted or interventional medical devices should overcome blood pH. The blood flow continues to wash away from the hemodynamic environment and does not interact with other substances in the blood.
  • the alcohol compound is selected from the group consisting of fatty alcohols or polyols selected from the group consisting of octanol, decyl alcohol, lauryl alcohol, myristyl alcohol, palmitol, stearyl alcohol, arachidyl alcohol or two Decylene glycol.
  • the polyol is selected from the group consisting of propylene glycol, glycerin or polyethylene glycol.
  • the fatty acid is selected from the group consisting of caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, soft oleic acid, oleic acid, linoleic acid, linolenic acid or peanuts. Oleic acid.
  • the aromatic acid is selected from the group consisting of benzoic acid, phenylacetic acid, syringic acid, cinnamic acid, o-hydroxybenzoic acid, p-hydroxybenzoic acid, p-aminobenzoic acid, p-aminomethylbenzoic acid, p-amino water.
  • Salicylic acid or phthalic acid is selected from the group consisting of benzoic acid, phenylacetic acid, syringic acid, cinnamic acid, o-hydroxybenzoic acid, p-hydroxybenzoic acid, p-aminobenzoic acid, p-aminomethylbenzoic acid, p-amino water.
  • the derivative comprises an ester, an amide, an acid anhydride or a salt
  • the salt comprises a magnesium salt, a sodium salt, a zinc salt, a calcium salt, a barium salt or a copper salt.
  • the penetration enhancer is selected from the group consisting of lauryl alcohol, myristyl alcohol, stearyl alcohol, lauric acid, palmitic acid, stearic acid, magnesium stearate, sodium stearate, zinc stearate, Stearic acid amide, isooctyl palmitate, linoleic acid, linolenic acid, glycerol monooleate, polyoxyethylene stearate, sodium benzoate, cinnamic acid, o-hydroxybenzoic acid, p-hydroxybenzoic acid, p-amino water At least one of salicylic acid or phthalic anhydride.
  • the dispersing agent is selected from the group consisting of acetate, maleate, polyvinylpyrrolidone, succinate, ascorbate, citrate, tartrate, lactate, oxalate, aspartate , niacin, gluconate, polyethylene glycol 1000, polyethylene glycol 2000, acetamide, poloxamer, pentaerythritol, glutamate, vanillate, hydroxypropyl methylcellulose Or at least one of lactobions.
  • the active drug is present in the balloon body surface in an amount ranging from 0.5 to 20 ⁇ g/mm 2 .
  • the drug coated balloon is used to deliver the active drug into a blood vessel or lumen.
  • the blood vessel includes a coronary artery, a peripheral artery, or a cerebral artery.
  • the lumen includes the esophagus, airway, intestine, biliary tract, cervix, urinary tract, prostate or cerebral access.
  • the peripheral arterial blood vessel includes a leg artery, and further includes a radial artery, an external iliac artery, a femoral artery, or a radial artery.
  • the present invention has at least the following advantages and benefits:
  • the drug-coated balloon of the present invention contains a penetration-enhancing agent, and the drug can be quickly absorbed by the vascular tissue after being released from the surface of the balloon to the blood vessel wall, thereby overcoming a large amount of the drug before being absorbed by the vascular tissue.
  • Example 2 is a H&E staining diagram of a pathological section of a drug-coated balloon after 28 days after the drug-coated balloon provided in Example 1 of the present invention is placed in a healthy miniature pig;
  • FIG. 3 is a staining diagram of the pathological section of the tissue surrounding the drug-coated balloon after 28 days after the drug-coated balloon provided in the first embodiment of the present invention is expanded into a healthy mini-piggy;
  • FIG. 4 is a three-color staining diagram of a pathological section of a drug-coated balloon after 28 days after the drug-coated balloon provided in the first embodiment of the present invention is expanded into a healthy mini-piggy;
  • FIG. 5 is a Movat staining diagram of a pathological section of a tissue surrounding a drug-coated balloon after 28 days after the drug-coated balloon provided in the first embodiment of the present invention is expanded into a healthy mini-pig;
  • Example 6 is a microscopic photograph of a microparticle shedding of a drug-coated balloon provided by Example 1 of the present invention after an in vitro simulation test;
  • Example 7 is a micrograph of microparticles falling off after in vitro simulation test of a drug-coated balloon provided by Example 2 of the present invention.
  • Example 8 is a microscopic photograph of a microparticle shedding of a drug-coated balloon provided by Example 3 of the present invention after in vitro simulation test;
  • Example 9 is a microscopic photograph of a microparticle shedding of a drug-coated balloon provided by Example 4 of the present invention after in vitro simulation test;
  • Example 10 is a microscopic photograph of a microparticle shedding of a drug-coated balloon provided by Example 5 of the present invention after in vitro simulation test;
  • Example 11 is a micrograph of microparticles falling off after in vitro simulation test of a drug-coated balloon provided by Example 6 of the present invention.
  • Example 12 is a microscopic photograph of a microparticle shedding of a drug-coated balloon provided by Example 7 of the present invention after in vitro simulation test;
  • Figure 13 is a photomicrograph of microparticle shedding after a drug-coated balloon of Comparative Example 1 was tested by in vitro simulation.
  • paclitaxel 11 mg was used as an active drug
  • 17 mg of lauric acid was used as a penetration enhancer
  • 5 mg of hydroxypropylmethylcellulose was used as a dispersing agent
  • a drug solution was prepared by mixing with 7 mL of ethanol and 4 mL of purified water.
  • the surface of the balloon was dried and repeatedly dispensed until the drug concentration on the surface of the balloon reached 3 ⁇ g/mm 2 , dried at room temperature for 24 hours, packaged, and sterilized with ethylene oxide to obtain the drug-coated balloon of the present example.
  • the total weight of the carrier was 22 mg
  • the mass ratio of the active drug to the carrier was 0.5
  • the mass ratio of the dispersing agent to the penetration enhancing agent in the carrier was 0.29.
  • paclitaxel 495 mg was used as an active drug
  • 10 mg of isooctyl palmitate was used as a penetration enhancer
  • 0.1 mg of sodium citrate was used as a dispersing agent
  • 20 mL of isopropyl alcohol was mixed to prepare a drug solution.
  • the drug solution is dripped onto the surface of the balloon after the flap in a 100-level clean environment. And drying, repeated application until the drug concentration on the surface of the balloon reached 0.5 ⁇ g/mm 2 , drying at room temperature for 24 hours, packaging, and ethylene oxide sterilization to obtain the drug-coated balloon of the present example.
  • the total weight of the carrier was 10.1 mg
  • the mass ratio of the active drug to the carrier was 49
  • the mass ratio of the dispersing agent to the penetration enhancing agent in the carrier was 0.01.
  • paclitaxel 120 mg was used as an active drug
  • 36 mg of sodium benzoate was used as a penetration enhancer
  • a drug solution was prepared by mixing with 10 mL of ethanol and 4 mL of purified water.
  • the drug solution is sprayed onto the surface of the balloon after the flap in a clean environment of 100 grades.
  • the drug concentration on the surface of the balloon was 2 ⁇ g/mm 2 , dried at room temperature for 24 hours, packaged, and sterilized with ethylene oxide to obtain a drug-coated balloon of the present example.
  • the mass ratio of the active drug to the carrier in this example was 3.33.
  • paclitaxel 100 mg was used as an active drug
  • 50 mg of magnesium stearate was used as a penetration enhancer
  • 5 mg of polyethylene glycol 1000 was used as a dispersing agent
  • a drug solution was prepared by mixing with 10 mL of ethanol and 4 mL of purified water.
  • the drug solution is sprayed onto the surface of the balloon after the flap in a clean environment of 100 grades.
  • the drug concentration on the surface of the balloon was 3 ⁇ g/mm 2 , dried at room temperature for 24 hours, packaged, and sterilized with ethylene oxide to obtain a drug-coated balloon of the present example.
  • the total weight of the carrier was 55 mg
  • the mass ratio of the active drug to the carrier was 1.82
  • the mass ratio of the dispersing agent to the penetration enhancing agent in the carrier was 0.1.
  • paclitaxel 120 mg was used as an active drug
  • 3 mg of lauryl alcohol was used as a penetration enhancer
  • 9 mg of acetamide was used as a dispersing agent
  • a drug solution was prepared by mixing with 2 mL of ethanol and 0.4 mL of purified water.
  • the drug solution is sprayed onto the surface of the balloon after the flap in a clean environment of 100 grades.
  • the drug concentration on the surface of the balloon was adjusted to 2.5 ⁇ g/mm 2 , dried at room temperature for 24 hours, packaged, and sterilized with ethylene oxide to obtain a drug-coated balloon of the present example.
  • the total weight of the carrier is 12 mg
  • the mass ratio of the active drug to the carrier is 10
  • the mass ratio of the dispersing agent to the penetration promoting agent in the carrier is 3.
  • paclitaxel 12 mg was used as an active drug
  • 1 mg of stearyl alcohol was used as a penetration enhancer
  • 5 mg of polyvinylpyrrolidone was used as a dispersing agent
  • a drug solution was prepared by mixing with 100 mL of isopropyl alcohol and 20 mL of purified water.
  • the drug concentration on the surface of the balloon was 1.5 ⁇ g/mm 2 , and dried at room temperature for 24 hours, and then packaged and sterilized with ethylene oxide to obtain a drug-coated balloon of the present example.
  • the total weight of the carrier is 6 mg
  • the mass ratio of the active drug to the carrier is 2
  • the mass ratio of the dispersing agent to the penetration enhancing agent in the carrier is 5.
  • paclitaxel 20 mg was used as an active drug
  • 0.5 mg of stearic acid amide was used as a penetration enhancer
  • 25 mg of polyethylene glycol 2000 was used as a dispersing agent
  • a drug solution was prepared by mixing with 10 mL of ethanol and 5 mL of purified water.
  • the drug solution is sprayed onto the surface of the balloon after the flap in a clean environment of 100 grades.
  • the drug concentration on the surface of the balloon was adjusted to 5 ⁇ g/mm 2 , dried at room temperature for 24 hours, packaged, and sterilized with ethylene oxide to obtain a drug-coated balloon of the present example.
  • the total weight of the carrier was 25.5 mg
  • the mass ratio of the active drug to the carrier was 0.78
  • the mass ratio of the dispersing agent to the penetration promoting agent in the carrier was 50.
  • rapamycin 120 mg was used as an active drug, 4 mg of glycerol monooleate as a penetration enhancer, and 24 mg of poloxamer as a dispersing agent were mixed with 2 mL of ethanol and 10 mL of purified water to prepare a drug solution.
  • the drug solution is sprayed onto the balloon surface after the flap in a 100-level clean environment.
  • the drug concentration on the surface of the balloon was adjusted to 10 ⁇ g/mm 2 , dried at room temperature for 24 hours, packaged, and sterilized with ethylene oxide to obtain a drug-coated balloon of the present example.
  • the total weight of the carrier was 28 mg
  • the mass ratio of the active drug to the carrier was 4.29
  • the mass ratio of the dispersing agent to the penetration enhancing agent in the carrier was 6.
  • rapamycin 210 mg was used as an active drug
  • 2 mg of polyoxyethylene stearate was used as a penetration enhancer
  • 40 mg of pentaerythritol was used as a dispersing agent
  • a drug solution was prepared by mixing with 45 mL of ethanol and 5 mL of purified water.
  • the drug solution is sprayed onto the balloon surface after the flap in a 100-level clean environment.
  • the drug concentration on the surface of the balloon was 20 ⁇ g/mm 2 , dried at room temperature for 24 hours, packaged, and sterilized with ethylene oxide to obtain a drug-coated balloon of the present example.
  • the total weight of the carrier was 42 mg
  • the mass ratio of the active drug to the carrier was 5
  • the mass ratio of the dispersing agent to the penetration enhancing agent in the carrier was 20.
  • rapamycin 10 mg was used as an active drug, and 2 mg of magnesium stearate was used as a penetration enhancer, and a drug solution was prepared by mixing with 20 mL of ethanol.
  • the drug solution was sprayed onto the balloon after the flap in a clean environment of 100 grades.
  • the drug concentration on the surface of the balloon was 3.5 ⁇ g/mm 2 , dried at room temperature for 24 hours, packaged, and sterilized with ethylene oxide to obtain a drug-coated balloon of the present example.
  • the total weight of the carrier in this example was 2 mg, and the mass ratio of the active drug to the carrier was 5.
  • paclitaxel 50 mg was used as an active drug, and 20 mg of iopromide was used as a carrier, and mixed with 5 mL of ethanol to prepare a drug solution.
  • the drug solution is sprayed onto the surface of the balloon after the flap in a clean environment of 100 grades.
  • the drug concentration on the surface of the balloon was 3 ⁇ g/mm 2 , dried at room temperature for 24 hours, packaged, and sterilized with ethylene oxide to obtain a drug-coated balloon of Comparative Example 1.
  • the mass ratio of the paclitaxel active drug to the carrier in Comparative Example 1 was 2.5.
  • the drug-coated balloons provided in Examples 1 to 7 and Comparative Example 1 were placed in healthy mini-pigs, and the pressure-expanded expansion was performed at the external iliac artery, and the drug-coated balloon was withdrawn to complete the balloon dilatation operation.
  • Follow-up was performed at 30 min, 24 h, 7 days, and 28 days, respectively.
  • the target vessel around the drug-coated balloon during balloon dilation surgery was freed, and the target vessel was slowly washed 3 times with heparin-containing 0.1 mol/L PBS solution (25,000 units of heparin per 1000 ml of PBS).
  • the three-layer structure is exfoliated and separated, and then the inner membrane, the middle membrane and the outer membrane are respectively obtained.
  • the content of the drug in the media of the target vessel of the balloon dilatation segment was measured by liquid chromatography-mass spectrometry (LC-MS/MS).
  • the test conditions for LC-MS/MS are:
  • Liquid chromatography instrument Agilent 1200 liquid chromatography system (Agilent), including G1312A quaternary infusion pump, G1322A vacuum degasser;
  • Mass spectrometer API4000 QTRAP triple quadrupole mass spectrometer (AB Sciex) equipped with electrospray ionization source (ESI);
  • phase A containing 0.1% aqueous formic acid
  • phase B containing 0.1% formic acid in acetonitrile
  • gradient elution
  • Mass spectrometry conditions ESI positive ion detection mode.
  • the results show that the drug coating of the drug-coated balloons of Examples 1 to 7 has a higher ability to be absorbed by the target vascular tissue at 30 min compared to Comparative Example 1.
  • the drug content of the membrane tissue in the target vessels of Examples 1 to 7 increased rapidly, while the drug-coated balloon of Comparative Example 1 did not increase the drug content at 24 hours, indicating the drug spheres of Examples 1 to 7 of the present invention.
  • the drug coating of the capsule rapidly penetrates into the membrane of the target vessel under the action of the penetration enhancer.
  • Comparative Example 1 The drug coating of Comparative Example 1 is more difficult to penetrate the biological barrier of the endothelium of the target vessel, and it undergoes instantaneous expansion and extrusion at the initial moment, and can only rely on the inherent concentration difference to allow a small amount of the drug to penetrate the endometrium; and in the following time The drug no longer enters the target blood vessel membrane, and a small amount of drug that has entered the target blood vessel membrane is gradually consumed, resulting in a monotonously decreasing rule of the drug content in the target blood vessel membrane. This further demonstrates the significant utility of the penetration enhancer in the present invention.
  • the drug content of the target vascular membranes of Examples 1 to 7 no longer increased, indicating that between 24 h and 7 days, the drug penetrated into the target vessel and absorbed into the target vessel.
  • the membrane balances the metabolism of the drug, and after 7 days, the total dose of the membrane in the target vessel gradually decreases.
  • the dose of the target vascular membrane was very small at 7 days of follow-up, and the dose at the 28-day follow-up was essentially zero.
  • the drugs of Examples 1 to 7 can be quickly absorbed and enter the target vessel wall over time, regardless of the amount of drug transfer at the moment of expansion, and gradually increase at 24 hours, and maintain Long time. This excellent drug retention capacity allows for higher drug concentrations in the long run, even at lower initial reloads.
  • the drug-coated balloons of Examples 1 to 7 can release the active ingredient to the lesion locally within a predetermined time, fully exert the therapeutic effect of the drug, prolong the action time of the drug, and improve the bioavailability of the drug.
  • the drug-coated balloon provided by Embodiments 1 to 7 of the present invention is absorbed by the vascular tissue in the same expansion time, the amount of the drug-coated balloon provided by Comparative Example 1 is absorbed by the vascular tissue.
  • the drug-coated balloon provided by the present invention can reduce the dose of the active drug in the drug coating, and reduce the drug on the lesion site and the drug-coated balloon provided in the drug coating when the same quality effect is required. The harm of other organs controls the side effects of the drug.
  • the drug-coated balloons provided in Examples 1 to 6 and Comparative Example 1 were respectively placed in healthy mini-pigs, and the pressure-expanded expansion was performed at the external iliac artery, the drug-coated balloon was withdrawn, and the balloon dilatation operation was completed.
  • Follow-up was performed 28 days after surgery.
  • the target vessels around the drug-coated balloon during balloon dilation surgery were freed, and the target vessel was slowly washed 3 times with heparin-containing 0.1 mol/L PBS solution (25,000 units of heparin per 1000 ml of PBS).
  • the branch vessels at the target vessel were ligated with thin wires, and 1 cm was kept at the proximal and distal ends of the target vessel. After formalin was infused and fixed, a plurality of paraffin-embedded tissue sections were prepared for histopathological analysis.
  • the histopathological analysis method includes the following steps: first, performing H&E staining, ⁇ -actin staining, Masso trichrome staining, and Movat staining on the plurality of tissue sections of the target blood vessel of Example 1. Obtained separately The staining diagram of Figures 2 to 5. The inflammatory cells, the blue area in the Masso trichrome staining, and the wall thickness loss were scored according to the staining diagrams of Figures 2 to 5, respectively, to examine the inflammatory response, collagen fibrin deposition, and medial smooth muscle loss.
  • the principle of investigation is that when the drug-coated balloon acts on the tissue, it inhibits the proliferation of smooth muscle cells, and at the same time initiates the inflammatory repair reaction, producing collagen fibrin deposition in the lost smooth muscle cells.
  • the scoring criteria for each of the three survey indices are as follows:
  • the inflammatory score calculation reference standard is divided into 4 levels. The average was calculated from multiple observations.
  • the blue area in the three-color dyeing is 25 to 50%.
  • the blue area in the three-color dyeing is 51 to 75%.
  • Example 1 Numbering Inflammatory score Membrane smooth muscle loss Fibrin deposition
  • Example 2 1.21 ⁇ 0.58 3.36 ⁇ 084 3.64 ⁇ 0.50
  • Example 3 1.36 ⁇ 0.5 2.56 ⁇ 0.5 3.31 ⁇ 0.48
  • Example 4 1.93 ⁇ 0.92 3.25 ⁇ 0.45 3.50 ⁇ 0.52
  • Example 5 1.31 ⁇ 0.63 2.36 ⁇ 0.30 3.36 ⁇ 0.41
  • the inflammatory scores of Examples 1 to 6 were higher, and the intima, media, and adventitia had a moderate amount of inflammatory cell infiltration, indicating that the surrounding target vascular tissue responded to the drug in the drug coatings of Examples 1 to 6.
  • the time is faster, that is, the time the drug acts on the vascular tissue is faster.
  • the smoothing muscle loss and fibrin deposition of the middle membranes of Examples 1 to 6 were higher, indicating that the initiation time of the drug inhibiting smooth muscle cells was faster.
  • the coatings of the drug-coated balloons provided in Examples 1 to 6 contain a penetration enhancer, which can promote absorption of the drug into the vascular membrane, accelerate the action time of the drug, and reduce the loss of blood flow.
  • the dose ensures the long-term drug content in the vascular tissue.
  • the particle-shedding of the drug-coated balloon provided in Examples 1 to 7 and Comparative Example 1 during the transport was examined by an in vitro simulation test.
  • the test method is as follows: the blood flow is simulated with purified water having a temperature of 37 ° C and a flow rate of 250 mL/min, and a silicone tube of a suitable size is used to simulate blood vessels to simulate a surgical procedure.
  • the drug-coated balloons of Examples 1 to 7 and Comparative Example 1 were separately delivered to the target site, the balloon was expanded to squeeze the simulated blood vessel, the drug coating on the surface of the balloon was eluted, and the particles were exfoliated and accompanied by simulated blood flow. Was flushed to the distal end of the simulated blood vessel.
  • the particle size and number of the distal end of the simulated blood vessel were detected by a particle detector, and the results are shown in Table 2.
  • the specific size and morphology of the large-sized particles of >100 ⁇ m were measured by photomicrographs.
  • the microparticle detachment micrographs of Examples 1 to 7 are shown in Figs. 6 to 12, respectively, and the microparticle detachment micrograph of Comparative Example 1 is shown in Fig. 13.
  • the dispersing agent added to the drug coatings of Examples 1 to 7 has a good dispersing ability, and can reduce the size and amount of particles which are peeled off during use of the drug-coated balloon.
  • the principle is that the dispersing agent has a spacing effect, which can improve the fineness of the drug coating particles and make the coating distribution uniform. Prevents the drug from being released prematurely before the drug balloon is placed in the target site.
  • the target vessels of the human coronary artery system were simulated with isolated porcine coronary vessels, and the in vitro simulated delivery process loss test was performed in an in vitro simulated vascular model. The dose loss during the delivery of the drug-coated balloon through the delivery sheath to the target site was examined.
  • the drug-coated balloons prepared in Examples 1 to 7 and Comparative Example 1 were inserted into an in vitro simulated blood vessel model, respectively. Float in the in vitro simulated vascular model for 90 seconds, then take out the drug-coated balloon, analyze the residual drug on the drug-coated balloon by high performance liquid chromatography (HPLC), and calculate the drug loss rate during the delivery process according to the following formula. :
  • Drug loss rate during delivery (drug content at initial load on the balloon surface - residual drug content) / drug content at initial load on the balloon surface x 100%.
  • HPLC test conditions are:
  • UV-visible detector detection wavelength 227nm
  • the present invention provides a drug-coated balloon comprising a penetration enhancer in the drug coating.
  • the drug-coated balloon When the drug-coated balloon is placed in the human body and the balloon is expanded and attached, the active drug is released at the target site and transferred to the inner wall of the blood vessel.
  • the permeabilizing agent carrier in the drug coating acts on the vascular endothelial cells, changes the structure of the endothelial cells, affects the permeability of the endothelial cells, accelerates the penetration of the drug into the intima of the lesion and diffuses into the intima, thereby
  • the drug is absorbed more quickly by the tissue, and the total dose absorbed by the tissue is increased, which is beneficial for the drug to remain in the middle layer of the blood vessel for a long time.
  • the drug-coated balloon provided by the invention can reduce the dosage of the active drug in the drug coating, reduce the harm of the drug to the lesion and other organs, and control the side effects of the drug.
  • the present invention can not only promote the rapid penetration of the active drug from the vascular intima into the vascular membrane, but also does not affect other properties of the drug coating, and reduces the delivery and expansion process. Particle shedding and process loss rate.
  • the mass ratio of the active drug to the carrier ranges from (0.5 to 49):1.
  • the mass ratio of the active drug to the carrier is too large, a large amount of the active drug cannot be firmly combined with the surface of the balloon body, the firmness of the drug coating is lowered, and the loss of the transport process is large; and the carrier cannot exert the effect of promoting drug absorption, The amount of vascular tissue absorbed is low, affecting the effect of inhibiting long-term restenosis.
  • the mass ratio of the active drug to the carrier is too small, the active drug content is too low, which may affect the effectiveness of the drug coating.
  • the drug-coated balloon provided by the invention may further comprise a dispersing agent in the carrier of the drug coating. Due to the synergistic effect of the penetration-enhancing agent and the dispersing agent in the carrier, under the premise of ensuring the transshipment rate of the drug coating, not only It promotes the osmotic absorption of the drug on the surface of the endothelium, increases the amount of drug entering the vascular membrane, and at the same time reduces the particle shedding and process loss of the drug coating on the surface of the balloon during the delivery process, thereby obtaining a better therapeutic effect.
  • the drug coated balloon provided by the present invention has a mass ratio of the dispersant and the penetration enhancer in the carrier of (0.01 to 50):1. This range allows for both dispersion and absorption properties of the drug coating.
  • the amount of the dispersing agent is too large, in order not to affect the mass ratio of the active drug to the carrier, the amount of the penetration promoting agent in the carrier will be correspondingly reduced, and the effect of promoting the penetration and absorption of the active drug into the blood vessel membrane cannot be achieved.
  • the active drug may agglomerate, forming more large particles, resulting in thrombosis; and in order not to affect the mass ratio of the active drug to the carrier, the amount of the penetration promoting agent will increase correspondingly, resulting in the firmness of the drug coating. Reduce, increase the loss of delivery process, reduce the immediate drug transfer rate.
  • the drug-coated balloon provided by the present invention can be used to deliver an active drug to a target site of a blood vessel or a lumen in a human body, to treat stenosis in a blood vessel or lumen, and to prevent intimal or epithelial hyperplasia.
  • the blood vessels include coronary blood vessels and peripheral arterial blood Tube or cerebral artery.
  • the lumen includes the esophagus, airway, intestine, biliary tract, cervix, urinary tract or prostate.
  • the peripheral arterial blood vessel includes a leg artery, and further includes a radial artery, an external iliac artery, a femoral artery, or a radial artery.
  • Embodiments 1 to 10 the specific embodiment of the present invention is schematically illustrated only by a PTA balloon or a PTCA balloon, the technical solution provided by the present invention can also be applied to other interventional drug loading.
  • Medical devices or implantable drug delivery medical devices For example, stents, occlusion devices, orthopedic implants, dental implants, sutures or bolts.
  • the stent includes a vascular stent, a tracheal stent, an esophageal stent, a urethral stent, an intestinal stent, or a biliary stent.
  • the orthopedic implant includes a fixation screw, a fixed rivet or a bone plate.
  • the drug can be absorbed by the human tissue and the blood is reduced. Flow scouring the amount of drug lost, increasing the amount of drug absorbed by human tissue, and improving the clinical treatment effect of invasive drug-loaded medical devices or implantable drug-loaded medical devices.

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Abstract

一种药物涂层球囊，包括球囊本体和覆盖在球囊本体表面的药物涂层，药物涂层含有活性药物和载体，活性药物包括抗增生药物，载体包括促透剂。使用能促进药物快速渗透吸收的促透剂作为载体，使得药物在释放后，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。可以解决在临床使用时，药物涂层球囊置入人体后，药物向靶病变部位的渗透过慢，药物还未被血管吸收就已经被高速血流冲刷而流失的缺点，并且由于提高了被组织吸收的药量，大量药物得以被保留在血管中膜，可以持续发挥药效抑制远期再狭窄。

Description

药物涂层球囊 技术领域
本发明涉及介入医疗器械，具体涉及药物涂层球囊。
背景技术
药物涂层球囊属于介入式器械，其原理是在普通球囊表面负载活性药物，输送至血管的靶病变部位后，通过球囊的充气膨胀，使药物与血管壁充分接触，从而消除靶病变部位的远期狭窄。
除毛细血管和毛细淋巴管以外，血管壁从管腔面向外一般依次分为内膜、中膜和外膜。内膜是血管壁的最内层，由内皮和内皮下层组成。内皮细胞和基板构成通透性致密屏障，液体、气体和大分子物质可选择性地透过此屏障进入中膜。中膜的厚度及组成成分因血管种类而异。大动脉以弹性膜为主，间有少许平滑肌；中动脉主要由平滑肌组成。
因此，在药物涂层球囊介入术中，球囊表面的药物涂层在到达靶病变部位后，由球囊表面洗脱、释放至病变部位血管，其实并不能全部发挥药效。其中只有被血管内膜吸收并进入血管中膜平滑肌细胞层的药物才能发挥疗效、抑制平滑肌细胞的恶性增生及降低再狭窄率。由于血管再狭窄是一个慢性过程，被血管内膜吸收并进入血管中膜的药量越多，药物在靶病变部位血管组织停留的时间也就相应越久，抑制血管再狭窄的效果越好。而在球囊与靶病变血管接触的短短若干分钟时间内，当药物涂层自球囊表面释放至血管内壁，由于药物被血管内皮吸收的速率很慢，大量药物还未被吸收就已经被高速血流冲刷，无法保证足够量的药物透过内膜进入血管中膜抑制平滑肌细胞的恶性增生，更无法保证长期抑制血管再狭窄。
现有的药物涂层球囊会在药物涂层中加入载体和添加剂，以增加药物的溶解性，并提高药物的即刻药物释放率(即：转载率)。而这些载体和添加剂通常只能保证活性药物在球囊与病变靶血管接触的短时间内，尽可能快速大量地释放至病变部位血管壁，无法保证释放至血管内壁的药物快速被血管组织吸收，不被血液冲刷损失；另外，由于没有足量活性药物透过内膜进入血管中膜，必然没有足量药物能长时间保留在血管中膜层持续发挥药效，抑制远期血管再狭窄。
发明内容
基于此，有必要提供一种药物涂层球囊，其既能满足在很短的介入手术过程中，大量药物快速从球囊表面转移到局部靶病变部位的血管壁这一前提，更重要的是，还能加快药物被血管内皮吸收的速度，使药物不易被持续的血流冲刷流失，进而提高透过血管内膜进入血管中膜的药物总量，保证在介入手术后，仍然有足量药物长时间保留在血管中膜层持续发挥药 效，抑制远期再狭窄。
抗再狭窄药物或抗增生药物由内皮表面进入中膜的吸收过程，主要是由于内皮表面的药物浓度与血管中膜存在药物浓度差，药物通过被动扩散渗透的方式透过内膜、进入中膜平滑肌细胞层到达靶位起作用。我们发现，将促透剂作为药物载体，可以降低药物通过内皮的阻力，辅助药物快速穿过内皮、扩散、通过基板到达中膜。因此，可以通过向药物洗脱球囊或药物洗脱支架等载药器械的药物涂层中添加促透剂，使药物更快速地渗透进入内皮和基板，到达血管中膜并发挥抑制平滑肌细胞增生的作用。
本发明提供一种药物涂层球囊，包括球囊本体和覆盖在所述球囊本体表面的药物涂层。所述药物涂层含有活性药物和载体。所述活性药物包括抗再狭窄药物或抗增生药物。所述载体包括促透剂。当所述药物涂层球囊被置入人体，药物涂层与血管壁挤压接触后，活性药物在置入靶位点释放并转移至血管内壁。药物涂层中的促透剂载体作用于血管内皮细胞，改变内皮细胞的结构，影响内皮细胞的通透性，加速药物穿透病变部位的血管内膜并向中膜渗透扩散，从而使药物更快速地被组织吸收，并且增加被组织吸收的总药量，有利于药物长时间保留在血管中膜层持续发挥药效。
在其中一个实施例中，所述活性药物与所述载体的质量比范围为(0.5～49)∶1。
在其中一个实施例中，所述载体还包括分散剂。由于亲脂性的抗再狭窄药物或抗增生性药物容易相互聚集，而亲水亲脂性的分散剂可以快速与亲脂性药物结合，间隔药物颗粒，从而降低了药物分子间团聚的机率，提高了涂层均匀性。其次，加入分散剂后，能提高药物涂层颗粒的细度，减小药物颗粒的尺寸，小尺寸的药物更易被吸收。另外，与分散剂结合的药物分子其比表面积增大，溶解度提高，与血管亲脂结构接触后的吸附能力提高，有助于药物涂层从球囊表面向血管壁的转移。另外，分散剂与亲脂性药物结合后，在球囊输送过程中对亲脂性药物形成保护，有利于药物涂层与球囊本体表面的粘附，降低药物涂层在输送过程中的损失，保证扩张贴壁前球囊具有充足的药物向组织转载。因此，当分散剂与促透剂协同作用，不仅能加快药物的释放过程并促进药物在内皮表面的渗透吸收，同时能减少球囊表面的药物涂层在输送过程的微粒脱落和过程损失，进而获得更好的治疗效果。
在其中一个实施例中，所述分散剂和所述促透剂的质量比范围为(0.01～50)∶1。
在其中一个实施例中，所述抗增生药物选自紫杉醇、紫杉醇衍生物、雷帕霉素或雷帕霉素衍生物中的至少一种。
在其中一个实施例中，所述促透剂选自醇类化合物及其衍生物、脂肪酸及其衍生物、芳香酸及其衍生物中的至少一种。不同于常规的透皮贴剂或其他经皮肤给药的药剂中使用的促 透剂，由于血管壁的组成与皮肤不同，血管内的生理环境也与经皮给药的环境不同，适合作为血管植入类或介入类医疗器械药物涂层的促透剂应当克服血液酸碱度，血流持续冲刷的血液动力学环境的影响，并且不能与血液中其他物质相互作用。
在其中一个实施例中，所述醇类化合物选自脂肪醇或多元醇，所述脂肪醇选自辛醇、癸醇、月桂醇、肉豆蔻醇、棕榈醇、硬脂醇、花生醇或二十二醇。所述多元醇选自丙二醇、甘油或聚乙二醇。
在其中一个实施例中，所述脂肪酸选自辛酸、癸酸、月桂酸、豆蔻酸、软脂酸、硬脂酸、花生酸、软油酸、油酸、亚油酸、亚麻酸或花生四烯酸。
在其中一个实施例中，所述芳香酸选自苯甲酸、苯乙酸、丁香酸、肉桂酸、邻羟基苯甲酸、对羟基苯甲酸、对氨基苯甲酸、对氨甲基苯甲酸、对氨基水杨酸或邻苯二甲酸。
在其中一个实施例中，所述衍生物包括酯类、酰胺类、酸酐类或盐类；所述盐类包括镁盐、钠盐、锌盐、钙盐、钡盐或铜盐。
在其中一个实施例中，所述促透剂选自月桂醇、肉豆蔻醇、硬脂醇、月桂酸、棕榈酸、硬脂酸、硬脂酸镁、硬脂酸钠、硬脂酸锌、硬脂酰胺、棕榈酸异辛酯、亚油酸、亚麻酸、单油酸甘油酯、硬脂酸聚氧乙烯酯、苯甲酸钠、肉桂酸、邻羟基苯甲酸、对羟基苯甲酸、对氨基水杨酸或邻苯二甲酸酐中的至少一种。
在其中一个实施例中，所述分散剂选自乙酸盐、马来酸盐、聚乙烯吡咯烷酮、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、聚乙二醇1000、聚乙二醇2000、乙酰胺、泊洛沙姆、季戊四醇、谷氨酸盐、香草酸盐、羟丙基甲基纤维素或乳糖酸盐中的至少一种。
在其中一个实施例中，所述活性药物在所述球囊本体表面的含量范围为0.5～20μg/mm2。
在其中一个实施例中，所述药物涂层球囊用于将所述活性药物输送到血管或管腔内。所述血管包括冠状动脉血管、外周动脉血管或脑动脉血管。所述管腔包括食道、气道、肠道、胆道、宫颈、泌尿道、前列腺或脑通道。所述外周动脉血管包括腿部动脉，进一步地，包括髂动脉、髂外动脉、股动脉或腘动脉。
本发明与现有技术相比，至少具有以下优点和有益效果：
(1)本发明的药物涂层球囊的药物涂层中含有促透剂，药物自球囊表面释放至血管壁后，能快速被血管组织吸收，克服了大量药物在被血管组织吸收前就被高速流动的血流冲刷损失的缺点；
(2)药物在促透剂的作用下，更快速地透过内膜到达中膜，因此被组织吸收的药量更 高，足量药物长时间保留在血管中膜层，可以延长药物的持续作用时间，保证药物能持续发挥最大疗效抑制远期再狭窄。
附图说明
图1为本发明实施例1至7及对比例1的药物涂层球囊置入健康小型猪体内扩张后，球囊扩张段靶血管的血管中膜药物释放曲线；
图2为本发明实施例1提供的药物涂层球囊置入健康小型猪体内扩张后，28天后药物涂层球囊周围组织的病理切片H&E染色图；
图3为本发明实施例1提供的药物涂层球囊置入健康小型猪体内扩张后，28天后药物涂层球囊周围组织的病理切片α-actin染色图；
图4为本发明实施例1提供的药物涂层球囊置入健康小型猪体内扩张后，28天后药物涂层球囊周围组织的病理切片Masso三色染色图；
图5为本发明实施例1提供的药物涂层球囊置入健康小型猪体内扩张后，28天后药物涂层球囊周围组织的病理切片Movat染色图；
图6为本发明实施例1提供的药物涂层球囊经体外模拟测试后的微粒脱落显微照片；
图7为本发明实施例2提供的药物涂层球囊经体外模拟测试后的微粒脱落显微照片；
图8为本发明实施例3提供的药物涂层球囊经体外模拟测试后的微粒脱落显微照片；
图9为本发明实施例4提供的药物涂层球囊经体外模拟测试后的微粒脱落显微照片；
图10为本发明实施例5提供的药物涂层球囊经体外模拟测试后的微粒脱落显微照片；
图11为本发明实施例6提供的药物涂层球囊经体外模拟测试后的微粒脱落显微照片；
图12为本发明实施例7提供的药物涂层球囊经体外模拟测试后的微粒脱落显微照片；
图13为对比例1的药物涂层球囊经体外模拟测试后的微粒脱落显微照片。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白，以下结合附图及实施例，对本发明进行进一步详细说明。应当理解，此处所描述的具体实施例仅仅用以解释本发明，并不用于限定本发明。
除非另有定义，本发明所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本发明在说明书中所使用的术语只是为了描述具体的实施例的目的，不是旨在于限制本发明。
实施例1
将11mg紫杉醇作为活性药物，17mg月桂酸作为促透剂，5mg羟丙基甲基纤维素作为分 散剂，与7mL乙醇和4mL纯化水混合配制药物溶液。将PTA球囊导管(尺寸为：直径4mm，长40mm)的球囊在万级洁净环境中折翼为三折后，在百级洁净环境下，将药物溶液用精密注射器滴涂到折翼后的球囊的表面上并干燥，重复滴涂直至球囊表面的药物浓度达到3μg/mm2，室温干燥24小时后，包装，环氧乙烷灭菌，得到本实施例的药物涂层球囊。本实施例中载体总重量为22mg，活性药物和载体的质量比为0.5，载体中分散剂和促透剂的质量比为0.29。
实施例2
将495mg紫杉醇作为活性药物，10mg棕榈酸异辛酯作为促透剂，0.1mg柠檬酸钠作为分散剂，与20mL异丙醇混合配制药物溶液。将PTA球囊导管(直径4mm，长40mm)的球囊在万级洁净环境中折翼为三折后，在百级洁净环境下，将药物溶液滴涂到折翼后的球囊的表面上并干燥，重复滴涂直至所述球囊表面的药物浓度达到0.5μg/mm2，室温干燥24小时后，包装，环氧乙烷灭菌，得到本实施例的药物涂层球囊。本实施例中载体总重量为10.1mg，活性药物和载体的质量比为49，载体中分散剂和促透剂的质量比为0.01。
实施例3
将120mg紫杉醇作为活性药物，36mg苯甲酸钠作为促透剂，与10mL乙醇和4mL纯化水混合配制药物溶液。将PTA球囊导管(直径4mm，长40mm)的球囊在万级洁净环境中折翼为三折后，在百级洁净环境下，将药物溶液用喷涂设备喷涂至折翼后的球囊表面，使球囊表面的药物浓度达到2μg/mm2，室温干燥24小时后，包装，环氧乙烷灭菌，得到本实施例的药物涂层球囊。本实施例中活性药物和载体的质量比为3.33。
实施例4
将100mg紫杉醇作为活性药物，50mg硬脂酸镁作为促透剂，5mg聚乙二醇1000作为分散剂，与10mL乙醇和4mL纯化水混合配制药物溶液。将PTA球囊导管(直径4mm，长40mm)的球囊在万级洁净环境中折翼为三折后，在百级洁净环境下，将药物溶液用喷涂设备喷涂到折翼后的球囊表面上，使球囊表面药物浓度达到3μg/mm2，室温干燥24小时后，包装，环氧乙烷灭菌，得到本实施例的药物涂层球囊。本实施例中载体总重量为55mg，活性药物和载体的质量比为1.82，载体中分散剂和促透剂的质量比为0.1。
实施例5
将120mg紫杉醇作为活性药物，3mg月桂醇作为促透剂，9mg乙酰胺作为分散剂，与2mL乙醇和0.4mL纯化水混合配制药物溶液。将PTA球囊导管(直径4mm，长40mm)的球囊在万级洁净环境中折翼为三折后，在百级洁净环境下，将药物溶液用喷涂设备喷涂到折翼后的球 囊表面上，使球囊表面的药物浓度达到2.5μg/mm2，室温干燥24小时后，包装，环氧乙烷灭菌，得到本实施例的药物涂层球囊。本实施例中载体总重量为12mg，活性药物和载体的质量比为10，载体中分散剂和促透剂的质量比为3。
实施例6
将12mg紫杉醇作为活性药物，1mg硬脂醇作为促透剂，5mg聚乙烯吡咯烷酮作为分散剂，与100mL异丙醇和20mL纯化水混合配制药物溶液。将PTCA球囊导管(直径3mm，长20mm)的球囊在万级洁净环境中折翼为三折后，在百级洁净环境下，将药物溶液用喷涂设备喷涂到折翼后的球囊表面上，使球囊表面药物浓度达到1.5μg/mm2，室温干燥24小时后，包装，环氧乙烷灭菌，得到本实施例的药物涂层球囊。本实施例中载体总重量为6mg，活性药物和载体的质量比为2，载体中分散剂和促透剂的质量比为5。
实施例7
将20mg紫杉醇作为活性药物，0.5mg硬脂酰胺作为促透剂，25mg聚乙二醇2000作为分散剂，与10mL乙醇和5mL纯化水混合配制药物溶液。将PTA球囊导管(直径4mm，长40mm)的球囊在万级洁净环境中折翼为三折后，在百级洁净环境下，将药物溶液用喷涂设备喷涂到折翼后的球囊表面上，使球囊表面的药物浓度达到5μg/mm2，室温干燥24小时后，包装，环氧乙烷灭菌，得到本实施例的药物涂层球囊。本实施例中载体总重量为25.5mg，活性药物和载体的质量比为0.78，载体中分散剂和促透剂的质量比为50。
实施例8
将120mg雷帕霉素作为活性药物，4mg单油酸甘油酯作为促透剂，24mg泊洛沙姆作为分散剂，与2mL乙醇和10mL纯化水混合配制药物溶液。将PTA球囊导管(直径5mm，长80mm)的球囊在万级洁净环境中折翼为五折后，在百级洁净环境下，将药物溶液用喷涂设备喷涂到折翼后的球囊表面上，使球囊表面的药物浓度达到10μg/mm2，室温干燥24小时后，包装，环氧乙烷灭菌，得到本实施例的药物涂层球囊。本实施例中载体总重量为28mg，活性药物和载体的质量比为4.29，载体中分散剂和促透剂的质量比为6。
实施例9
将210mg雷帕霉素作为活性药物，2mg硬酯酸聚氧乙烯酯作为促透剂，40mg季戊四醇作为分散剂，与45mL乙醇和5mL纯化水混合配制药物溶液。将PTA球囊导管(直径7mm，长120mm)的球囊在万级洁净环境中折翼为五折后，在百级洁净环境下，将药物溶液用喷涂设备喷涂到折翼后的球囊表面上，使球囊表面的药物浓度达到20μg/mm2，室温干燥24小时后，包装，环氧乙烷灭菌，得到本实施例的药物涂层球囊。本实施例中载体总重量为42mg，活 性药物和载体的质量比为5，载体中分散剂和促透剂的质量比为20。
实施例10
将10mg雷帕霉素作为活性药物，2mg硬酯酸镁作为促透剂，与20mL乙醇混合配制药物溶液。将PTCA球囊导管(直径2.5mm，长18mm)的球囊在万级洁净环境中折翼为三折后，在百级洁净环境下，将药物溶液用喷涂设备喷涂到折翼后的球囊表面上，使球囊表面的药物浓度达到3.5μg/mm2，室温干燥24小时后，包装，环氧乙烷灭菌，得到本实施例的药物涂层球囊。本实施例中载体总重量为2mg，活性药物和载体的质量比为5。
对比例1
将50mg紫杉醇作为活性药物，20mg碘普罗胺作为载体，与5mL乙醇混合配制药物溶液。将PTA球囊导管(直径4mm，长40mm)的球囊在万级洁净环境中折翼为三折后，在百级洁净环境下，将药物溶液用喷涂设备喷涂到折翼后的球囊表面上，使球囊表面的药物浓度为3μg/mm2，室温干燥24小时，包装，环氧乙烷灭菌，得到对比例1的药物涂层球囊。对比例1中紫杉醇活性药物和载体的质量比为2.5。
药物释放试验
将实施例1至7和对比例1提供的药物涂层球囊分别置入健康小型猪体内，于髂外动脉血管处进行充压扩张，撤出药物涂层球囊，完成球囊扩张手术，并分别在30min、24h、7天和28天时随访。随访时，先游离出球囊扩张手术时药物涂层球囊周围的靶血管，用含肝素的0.1mol/L PBS溶液(每1000mlPBS含肝素25000单位)慢速冲洗靶血管3次，将靶血管的三层结构剥脱分离，再归集后分别得到内膜、中膜和外膜。利用液相色谱-质谱联用仪(简称：LC-MS/MS)测量球囊扩张段靶血管的中膜组织内的药物含量。LC-MS/MS的测试条件为：
液相色谱仪器：Agilent 1200型液相色谱系统(安捷伦公司)，含G1312A型四元输液泵，G1322A型真空脱气机；
质谱仪器：API4000 QTRAP型三重四极杆串联质谱仪(AB Sciex公司)，配备电喷雾电离源(简称：ESI)；
分析柱：VenusilXBP C8色谱柱(博纳艾杰尔科技公司)，尺寸：2.1×50mm，5μm；
流动相条件：A相(含有0.1％甲酸水溶液)、B相(含有0.1％甲酸乙腈溶液)，梯度洗脱；
柱温：30℃；
质谱条件：ESI正离子检测模式。
以四个随访时间点作为横坐标，每个时间点测得的靶血管中膜的药物含量作为纵坐标，分别绘制实施例1至7和对比例1的靶血管中膜的药物释放曲线，如图1所示。该曲线反映了药 物被靶血管组织吸收及药物在靶血管中膜组织内的保留行为。
请参阅图1，结果表明：与对比例1相比，30min时，实施例1至7的药物涂层球囊的药物涂层，具备较高的被靶血管组织吸收的能力。24h时，实施例1至7的靶血管中膜组织的药物含量迅速增加，而对比例1的药物涂层球囊，24h时药物含量并未增加，说明本发明实施例1至7的药物球囊的药物涂层在促透剂的作用下，快速地渗透进入靶血管中膜。而对比例1的药物涂层较难透过靶血管内膜的生物屏障，其在初始时刻经过瞬时扩张挤压，只能依靠固有的浓度差使少量药物透过内膜；而在之后的时间里，药物不再进入靶血管中膜，已经进入靶血管中膜的少量药物逐渐消耗，导致靶血管中膜的药物含量呈现单调递减的规律。这进一步证明了本发明中加入促透剂的显著作用。在7天和28天的长时间随访时，实施例1至7的靶血管中膜的药物含量不再增加，说明在24h和7天之间，药物向靶血管中膜渗透吸收和靶血管中膜对药物的代谢利用达到平衡，7天之后，靶血管中膜的总药量逐渐降低。而对比例1在7天随访时靶血管中膜的药量已经很少，28天随访时的药量基本为零。
由图1可以看出，无论扩张瞬时的药物转载量大小，随着时间的推移，实施例1至7的药物能够快速吸收并进入靶血管壁内，并在24h时开始逐渐增加，且维持较长的时间。这种优异的药物保留能力，使得即使是较低的初始转载，在远期也具备较高的药物浓度。说明实施例1至7的药物涂层球囊，能够在预定时间内向病灶局部释放出活性成分，充分发挥药物的治疗作用，延长药物作用时间，提高药物的生物可利用度。
并且，由于在同样的扩张时间内，本发明实施例1至7提供的药物涂层球囊被血管组织吸收的药量大于对比例1的提供的药物涂层球囊被血管组织吸收的药量，也减少了被血流冲刷损失的药量，在需要达到同样质量效果时，本发明提供的药物涂层球囊可以降低药物涂层中的活性药物给药剂量，减轻了药物对病变部位及其他器官的危害，控制了药物毒副作用。
组织病理学研究
将实施例1至6和对比例1提供的药物涂层球囊分别置入健康小型猪体内，于髂外动脉血管处充压扩张，撤出药物涂层球囊，完成球囊扩张手术，并分别在术后28天随访。随访时，先游离出球囊扩张手术时药物涂层球囊周围的靶血管，用含肝素的0.1mol/L PBS溶液(每1000mlPBS含肝素25000单位)慢速冲洗靶血管3次。将靶血管处的分支血管用细线结扎，在靶血管近远两端各保留1cm，灌注福尔马林后再结扎固定，制作多个石蜡包埋组织切片用于组织病理学分析。
以实施例1为例，详细说明组织病理学分析方法，具体包括如下步骤：先对实施例1的靶血管多个组织切片分别进行H&E染色、α-actin染色、Masso三色染色及Movat染色，分别得到 图2至图5的染色图。分别根据图2至图5的染色图中的炎症细胞、Masso三色染色中的蓝色面积及壁厚丢失进行打分，以考察炎性反应、胶原纤维蛋白沉积和中膜平滑肌丢失情况。
考察原理是当药物涂层球囊的药物作用于组织，对平滑肌细胞增生产生抑制作用，同时启动炎性修复反应，在丢失平滑肌细胞部位产生胶原纤维蛋白沉积。
三项考察指数各自的打分标准如下：
a、炎性反应打分标准
炎症积分计算参考文献标准分为4级。多次观测计算平均值。
0分：在中膜和内膜周围没有炎症细胞(淋巴细胞、嗜酸性粒细胞、巨噬细胞等)。
1分：在中膜和内膜周围有少量的炎症细胞浸润。
2分：在内膜、中膜和外膜有中等量的炎症细胞浸润，占25～50％血管面积。
3分：在内膜、中膜和外膜有大量的炎症细胞，环绕整个血管，占据50％以上血管面积。
b、胶原纤维蛋白沉积打分标准
0分：没有任何丢失。
1分：三色染色中的蓝色面积＜25％。
2分：三色染色中的蓝色面积为25～50％。
3分：三色染色中的蓝色面积为51～75％。
4分：三色染色中的蓝色面积为＞75％。
c、中膜平滑肌丢失打分标准
0分：没有任何丢失。
1分：＜25％的壁厚丢失。
2分：25～50％的壁厚丢失。
3分：51～75％的壁厚丢失。
4分：＞75％的壁厚丢失。
对实施例2至6以及对比例1的组织切片进行相同的组织病理学分析，在此不再赘述。
实施例1至6与对比例1的药物涂层球囊组织病理学分析结果见下表1。
表1 药物涂层球囊治疗后28天的组织病理学积分结果
编号 炎性积分 中膜平滑肌丢失 纤维蛋白沉积
实施例1 1.29±0.64 3.00±0.88 3.21±0.70
实施例2 1.21±0.58 3.36±084 3.64±0.50
实施例3 1.36±0.5 2.56±0.5 3.31±0.48
实施例4 1.93±0.92 3.25±0.45 3.50±0.52
实施例5 1.31±0.63 2.36±0.30 3.36±0.41
实施例6 1.15±0.8 3.31±0.48 3.33±0.49
对比例1 0.46±0.66 1.07±0.27 1.00±0.00
结果表明：实施例1至6的药物涂层球囊与对比例1的药物涂层球囊相比，其对周边血管组织的影响有显著差异。
首先，实施例1至6的炎性积分较高，内膜、中膜和外膜有中等量的炎症细胞浸润，说明周围靶血管组织对实施例1至6的药物涂层中的药物产生反应的时间更快，即药物作用到血管组织的时间更快。其次，实施例1至6的中膜平滑肌丢失和纤维蛋白沉积较高，说明药物对平滑肌细胞产生抑制作用的启动时间更快。
上述差异进一步证明，由于实施例1至6提供的药物涂层球囊的涂层中含有促透剂，其可以促进药物吸收进入血管中膜，加快药物的作用时间，减少了被血流冲刷损失的药量，保证了血管组织内的远期药物含量。
体外模拟微粒脱落测试
通过体外模拟测试，检测实施例1至7及对比例1提供的药物涂层球囊在输送过程中的微粒脱落情况。测试方法如下：以温度为37℃、流量为250mL/min的纯化水模拟血流，适宜尺寸规格的硅胶管模拟血管，模拟手术过程。分别输送实施例1至7及对比例1的药物涂层球囊至靶位点，扩张球囊使其挤压模拟血管，球囊表面的药物涂层被洗脱，微粒脱落并随模拟血流被冲刷至模拟血管远端。
通过微粒检测仪检测模拟血管远端的微粒大小和数量，结果如表2所示。并通过显微照片，测量＞100μm的大尺寸微粒的具体尺寸及形貌。实施例1至7的微粒脱落显微照片分别如图6至12所示，对比例1的微粒脱落显微照片如图13所示。
表2 体外模拟微粒脱落测试结果
Figure PCTCN2017099022-appb-000001
由表2可知：与对比例1相比，实施例1至7的药物涂层球囊在模拟血管经过输送及扩张过程后，各尺寸范围脱落的微粒数量更少，脱落微粒的最大粒径尺寸更小，即微粒脱落水平优 于对比例1。
由此说明，实施例1至7的药物涂层中添加的分散剂具有很好的分散能力，可以降低药物涂层球囊使用过程中脱落的微粒尺寸及数量。原理是，分散剂具有间隔作用，可以提高药物涂层颗粒的细度，使涂层分布均匀。防止药物在药物球囊被置入到靶位点之前过早释放。
体外模拟输送过程损失测试
用离体猪冠脉血管模拟人体冠状动脉系统的靶血管，在体外模拟血管模型中进行体外模拟输送过程损失测试。考察在药物涂层球囊经输送鞘管输送至靶位点的过程中的药量损失。
分别将实施例1至7和对比例1制备的药物涂层球囊插入体外模拟血管模型中。在体外模拟血管模型中漂浮90秒，然后取出药物涂层球囊，分别利用高效液相色谱(简称：HPLC)分析药物涂层球囊上残余的药物，并按下式计算输送过程药物损失率：
输送过程药物损失率＝(球囊表面初始负载的药物含量-残余的药物含量)/球囊表面初始负载的药物含量×100％。
HPLC测试条件为：
仪器：日本岛津LC-20A型高效液相色谱仪；
色谱柱：Agilent ZORBAX SB-C18色谱柱，尺寸：4.6×250mm，5μm；
流动相：甲醇∶乙腈∶水＝230∶360∶410；
柱温：30℃；
检测器：紫外可见检测器，检测波长227nm；
流速：1.0mL/min。
HPLC测定结果如表3所示：
表3 体外模拟输送过程损失测试结果
Figure PCTCN2017099022-appb-000002
表3结果表明：与对比例1相比，本发明实施例1至7提供的药物涂层球囊在输送至靶位点的过程中，药物在模拟血管系统中的损失减少。说明本发明的药物涂层中添加的促透剂不仅 没有影响药物涂层与球囊的结合力，还可以作为亲和剂，增强球囊表面与药物涂层之间的结合力。同时，由于分散剂降低了药物涂层颗粒的细度，因此二者协同作用，进一步增加了球囊表面与药物涂层之间的结合力，提高了输送过程中，药物涂层抵御弯曲路径及摩擦力的影响的能力。
综上，本发明提供的药物涂层球囊，药物涂层中包括促透剂。当药物涂层球囊被置入人体，球囊扩张贴壁后，活性药物在置入靶位点释放并转移至血管内壁。此时，药物涂层中的促透剂载体作用于血管内皮细胞，改变内皮细胞的结构，影响内皮细胞的通透性，加速药物穿透病变部位的血管内膜并向中膜渗透扩散，从而使药物更快速地被组织吸收，并且增加被组织吸收的总药量，有利于药物长时间保留在血管中膜层持续发挥药效。并且，在需要达到同样质量效果时，本发明提供的药物涂层球囊可以降低药物涂层中的活性药物给药剂量，减轻了药物对病变部位及其他器官的危害，控制了药物毒副作用。
本发明通过选择适当促透剂的种类及其与活性药物的比例，不仅可以促进活性药物从血管内膜快速渗透进入血管中膜，同时不影响药物涂层的其他性能，减少输送及扩张过程的微粒脱落和过程损失率等。本发明提供的药物涂层球囊中，活性药物与载体的质量比范围为(0.5～49)∶1。当活性药物与载体的质量比太大，大量的活性药物不能与球囊本体表面牢固结合，药物涂层的牢固性降低，输送过程损失较大；而载体也不能发挥促进药物吸收的效果，被血管组织吸收的药量较低，影响抑制远期再狭窄的效果。当活性药物与载体的质量比太小，活性药物含量过低，又会影响药物涂层的有效性。
本发明提供的药物涂层球囊，药物涂层的载体中还可以包括分散剂，由于载体中的促透剂与分散剂产生协同作用，在保证药物涂层的转载率的前提下，不仅能促进药物在内皮表面的渗透吸收，提高进入血管中膜的药量，同时能减少球囊表面的药物涂层在输送过程的微粒脱落和过程损失，进而获得更好的治疗效果。
本发明提供的药物涂层球囊，载体中分散剂和促透剂的质量比范围为(0.01～50)∶1。此范围能同时兼顾药物涂层的分散性能和促吸收性能。当分散剂用量过大，为了不影响活性药物与载体的质量比，载体中促透剂用量会相应减少，无法达到促进活性药物向血管中膜渗透吸收的作用。当分散剂用量过小，活性药物可能发生团聚，形成较多的大颗粒，导致血栓；且为了不影响活性药物与载体的质量比，促透剂用量会相应增大，导致药物涂层的牢固度降低，增加输送过程损失，降低即刻药物转载率。
本发明提供的药物涂层球囊可以用于将活性药物输送到人体内的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。所述血管包括冠状动脉血管、外周动脉血 管或脑动脉血管。所述管腔包括食道、气道、肠道、胆道、宫颈、泌尿道或前列腺。所述外周动脉血管包括腿部动脉，进一步地，包括髂动脉、髂外动脉、股动脉或腘动脉。
需要说明的是，尽管在实施例1至10中，仅以PTA球囊或PTCA球囊对本发明的具体实施方式作了示意性说明，本发明提供的技术方案也可以用于其它介入式载药医疗器械或植入式载药医疗器械。例如支架、封堵器、骨科植入物、齿科植入物、缝合线或螺栓。所述支架包括血管支架、气管支架、食道支架、尿道支架、肠道支架或胆道支架。所述骨科植入物包括固定螺钉、固定铆钉或骨板。只要向药物涂层中加入促透剂，将之与所述介入式载药医疗器械或植入式载药医疗器械表面接触或填充在其内部，即可促进药物被人体组织吸收，降低被血流冲刷流失的药量、提高被人体组织吸收的药量，提高介入式载药医疗器械或植入式载药医疗器械的临床治疗效果。
以上结合附图对本发明的实施方式进行了描述，但是本发明并不局限于上述的具体实施方式，上述的具体实施方式仅仅是示意性的，而不是限制性的，本领域的普通技术人员在本发明的启示下，在不脱离本发明宗旨和权利要求所保护的范围情况下，还可做出很多形式，这些均属于本发明的保护之内。

Claims (14)

  1. 一种药物涂层球囊，包括球囊本体和覆盖在所述球囊本体表面的药物涂层，所述药物涂层含有活性药物和载体，所述活性药物包括抗增生药物，其特征在于，所述载体包括促透剂。
  2. 根据权利要求1所述的药物涂层球囊，其特征在于，所述活性药物与所述载体的质量比范围为(0.5～49)∶1。
  3. 根据权利要求1所述的药物涂层球囊，其特征在于，所述载体还包括分散剂。
  4. 根据权利要求3所述的药物涂层球囊，其特征在于，所述分散剂和所述促透剂的质量比范围为(0.01～50)∶1。
  5. 根据权利要求1所述的药物涂层球囊，其特征在于，所述抗增生药物选自紫杉醇、雷帕霉素、紫杉醇衍生物或雷帕霉素衍生物中的至少一种。
  6. 根据权利要求1所述的药物涂层球囊，其特征在于，所述促透剂选自醇类化合物及其衍生物、脂肪酸及其衍生物、芳香酸及其衍生物中的至少一种。
  7. 根据权利要求6所述的药物涂层球囊，其特征在于，所述醇类化合物选自脂肪醇或多元醇，所述脂肪醇选自辛醇、癸醇、月桂醇、肉豆蔻醇、棕榈醇、硬脂醇、花生醇或二十二醇，所述多元醇选自丙二醇、甘油或聚乙二醇。
  8. 根据权利要求6所述的药物涂层球囊，其特征在于，所述脂肪酸选自辛酸、癸酸、月桂酸、豆蔻酸、软脂酸、硬脂酸、花生酸、软油酸、油酸、亚油酸、亚麻酸或花生四烯酸。
  9. 根据权利要求6所述的药物涂层球囊，其特征在于，所述芳香酸选自苯甲酸、苯乙酸、丁香酸、肉桂酸、邻羟基苯甲酸、对羟基苯甲酸、对氨基苯甲酸、对氨甲基苯甲酸、对氨基水杨酸或邻苯二甲酸。
  10. 根据权利要求6所述的药物涂层球囊，其特征在于，所述衍生物包括酯类、酰胺类、酸酐类或盐类；所述盐类包括镁盐、钠盐、锌盐、钙盐、钡盐或铜盐。
  11. 根据权利要求1所述的药物涂层球囊，其特征在于，所述促透剂选自月桂醇、肉豆蔻醇、硬脂醇、月桂酸、棕榈酸、硬脂酸、硬脂酸镁、硬脂酸钠、硬脂酸锌、硬脂酰胺、棕榈酸异辛酯、亚油酸、亚麻酸、单油酸甘油酯、硬脂酸聚氧乙烯酯、苯甲酸钠、肉桂酸、邻羟基苯甲酸、对羟基苯甲酸、对氨基水杨酸或邻苯二甲酸酐中的至少一种。
  12. 根据权利要求3所述的药物涂层球囊，其特征在于，所述分散剂选自乙酸盐、马来酸盐、聚乙烯吡咯烷酮、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、聚乙二醇1000、聚乙二醇2000、乙酰胺、泊洛沙姆、季戊四醇、谷氨酸盐、香草酸盐、羟丙基甲基纤维素或乳糖酸盐中的至少一种。
  13. 根据权利要求1所述的药物涂层球囊，其特征在于，所述活性药物在所述球囊本体表面的含量范围为0.5～20μg/mm2。
  14. 权利要求1至13任一项所述的药物涂层球囊在将所述活性药物输送到血管或管腔内中的应用，所述血管包括冠状动脉血管、外周动脉血管或脑动脉血管；所述管腔包括食道、气道、肠道、胆道、宫颈、泌尿道或前列腺；所述外周动脉血管包括腿部动脉，进一步地，包括髂动脉、髂外动脉、股动脉或腘动脉。
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