WO2019019043A1 - 一种表面液化药物涂层球囊 - Google Patents

一种表面液化药物涂层球囊 Download PDF

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WO2019019043A1
WO2019019043A1 PCT/CN2017/094445 CN2017094445W WO2019019043A1 WO 2019019043 A1 WO2019019043 A1 WO 2019019043A1 CN 2017094445 W CN2017094445 W CN 2017094445W WO 2019019043 A1 WO2019019043 A1 WO 2019019043A1
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Prior art keywords
drug
balloon
coating
triglyceride
total weight
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PCT/CN2017/094445
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English (en)
French (fr)
Inventor
翁玉麟
石全
刘宝瑞
谷卓阳
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鼎科医疗技术（苏州）有限公司
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Priority to US16/634,031 priority Critical patent/US11931536B2/en
Priority to CN201780001253.2A priority patent/CN107995869B/zh
Priority to PCT/CN2017/094445 priority patent/WO2019019043A1/zh
Priority to JP2020503755A priority patent/JP7005742B2/ja
Publication of WO2019019043A1 publication Critical patent/WO2019019043A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • 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
    • A61M25/1027—Making of balloon catheters
    • A61M25/1029—Production methods of the balloon members, e.g. blow-moulding, extruding, deposition or by wrapping a plurality of layers of balloon material around a mandril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • 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
    • A61M25/104—Balloon catheters used for angioplasty
    • 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
    • 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
    • A61M25/1002—Balloon catheters characterised by balloon shape
    • A61M2025/1004—Balloons with folds, e.g. folded or multifolded
    • 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
    • A61M25/1027—Making of balloon catheters
    • A61M25/1029—Production methods of the balloon members, e.g. blow-moulding, extruding, deposition or by wrapping a plurality of layers of balloon material around a mandril
    • A61M2025/1031—Surface processing of balloon members, e.g. coating or deposition; Mounting additional parts onto the balloon member's surface
    • 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
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05D—PROCESSES FOR APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05D1/00—Processes for applying liquids or other fluent materials
    • B05D1/02—Processes for applying liquids or other fluent materials performed by spraying
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05D—PROCESSES FOR APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05D2254/00—Tubes
    • B05D2254/02—Applying the material on the exterior of the tube
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05D—PROCESSES FOR APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05D7/00—Processes, other than flocking, specially adapted for applying liquids or other fluent materials to particular surfaces or for applying particular liquids or other fluent materials
    • B05D7/02—Processes, other than flocking, specially adapted for applying liquids or other fluent materials to particular surfaces or for applying particular liquids or other fluent materials to macromolecular substances, e.g. rubber

Definitions

  • the present invention relates to a surface liquefied drug coated balloon, a process for its preparation and its use for treating intravascular stenosis, including coronary arteries and peripheral blood vessels.
  • Atherosclerosis is a chronic inflammatory response in the arterial wall, primarily due to accumulation of blood cells and the formation of plaque on the arterial wall by low-density lipoprotein. Atherosclerosis is the most common and most dangerous disease, often leading to thrombosis, vascular stenosis, blood supply disorders, etc., which in turn affect other functions of the body.
  • Angioplasty is a vascular intervention technique involving mechanical widening of obstructed blood vessels, usually caused by atherosclerosis.
  • a catheter having a tightly folded balloon is typically inserted into the patient's vasculature and sent to a lesion site where a certain pressure is used to inflate the balloon.
  • the balloon can expand to a certain diameter and length.
  • PCI Percutaneous coronary intervention
  • PTA Percutaneous transluminal angioplasty
  • Balloon catheters are the most commonly used instruments for PCI surgery.
  • the balloon catheter has a balloon and a catheter tube, and the balloon is connected to the catheter tube at the distal end of the tube body.
  • the user of the balloon catheter enters the balloon at the site of the intravascular stenosis and expands to treat the site.
  • the drug-coated balloon catheter is coated with a layer of drug on the balloon surface of the balloon catheter and can be used to treat intravascular stenosis, including coronary and peripheral blood vessels. It can evenly spread the drug to the diseased blood vessels, and does not leave implants such as stents in the human body, providing a window for secondary treatment.
  • the coronary drug-coated balloon generally has a swelling time of no more than 1 minute during use. The drug must be effectively transferred from the balloon surface to the vessel wall within one minute.
  • the drug balloon loses the drug content on the surface of the balloon due to the scouring of the blood, which further affects the transfer of the drug from the surface of the balloon to the lesion site.
  • Chinese patent application CN201010121627.4 designed the outer surface of the balloon to be non-planar with irregularities The structure increases the amount of adsorbed drugs, and at the same time keeps the drug adsorbed on the outer wall of the balloon as much as possible without being washed away by the blood in the blood vessel, but damages the balloon and affects its rated burst pressure;
  • Chinese patent application CN201110176942.1 describes a method for preparing a drug balloon by electrostatic self-assembly, which is covered by a drug coating of a different material by a self-assembly method. Due to the high number of cycles, the amount of drug can be superimposed by layers. However, due to the gradual decrease of surface charge after three times, the amount of drug and binding force of the outer layer assembly tends to decrease.
  • a plasma etching method is used to form a nano-scale microporous structure on the surface of the balloon to improve the binding force between the balloon surface and the drug coating, increase the drug loading amount and avoid loss during drug delivery.
  • plasma etching has an effect on the performance of the balloon, which reduces its burst pressure.
  • the present invention has been proposed to reduce the loss of the drug during the delivery process and to improve the efficiency of the drug from the balloon surface to the lesion site.
  • the present invention has now surprisingly and unexpectedly discovered that a certain proportion of lipophilic excipients and drugs are mixed, dissolved in a solvent and applied to the surface of the balloon to form a liquefied drug coating on the surface of the balloon.
  • the excipients employed in the present invention are lipophilic as compared to the prior art, and the coating on the surface of the balloon is liquefied rather than the current conventional solid coating.
  • the invention intends to form a liquefied drug coating with a certain viscosity on the surface of the balloon, which can reduce the drug loss on the one hand and improve the efficiency of drug transfer to the lesion on the other hand.
  • a lipophilic excipient, a drug, and a solvent are mixed to prepare a drug solution, and the drug solution is applied to the surface of the balloon by spraying. After the solvent in the drug solution is volatilized, a drug coating composed of a drug and an excipient is formed on the surface of the balloon.
  • lipophilic excipients prevents the drug from being washed away during vascular delivery.
  • the formed liquefied coating can transfer the drug from the surface of the balloon to the lesion site quickly and effectively during a short period of contact with the lesion site, and the balloon does not fall off during the expansion of the balloon.
  • a drug coated balloon comprising surface liquefaction is provided Drug coating and balloon.
  • the drug coating comprises a lipophilic excipient and a drug.
  • the lipophilic excipient comprises triglycerides, triacetin triglycerides, triglycerides and caprylic triglycerides, preferably triglycerides.
  • the medicament comprises paclitaxel, docetaxel, albumin-bound paclitaxel, rapamycin, everolimus, temsirolimus, zotarolimus, and olimus, He komos.
  • the drug is paclitaxel.
  • the drug in the drug coating on the surface of the balloon, comprises from 9% to 91%, preferably from 20% to 50%, more preferably from 20% to 50% by weight based on the total weight of the drug coating. 30% to 40%.
  • the excipients comprise from 9% to 91%, preferably from 50% to 80%, more preferably from 60% to 70%, by total weight of the drug coating.
  • the drug coating composition on the surface of the balloon is paclitaxel and triglycerides, which account for 33% and 67%, respectively, of the total weight of the drug coating.
  • the drug is present on the surface of the balloon in an amount of from 1 to 100 ⁇ g/mm 2 , preferably from 2 to 5 ⁇ g/mm 2 .
  • the drug coating is liquefied.
  • a method of making the drug coated balloon comprising the steps of:
  • step c) spraying the liquid formed in step a) on the surface of the balloon;
  • the components of the drug coating may be from 1% to 90%, preferably 1%, based on the total weight of the drug solution. ⁇ 10%, more preferably 2% ⁇ 8%, most preferably 2% to 6%.
  • the excipients comprise from 1% to 90%, preferably from 1% to 20%, more preferably from 4% to 10%, by total weight of the liquid.
  • the solvent accounts for 5% to 98%, preferably 79% to 98%, more preferably 82% to 94%, based on the total weight of the chemical liquid.
  • the lipophilic excipient comprises triglycerides, triacetin triglycerides, triglycerides and caprylic triglycerides, preferably triglycerides.
  • the medicament comprises paclitaxel, docetaxel, albumin-bound paclitaxel, rapamycin, everolimus, temsirolimus, zotarolimus, and olimus, He komos.
  • the drug is paclitaxel.
  • the solvent comprises acetone, water, methanol, ethanol, isopropanol, acetonitrile, ethyl acetate, and methyl formate.
  • the solvent is acetone.
  • the liquid medicine is a mixture of paclitaxel, triglyceride and acetone, preferably, wherein the weight percentage of the paclitaxel, the triglyceride and the acetone are respectively 2% by weight based on the total weight of the liquid medicine -6%, 4% to 10%, and 82% to 94%. More preferably, wherein the weight percentages of the paclitaxel, triglyceride and acetone are in the range of 2%, 4% and 94%, respectively, based on the total weight of the liquid medicine.
  • the lipophilic excipient, drug, and solvent are mixed in a ratio and sprayed onto the surface of the folded balloon. After the acetone is volatilized, a mixture of excipients and drugs covers the surface of the balloon to form a liquefied drug coating.
  • the balloon folding process is generally as follows: the inside of the balloon is inflated to a certain pressure and then folded using a balloon folding machine.
  • the balloon is cylindrical before folding, and the balloon forms a certain number of wings after folding, and the formed wings are curled to protect the drug on the surface of the balloon and reduce the outer diameter of the balloon.
  • a balloon having a liquefied coating can be further shaped to protect the liquefied coating on the balloon.
  • the process of setting is generally as follows: the gas inside the balloon is withdrawn to form a negative pressure inside, and the balloon is shaped according to the folded shape.
  • intravascular stenosis may be intracoronary stenosis or peripheral intravascular narrow.
  • FIG. 1 is a cross-sectional view of the balloon in a preferred embodiment of the present invention after folding.
  • FIG. 2 is a schematic view of a balloon coating in accordance with a preferred embodiment of the present invention.
  • Figure 3 is an electron microscopic image of a commercially available Berenger drug balloon and a drug balloon of Example 1 of the present invention.
  • the left panel shows a commercially available Berenger drug balloon, and the right panel shows the drug balloon of Example 1 of the present invention.
  • Example 4 is an electron micrograph of a drug balloon of Example 1 of the present invention.
  • Figure 5 is a schematic illustration of drug content at different times for an embodiment of the invention (1) and a commercially available Braun drug balloon.
  • Paclitaxel, triglyceride and acetone were mixed at a weight ratio of 2%, 4% and 94%, heated to 30 ° C, and stirred at a constant temperature for 30 minutes to form a chemical solution.
  • the balloon was inflated to 1 atm, folded into 3 wings using a balloon folding device, and folded for 3 minutes while heating to 45 °C.
  • the drug solution was injected into the coating machine to adjust the ultrasonic power to 20 watts, the internal pressure of the balloon to 2 atm, the balloon rotation speed to 3 rev / sec, and the axial 2 mm / sec reciprocating motion.
  • the axial length of the balloon is completed in one cycle.
  • a total of 10 cycles were sprayed.
  • a drug coated balloon is obtained after the acetone is volatilized.
  • the balloon was inflated to 1 atm, folded into 3 wings using a balloon folding device, and folded for 3 minutes under heating to 45 °C.
  • the drug solution was injected into the coating machine to adjust the ultrasonic power to 20 watts, the internal pressure of the balloon to 2 atm, the balloon rotation speed to 3 rev / sec, and the axial 2 mm / sec reciprocating motion.
  • the axial length of the balloon is completed in one cycle.
  • a total of 10 cycles were sprayed.
  • a drug coated balloon is obtained after the acetone is volatilized.
  • Paclitaxel, triglyceride and acetone were mixed at a weight ratio of 15%, 50% and 35%, heated to 30 ° C, and stirred at a constant temperature for 30 minutes to form a drug solution.
  • the balloon was inflated to 1 atm, folded into 3 wings using a balloon folding device, and folded for 3 minutes while heating to 45 °C.
  • the drug solution was injected into the coating machine to adjust the ultrasonic power to 20 watts, the internal pressure of the balloon to 2 atm, the balloon rotation speed to 3 rev / sec, and the axial 2 mm / sec reciprocating motion.
  • the axial length of the balloon is completed in one cycle.
  • a total of 10 cycles were sprayed.
  • a drug coated balloon is obtained after the acetone is volatilized.
  • Paclitaxel, triglyceride and acetone were mixed at a weight ratio of 2%, 10% and 88%, heated to 30 ° C, and stirred at a constant temperature for 30 minutes to form a drug solution.
  • the balloon was inflated to 1 atm, folded into 3 wings using a balloon folding device, and folded for 3 minutes while heating to 45 °C.
  • the drug solution was injected into the coating machine to adjust the ultrasonic power to 20 watts, the internal pressure of the balloon to 2 atm, the balloon rotation speed to 3 rev / sec, and the axial 2 mm / sec reciprocating motion.
  • the axial length of the balloon is completed in one cycle.
  • a total of 10 cycles were sprayed.
  • a drug coated balloon is obtained after the acetone is volatilized.
  • Paclitaxel, triglyceride and acetone were mixed at a weight ratio of 4%, 16% and 80%, heated to 30 ° C, and stirred at a constant temperature for 30 minutes to form a chemical solution.
  • the balloon was inflated to 1 atm and folded into 3 wings using a balloon folding device, heated to 45 Fold for 3 minutes at °C.
  • the drug solution was injected into the coating machine to adjust the ultrasonic power to 20 watts, the internal pressure of the balloon to 2 atm, the balloon rotation speed to 3 rev / sec, and the axial 2 mm / sec reciprocating motion.
  • the axial length of the balloon is completed in one cycle.
  • a total of 10 cycles were sprayed.
  • a drug coated balloon is obtained after the acetone is volatilized.
  • Paclitaxel, triglyceride and acetone were mixed at a weight ratio of 2%, 20% and 78%, heated to 30 ° C, and stirred at a constant temperature for 30 minutes to form a chemical solution.
  • the balloon was inflated to 1 atm, folded into 3 wings using a balloon folding device, and folded for 3 minutes while heating to 45 °C.
  • the drug solution was injected into the coating machine to adjust the ultrasonic power to 20 watts, the internal pressure of the balloon to 2 atm, the balloon rotation speed to 3 rev / sec, and the axial 2 mm / sec reciprocating motion.
  • the axial length of the balloon is completed in one cycle.
  • a total of 10 cycles were sprayed.
  • a drug coated balloon is obtained after the acetone is volatilized.
  • Paclitaxel, triglyceride and acetone were mixed at a weight ratio of 6%, 24% and 70%, heated to 30 ° C, and stirred at a constant temperature for 30 minutes to form a chemical solution.
  • the balloon was inflated to 1 atm, folded into 3 wings using a balloon folding device, and folded for 3 minutes while heating to 45 °C.
  • the drug solution was injected into the coating machine to adjust the ultrasonic power to 20 watts, the internal pressure of the balloon to 2 atm, the balloon rotation speed to 3 rev / sec, and the axial 2 mm / sec reciprocating motion.
  • the axial length of the balloon is completed in one cycle.
  • a total of 10 cycles were sprayed.
  • a drug coated balloon is obtained after the acetone is volatilized.
  • Example 8 Viscosity measurement of the drug-coated balloons of Inventive Examples 1-7 and observation of commercially available Berenger drug balloons and drug-coated balloons of Examples 1-7 using an electron microscope (Leica DM4000M metallographic microscope) Surface uniformity.
  • the drug coating of the present invention is liquefied and adheres to the surface of the balloon.
  • an advantageous viscosity range is from about 500 to 5000 cp, more preferably from 500 to 1000 cp, and most preferably from 800 to 1000 cp. Found this
  • the drug coatings of Inventive Examples 1-7 have a viscosity of about 500-5000 cp.
  • the drug coating of the Braun drug balloon is a solid coating and therefore cannot be characterized by viscosity.
  • a liquefied drug coating of suitable viscosity facilitates adhesion of the drug coating and the balloon, preventing the balloon from being washed away by blood as it passes through the blood vessel.
  • the Braun drug balloon on the left has a granular drug on the surface and uneven distribution on the surface of the balloon.
  • the drug distribution on the surface of the balloon is uneven, the roughness of the surface of the balloon is increased, thereby increasing the shearing force of the drug and blood on the surface of the balloon, resulting in easier drug on the surface of the balloon during delivery of the balloon catheter.
  • washed away by the blood when the surface drug particles of non-uniform size are in contact with the lesion site, since only a part of the particles can be attached to the blood vessel wall, it is unfavorable for the drug to be released onto the blood vessel wall.
  • the balloon drug (Fig. 3, right) of the embodiment (1) of the present invention covers the entire surface of the balloon and is evenly distributed, which reduces the shearing force of the balloon and blood, facilitates transportation, and can reduce blood to drugs. Scour. At the same time, because the drug is in a liquefied state, it is easier to fit the blood vessel wall and release the drug.
  • the drug shedding rate test is used to characterize the percentage of drug weight on the balloon when the drug balloon is washed away by blood during delivery. This experiment uses a simulation test, the experimental steps are as follows:
  • the shedding rate (Mn - M1) / Mn ⁇ 100%. Where Mn is the nominal content of the drug.
  • the rate of exfoliation of the drug during delivery indicates the firmness of the drug coating on the balloon.
  • the lower the shedding rate the less drug is lost during delivery and the more drug is reached at the target site.
  • the more drugs that can exert therapeutic effects As can be seen from Table 2, the drug shedding rate of Examples 1-5 of the present invention is far lower than the drug shedding rate of the commercially available Bereng drug balloon, indicating that the drug coating of Examples 1-5 of the present invention and the commercially available Berenger drug are shown.
  • the drug on the balloon is stronger on the balloon, and fewer drugs are lost during delivery, so that more drugs reach the target site.
  • Example 10 Content/time curve of drug in blood vessels
  • the content/time curve of the drug in the blood vessel is used to characterize the change of the drug remaining on the blood vessel over time after the drug balloon is attached to the blood vessel.
  • the drug balloon expands on a narrow blood vessel, it causes tearing of the intima of the blood vessel.
  • Drugs are needed to inhibit intimal hyperplasia and reduce restenosis. Restenosis is a chronic process that requires repeated administration of the drug over a long period of time. Ensuring sustained drug release through topical drug delivery is important to prevent restenosis. Therefore, the decay of the drug's content in the blood vessel over time plays an important role in preventing restenosis.
  • the content/time profile of the drug in the blood vessels was performed using animal experiments.
  • Miniature pigs are recognized as standard animals in experimental research.
  • Bama mini-pig is an excellent experimental animal because it is small in size and similar to human beings in various organs and physiological and biochemical indexes. It is an animal model for studying coronary heart disease. Therefore, this experiment uses small pigs as experimental animals.
  • the experimental steps are as follows:
  • femoral arteriotomy is implanted with a 6/7F sheath
  • the test specimen or reference substance is sent along the PTCA guide wire to the target vessel position, the expansion pressure is 10 atm, and the balloon catheter is withdrawn after 30 s of expansion; the contrast machine records the imaging when the balloon is propped up, and save.
  • Example 1 of the present invention After the operation of the drug-coated balloon of Example 1 of the present invention, 2 animals were sacrificed at 30 ⁇ 3 min, 1d ⁇ 2h, 7d ⁇ 4h, 14d ⁇ 4h, 28d ⁇ 1d, 90d ⁇ 3d, respectively.
  • the control substance was treated with a Braun drug balloon, and one animal was sacrificed at 30 ⁇ 3 min, 1 d ⁇ 2 h, and 7 d ⁇ 4 h after surgery. After the animal was sacrificed, the blood vessels of the balloon dilatation were dissected from the myocardium.
  • Figure 5 is a schematic illustration of drug content at different times for Example (1) and Braun drug balloon of the present invention.
  • the rate of decay of the drug in the blood vessels of the embodiments of the present invention over time is lower than that of the Braun drug balloon product. It is indicated that the drug of the embodiment of the invention remains in the blood vessel for a longer period of time, and is more favorable for continuously inhibiting intimal hyperplasia and reducing the probability of occurrence of restenosis.

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Abstract

一种药物涂层球囊及其制备方法，该药物涂层球囊包括表面液化的药物涂层和球囊，药物涂层包含亲脂性赋形剂和药物。该球囊能够降低输送过程中药物的损失，提高转移至病变位置的效率。

Description

一种表面液化药物涂层球囊 技术领域
本发明涉及一种表面液化药物涂层球囊、其制备方法及其用于治疗血管内狭窄的用途，所述血管包括冠状动脉和外周血管等。
背景技术
动脉粥样硬化是动脉壁中的慢性炎性反应，主要是由于血细胞积累，并由低密度脂蛋白在动脉壁上形成斑块。动脉粥样硬化是最常见的和最具有危害性的疾病，常导致血栓形成、血管狭窄、供血障碍等，进而影响身体其他功能。
血管成形术是涉及机械加宽通常由动脉粥样硬化引起的阻塞血管的血管介入技术。一般是将具有紧密折叠的球囊的导管插入患者的血管系统并被送到病变位置，在该位置使用一定的压力使球囊膨胀。球囊可以膨胀至一定的直径和长度。冠状动脉血管成形术的经皮冠状动脉介入(PCI)治疗心脏冠状动脉狭窄。外周血管的经皮腔内血管成形术(PTA)治疗除冠状动脉外的血管。
球囊导管是PCI手术最常用的器械。球囊导管具备球囊和导管管体，球囊和导管管体相连，位于管体的远端。球囊导管的使用者在血管内狭窄部位置入球囊并扩张，以对该部位进行治疗。
药物涂层球囊导管是在球囊导管的球囊表面涂覆一层药物，可以用于治疗血管内狭窄，所述血管包括冠脉和外周血管等。其能将药物均匀涂布至病变血管，且不会在人体内留下支架等植入物，为二次治疗提供了窗口。冠脉药物涂层球囊在使用过程中一般膨胀时间不超过1分钟。药物必须在一分钟内有效的由球囊表面转移至血管壁。另外，药物球囊在血管输送过程中，由于血液的冲刷，会使球囊表面的药物含量损失，进一步的影响了药物从球囊表面表面传递至病变位置。
中国专利申请CN201010121627.4设计了球囊外表面为具有凹凸的非平面 结构，使吸附药物的量增加，同时能够尽可能的保持吸附在球囊外壁的药物不会被血管中的血液冲洗损失，但是会对球囊造成损伤，影响其额定爆破压力；
中国专利申请CN201110176942.1介绍了一种静电自组装制备药物球囊的方法，通过自组装方法不同材质的球囊进行药物涂层覆盖。静电自组装由于循环次数较多，药物量的多少可通过层层叠加，但由于三次后表面电荷逐渐减少，外层组装的药物量及结合力呈下降趋势。
中国专利申请201410289533.6中使用等离子刻蚀方法在球囊表面形成纳米级的微孔结构，以提高球囊表面和药物涂层的结合力，提升载药量和避免药物输送过程中的损失。但是等离子刻蚀对球囊的性能有影响，会降低其爆破压力。
因此提出本发明，一方面降低了输送过程中药物被冲刷而造成的损失，另一方面提升了药物从球囊表面转移至病变位置的效率。
发明内容
本发明现在已经令人惊讶和意外地发现，采用一定比例的亲脂性的赋形剂和药物进行混合，经溶剂溶解后涂覆在球囊表面，在球囊表面形成液化的药物涂层。与现有技术相比，本发明采用的赋形剂为亲脂性的，另外在球囊表面的涂层为液化的，而非目前常规的固态涂层。
本发明拟在球囊表面形成液化的有一定粘度的药物涂层，一方面可以减少药物损失，一方面可以提升药物转移至病变的效率。为了实现以上目的，将亲脂性的赋形剂、药物和溶剂混合制备成药液，采用喷涂的方式，将药液涂覆在球囊表面。药液中的溶剂挥发后，在球囊表面形成由药物及赋形剂构成的药物涂层。
采用亲脂性的赋形剂，可以避免药物在血管输送的过程中被冲刷损失掉。形成的液化涂层在与病变位置的短时间接触过程中，能使药物快速有效的由球囊表面转移至病变位置，且扩张球囊的过程中不会造成球囊上药物的脱落。
因此，在本发明的一个方面，提供了一种药物涂层球囊，其包括表面液化 的药物涂层和球囊。
所述药物涂层包含亲脂性的赋形剂和药物。
在本发明的另一方面中，所述亲脂性的赋形剂包括甘油三酯、三乙酸甘油三酯、葵酸甘油三酯和辛酸甘油三酯，优选为甘油三酯。
在本发明的另一方面中，所述药物包括紫杉醇、多西紫杉醇、白蛋白结合型紫杉醇、雷帕霉素、依维莫司、坦罗莫司、唑罗莫司、比奥莫司、他克莫司。优选地，所述药物为紫杉醇。
在本发明的另一方面中，在所述球囊表面的药物涂层中，所述药物占所述药物涂层总重量的9％～91％，优选为20％～50％，更优选为30％～40％。所述赋形剂占所述药物涂层总重量的9％～91％，优选为50％～80％，更优选为60％～70％。
优选地，所述球囊表面的药物涂层组成为紫杉醇和甘油三酯，其分别占所述药物涂层总重量的33％和67％。
在本发明的另一方面中，所述药物在所述球囊表面的含量为1-100μg/mm2，优选为2-5μg/mm2。
在本发明的另一方面中，所述药物涂层为液化的。
在本发明的又一方面，提供制备所述药物涂层球囊的方法，其包括如下步骤：
a)将亲脂性的赋形剂、药物和溶剂按一定比例混合，加热搅拌，从而形成药液；
b)将球囊折叠；
c)将步骤a)中形成的药液喷涂在球囊表面；
d)溶剂挥发，在球囊表面形成药物涂层。
在本发明的另一方面中，按所述药液的总重量计，所述药物涂层的各组分可以为，所述药物占药液总重量的1％～90％，优选为1％～10％，更优选为2％～ 8％，最优选为2％～6％。所述赋形剂占药液总重量的1％～90％，优选为1％～20％，更优选为4％～10％。所述溶剂占药液总重量的5％～98％，优选为79％～98％，更优选为82％～94％。
在本发明的另一方面中，所述亲脂性的赋形剂包括甘油三酯、三乙酸甘油三酯、葵酸甘油三酯和辛酸甘油三酯，优选为甘油三酯。
在本发明的另一方面中，所述药物包括紫杉醇、多西紫杉醇、白蛋白结合型紫杉醇、雷帕霉素、依维莫司、坦罗莫司、唑罗莫司、比奥莫司、他克莫司。优选地，所述药物为紫杉醇。
在本发明的另一方面中，所述溶剂包括丙酮、水、甲醇、乙醇、异丙醇、乙腈、乙酸乙酯和甲酸甲酯。优选地，所述溶剂为丙酮。
优选地，所述药液为紫杉醇、甘油三酯和丙酮的混合物，优选地，其中，按所述药液的总重量计，所述紫杉醇、甘油三酯和丙酮的重量百分比范围分别为2％-6％、4％～10％和82％～94％。更优选地，其中，按所述药液的总重量计，所述紫杉醇、甘油三酯和丙酮的重量百分比范围分别为2％、4％和94％。
在本发明的另一方面中，将亲脂性的赋形剂、药物和溶剂按照一定的比例混合后，喷涂在折叠后的球囊表面。待丙酮挥发后，赋形剂和药物的混合物覆盖在的球囊表面，形成液化的药物涂层。
球囊折叠过程一般如下：在球囊内部充气达到一定的压力，然后使用球囊折叠机对其进行折叠。折叠前球囊为圆柱形，折叠后球囊形成一定的翼数，且所形成的翼会卷曲，以保护球囊表面的药物和减小球囊的外径。
在本发明的另一方面中，可进一步将具有液化涂层的球囊进行定型，以保护球囊上的液化涂层。
定型的过程一般如下：将球囊内部的气体抽出，使其内部形成负压，则球囊会按照折叠后的形状定型。
因此，在本发明的另一方面中，提供根据本发明获得的药物涂层球囊在治疗血管内狭窄中的用途。所述血管内狭窄可以为冠状动脉内狭窄或外周血管内 狭窄。
现在通过下列实施例特别描述本发明。
附图说明
图1所示为本发明一个优选实施方式中的球囊折叠后的截面图。
图2所示为本发明一个优选实施方式的球囊涂层示意图。
图3所示为市售贝朗药物球囊与本发明实施例1的药物球囊的电镜图像。左图所示为市售贝朗药物球囊，右图所示为本发明实施例1的药物球囊。
图4所示为本发明实施例1的药物球囊的电镜照片。
图5为本发明实施例(1)和市售贝朗药物球囊的不同时间的药物含量示意图。
具体实施方式
本发明的其它方面在下面进行详细描述。阅读以下公开的实施方案的详细描述和所附权利要求后，本发明的这些和其它特征和优点将变得显而易见。
除非另有定义，否则本文使用的所有技术和科学术语具有本发明所属领域的技术人员通常理解的含义。
实施例1：药物涂层球囊的制备
将紫杉醇、甘油三酯和丙酮以重量比2％、4％和94％的比例混合，加热至30℃，恒温搅拌30分钟，形成药液。
将球囊充气压至1atm，使用球囊折叠设备将其折叠成3翼，在加热至45℃条件下折叠3分钟。
将药液注入到涂层机内，调整超声功率为20瓦，球囊内部压力为2atm，球囊旋转速度为3转/秒，轴向2mm/秒做往复运动。轴向走完球囊长度全程为一个周期。共喷涂10个周期。待丙酮挥发后得到药物涂层球囊。
实施例2：药物涂层球囊的制备
将紫杉醇、甘油三酯和丙酮以重量比64％、6％和30％的比例混合，加热至 30℃，恒温搅拌30分钟，形成药液。
将球囊充气压至1atm，使用球囊折叠设备将其折叠成3翼，在加热至45℃的条件下折叠3分钟。
将药液注入到涂层机内，调整超声功率为20瓦，球囊内部压力为2atm，球囊旋转速度为3转/秒，轴向2mm/秒做往复运动。轴向走完球囊长度全程为一个周期。共喷涂10个周期。待丙酮挥发后得到药物涂层球囊。
实施例3：药物涂层球囊的制备
将紫杉醇、甘油三酯和丙酮以重量比15％、50％和35％的比例混合，加热至30℃，恒温搅拌30分钟，形成药液。
将球囊充气压至1atm，使用球囊折叠设备将其折叠成3翼，在加热至45℃条件下折叠3分钟。
将药液注入到涂层机内，调整超声功率为20瓦，球囊内部压力为2atm，球囊旋转速度为3转/秒，轴向2mm/秒做往复运动。轴向走完球囊长度全程为一个周期。共喷涂10个周期。待丙酮挥发后得到药物涂层球囊。
实施例4：药物涂层球囊的制备
将紫杉醇、甘油三酯和丙酮以重量比2％、10％和88％的比例混合，加热至30℃，恒温搅拌30分钟，形成药液。
将球囊充气压至1atm，使用球囊折叠设备将其折叠成3翼，在加热至45℃条件下折叠3分钟。
将药液注入到涂层机内，调整超声功率为20瓦，球囊内部压力为2atm，球囊旋转速度为3转/秒，轴向2mm/秒做往复运动。轴向走完球囊长度全程为一个周期。共喷涂10个周期。待丙酮挥发后得到药物涂层球囊。
实施例5：药物涂层球囊的制备
将紫杉醇、甘油三酯和丙酮以重量比4％、16％和80％的比例混合，加热至30℃，恒温搅拌30分钟，形成药液。
将球囊充气压至1atm，使用球囊折叠设备将其折叠成3翼，在加热至45 ℃条件下折叠3分钟。
将药液注入到涂层机内，调整超声功率为20瓦，球囊内部压力为2atm，球囊旋转速度为3转/秒，轴向2mm/秒做往复运动。轴向走完球囊长度全程为一个周期。共喷涂10个周期。待丙酮挥发后得到药物涂层球囊。
实施例6：药物涂层球囊的制备
将紫杉醇、甘油三酯和丙酮以重量比2％、20％和78％的比例混合，加热至30℃，恒温搅拌30分钟，形成药液。
将球囊充气压至1atm，使用球囊折叠设备将其折叠成3翼，在加热至45℃条件下折叠3分钟。
将药液注入到涂层机内，调整超声功率为20瓦，球囊内部压力为2atm，球囊旋转速度为3转/秒，轴向2mm/秒做往复运动。轴向走完球囊长度全程为一个周期。共喷涂10个周期。待丙酮挥发后得到药物涂层球囊。
实施示例7：药物涂层球囊的制备
将紫杉醇、甘油三酯和丙酮以重量比6％、24％和70％的比例混合，加热至30℃，恒温搅拌30分钟，形成药液。
将球囊充气压至1atm，使用球囊折叠设备将其折叠成3翼，在加热至45℃条件下折叠3分钟。
将药液注入到涂层机内，调整超声功率为20瓦，球囊内部压力为2atm，球囊旋转速度为3转/秒，轴向2mm/秒做往复运动。轴向走完球囊长度全程为一个周期。共喷涂10个周期。待丙酮挥发后得到药物涂层球囊。
实施例8：对本发明实施例1-7的药物涂层球囊进行粘度测量并用电子显微镜(莱卡DM4000M金相显微镜)观察市售贝朗药物球囊和实施例1-7的药物涂层球囊的表面均匀度。
粘度：
本发明的药物涂层为液化的，粘附在球囊表面。对于药物涂层，有利的粘度范围约为500-5000cp，更优选为500-1000cp，最优选为800-1000cp。发现本 发明实施例1-7的药物涂层的粘度约为500-5000cp。而贝朗药物球囊的药物涂层为固体涂层，因此未能用粘度来表征。
表：本发明实施例的粘度
实施示例 1 2 3 4 5 6 7
粘度 800 3000 1000 1200 1000 500 1000
合适粘度的液化药物涂层有利于药物涂层和球囊的附着，避免球囊在血管内穿越时被血液冲刷掉。
电镜：
从图3可以看出，左图的贝朗药物球囊，其表面的药物呈颗粒状，且在球囊表面分布不均匀。当球囊表面的药物分布不均匀时，增加球囊表面的粗糙度，进而增大了球囊表面药物和血液的剪切力，导致在球囊导管输送的过程中球囊表面的药物更容易被血液冲刷掉。另外，大小不均匀的表面药物颗粒与病变位置接触时，由于只有部分颗粒可以和血管壁贴合，不利于药物释放到血管壁上。
而本发明实施例(1)的球囊药物(图3，右图)覆盖整个球囊表面，且分布均匀，降低了球囊和血液的剪切力，利于输送，并能减少血液对药物的冲刷。同时，因为药物为液化状态，更容易和血管壁贴合，进而释放药物。
实施例9：药物脱落率实验：
药物脱落率实验用于表征药物球囊在输送过程中被血液冲涮掉的药物占球囊上药物重量的百分比。本实验采用模拟试验，其实验步骤如下：
a)将导引导丝插入到球囊导管的导丝腔；
b)沿导引导丝推送药物涂层球囊导管，模拟手术应用；
c)将球囊推送至目标模拟病变位置；
d)不扩张球囊，直接撤回球囊；
e)将撤回药物球囊上剩余的药物洗脱；
f)使用高效液相测定撤回球囊上的药物残留量M1。
脱落率＝(Mn-M1)/Mn·100％。其中Mn为药物标称含量。
测得结果如下：
表2：本发明实施例和贝朗药物球囊的药物脱落率
Figure PCTCN2017094445-appb-000001
药物在输送过程中的脱落率表明了药物涂层在球囊上的牢固度。脱落率越低说明在输送过程中损失的药物越少，进而达到目标位置的药物越多。进而能发挥治疗效果的药物就越多。由表2可知，本发明实施例1-5的药物脱落率远远低于市售贝朗药物球囊的药物脱落率，表明本发明实施例1-5的药物涂层与市售贝朗药物球囊相比，其上的药物在球囊上更牢固，在输送过程中损失的药物更少，从而其到达目标位置的药物更多。
实施例10：药物在血管中的含量/时间曲线
药物在血管中的含量/时间曲线用于表征药物球囊在和血管贴壁后，残留在血管上的药物随时间的变化情况。药物球囊在对狭窄血管进行扩张时，对造成血管内膜的撕裂。需要通过药物来抑制内膜增生而减少再狭窄。再狭窄是一个慢性过程，需要长期反复给予药物。通过局部药物输送保证持续药物释放对预防再狭窄来说很重要。因此，药物在血管中的含量随时间的衰减情况对防止再狭窄有很重要的作用。
药物在血管中的含量/时间曲线采用动物实验进行。小型猪是试验研究中公认的标准动物。巴马小型猪因其体型小，与人类在各种器官及生理生化指标上与人类相似而成为一种优异的实验动物，是研究冠心病的动物模型，故本试验采用小型猪作为实验动物。实验步骤如下：
a)猪经麻醉后，腹股沟处备皮、消毒、铺巾，心电图、血压、血氧饱和度和温度持续监测，并测量一次血压与左心室射血分数；
b)行股动脉切开术植入6/7F鞘管；
c)选择6F L(或R)3.5造影导管用造影剂进行造影，选择球囊血管比为1.2～1.4左右的血管进行手术，观察血管直径并记录。按标准的操作规范进行，造影机记录成像；
d)冠状动脉造影后，沿PTCA导丝送入供试品或对照品至靶血管位置，扩张压力为10atm，扩张30s后撤出球囊导管；造影机记录撑起球囊时的成像，并保存。
e)即刻复查冠状动脉造影明确血流是否通畅、血管是否有夹层及血栓形成，评价各项指标。
f)撤出导管，处理右腹股沟手术切口，查看猪健康状况。
g)采用本发明实施例1的药物涂层球囊进行手术后，分别于30±3min，1d±2h，7d±4h，14d±4h，28d±1d，90d±3d各处死2只动物。对照品采用贝朗药物球囊，手术后分别于30±3min，1d±2h，7d±4h各处死1只动物。动物处死后从心肌上解剖分离出球囊扩张处血管。
h)血管称重并匀浆，得组织匀浆液。离心，取上清液进样，采用LC-MS/MS检测。
i)计算各时间点的血管中药物浓度，绘制浓度-时间曲线。
结果如图5所示。图5为本发明实施例(1)和贝朗药物球囊的不同时间的药物含量示意图。
从图5中可以看出，本发明实施例的药物在血管中的含量随时间衰减的速率要低于贝朗药物球囊产品。说明本发明实施例的药物在血管中保留的时间更长，更有利于持续抑制内膜增生，降低再狭窄发生的概率。
本发明不局限于上述实施方案，并且本领域技术人员将理解，在不偏离所附权利要求所公开的本发明的范围和精神的情况下，可进行各种修改、添加和替换。

Claims (12)

  1. 一种药物涂层球囊，其包括表面液化的药物涂层和球囊，所述药物涂层包含亲脂性的赋形剂和药物。
  2. 如权利要求1所述的药物涂层球囊，其中所述亲脂性的赋形剂包括甘油三酯、三乙酸甘油三酯、葵酸甘油三酯和辛酸甘油三酯。
  3. 如权利要求1所述的药物涂层球囊，其中所述药物包括紫杉醇、多西紫杉醇、白蛋白结合型紫杉醇、雷帕霉素、依维莫司、坦罗莫司、唑罗莫司、比奥莫司、他克莫司。
  4. 如权利要求1-3中任一项所述的药物涂层球囊，其中所述药物占药物涂层总重量的9％～91％，且赋形剂占药物涂层总重量的9％～91％。
  5. 如权利要求1-4中任一项所述的药物涂层球囊，其中所述药物涂层为液化的。
  6. 制备如权利要求1所述的药物涂层球囊的方法，包括如下步骤：
    a)将亲脂性的赋形剂、药物和溶剂按一定比例混合，加热搅拌，从而形成药液；
    b)将球囊折叠；
    c)将步骤a)中形成的药液喷涂球囊；
    d)溶剂挥发，在球囊表面形成药物涂层。
  7. 如权利要求6所述的方法，其中所述亲脂性的赋形剂包括甘油三酯、三乙酸甘油三酯、葵酸甘油三酯和辛酸甘油三酯。
  8. 如权利要求6所述的方法，其中所述药物包括紫杉醇、多西紫杉醇、白蛋白结合型紫杉醇、雷帕霉素、依维莫司、坦罗莫司、唑罗莫司、比奥莫司、他克莫司。
  9. 如权利要求6所述的方法，其中所述溶剂包括丙酮、水、甲醇、乙醇、异丙醇、乙腈、乙酸乙酯和甲酸甲酯。
  10. 如权利要求6-9中任一项所述的方法，其中所述亲脂性的赋形剂占所述药液总重量的1％～90％，药物占所述药液总重量的1％～90％，和溶剂占所述药液总重量的5％～98％。
  11. 如权利要求1-5中任一项所述的药物涂层球囊在治疗血管内狭窄中的用 途。
  12. 如权利要求11所述的用途，其中所述血管内狭窄为冠状动脉内狭窄或外周血管内狭窄。
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