WO2016101771A1 - 药物球囊扩张导管的制备方法及折翼卷绕球囊 - Google Patents

药物球囊扩张导管的制备方法及折翼卷绕球囊 Download PDF

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Publication number
WO2016101771A1
WO2016101771A1 PCT/CN2015/096034 CN2015096034W WO2016101771A1 WO 2016101771 A1 WO2016101771 A1 WO 2016101771A1 CN 2015096034 W CN2015096034 W CN 2015096034W WO 2016101771 A1 WO2016101771 A1 WO 2016101771A1
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Prior art keywords
balloon
drug
flap
flaps
wound
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PCT/CN2015/096034
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English (en)
French (fr)
Inventor
卢金华
谢琦宗
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先健科技(深圳)有限公司
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Publication of WO2016101771A1 publication Critical patent/WO2016101771A1/zh

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00—Catheters; Hollow probes
    • A61M25/10—Balloon catheters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • 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
    • A61M2025/1043—Balloon catheters with special features or adapted for special applications
    • A61M2025/105—Balloon catheters with special features or adapted for special applications having a balloon suitable for drug delivery, e.g. by using holes for delivery, drug coating or membranes

Definitions

  • the invention relates to the field of medical instruments, in particular to a method for preparing a drug balloon dilatation catheter and a flap winding balloon.
  • PCI percutaneous coronary intervention
  • Cardiovascular interventional therapy has undergone percutaneous transluminal coronary angioplasty (Percutaneous Transluminal Coronary Angioplasty: PTCA) using nude balloon expansion to bare metal stents (Bare Metal Stents, referred to as: BMS) to drug stents (Drug) Eluting Stents (referred to as: DES) three milestone development.
  • PTCA can eliminate coronary stenosis, but the elastic retraction of the vessel wall, hyperplasia of the intima and tearing of the intima of the wall can promote vascular restenosis.
  • the rate of restenosis after target vessel is 3 to 6 months is as high as 30 ⁇ 50%.
  • BMS can eliminate immediate stenosis and greatly reduce the incidence of acute reocclusion, but the incidence of target vascular restenosis is still as high as 20 to 30%.
  • the implantation of DES can reduce the incidence of target vessel restenosis to about 10%, but may increase the incidence of late thrombosis.
  • in-stent restenosis, small vessel disease, bifurcation lesions, peripheral vascular disease and other fields also limit the application of DES.
  • DEB Drug Eluting Balloon
  • drug balloon drug balloon
  • It is a new therapeutic balloon drug release technology developed on the basis of interventional techniques such as balloon dilation or balloon angioplasty. It is a drug that adsorbs anti-vascular intimal hyperplasia on the surface of the balloon when the balloon arrives.
  • the stenosis of the vascular lesion is opened by expanding the balloon, and when the drug coating contacts the endometrium of the blood vessel wall, the drug is quickly released and transferred to the disease. Transform the blood vessel wall.
  • the drug acts as an anti-vascular intimal hyperplasia at the site of vasodilation, thereby preventing restenosis after vascular intervention.
  • DEB Compared with DES, DEB has the following advantages: (1) The contact area of DES with the surface of the blood vessel is only about 15%, DEB can uniformly apply the drug to the surface of the blood vessel, thereby enhancing the effect of the drug; (2) DEB is not required Similar to DES polymer material, avoiding chronic inflammatory stimuli triggering thrombosis; (3) reducing the application time of dual antiplatelet drugs, thereby reducing costs and reducing complications caused by oral antiplatelet drugs (4) For lesions that DES cannot handle well, such as in-stent restenosis, small blood vessels, anatomically curved blood vessels, highly calcified blood vessels, and bifurcation lesions, DEB operation is more flexible and more suitable for treating such lesions.
  • Paclitaxel is an anti-tumor drug that can promote cell microtubule polymerization and stabilize polymerized microtubules, thereby inhibiting various functions of cells, such as Proliferation, migration and signal transduction; paclitaxel is highly liposoluble and can bind to tissues quickly and tightly, resulting in a high retention rate. At the same time, paclitaxel changes the structure of the cytoskeleton and therefore has a longer pharmacological effect. Inhibition of vascular smooth muscle cell proliferation;
  • the preparation process will affect the degree of loss of paclitaxel in the preparation and delivery of DEB: when the drug loss in the preparation and delivery of DEB is too large, the less the amount of drug contained in the drug coating, the lower the trans-loading rate of DEB may be caused. Affect product effectiveness;
  • the preparation process will affect the crystallization state of paclitaxel.
  • the paclitaxel in the DEB coating is crystalline, its particle release properties, drug transfer capacity, drug retention on the tissue surface and biological effectiveness Is superior to paclitaxel in an amorphous state;
  • the preparation process will affect the morphology and integrity of the drug coating.
  • Intimal hyperplasia reduces the incidence of vascular restenosis.
  • the drug balloon catheter whose outer surface of the balloon is a non-planar structure having irregularities.
  • the drug balloon catheter uses ultraviolet laser to grind the outer surface of the balloon, so that the outer surface of the balloon forms a non-planar structure with irregularities.
  • the non-planar structure improves the storage of the drug on the surface of the balloon, and the first is adsorption. The amount of the drug is greatly increased.
  • the drug adsorbed by the balloon passes through the blood vessel to reach the lesion site, and the drug adsorbed on the outer wall of the balloon is not lost by the blood in the blood vessel, and can effectively pass the ball.
  • the capsule is delivered to the lesion for effective therapeutic action.
  • a drug eluting balloon catheter comprising a balloon catheter body and a drug coating
  • the balloon catheter body comprising a balloon, the balloon having a plurality of grooves on the outer surface thereof, on the outer surface of the balloon
  • the drug coating is applied to the groove portion and the flat portion, and the groove is converted into a reverse protrusion after the balloon is filled.
  • the drug-eluting balloon catheter can not only carry more drugs, but also reduce the loss of the drug during transportation, and can also dump the drug left in the groove directly into the blood by the action of the reverse protrusion, and accelerate the drug. Release, and increase the concentration of the drug at the target position, so that it can concentrate on the target position quickly, and better prevent the proliferation and restenosis of the vascular tissue at the target position.
  • the groove structure directly causes the drug content in the drug coating to be uneven, and the drug in the groove portion is formed to accumulate.
  • the drug loading amount in other parts may be low. Influencing the transfer of the drug to the tissue; 2 from the beginning of the balloon to the surface of the balloon to fully contact the vessel wall, the action of the reverse protrusion directly dumps the drug left in the groove and throws it into the blood.
  • the blood flowing by the high-speed coronary artery is washed away, so it only ensures the reduction of the drug loss of the DEB during the delivery process, but increases the probability of drug loss in the instant of balloon expansion, and does not fully guarantee the retransmission of the drug to the vascular tissue of the lesion; 3
  • the accumulation of drugs in the groove is also easier to form larger particles, resulting in blockage and thrombus, and there are certain safety hazards.
  • a drug balloon based on hydrogen hydration which comprises a balloon surface and a drug layer containing an active drug, wherein the balloon surface is treated or modified to carry a hydrophilic group, and There is hydrogen bonding between the balloon surface and the drug layer.
  • hydrogen bonding By hydrogen bonding, the adhesion between the drug layer and the balloon surface is increased to ensure the ductility of the coating and to facilitate the loading of the drug on the surface of the balloon.
  • the drug release mode in the drug balloon coating is a violent release.
  • the hydrogen bonding effect is beneficial to the loading of the drug on the surface of the balloon, the hydrogen bonding force hinders to some extent. Rapid release of paclitaxel drugs.
  • a novel balloon catheter carrying a drug microcapsule consisting of a proximal tube, a distal tube, a balloon, a drug microcapsule, and a flexible tip, wherein the balloon is a memory folding balloon and folded
  • the inner surface of the wrinkle of the balloon is wrapped with a drug microcapsule, which is a special infiltration technique for wrapping the drug microcapsule on the inner surface of the fold of the folded balloon.
  • the drug encapsulated by the drug microcapsule is a traditional Chinese medicine for preventing and treating vascular restenosis.
  • the extract is concentrated and added with corresponding auxiliary materials to form a powdery granular drug microcapsule, which improves the targeting of the drug carrying, can accurately locate and release the drug slowly, and achieve the purpose of long-term treatment.
  • the disadvantages of the invention are: 1 the surface of the balloon is incompletely loaded: the drug-loading position is limited to the drug microcapsules wrapped around the inner surface of the balloon fold, and after the balloon is folded, the inner surface of the fold is only a part of the entire surface of the balloon.
  • the drug coverage is not uniform; 2
  • the release effect of the drug microcapsule on the drug is a slow release at a fixed time, which can not satisfy the rapid drug release mode of the drug balloon.
  • the key evaluation index of drug balloon performance is the drug transfer rate, that is, the amount of drug that can be transferred to the tissue.
  • 1 the drug transfer rate to the vascular tissue is low; 2 the drug to the vascular tissue The transfer rate is unstable and the fluctuation range is large.
  • a flap-wound balloon is provided that can increase the efficiency of drug delivery of a drug balloon dilatation catheter.
  • a method for preparing a drug balloon dilatation catheter comprises the following steps:
  • n flaps Folding the balloon to form n flaps, winding each of the flaps to the flaps to form an arcuate structure, and forming a tangent to the midpoint of the arc of the adjacent two of the flaps An acute angle of 30 ° ⁇ 75 °, resulting in a flap winding balloon, the n is an integer greater than or equal to 2;
  • the drug-attached flap-wound balloon is wrapped with a flexible material, and each of the flaps is wound, the flexible material is removed, and sterilized to obtain the drug balloon expansion catheter.
  • the n is 3, 4, 5 or 6.
  • the balloon prior to the step of folding the balloon, is further subjected to an alcoholation treatment or a plasma treatment.
  • the drug solution comprises an active drug, a water-soluble additive, and a solvent, wherein the concentration of the active drug is 0.1 to 30 mg/mL, and the concentration of the water-soluble additive is 0.1 to 15 mg/mL;
  • the active drug is an anti-intimal proliferative drug, an anticoagulant drug, an anti-platelet adhesion drug, an anti-infective drug, an antibacterial drug or an anti-tumor drug for treating vascular restenosis, and the water-soluble additive contains a polar group.
  • the density of the active drug on the outer surface of the balloon of the drug balloon expansion catheter is 0.1 to 10 ⁇ g/mm 2 .
  • the water soluble additive is selected from the group consisting of sodium ferulate, L-phenylalanine, benzoate, methionine, proline, lysine, leucine, hydroxypropyl-beta -cyclodextrin, sorbitol, L-valine, nicotinamide, acetamide, meglumine, L-isoleucine, glucose, maltose, Tween 80, mannitol, lecithin, tryptophan, L - threonine, salicylic acid, sodium p-aminosalicylate, sodium heparin, vitamin C, polyethylene glycol, polylysine, sodium hyaluronate, poloxamer, polyvinylpyrrolidone, At least one of polyvinyl alcohol, polyethylene oxide, polyacrylate, and polyacrylamide.
  • step of removing the flexible material before the step of sterilizing, further comprising the step of recoating the drug solution on the outer surface of the flap-wound balloon and drying .
  • the step of obtaining the flap-wound balloon is specifically: applying a pressure of 1 to 50 psi to the balloon at 0 to 60 ° C to fill the balloon, and then The outer surface of the balloon is biased to fold to form the flap; at 0 to 60 ° C, a pressure of 0 to -50 psi is applied to the balloon, and each of the flaps is wound for 2 to 30 minutes. .
  • a flap winding balloon comprising n arcuate flaps, the n being an integer greater than or equal to 2, in the middle of an arc of two adjacent flaps
  • the acute angle formed by the tangent of the point is 30° to 75°.
  • the drug balloon dilatation catheter prepared according to the preparation method of the above drug balloon dilatation catheter after the balloon flap is wound, the flap winding balloon is prepared, and each adjacent two flaps have a certain angle between the adjacent flaps,
  • the coating of the drug solution leaves room to ensure uniform and complete application of the drug to the surface of the balloon while ensuring the stability of the drug content; since the flap is wound and has an arc structure, the drug coating is dried
  • each flap of the balloon will only undergo a small curl deformation in the direction of winding and bending, and the dried drug coating will not fall off due to excessive winding deformation, the ball
  • Each flap of the capsule will not wrinkle due to the winding action; after wrapping the balloon with the drug-attached flap wrapped with a flexible material, a second winding of each flap is performed to promote the balloon.
  • Each of the flaps fits snugly and also enhances the bond between the drug and the outer surface of the balloon while allowing the drug to be structurally tight. This is beneficial to reduce the amount of the drug on the balloon being washed away by the blood during the delivery process, so as to reduce the loss of the drug and improve the delivery efficiency of the drug to the vascular lesion site.
  • FIG. 1 is a flow chart of a method of preparing a drug balloon dilatation catheter of an embodiment
  • FIG. 2 is a schematic cross-sectional view showing a plurality of flaps formed by folding the balloon of FIG. 1;
  • Figure 3 is a schematic cross-sectional view of the flap-wound balloon obtained after the first winding of the flap of Figure 1;
  • Figure 4 is a magnified 20-fold microscopic microscope image of the drug-attached flap of Figure 1.
  • a method for preparing a drug balloon dilatation catheter is for preparing the above drug balloon dilatation catheter.
  • the preparation method of the drug balloon dilatation catheter comprises the following steps:
  • Step S210 Folding the balloon to form n flaps, winding each flap to the flap to form an arc structure, and forming an acute angle formed by a tangent of the midpoint of the arc where the adjacent two flaps are located From 30° to 75°, a flap-wound balloon is obtained.
  • n is an integer greater than or equal to 2.
  • each flap coated with the drug will only follow the first roll during the subsequent winding process.
  • the winding bending direction formed after the winding is less deformed, and the dried drug coating does not break off due to excessive winding curvature, thereby reducing the damage of the drug coating in the subsequent winding process.
  • the balloon is a nylon balloon.
  • the balloon is folded by a flapping machine.
  • the step of obtaining the flap-wound balloon in step S210 is specifically: applying a pressure of 1 to 50 psi to the balloon at 0 to 60 ° C to fill the balloon, and then applying force to the outer surface of the balloon. Folding to form flaps; applying a negative pressure of 0-50 psi to the balloon at 0-60 ° C, and winding each flap for 2 s to 30 min, wherein applying 0 psi to the balloon is not the ball
  • the capsule exerts a negative pressure.
  • the purpose of applying a negative pressure is to cause the flap winding balloon to be in a collapsed state, which facilitates the winding of the flap.
  • FIG. 2 is a schematic view of the balloon after being folded.
  • the balloon 300 is formed with three flaps 320. It will be understood that the flaps 320 are not limited to three.
  • n 3, 4, 5 or 6.
  • the acute angle formed by the tangent of the midpoint of the arc of the adjacent two flaps of the flap winding balloon is 30° to 75°, whereby, it is possible to leave room for subsequent application of the drug, ensuring that the drug can be completely applied to the surface of the balloon.
  • FIG. 3 is a cross-sectional view of the balloon 300 after the first winding of the flap 320, that is, a cross-sectional view of the flap-wound balloon.
  • the flap The number of 320 is three.
  • the angle ⁇ is the angle between the tangent of the midpoint of the arc of the adjacent two flaps.
  • FIG. 4 is a three-dimensional microscope image showing a 20-fold magnification of a drug-attached flap.
  • the drug (white portion in Figure 4) is evenly distributed on the surface of the flap, indicating that the first winding and application process of the present invention ensures uniformity and integrity of the drug coating on the balloon surface.
  • Sexuality so that after the second winding, each wing has a certain curvature, and when the second winding is applied, the flap only needs to undergo relatively small curl deformation, and the dried drug is coated.
  • the layer does not break off due to excessive winding curvature; and more drugs on the balloon are wrapped by the flaps, the wrapped drug can avoid the direct flushing of the blood during the delivery process, and the drug coating is reduced during the delivery process. Drug loss.
  • the balloon before the step of folding the balloon, the balloon is further subjected to an alcoholization treatment or a plasma treatment. That is, the outer surface of the balloon is surface treated.
  • the step of the alcoholization treatment is specifically: immersing the balloon in an ethanol solution having a volume concentration of 50 to 99.5% at 10 to 70 ° C for 5 to 120 minutes, taking out and drying.
  • the step of plasma treatment is specifically: at room temperature, in an atmosphere of at least one of nitrogen, oxygen, and argon, at an output of 50 to 2000 W, a frequency of 10 to 100 MHz, and a gas pressure of 1 to 100 Pa. Plasma treatment under conditions of 5 seconds to 30 minutes.
  • Step S220 coating the drug solution on the outer surface of the flap-wound balloon and drying to obtain a flap-wound balloon to which the drug is adhered.
  • the drug solution includes an active drug, a water-soluble additive and a solvent, wherein the concentration of the active drug is 0.1 to 30 mg/mL, and the concentration of the water-soluble additive is 0.1 to 15 mg/mL.
  • the active drug is an anti-intimal hyperplasia drug, an anticoagulant drug, an anti-platelet adhesion drug, an anti-infective drug, an antibacterial drug or an anti-tumor drug for treating vascular restenosis.
  • the anti-intimal hyperplasia drug is at least one selected from the group consisting of everolimus, rapamycin, paclitaxel, docetaxel, taxol, paclitaxel derivatives, probucol and colchicine.
  • the anticoagulant drug is selected from at least one of heparin, warfarin sodium and a vitamin K antagonist.
  • the anti-platelet adhesion drug is selected from at least one of aspirin, prostaglandin, salvianolic acid, nitrate drug, lysine and dipyridamole.
  • the anti-infective drug is at least one selected from the group consisting of ampicillin, cephalosporin, sulfadiazine and streptomycin sulfate.
  • the antibacterial agent is selected from at least one of chitosan, a derivative of chitosan, cefoxitin, nalidixic acid and pipemidic acid.
  • the antitumor drug is selected from at least one of daunorubicin, doxorubicin, carboplatin and macrolide.
  • the water-soluble additive is an organic substance containing a polar group.
  • the polar group is relatively hydrophilic, which is beneficial to the more efficient and rapid transfer of the drug after contact with the water containing water.
  • the water-soluble additive is selected from the group consisting of sodium ferulate, L-phenylalanine, benzoate, methionine, proline, lysine, leucine, hydroxypropyl- ⁇ -cyclodextrin, sorbus Alcohol, L-valine, nicotinamide, acetamide, meglumine, L-isoleucine, glucose, maltose, Tween 80, mannitol, lecithin, tryptophan, L-threonine, water Salicylic acid, sodium p-aminosalicylate, sodium heparin, vitamin C, polyethylene glycol, polylysine, sodium hyaluronate, poloxamer, polyvinylpyrrolidone, polyvinyl alcohol, polyoxidation At least one of ethylene, polyacrylate, and polyacrylamide.
  • Sodium salicylate, sodium heparin, and vitamin C are small molecular organic compounds containing polar groups such as -OH, -SO 3 H, -NH 2 , -NHR, -COOH, and the like.
  • polyethylene glycol, polylysine, sodium hyaluronate, poloxamer, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene oxide, polyacrylate and polyacrylamide contain -OH, a high molecular polymer of a polar group such as -SO 3 H, -NH 2 , -NHR or -COOH.
  • the solvent is an organic solvent or a mixture of an organic solvent and water.
  • the volume percentage of the organic solvent in the solvent is 50% or more.
  • the organic solvent is selected from the group consisting of dioxane, dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, acetonitrile, N,N-dimethylacetamide, tetrahydrofuran, acetone, methanol, hexane, At least one of butanol and n-heptane.
  • the drying step may be air drying at room temperature, air drying, vacuum drying, freeze drying or heat drying.
  • the drying temperature of the heat drying is 25 to 60 °C.
  • Step S230 wrapping the drug-applied flap-wound balloon with a flexible material, and then folding each of the flaps The winding is performed, the flexible material is removed, and sterilization is performed to obtain a drug balloon expansion catheter.
  • each flap After wrapping the drug-applied flap-wound balloon with a flexible material, each flap is wound a second time, causing each flap of the balloon to fit snugly and enhancing the drug and The outer surface of the balloon and the adhesion between the drug and the outer surface of the flap make the drug structure moderately tight. This not only ensures that the drug on the balloon is not easily washed away by the blood during the delivery process, but also improves the delivery efficiency of the drug delivery to the vascular lesion site; at the same time, the polar group in the water-soluble additive can promote the drug on the balloon. It can be released quickly after reaching the target site.
  • the flexible material is polytetrafluoroethylene (abbreviation: PTFE) or polyethylene terephthalate resin (abbreviation: PET).
  • PTFE polytetrafluoroethylene
  • PET polyethylene terephthalate resin
  • the step of performing the second winding for each flap is specifically: applying a negative pressure of 0 to -50 psi to the balloon at 0 to 60 ° C, and winding each flap for 2 to 30 minutes.
  • the purpose of applying a negative pressure is to cause the balloon to be in a collapsed state, which facilitates the winding of the flap.
  • the step of sterilizing further comprises the step of coating the drug solution again on the outer surface of the flap-wound balloon and drying. After removal of the flexible material, the drug solution is again applied to ensure that the entire flap is wrapped around the outer surface of the balloon.
  • the drug solution is the drug solution of step S220.
  • the step of sterilizing further includes a step of sizing.
  • the tool used in the setting step is to protect the sleeve, that is, to protect the sleeve on the entire balloon.
  • the sterilization step is carried out in ethylene oxide.
  • the density of the active drug on the outer surface of the balloon of the drug balloon dilatation catheter is 0.1 to 10 ⁇ g/mm 2 .
  • each flap still has a certain angle between them, leaving a space for coating the drug solution, ensuring uniform and complete drug.
  • the preparation method of the above drug balloon dilatation catheter has the following advantages:
  • the first winding process is performed.
  • the flaps of the balloon have a certain curvature.
  • each of the flaps adhered with the drug coating only needs to undergo relatively small curl deformation, and the dried drug coating is not It will break off due to excessive winding curvature, thus reducing the damage to the drug coating. Therefore, when used, pressure is applied to the balloon, so that the balloon returns to a spherical shape under the action of internal pressure, ie The entire surface of the balloon that has been restored to a spherical shape is adhered with a drug, which ensures the integrity of the drug layer on the surface of the balloon while ensuring the stability of the drug content;
  • the drug balloon is prepared by the repeated winding process, so that the drug on the surface of the capsule is more firmly adhered and more uniform, and at the same time, the medicine volume is stable and controllable, and it is beneficial to reduce the blood flushing of the medicine during the transportation process.
  • the loss rate ensures rapid drug release and improves product performance
  • the flap-wound balloon of one embodiment can be applied to the preparation of a drug balloon dilatation catheter.
  • the flap-wound balloon can be prepared by the step S210 in the preparation method of the above-described drug balloon dilatation catheter.
  • the flap-wound balloon includes n arc-shaped flaps, n is an integer greater than or equal to 2, and an acute angle formed by a tangent to a midpoint of an arc of adjacent two flaps is 30° to 75°.
  • the flap-wound balloon can be used to prepare a drug-wound balloon catheter, which enables the drug balloon dilatation catheter to have higher drug delivery efficiency.
  • paclitaxel is an active drug.
  • a balloon (3 mm in diameter, 20 mm in length, nylon balloon) is surface-pretreated at room temperature using a plasma machine.
  • the plasma is a mixture of argon and oxygen, of which argon is used.
  • the volume of gas and oxygen is 1:1, the output power is 500W, the frequency is 30MHz, and the air pressure is 50Pa.
  • the processing time is 10 minutes.
  • the outer surface of the balloon was folded using a flapping machine to form three flaps; then at 60 ° C. Applying a negative pressure of -20 psi to the balloon to bring the entire balloon to a collapsed state, and then each of the flaps is wound for the first time, wound for 10 s, and the flaps are curved to obtain a flap winding.
  • the balloon wherein, after winding, the acute angle formed by the tangent of the midpoint of the arc of the adjacent flap is about 55°.
  • the drug solution is dripped onto the outer surface of the flap-wound balloon with a precision syringe, dried at 40 ° C, and the drug solution is again dispensed on the outer surface of the flap-wound balloon. After drying at 40 ° C until the average density of the active drug of the balloon was 3 ⁇ g / mm 2 and drying again at 40 ° C for 3 hours, a drug-wound flap-wound balloon was obtained.
  • the drug-coated flap-wound balloon was coated with a polytetrafluoroethylene film, and then a negative pressure of -20 psi was applied to the balloon at 60 ° C to cause the entire balloon to be in a collapsed state, and then each folded
  • the wings were wound a second time and wound for 30 s; then the Teflon film was removed, a protective sleeve was placed, packaged, and sterilized in ethylene oxide to obtain a drug balloon dilatation catheter of the present example.
  • paclitaxel is an active drug.
  • a balloon (3 mm in diameter, 20 mm in length, nylon balloon) is surface-pretreated at room temperature using a plasma machine.
  • the plasma-treated gas is a mixture of argon and oxygen, of which nitrogen and The volume of oxygen is 3:1, the output power is 50W, the frequency is 10MHz, the air pressure is 10Pa, and the processing time is 30 minutes.
  • the outer surface of the balloon is folded by a flapping machine to form three flaps; and then at 30 ° C, Applying a negative pressure of -1 psi to the balloon causes the entire balloon to be in a collapsed state, and then each of the flaps is wound, wound for 3 s, and the flap is curved to obtain a flap-wound balloon, wherein After winding, the tangent to the midpoint of the arc where the adjacent flaps are located forms an acute angle of approximately 60°.
  • the drug solution is sprayed onto the outer surface of the flap-wound balloon by spraying equipment until the density of the active drug on the balloon is 3 ⁇ g/mm 2 , and naturally dried for 24 hours to obtain a viscosity.
  • a flap-wound balloon with a drug attached In a Class 100 clean environment, the drug solution is sprayed onto the outer surface of the flap-wound balloon by spraying equipment until the density of the active drug on the balloon is 3 ⁇ g/mm 2 , and naturally dried for 24 hours to obtain a viscosity.
  • a flap-wound balloon with a drug attached is sprayed onto the outer surface of the flap-wound balloon by spraying equipment until the density of the active drug on the balloon is 3 ⁇ g/mm 2 , and naturally dried for 24 hours to obtain a viscosity.
  • the drug-coated flap-wound balloon was coated with a Teflon membrane, and then a negative pressure of -1 psi was applied to the balloon at 40 ° C to cause the entire balloon to be in a collapsed state, followed by each The flap is wound for a second time and wound for 5 minutes; then the PTFE membrane is removed, the protective sleeve is placed, packaged, and sterilized in ethylene oxide to obtain the drug balloon expansion of the present embodiment. catheter.
  • paclitaxel is an active drug.
  • the surface of the balloon (6 mm in diameter, 40 mm in length, nylon balloon) was pretreated with a plasma machine at room temperature.
  • the gas during plasma treatment was argon, the output power was 2000 W, and the frequency was 100 MHz.
  • the air pressure is 1 Pa and the processing time is 5 seconds.
  • the outer surface of the balloon was folded using a flapping machine to form six flaps; and at 0 ° C, A negative pressure of -50 psi was applied to the balloon to bring the entire balloon to a collapsed state, and then each of the flaps was wound for the first time, wound for 3 minutes, and the flaps were curved to obtain a flap winding.
  • the balloon wherein, after winding, the acute angle formed by the tangent of the midpoint of the arc of the adjacent flap is about 45°.
  • the drug solution is dripped onto the outer surface of the flap-wound balloon with a precision syringe, and naturally dried for 3 hours to obtain a flap-wound balloon to which the drug is adhered;
  • the vinyl fluoride film is coated with a drug-applied flap-wound balloon, and a negative pressure of 1 psi is applied to the balloon at 0 ° C to make the entire balloon into a collapsed state, and then each flap is individually
  • the second winding was performed and wound for 30 minutes; then the Teflon film was removed, and the drug solution was dispensed by a precision syringe on the flap-wound balloon until the density of the active drug on the balloon was 10 ⁇ g/ mm 2, air dry for 3 hours and put on the protective sleeve, packaged, and sterilized in ethylene oxide, the present embodiment is to obtain a pharmaceutical balloon dilation catheter.
  • paclitaxel is an active drug.
  • the surface of the balloon (4 mm in diameter, 60 mm in length, nylon balloon) is alcoholized: at 70 ° C, the balloon is soaked in 99.5% alcohol solution for 5 minutes, then Remove the balloon and dry it.
  • each of the flaps was wound for the first time, wound for 2 seconds, and the flaps were curved to obtain a flap-wound balloon, wherein after winding, the arc of the adjacent flaps was obtained.
  • the acute angle formed by the tangent to the midpoint of the line is approximately 70°.
  • the drug solution was dripped onto the outer surface of the flap-wound balloon with a precision syringe, and air-dried for 3 hours to obtain a flap-wound balloon to which the drug adhered.
  • the drug-applied flap-wound balloon was coated with a polyethylene terephthalate resin film (PET), and then each of the flaps was wound a second time at 60 ° C. 2 seconds; then remove the polyethylene terephthalate resin film, and then apply the drug solution on the flap-wound balloon with a precision syringe until the density of the active drug on the balloon is 0.1 ⁇ g / mm 2 , after drying naturally for 3 hours, the protective sleeve was placed, packaged, and sterilized in ethylene oxide to obtain the drug balloon dilatation catheter of the present example.
  • PET polyethylene terephthalate resin film
  • paclitaxel is an active drug.
  • the surface of the balloon (3 mm in diameter, 20 mm in length, nylon balloon) is alcoholized: at 65 ° C, the balloon is immersed in a 95% alcohol solution for 15 minutes, and then Remove the balloon and dry it.
  • the outer surface of the balloon is biased using a flapping machine to form three spaced flaps;
  • a negative pressure of -20 psi was applied to the balloon to bring the entire balloon to a collapsed state, and then each of the flaps was wound for the first time, wound for 3 seconds, and the flaps were curved to obtain a flap winding.
  • the balloon wherein, after winding, the acute angle formed by the tangent to the midpoint of the arc of the adjacent flap is about 60°.
  • the drug solution is dripped onto the outer surface of the flap-wound balloon with a precision syringe, and after drying for 3 hours, the drug is adhered to the outer surface of the flap-wound balloon.
  • the drug-coated flap-wound balloon was coated with a Teflon membrane, and then a negative pressure of -20 psi was applied to the balloon at 40 ° C to cause the entire balloon to be in a collapsed state, and then each Each of the flaps is wound for a second time, wound for 5 minutes; then the PTFE membrane is removed, and the drug solution is dripped on the flap-wound balloon with a precision syringe until the density of the active drug on the balloon All were 3 ⁇ g/mm 2 , and after drying naturally for 3 hours, a protective sleeve was placed, packaged, and sterilized in ethylene oxide to obtain a drug balloon dilatation catheter of the present example.
  • paclitaxel is an active drug.
  • the surface of the balloon (diameter 3mm, length 20mm, nylon balloon) was pretreated with a plasma machine at room temperature.
  • the gas during plasma treatment was nitrogen, the output power was 500W, and the frequency was 50MHz.
  • the pressure is 50 Pa and the treatment time is 15 minutes.
  • the drug solution is dripped onto the outer surface of the flap-wound balloon with a precision syringe, and naturally dried for 3 hours to obtain a flap-wound balloon to which the drug is adhered;
  • the vinyl fluoride film is coated with a drug-applied flap-wound balloon, and then a negative pressure of -15 psi is applied to the balloon at 40 ° C, so that the entire balloon is in a collapsed state, and then each flap is placed.
  • rapamycin is an active drug.
  • the surface of the balloon (diameter 5mm, length 40mm, nylon balloon) is pretreated with a plasma machine at room temperature.
  • the gas during plasma treatment is oxygen, the output power is 100W, and the frequency is 10MHz.
  • the pressure is 5 Pa and the treatment time is 25 minutes.
  • the outer surface of the balloon was folded by a flapping machine to form five flaps; and at 10 ° C, Each of the flaps is wound for the first time and wound for 20 seconds, and the flaps are curved, wherein after the winding, the tangent of the midpoint of the arc where the adjacent flaps are located forms an acute angle of about 50 °.
  • the drug solution is dripped onto the outer surface of the flap-wound balloon with a precision syringe, and after drying for 3 hours, a flap-wound balloon with the drug adhered is obtained, and the pair is used.
  • a polyethylene terephthalate resin film (PET) was coated with a drug-coated flap-wound balloon, and then each of the flaps was wound twice at 20 ° C for 10 minutes. Then, the polyethylene terephthalate resin film was removed, and the drug solution was dripped on the flap-wound balloon with a precision syringe until the density of the active drug on the balloon was 5 ⁇ g/mm 2 , freeze-dried. After 12 hours, the protective cannula was placed, packaged, and sterilized in ethylene oxide to obtain the drug balloon dilatation catheter of the present example.
  • paclitaxel is an active drug.
  • the gas in the plasma treatment is a mixture of argon and oxygen in a volume ratio of 5:1, the output power is 2000W, the frequency is 10MHz, the air pressure is 100Pa, and the processing time is 30 minutes.
  • the outer surface of the balloon was folded by a flapping machine to form three flaps; and at 60 ° C, Applying a negative pressure of -20 psi to the balloon causes the entire balloon to be in a collapsed state, and then each of the flaps is wound for the first time, wound for 3 seconds, and the flaps are curved to obtain a flap winding.
  • the balloon wherein, after winding, the acute angle formed by the tangent of the midpoint of the arc of the adjacent flap is 75°.
  • the drug solution is dripped onto the outer surface of the flap-wound balloon with a precision syringe, and vacuum-dried at 20 ° C for 3 hours to obtain a flap-wound balloon to which the drug is adhered;
  • the tetrafluoroethylene film is coated with a drug-applied flap-wound balloon, and then a negative pressure of -20 psi is applied to the balloon at 60 ° C, so that the entire balloon is in a collapsed state, and then each fold is folded.
  • the wings are each wound for a second time and wound for 10 minutes; then the PTFE membrane is removed, and the drug solution is dripped on the flap-wound balloon with a precision syringe until the density of the active drug on the balloon is After 6 hours of vacuum drying at 6 ⁇ g/mm 2 at 20 ° C, a protective cannula was placed, packaged, and sterilized in ethylene oxide to obtain a drug balloon dilatation catheter of the present example.
  • rapamycin is an active drug.
  • the surface of the balloon (diameter 4mm, length 40mm, nylon balloon) is alcoholized.
  • the specific operation is as follows: at 10 ° C, the balloon is in 50% alcohol solution. Soak for 120 minutes, then remove the balloon and dry it.
  • the outer surface of the balloon was folded by a flapping machine to form three flaps; and at 50 ° C, Applying a negative pressure of -35 psi to the balloon causes the entire balloon to collapse, and then each of the flaps is wound for the first time. After winding for 5 seconds, the flaps are curved to obtain a flap-wound balloon, wherein after winding, the acute angle of the tangent of the arc of the arc where the adjacent flaps are formed forms an acute angle of about 60°.
  • the drug solution is dripped onto the outer surface of the flap-wound balloon with a precision syringe, and naturally dried for 12 hours to obtain a flap-wound balloon to which the drug is adhered;
  • the vinyl fluoride film is coated with a drug-coated flap-wound balloon, and then a negative pressure of -35 psi is applied to the balloon at 60 ° C to cause the entire balloon to be in a collapsed state, and then each flap is placed.
  • the preparation method of the drug balloon dilatation catheter of Comparative Example 1 is as follows:
  • paclitaxel 50 mg of paclitaxel, 18 mg of sodium benzoate, 18 mg of PEG2000 and 7 mL of ethanol and 2 mL of water for injection were mixed to prepare a drug solution; the PTCA balloon (diameter 3 mm, length 20 mm) was placed in a clean environment at 60 ° C at 60 ° C.
  • the outer surface of the balloon was folded using a flapping machine to form three flaps; the flap was then wound at 60 ° C for 3 minutes; In the 100-level clean environment, the drug solution was dripped onto the outer surface of the balloon after the flap was wound, so that the drug concentration on the surface of the balloon was 3 ⁇ g/mm 2 , and after drying for 24 hours, the protective sleeve was placed and packaged. , ethylene oxide sterilization.
  • Comparative Example 2 is the German B.braun company Please drug balloon dilatation catheter, where: The total dose of the drug balloon dilatation catheter was calculated according to the drug density of 3.0 ⁇ g/mm 2 indicated in the specification.
  • the drug balloon (referred to as DEB) transport process loss refers to the drug balloon from the insertion of the guiding catheter, the balloon is pushed to the target lesion site, and the drug loss during the period before DEB expansion. Drug loss during delivery can be used to directly assess the binding of the drug to the balloon.
  • Example 1 The drug balloon dilatation catheters prepared in Example 1, Example 2, Example 5, Example 6 and Comparative Example 1 were subjected to a transport process loss simulation test.
  • the test method was as follows: the drug balloon dilatation catheters of Example 1, Example 2, Example 5, Example 6 and Comparative Example 1 were inserted into an in vitro simulated blood vessel model, simulating the delivery conditions of the actual use process, and controlling the delivery time was 90s, the content of the remaining drug on the balloon was analyzed by high performance liquid chromatography (HPLC).
  • the total dose on the balloon of the drug balloon dilatation catheter of Example 1, Example 2, Example 5, Example 6 and Comparative Example 1, the remaining drug amount, and the drug loss rate during the delivery process are shown in Table 1.
  • Example 1 Example 2 Example 5 Example 6 Comparative example 1 Remaining dose ( ⁇ g) 512.301 494.198 486.33 496.515 316.87 Total dose ( ⁇ g) 544.218 557.253 551.24 566.312 568.73 Loss rate (%) 5.86 11.315 11.78 12.325 44.28
  • the drug loss rate of the drug balloon dilatation catheters of Examples 1, 2, 5, and 6 was only 12.325% at most, and the drug balloon dilatation catheter delivery process of Comparative Example 1 was only subjected to one winding treatment.
  • the loss rate was 50.345%, which was much higher than the drug loss rate of the drug balloon dilatation catheters of Examples 1, 2, 5 and 6, and the drug loss rate of the drug balloon dilatation catheter of Example 1 was only 5.86%, which was much lower.
  • the drug loss rate of the drug balloon dilatation catheter of Comparative Example 1. It can be explained by Table 1 that the secondary winding or multiple windings can increase the strength of the drug structure on the balloon and the binding force of the drug to the balloon, increasing the ability of the drug to resist blood scouring.
  • Example 1 The drug balloon dilatation catheters prepared in Example 1, Example 2, Example 5, Example 6 and Comparative Example 1 were inserted into the target blood vessels of the coronary artery system of the porcine coronary artery, and the balloon fluid was filled. 12atm.
  • the rate of hyperswell (the ratio of balloon diameter to vessel diameter) is about 1.10 to 1.20; the drug is delivered to the target tissue during the 45 s liquid filling time; the balloon is then deflated and removed from the in vitro simulation test system; Target vascular tissue.
  • Example 1 Example 2 Example 5 Example 6 Comparative example 1 Total dose ( ⁇ g) 544.218 557.253 551.24 566.312 568.73 Tissue dose ( ⁇ g) 120.464 131.856 83.45 117.082 35.66 Reprint rate (%) 22.135 23.662 15.139 20.674 6.27
  • the drug balloon dilatation catheters prepared in Example 1, Example 2, Example 5 and Example 6 have a transshipment rate of at least 15.139%, which is much higher than that of the first-volume drug of Comparative Example 1.
  • the transfer rate of the balloon dilatation catheter indicates that the secondary winding can greatly improve the transfusion rate of the drug balloon dilatation catheter. This is because the angle between the flaps is drug coated after the first winding of the balloon. Leaving the applicator space, the drug can be evenly applied to the surface of the balloon after the flap is wound, and the wings that have adhered to the drug due to the curvature of the first winding are ensured during the second winding.
  • a relatively small deformation will occur, reducing the shedding of the drug coating, and more drugs will be wrapped by the wings of the balloon to avoid direct flushing of the blood during the delivery process, so that more drugs can be delivered to the ball expansion position, and It is transferred to the vascular tissue.
  • Example 1 The drug balloon dilatation catheters of Example 1 and Comparative Example 1 and Comparative Example 2 were subjected to an animal tissue transfer rate experiment.
  • the specific method is as follows: a pig with a diameter of about 3 months and a weight of about 30 kg is passed through a right femoral artery by standard angiography.
  • the balloon is placed with a stainless steel bare stent, and the stent is delivered to the coronary artery position, expanded, and then contracted. And withdraw, leaving the stainless steel stent for sampling mark; then taking the drug balloon sample to the animal coronary artery through the guiding catheter, filling the balloon at 5mm from the marker stent, filling time 45s, over-expansion ratio (ball balloon expansion)
  • the ratio of diameter to vessel diameter was 1.10 to 1.20, then the balloon was contracted and withdrawn. After 30 minutes, the sample was dissected and extracted by methanol. HPLC was used.
  • Example 1 Comparative example 1 Comparative example 2 Total dose ( ⁇ g) 544.218 568.73 480.42 Tissue dose ( ⁇ g) 82.786 33.465 24.372 Reprint rate (%) 15.212 5.88 5.073
  • the re-loading rate of the drug balloon dilatation catheter of Example 1 which was subjected to secondary winding was much higher than that of Comparative Example 1 and Comparative Example 2, indicating that the secondary winding process can improve the surface of the drug and the balloon.
  • the cohesive force, as well as the strength of the drug itself, avoids excessive scouring of the blood, ensuring that the drug balloon dilatation catheter delivers more drug to the diseased blood vessel site, thereby increasing the transfection rate of the drug balloon dilatation catheter.

Abstract

一种药物球囊扩张导管的制备方法及折翼卷绕球囊。该制备方法包括如下步骤：将球囊进行折叠(S210)，形成n个折翼，卷绕每个折翼至该折翼形成弧形结构，且使相邻两个折翼所在的弧线的中点的切线形成的锐角为30°～75°，得到该折翼卷绕球囊，其中，n为大于或者等于2的整数；在折翼卷绕球囊的外表面上涂敷药物溶液，干燥，得到粘附有药物的折翼卷绕球囊(S220)；使用柔性材料包裹附有药物的折翼卷绕球囊，再对每个折翼进行卷绕，去除柔性材料，灭菌，得到药物球囊扩充导管(S230)。该药物球囊扩张导管的制备方法制备得到的药物球囊扩张导管具有较高的药物输送效率。

Description

药物球囊扩张导管的制备方法及折翼卷绕球囊 技术领域
本发明涉及医疗器械领域，尤其涉及一种药物球囊扩张导管的制备方法及折翼卷绕球囊。
背景技术
目前全世界每年有大约150万患者接受经皮冠状动脉介入治疗(percutaneous coronary intervention,PCI)。介入治疗作为现代临床治疗学中的第3大诊疗体系，正以其微创性、定位准确、可重复性强、并发症发生率低及疗效高的鲜明特点，得到医疗学术界和广大患者的认同。
心血管介入治疗领域经历了从经皮冠状动脉腔内血管成形术(Percutaneous Transluminal Coronary Angioplasty简称：PTCA)采用裸球囊扩张到裸金属支架(Bare Metal Stents，简称：BMS)再到药物支架(Drug Eluting Stents，简称：DES)三个里程碑式的发展。PTCA可以消除冠脉狭窄，但血管管壁的弹性回缩、内膜过度增生及管壁内膜撕裂等可促发血管再狭窄，靶血管术后3～6个月再狭窄率高达30～50％。BMS可以消除即刻血管狭窄，同时大大降低急性再闭塞的发生率，但靶血管再狭窄的发生率仍高达20～30％。DES的植入可以使靶血管再狭窄的发生率降低至10％左右，但可能增加晚期血栓的发生率。另外，支架内再狭窄、小血管病变、分叉病变、外周血管病变等领域也限制了DES的应用。
药物洗脱球囊(Drug Eluting Balloon，简称：DEB，亦称：药物球囊)的出现为解决上述问题带来了新的希望。DEB是在球囊扩张术或球囊成形术等介入技术基础上发展起来的新型治疗性球囊药物释放技术，它是将抗血管内膜增生的药物涂置于球囊表面，当球囊到达血管病变处，通过扩张球囊将血管病变狭窄部位撑开，当药物涂层与血管壁内膜接触时，通过快速释放并转移药物到病 变血管壁。药物在血管扩张部位起到抗血管内膜增生的作用，从而预防血管介入术后再狭窄。
相对于DES，DEB具有如下优点：(1)DES与血管表面的接触面积大约仅为15％，DEB能将药物均匀的涂布于血管表面，从而增强了药物的效果；(2)DEB不需类似于DES的高聚物材料，从而避免了慢性的炎症刺激触发血栓形成；(3)减少了双联抗血小板药物的应用时间，从而降低费用，还可以减少口服抗血小板药物带来的并发症；(4)对于DES不能很好处理的病变，如支架内再狭窄、小血管、解剖弯曲的血管、高度钙化的血管、分叉病变，DEB操作更为灵活，更适合处理此类病变。
影响药物球囊有效性的因素主要有三个：
(1)药物的选择：目前上市DEB产品均采用紫杉醇为洗脱药物，紫杉醇是一种抗肿瘤药物，能够促进细胞微管聚合和稳定已聚合的微管，从而抑制细胞的多种功能，如增殖、迁移和信号传导；紫杉醇具有高度的脂溶性，能够快速紧密的与组织结合，从而具有较高的保留率，同时，紫杉醇改变了细胞骨架的结构，因此具有更长的药理作用，能明显的抑制血管平滑肌细胞增殖；
(2)载体的选择：不同载体的选择决定了DEB药物涂层本身的性质，也决定了药物涂层与球囊之间粘结力的大小，如果药物涂层与球囊表面之间的粘结力太小，则药物在球囊折叠过程中易脱落，或在植入病变处的输送过程中损失，或在与靶病变组织接触之前的膨胀过程中破裂脱落并被冲走；如果药物涂层与球囊表面之间的粘结力太大，则在球囊与靶病变组织接触过程中，药物不容易转载到组织上；
(3)制备工艺的选择：不同的制备工艺会影响DEB的有效性和安全性，原因如下：
制备工艺会影响紫杉醇药物在DEB制备和输送过程中的损失程度：当DEB制备和输送过程药物损失过多时，药物涂层内所含有的药量会越少，则可能导致DEB的转载率降低，影响产品有效性；
制备工艺会影响紫杉醇药物的结晶状态，当DEB涂层中的紫杉醇呈结晶状态，其颗粒释放性能、药物转载能力、药物在组织表面的保留能力和生物有效 性均优于非结晶状态的紫杉醇；
制备工艺会影响药物涂层的形貌和完整程度，DEB涂层表面形貌越好，涂层越完整，产品性能越稳定，药物才能更加均匀地覆盖在血管组织内壁，更充分地起到抑制内膜增生，减少血管再狭窄的发生概率。
目前，有一种药物球囊导管，它的球囊外表面为具有凹凸的非平面结构。该药物球囊导管采用紫外激光磨削加工球囊外表面，使球囊外表面形成具有凹凸的非平面结构，该非平面结构使药物在球囊表面的贮存得到很好的改善，一是吸附药物的量极大增加，二是球囊吸附的药物在血管中通过达到病变部位的过程中，能够尽可能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，能够有效通过球囊输送到病变部位，起到有效的治疗作用。但是仍存在以下缺点：①这种凹凸的非平面结构直接导致药物涂层中的药物分布不均匀，凹陷部分药物堆积较多，凸出部分药物较少；②凹凸的非平面结构保护了凹陷部位的药物不被血液冲刷，但是增加了凸出部位被血液冲刷的概率，更加导致了球囊表面的药物涂层的不均匀程度；③凹陷部位的药物堆积容易在球囊扩张的时候发生脱落，形成较大的颗粒，导致堵塞和血栓，存在安全隐患。
还有一种药物洗脱球囊导管，包括球囊导管本体和药物涂层，球囊导管本体包括球囊，所述球囊的外表面上设有多个凹槽，在球囊的外表面的凹槽部分及平坦部分上涂覆所述药物涂层，所述凹槽在球囊充盈后转变为反向突起。该药物洗脱球囊导管不仅可携带更多的药物，减少药物在输送过程中的损失，还能够通过反向凸起的作用将凹槽内留置的药物直接倾倒抛向血液中，加速药物的释放，并且提高了在靶位置的药物浓度，从而能够集中迅速作用于靶位置，更好防止靶位置的血管组织产生增生和再狭窄。但是仍存在以下缺点：①凹槽结构直接导致药物涂层中的药物含量不均匀，凹槽部分药物会形成堆积，药物总载药量一定的情况下，其他部位的载药量会偏低，影响药物向组织的转载；②从球囊开始扩张到球囊表面充分接触血管壁的过程中，反向凸起的作用将凹槽内留置的药物直接倾倒抛向血液中，这些药物会在瞬间被冠脉高速流动的血液冲刷走，因此只是保证了DEB在输送过程的药物损失减少，却增加了在球囊扩张瞬间药物损失的概率，也不能充分保证药物向病变部位血管组织的转载； ③凹槽内的药物堆积也较容易形成较大的颗粒，导致堵塞和血栓，存在一定的安全隐患。
另外还有一种基于氢健作用的药物球囊，它包括球囊表面和含有活性药物的药物层，其中所述球囊表面通过处理或修饰，使其带上亲水性基团，以及所述球囊表面与所述药物层之间存在氢键作用。通过氢键作用，增加药物层与球囊表面之间的粘结力，保证涂层的延展性，并利于药物在球囊表面的负载。但是从药物球囊的作用机制来看，药物球囊涂层中的药物释放模式属于暴释，氢键作用虽然有利于药物在球囊表面的负载，氢键作用力却在一定程度上阻碍了紫杉醇药物的快速释放。
再有一种新型携带药物微囊的球囊导管，该球囊导管由近端管、远端管、球囊、药物微囊和灵活尖端组成，其中球囊是一个记忆性折叠球囊，并且折叠球囊的皱褶内表面包裹着药物微囊，是运用了特殊的浸润技术将药物微囊包裹于折叠式球囊的皱褶内表面，药物微囊包裹的药物为可防治血管再狭窄的中药提取物，经浓缩后加入相应辅料，制成粉粒状药物微囊，其提高了携带药物的靶向性，能够准确定位、定时缓慢释放药物，实现长效治疗的目的。其存在的缺点是：①球囊表面载药不完整：载药位置局限于球囊褶皱内表面包裹着的药物微囊，而球囊折翼后，褶皱内表面只是球囊表面整体的一部分，药物覆盖不均匀；②药物微囊对药物的释放作用是定时缓慢释放，满足不了药物球囊的药物快速释放模式。药物球囊性能的关键评价指标是药物转载率，即：药物能够转移到组织上的量，目前已上市产品普遍存在两个问题：①药物向血管组织的转载率偏低；②药物向血管组织的转载率不稳定，波动范围较大。有一种欧洲上市产品由造影剂碘普罗胺作为载体与紫杉醇构成药物涂层涂覆在球囊导管上，该产品临床文献资料显示：该产品在冠脉血管再狭窄的临床和治疗中取得了一定的效果，提高了药物的转载率，但是转载率范围较大，存在不稳定的情况。
显然，现有的药物球囊仍然存在药物输送效率较低的问题。
发明内容
鉴于此，有必要提供一种药物球囊扩张导管的制备方法，该制备方法制备出的药物球囊扩张导管具有较高的药物输送效率。
此外，还提供一种折翼卷绕球囊，该折翼卷绕球囊能够提高药物球囊扩张导管的药物输送效率。
一种药物球囊扩张导管的制备方法，包括如下步骤：
将球囊进行折叠，形成n个折翼，卷绕每个所述折翼至所述折翼形成弧形结构，且使相邻两个所述折翼所在的弧线的中点的切线形成的锐角为30°～75°，得到折翼卷绕球囊，所述n为大于或者等于2的整数；
在所述折翼卷绕球囊的外表面上涂覆药物溶液，干燥，得到粘附有药物的折翼卷绕球囊；
使用柔性材料包裹所述粘附有药物的折翼卷绕球囊，再对每个所述折翼进行卷绕，去除所述柔性材料，灭菌，得到所述药物球囊扩充导管。
在其中一个实施例中，所述n为3、4、5或6。
在其中一个实施例中，在将所述球囊进行折叠的步骤之前，还包括对所述球囊进行醇化处理或等离子处理。
在其中一个实施例中，所述药物溶液包括活性药物、水溶性添加剂及溶剂，所述活性药物的浓度为0.1～30mg/mL，所述水溶性添加剂的浓度为0.1～15mg/mL；其中，所述活性药物为用于治疗血管再狭窄的抗内膜增生药物、抗凝血药物、抗血小板粘附药物、抗感染药物、抗菌药物或抗肿瘤药物，所述水溶性添加剂为含有极性基团的有机物。
在其中一个实施例中，所述药物球囊扩充导管的球囊的外表面上的活性药物的密度为0.1～10μg/mm2。
在其中一个实施例中，所述水溶性添加剂选自阿魏酸钠、L-苯丙氨酸、苯甲酸盐、蛋氨酸、脯氨酸、赖氨酸、亮氨酸、羟丙基-β-环糊精、山梨醇、L-缬氨酸、烟酰胺、乙酰胺、葡甲胺、L-异亮氨酸、葡萄糖、麦芽糖、吐温80、甘露醇、卵磷脂、色氨酸、L-苏氨酸、水杨酸、对氨基水杨酸钠、肝素钠、维生素C、聚乙二醇、聚赖氨酸、透明质酸钠、泊洛沙姆、聚乙烯基吡罗烷酮、聚乙烯醇、聚氧化乙烯、聚丙烯酸酯及聚丙烯酰胺中的至少一种。
在其中一个实施例中，在去除所述柔性材料的步骤之后，所述灭菌的步骤之前，还包括在所述折翼卷绕球囊的外表面再次涂覆所述药物溶液并干燥的步骤。
在其中一个实施例中，得到所述折翼卷绕球囊的步骤具体为：于0～60℃，向所述球囊内施加1～50psi的压力使所述球囊充盈，接着对所述球囊的外表面施力进行折叠，以形成所述折翼；再于0～60℃，对所述球囊施加0～-50psi的压力，再将每个所述折翼卷绕2s～30min。
一种折翼卷绕球囊，所述折翼卷绕球囊包括n个弧形折翼，所述n为大于或者等于2的整数，相邻两个所述折翼所在的弧线的中点的切线形成的锐角为30°～75°。
按上述药物球囊扩张导管的制备方法制备的药物球囊扩张导管，在球囊折翼后即制得折翼卷绕球囊，每相邻两个折翼之间具有一定的夹角，给药物溶液的涂覆留下空间，确保药物能够均匀、完整的涂覆到球囊表面，同时确保药物含量的稳定性；由于折翼是卷绕的，并成弧形结构，药物涂层干燥后，在进行二次卷绕时，球囊每个折翼只会顺着卷绕弯曲的方向发生较小的卷曲形变，已经干燥的药物涂层不会因为过大的卷绕形变而脱落，球囊的每个折翼也不会因为卷绕作用发生褶皱；通过使用柔性材料包裹粘附有药物的折翼卷绕球囊之后，再对每个折翼进行第二次卷绕，促使球囊的每个折翼能够紧密贴合，并且还能加强药物与球囊的外表面之间的粘结力，同时使药物结构适度紧密。这样有利于减少在输送过程中球囊上的药物被血液冲走的量，以降低药物的损失，提高药物输送到血管病变部位的输送效率。
附图说明
图1为一实施方式的药物球囊扩张导管的制备方法的流程图；
图2为图1中的球囊折叠后形成有多个折翼的截面示意图；
图3为图1中的折翼进行第一次卷绕后得到的折翼卷绕球囊的截面示意图；
图4为图1中的粘附有药物的折翼的放大20倍的三维显微镜图。
具体实施方式
为使本发明的上述目的、特征和优点能够更加明显易懂，下面结合实施例对本发明的具体实施方式做详细的说明。在下面的描述中阐述了很多具体细节以便于充分理解本发明。但是本发明能够以很多不同于在此描述的其它方式来实施，本领域技术人员可以在不违背本发明内涵的情况下做类似改进，因此本发明不受下面公开的具体实施的限制。
如图1所示，一实施方式的药物球囊扩张导管的制备方法，用于制备上述药物球囊扩张导管。该药物球囊扩张导管的制备方法包括如下步骤：
步骤S210：将球囊进行折叠，形成n个折翼，卷绕每个折翼至折翼形成弧形结构，且使相邻两个折翼所在的弧线的中点的切线形成的锐角为30°～75°，得到折翼卷绕球囊。其中，n为大于或者等于2的整数。
通过将每个折翼进行第一次卷绕，并使卷绕后的折翼成弧形结构，在后续卷绕过程中，涂覆有药物的每个折翼只会顺着第一次卷绕后形成的卷绕弯曲方向发生较小的形变即可，已经干燥的药物涂层不会因为过大的卷绕弧度而发生断裂脱落，从而降低了后续卷绕过程对药物涂层的破坏。
其中，球囊为尼龙球囊。
其中，采用折翼机将球囊进行折叠。
在本实施例中，步骤S210得到折翼卷绕球囊的步骤具体为：于0～60℃，向球囊内施加1～50psi的压力使球囊充盈，接着对球囊的外表面施力进行折叠，以形成折翼；再于0～60℃，对球囊施加0～-50psi的负压，再将每个折翼卷绕2s～30min，其中，对球囊施加0psi即为不对球囊施加负压。施加负压的目的是使折翼卷绕球囊处于缩瘪状态，有利于折翼的卷绕。
请参阅图2，图2为球囊折叠后的示意图，图2中球囊300形成有三个折翼320。可以理解，折翼320不限于三个。
优选的，n为3、4、5或6。
其中，在将每个折翼进行第一次卷绕的步骤之后，折翼卷绕球囊的相邻两个折翼所在的弧线的中点的切线形成的锐角为30°～75°，从而能够为后续涂药留下空间，保证药物能够完整的涂覆到球囊的表面。
请一并参阅图3，图3为折翼320进行第一次卷绕后的球囊300的截面图，即为折翼卷绕球囊的截面图，在图示的实施例中，折翼320的数量为三个。角α为相邻两个折翼所在弧线的中点的切线之间的夹角。
请参阅图4，图4为粘附有药物的折翼放大20倍的三维显微镜图。从图4中可以看出，药物(图4中白色部分)均匀分布在折翼表面，说明本发明的第一次卷绕并涂药的过程可以保证球囊表面药物涂层的均匀性和完整性，从而保证在第二次卷绕后，每个翼已经具有一定弧度，涂药后第二次卷绕的时候，折翼只需要发生相对较小的卷曲形变即可，已经干燥的药物涂层不会因为过大的卷绕弧度而发生断裂脱落；并且球囊上有更多的药物被折翼包裹，被包裹的药物能够避免输送过程血液的直接冲刷，减少了药物涂层在输送过程的药物损失。
在本实施例中，在将球囊进行折叠的步骤之前，还包括对球囊进行醇化处理或等离子处理。即对球囊的外表面进行表面处理。
其中，醇化处理的步骤具体为：在10～70℃下，将球囊于体积浓度为50～99.5％的乙醇溶液中浸泡5～120分钟，取出并干燥。
其中，等离子处理的步骤具体为：在室温下，在氮气、氧气及氩气中的至少一种气体的气氛下，于输出功率为50～2000W、频率为10～100MHz、气压为1～100Pa的条件下等离子处理5秒～30分钟。
步骤S220：在折翼卷绕球囊的外表面上涂覆药物溶液，干燥，得到粘附有药物的折翼卷绕球囊。
其中，药物溶液包括活性药物、水溶性添加剂及溶剂，其中，活性药物的浓度为0.1～30mg/mL，水溶性添加剂的浓度为0.1～15mg/mL。
在本实施例中，活性药物为用于治疗血管再狭窄的抗内膜增生药物、抗凝血药物、抗血小板粘附药物、抗感染药物、抗菌药物或抗肿瘤药物。
其中，抗内膜增生药物选自依维莫司、雷帕霉素、紫杉醇、多西紫杉醇、紫杉酚、紫杉醇衍生物、普罗布考及秋水仙碱中的至少一种。
其中，抗凝血药物选自肝素、华法林钠及维生素K拮抗剂中的至少一种。
其中，抗血小板粘附药物选自阿司匹林、前列腺素、丹酚酸、硝酸脂类药物、赖氨匹林及潘生丁中的至少一种。
其中，抗感染药物选自氨苄青霉素、头孢霉素、磺胺嘧啶及硫酸链霉素中的至少一种。
其中，抗菌药物选自壳聚糖、壳聚糖的衍生物、头孢西丁、萘啶酸及吡哌酸中的至少一种。
其中，抗肿瘤药物选自柔红霉素、阿霉素、卡铂及大环内酯类中的至少一种。
在本实施例中，水溶性添加剂为含有极性基团的有机物。其中，极性基团亲水性较强，有利于药物与含水的血液接触后，更高效快速地转载。
具体的，水溶性添加剂选自阿魏酸钠、L-苯丙氨酸、苯甲酸盐、蛋氨酸、脯氨酸、赖氨酸、亮氨酸、羟丙基-β-环糊精、山梨醇、L-缬氨酸、烟酰胺、乙酰胺、葡甲胺、L-异亮氨酸、葡萄糖、麦芽糖、吐温80、甘露醇、卵磷脂、色氨酸、L-苏氨酸、水杨酸、对氨基水杨酸钠、肝素钠、维生素C、聚乙二醇、聚赖氨酸、透明质酸钠、泊洛沙姆、聚乙烯基吡罗烷酮、聚乙烯醇、聚氧化乙烯、聚丙烯酸酯及聚丙烯酰胺中的至少一种。其中，阿魏酸钠、L-苯丙氨酸、苯甲酸盐、蛋氨酸、脯氨酸、赖氨酸、亮氨酸、羟丙基-β-环糊精、山梨醇、L-缬氨酸、烟酰胺、乙酰胺、葡甲胺、L-异亮氨酸、葡萄糖、麦芽糖、吐温80、甘露醇、卵磷脂、色氨酸、L-苏氨酸、水杨酸、对氨基水杨酸钠、肝素钠和维生素C为含有-OH、-SO3H、-NH2、-NHR、-COOH等的极性基团的小分子有机物。其中的聚乙二醇、聚赖氨酸、透明质酸钠、泊洛沙姆、聚乙烯基吡罗烷酮、聚乙烯醇、聚氧化乙烯、聚丙烯酸酯及聚丙烯酰胺为含有-OH、-SO3H、-NH2、-NHR、-COOH等的极性基团的高分子聚合物。
其中，溶剂为有机溶剂或者是有机溶剂和水的混合物。当溶剂为有机溶剂和水的混合物时，溶剂中的有机溶剂的体积百分数在50％以上。优选的，有机溶剂选自二噁烷、二甲基甲酰胺、二甲基亚砜、N-甲基吡咯烷酮、乙腈、N,N-二甲基乙酰胺、四氢呋喃、丙酮、甲醇、已醇、丁醇及正庚烷中的至少一种。
步骤S220中，干燥步骤可以为常温晾干、鼓风干燥、真空干燥、冷冻干燥或者加热干燥。其中，加热干燥的干燥温度25～60℃。
步骤S230：使用柔性材料包裹粘附有药物的折翼卷绕球囊，再对每个折翼 进行卷绕，去除柔性材料，灭菌，得到药物球囊扩充导管。
通过使用柔性材料包裹粘附有药物的折翼卷绕球囊之后，再对每个折翼进行第二次卷绕，促使球囊的每个折翼能够紧密贴合，并且还能加强药物与球囊的外表面、及药物与折翼的外表面之间的粘结力，使药物结构适度紧密。这样既保证了球囊上的药物在输送过程中不会轻易被血液冲走，提高药物输送到血管病变部位的输送效率；同时，水溶性添加剂中的极性基团可以促进球囊上的药物到达靶向部位后可以快速释放。
其中，柔性材料为聚四氟乙烯(简称：PTFE)或聚对苯二甲酸乙二醇酯树脂(简称：PET)。
其中，对每个折翼进行第二次卷绕的步骤具体为：于0～60℃，对球囊施加0～-50psi的负压，再将每个折翼卷绕2s～30min。施加负压的目的是使球囊处于缩瘪状态，有利于折翼的卷绕。
优选的，在去除柔性材料的步骤之后，灭菌的步骤之前，还包括在折翼卷绕球囊的外表面上再次涂覆药物溶液并干燥的步骤。在去除柔性材料之后，再次涂覆药物溶液以保证整个折翼卷绕球囊的外表面上的药物的含量。该药物溶液为步骤S220的药物溶液。
具体的，在去除柔性材料的步骤之后，灭菌的步骤之前，还包括定型的步骤。其中，定型步骤使用的工具为保护管套，即将保护套管套于整个球囊上。灭菌步骤是在环氧乙烷中进行的。
其中，药物球囊扩张导管的球囊的外表面上的活性药物的密度均为0.1～10μg/mm2。
上述制备方法操作十分简单，而且球囊折翼并第一次卷绕后，每个折翼之间仍然具有一定的夹角，给药物溶液的涂覆留下空间，确保药物能够均匀、完整的涂覆到球囊表面，这是由于球囊涂药采用的方法一般是注射器滴涂或者支架喷涂设备喷涂，如果每个翼之间没有夹角，没有留下涂药空间，那么药物溶液喷涂不到这个部位的球囊表面，这个部位会形成涂层缺失，影响涂层完整性。
与现有技术相比，上述药物球囊扩张导管的制备方法具备以下优点：
(1)通过在对球囊表面进行涂药之前，先对球囊进行了第一次卷绕的工艺， 使球囊的折翼具有一定的弧度，在第二次卷绕过程中，每个粘附有药物涂层的折翼只需要发生相对较小的卷曲形变即可，已经干燥的药物涂层不会因为过大的卷绕弧度而发生断裂脱落，从而降低了对药物涂层的破坏，因此当使用时，对球囊内施加压力，使得球囊在内部压力的作用下，恢复成球状，即恢复为球状的球囊的整个外表面上均粘附有药物，保证了球囊表面的药物层是完整性，同时确保药物含量的稳定性；
(2)通过控制重复卷绕工艺条件来控制药物与球囊表面的作用力，以及球囊表面的药物的紧密程度，避免了采用其它方式(如，球囊表面化学蚀刻处理、球囊表面粗糙刻槽处理等)对球囊带来的损伤，同时避免了添加新的物质，降低了球囊安全风险；
(3)通过重复卷绕工艺制备药物球囊，不仅使囊表面上的药物附着得更加牢固，且较为均匀，同时，药量稳定可控，而且有利于减少药物在输送过程中被血液冲洗导致的损失率，保证药物快速释放，提高产品性能；
(4)上述制备方法简单、稳定，操作简便，快捷。
一实施方式的折翼卷绕球囊，能够应用于制备药物球囊扩张导管。该折翼卷绕球囊可通过上述药物球囊扩张导管的制备方法中的步骤S210制备得到。
该折翼卷绕球囊包括n个弧形折翼，n为大于或者等于2的整数，相邻两个折翼所在的弧线的中点的切线形成的锐角为30°～75°。该折翼卷绕球囊能够用于制备药物卷绕球囊导管，使药物球囊扩张导管具有较高的药物输送效率。
以下为具体实施例部分：
实施例1
本实施例的药物球囊扩张导管的制备方法如下：
在万级洁净环境下，将50mg紫杉醇、18mg苯甲酸钠、18mg PEG2000与7mL乙醇和2mL注射用水混合配制药物溶液。其中，紫杉醇为活性药物。
在万级洁净环境中，在室温下，采用等离子机对球囊(直径3mm，长20mm，尼龙球囊)进行表面预处理，等离子处理使的气体为氩气和氧气的混合气体，其中，氩气和氧气的体积1:1，输出功率为500W，频率为30MHz，气压50Pa， 处理时间为10分钟。
预处理完成后，于60℃，向球囊内施加10psi的压力使球囊充盈后，使用折翼机对球囊的外表面施力进行折叠，以形成三个折翼；然后再于60℃，向球囊内施加-20psi的负压使整个球囊至缩瘪状态，然后将每个折翼各自进行第一次卷绕，卷绕10s，折翼为弧形结构，得到折翼卷绕球囊，其中，卷绕后，相邻折翼所在的弧线的中点的切线形成的锐角大约为55°。
在百级洁净环境下，将药物溶液用精密注射器滴涂到折翼卷绕球囊的外表面上，于40℃干燥，再次在折翼卷绕球囊的外表面上滴涂药物溶液，再次于40℃干燥，直至球囊的活性药物的均密度为3μg/mm2，再次于40℃干燥3小时后，得到粘附有药物的折翼卷绕球囊。
使用聚四氟乙烯膜包覆粘附有药物的折翼卷绕球囊，接着于60℃，向球囊内施加-20psi的负压，使整个球囊为缩瘪状态，接着将每个折翼进行第二次卷绕，卷绕30s；接着去掉聚四氟乙烯膜，套上保护套管，进行包装，并在环氧乙烷中灭菌，得到本实施例的药物球囊扩张导管。
实施例2
本实施例的药物球囊扩张导管的制备方法如下：
在万级洁净环境下，将80mg紫杉醇、10mg苯甲酸钠、24mg PEG2000与7mL乙醇和2mL注射用水混合配制药物溶液。其中，紫杉醇为活性药物。
在万级洁净环境中，在室温下，采用等离子机对球囊(直径3mm，长20mm，尼龙球囊)进行表面预处理，等离子处理的气体为氩气和氧气的混合气体，其中，氮气和氧气的体积3:1，输出功率为50W，频率为10MHz，气压10Pa，处理时间为30分钟。
预处理完成后，于30℃，对球囊施加20psi的压力使球囊充盈后，使用折翼机对球囊的外表面施力进行折叠，以形成三个折翼；然后再于30℃，向球囊内施加-1psi的负压使整个球囊至缩瘪状态，然后将每个折翼各自进行卷绕，卷绕3s，折翼为弧形，得到折翼卷绕球囊，其中，卷绕后，相邻折翼所在的弧线的中点的切线形成的锐角大约为60°。
在百级洁净环境下，将药物溶液用喷涂设备喷涂到折翼卷绕球囊的外表面上，直至球囊上的活性药物的密度均为3μg/mm2，自然晾干24小时，得到粘附有药物的折翼卷绕球囊。
使用聚四氟乙烯膜将粘附有药物的折翼卷绕球囊进行包覆，接着于40℃，对球囊施加-1psi的负压，使整个球囊为缩瘪状态，接着将每个折翼进行第二次卷绕，卷绕5分钟；接着去掉聚四氟乙烯膜，套上保护套管，进行包装，并在环氧乙烷中灭菌，得到本实施例的药物球囊扩张导管。
实施例3
本实施例的药物球囊扩张导管的制备方法如下：
在万级洁净环境下，将270mg紫杉醇、50mg赖氨酸、5mg聚赖氨酸与7mL乙醇和2mL注射用水混合配制药物溶液。其中，紫杉醇为活性药物。
在万级洁净环境中，在室温下，采用等离子机对球囊(直径6mm，长40mm，尼龙球囊)进行表面预处理，等离子处理时的气体为氩气，输出功率为2000W，频率为100MHz，气压1Pa，处理时间为5秒。
预处理完成后，于0℃，向球囊内施加1psi的压力使球囊充盈后，使用折翼机对球囊的外表面施力进行折叠，以形成六个折翼；再于0℃，向球囊内施加-50psi的负压使整个球囊至缩瘪状态，然后将每个折翼各自进行第一次卷绕，卷绕3分钟，折翼为弧形结构，得到折翼卷绕球囊，其中，卷绕后，相邻折翼所在的弧线的中点的切线形成的锐角大约为45°。
在百级洁净环境下，将药物溶液用精密注射器滴涂到折翼卷绕球囊的外表面上，自然晾干3小时后，得到粘附有药物的折翼卷绕球囊；使用聚四氟乙烯膜将粘附有药物的折翼卷绕球囊进行包覆，在0℃下，向球囊内施加1psi的负压，使整个球囊为缩瘪状态，接着将每个折翼各自进行第二次卷绕，卷绕30分钟；接着去掉聚四氟乙烯膜，再在折翼卷绕球囊上用精密注射器滴涂药物溶液，直至球囊上的活性药物的密度均为10μg/mm2，自然晾干3小时后，套上保护套管，进行包装，并在环氧乙烷中灭菌，得到本实施例的药物球囊扩张导管。
实施例4
本实施例的药物球囊扩张导管的制备方法如下：
在万级洁净环境下，将1mg紫杉醇、1mg水杨酸、1mg透明质酸钠与5mL乙醇和5mL注射用水混合配制药物溶液。其中，紫杉醇为活性药物。
在万级洁净环境中，对球囊(直径4mm，长60mm，尼龙球囊)的表面进行醇化处理：在70℃的条件下，将球囊于99.5％的酒精溶液中浸泡5分钟，然后将球囊取出晾干。
使用折翼机将醇化处理后，于60℃，向球囊内施加50psi的压力使球囊充盈后，使用折翼机对球囊的外表面施力进行折叠，以形成四个折翼；再于60℃，将每个折翼各自进行第一次卷绕，卷绕2秒，折翼为弧形结构，得到折翼卷绕球囊，其中，卷绕后，相邻折翼所在的弧线的中点的切线形成的锐角大约为70°。
在百级洁净环境下，将药物溶液用精密注射器滴涂到折翼卷绕球囊的外表面上，自然晾干3小时后，得到粘附有药物的折翼卷绕球囊。
使用聚对苯二甲酸乙二醇酯树脂膜(PET)将粘附有药物的折翼卷绕球囊进行包覆，接着于60℃，将每个折翼各自进行第二次卷绕，卷绕2秒；接着去掉聚对苯二甲酸乙二醇酯树脂膜，再在折翼卷绕球囊上用精密注射器滴涂药物溶液，直至球囊上的活性药物的密度均为0.1μg/mm2，自然晾干3小时后，套上保护套管，进行包装，并在环氧乙烷中灭菌，得到本实施例的药物球囊扩张导管。
实施例5
本实施例的药物球囊扩张导管的制备方法如下：
在万级洁净环境下，将30mg紫杉醇、40mg烟酰胺、30mg PEG2000与10mL乙醇配制药物溶液。其中，紫杉醇为活性药物。
在万级洁净环境中，对球囊(直径3mm，长20mm，尼龙球囊)的表面进行醇化处理：在65℃的条件下，将球囊于95％的酒精溶液中浸泡15分钟，然后将球囊取出晾干。
将球囊醇化处理后，于60℃，向球囊内施加20psi的压力使球囊充盈后，使用折翼机对球囊的外表面施力进行折叠，以形成三个间隔的折翼；再于60℃， 向球囊内施加-20psi的负压使整个球囊至缩瘪状态，然后将每个折翼各自进行第一次卷绕，卷绕3秒，折翼为弧形结构，得到折翼卷绕球囊，其中，卷绕后，相邻折翼所在的弧线的中点的切线形成的锐角大约为60°。
在百级洁净环境下，将药物溶液用精密注射器滴涂到折翼卷绕球囊的外表面上，自然晾干3小时后，在折翼卷绕球囊的外表面上粘附有药物，使用聚四氟乙烯膜将粘附有药物的折翼卷绕球囊进行包覆，接着于40℃，向球囊内施加-20psi的负压，使整个球囊为缩瘪状态，接着将每个折翼各自进行第二次卷绕，卷绕5分钟；接着去掉聚四氟乙烯膜，再在折翼卷绕球囊上用精密注射器滴涂药物溶液，直至球囊上的活性药物的密度均为3μg/mm2，自然晾干3小时后，套上保护套管，进行包装，并在环氧乙烷中灭菌，得到本实施例的药物球囊扩张导管。
实施例6
本实施例的药物球囊扩张导管的制备方法如下：
在万级洁净环境下，将120mg紫杉醇、36mg苯甲酸钠、36mg PEG2000与7mL乙醇和2mL注射用水混合配制药物溶液。其中，紫杉醇为活性药物。
在万级洁净环境中，在室温条件下，采用等离子机对球囊(直径3mm，长20mm，尼龙球囊)进行表面预处理，等离子处理时的气体为氮气，输出功率为500W，频率为50MHz，气压50Pa，处理时间为15分钟。
预处理完成后，于60℃，向球囊内施加30psi的压力使球囊充盈后，使用折翼机对球囊的外表面施力进行折叠，以形成三个折翼；再于60℃，向球囊内施加-15psi的负压使整个球囊至缩瘪状态，然后将每个折翼各自进行第一次卷绕，卷绕3分钟，折翼为弧形结构，其中，卷绕后，相邻所在的弧线的中点的切线形成的锐角大约为30°。
在百级洁净环境下，将药物溶液用精密注射器滴涂到折翼卷绕球囊的外表面上，自然晾干3小时后，得到粘附有药物的折翼卷绕球囊；使用聚四氟乙烯膜将粘附有药物的折翼卷绕球囊进行包覆，接着于40℃，向球囊内施加-15psi的负压，使整个球囊为缩瘪状态，接着将每个折翼各自进行第二次卷绕，卷绕 50秒；接着去掉聚四氟乙烯膜，再在折翼卷绕球囊上用精密注射器滴涂药物溶液，直至球囊上的活性药物的密度均为3μg/mm2，自然晾干3小时后，套上保护套管，进行包装，并在环氧乙烷中灭菌，得到本实施例的药物球囊扩张导管。
实施例7
本实施例的药物球囊扩张导管的制备方法如下：
在万级洁净环境下，将200mg雷帕霉素、30mg烟酰胺、30mg吐温80与8mL丙酮和2mL注射用水混合配制药物溶液。其中，雷帕霉素为活性药物。
在万级洁净环境中，在室温条件下，采用等离子机对球囊(直径5mm，长40mm，尼龙球囊)进行表面预处理，等离子处理时的气体为氧气，输出功率为100W，频率为10MHz，气压5Pa，处理时间为25分钟。
预处理完成后，于10℃，向球囊内施加5psi的压力使球囊充盈后，使用折翼机对球囊的外表面施力进行折叠，以形成五个折翼；再于10℃，将每个折翼各自进行第一次卷绕，卷绕20秒，折翼为弧形结构，其中，卷绕后，相邻折翼所在的弧线的中点的切线形成的锐角大约为50°。
在百级洁净环境下，将药物溶液用精密注射器滴涂到折翼卷绕球囊的外表面上，自然晾干3小时后，得到粘附有药物的折翼卷绕球囊，使用聚对苯二甲酸乙二醇酯树脂膜(PET)将粘附有药物的折翼卷绕球囊进行包覆，接着于20℃，将每个折翼各自进行第二次卷绕，卷绕10分钟；接着去掉聚对苯二甲酸乙二醇酯树脂膜，再在折翼卷绕球囊上用精密注射器滴涂药物溶液，直至球囊上的活性药物的密度均为5μg/mm2，冷冻干燥12小时后，套上保护套管，进行包装，并在环氧乙烷中灭菌，得到本实施例的药物球囊扩张导管。
实施例8
本实施例的药物球囊扩张导管的制备方法如下：
在万级洁净环境下，将10mg紫杉醇、150mg葡甲胺、150mg甘露醇与5mL甲醇和5mL注射用水混合配制药物溶液。其中，紫杉醇为活性药物。
在万级洁净环境中，在室温条件下，采用等离子机对球囊(直径3mm，长 40mm，尼龙球囊)进行表面预处理，等离子处理时的气体为体积比为5:1的氩气和氧气的混合气体，输出功率为2000W，频率为10MHz，气压100Pa，处理时间为30分钟。
预处理完成后，于60℃，向球囊内施加20psi的压力使球囊充盈后，使用折翼机对球囊的外表面施力进行折叠，以形成三个折翼；再于60℃，向球囊内施加-20psi的负压使整个球囊至缩瘪状态，然后将每个折翼各自进行第一次卷绕，卷绕3秒，折翼成弧形结构，得到折翼卷绕球囊，其中，卷绕后，相邻折翼所在的弧线的中点的切线形成的锐角为75°。
在百级洁净环境下，将药物溶液用精密注射器滴涂到折翼卷绕球囊的外表面上，20℃真空干燥3小时后，得到粘附有药物的折翼卷绕球囊；使用聚四氟乙烯膜将粘附有药物的折翼卷绕球囊进行包覆，接着于60℃，向球囊内施加-20psi的负压，使整个球囊为缩瘪状态，接着将每个折翼各自进行第二次卷绕，卷绕10分钟；接着去掉聚四氟乙烯膜，再在折翼卷绕球囊上用精密注射器滴涂药物溶液，直至球囊上的活性药物的密度均为6μg/mm2，20℃真空干燥3小时后，套上保护套管，进行包装，并在环氧乙烷中灭菌，得到本实施例的药物球囊扩张导管。
实施例9
本实施例的药物球囊扩张导管的制备方法如下：
在万级洁净环境下，将100mg雷帕霉素、30mg羟丙基-β-环糊精、5mg帕洛沙姆与8mL甲醇和2mL注射用水混合配制药物溶液。其中，雷帕霉素为活性药物。
在万级洁净环境中，对球囊的表面(直径4mm，长40mm，尼龙球囊)的表面进行醇化处理，具体操作为：在10℃的条件下，将球囊于50％的酒精溶液中浸泡120分钟，然后将球囊取出晾干。
预处理完成后，于50℃，向球囊内施加10psi的压力使球囊充盈后，使用折翼机对球囊的外表面施力进行折叠，以形成三个折翼；再于50℃，向球囊内施加-35psi的负压使整个球囊至缩瘪状态，然后将每个折翼各自进行第一次卷绕， 卷绕5秒，折翼成弧形结构，得到折翼卷绕球囊，其中，卷绕后，相邻折翼所在的弧线的中点的切线形成的锐角大约为60°。
在百级洁净环境下，将药物溶液用精密注射器滴涂到折翼卷绕球囊的外表面上，自然晾干12小时后，得到粘附有药物的折翼卷绕球囊；使用聚四氟乙烯膜将粘附有药物的折翼卷绕球囊进行包覆，接着于60℃，向球囊内施加-35psi的负压，使整个球囊为缩瘪状态，接着将每个折翼各自进行第二次卷绕，卷绕10分钟；接着去掉聚四氟乙烯膜，再在折翼卷绕球囊上用精密注射器滴涂药物溶液，直至球囊上的活性药物的密度均为3μg/mm2，自然晾干24小时后，套上保护套管，进行包装，并在环氧乙烷中灭菌，得到本实施例的药物球囊扩张导管。
对比例1
对比例1的药物球囊扩张导管的制备方法如下：
在万级环境下，将50mg紫杉醇、18mg苯甲酸钠、18mg PEG2000与7mL乙醇和2mL注射用水混合配制药物溶液；将PTCA球囊(直径3mm，长20mm)在万级洁净环境下，于60℃，对球囊施加30psi的压力使球囊充盈后，使用折翼机对球囊的外表面施力进行折叠，以形成三个的折翼；再于60℃，将折翼卷绕3分钟；在百级洁净环境下将药物溶液滴涂到折翼卷绕后的球囊外表面上，使球囊表面的药物浓度为3μg/mm2，自然晾干24小时后，套上保护套管，包装，环氧乙烷灭菌。
对比例2
对比例2为德国B.braun公司的
Figure PCTCN2015096034-appb-000001
Please药物球囊扩张导管，其中：
Figure PCTCN2015096034-appb-000002
Please药物球囊扩张导管的总药量按照其说明书中标明的药物密度3.0μg/mm2计算。
(一)输送过程损失模拟测试
药物球囊(简称：DEB)输送过程损失是指药物球囊从插入导引导管开始，球囊推送至靶病变位点，至DEB扩张前的这段时间内药物的损失。输送过程药物损失可以用来直接评价药物和球囊的结合力。
将实施例1、实施例2、实施例5、实施例6及对比例1制备的药物球囊扩张导管进行输送过程损失模拟测试。
测试方法为：将实施例1、实施例2、实施例5、实施例6及对比例1的药物球囊扩张导管插入到体外模拟血管模型中，模拟实际使用过程的输送条件，控制输送时间为90s，利用高效液相色谱法(简称：HPLC)分析球囊上剩余的药物含量，其中，HPLC检测条件为：日本岛津LC-20A型高效液相色谱仪，色谱柱：Aglilent ZOBAX SB-C18 4.6×250mm，5um，流动相为：甲醇:乙腈:水＝230:360:410，柱温：30℃，检测波长：227nm(紫外检测器)，流速：1.0mL/min。实施例1、实施例2、实施例5、实施例6及对比例1的药物球囊扩张导管的球囊上的总药量、剩余药量及输送过程的药物损失率见表1。
表1
  实施例1 实施例2 实施例5 实施例6 对比例1
剩余药量(μg) 512.301 494.198 486.33 496.515 316.87
总药量(μg) 544.218 557.253 551.24 566.312 568.73
损失率(％) 5.86 11.315 11.78 12.325 44.28
从表1中可以看出，实施例1、2、5和6的药物球囊扩张导管的药物损失率最多只有12.325％，而对比例1仅经过一次卷绕处理的药物球囊扩张导管输送过程损失率为50.345％，远高于实施例1、2、5和6的药物球囊扩张导管的药物损失率，且实施例1的药物球囊扩张导管的药物损失率仅为5.86％，远低于对比例1的药物球囊扩张导管的药物损失率。通过表1说明二次卷绕或多次卷绕可以增加球囊上的药物结构的强度、以及药物与球囊的结合力，增加了药物的抗血液冲刷的能力。
(二)体外模拟测试
将实施例1、实施例2、实施例5、实施例6及对比例1制备的药物球囊扩张导管插入到猪冠脉血管模拟的冠状动脉系统的靶血管中，对球囊液充至约12atm。过扩率(球囊直径与血管直径的比例)约为1.10～1.20；药物在45s的液充时间内被输送到靶组织中；然后将球囊放气并从体外模拟测试系统中取出；收集靶血管组织。
通过组织提取和HPLC(日本岛津LC-20A高效液相色谱仪，色谱柱：Aglilent ZOBAX SB-C18 4.6×250mm，5um，流动相：甲醇:乙腈:水＝230:360:410，柱温：30℃，检测波长：227nm(紫外检测器)，流速：1.0mL/min)，检测血管组织中的药物含量，评价药物球囊向血管组织的药物转载率。表1表示的是实施例1、实施例2、实施例5、实施例6及对比例1的药物球囊扩张导管的总药量、血管组织上的组织药量以及药物转载到血管组织上的转载率。
表2
  实施例1 实施例2 实施例5 实施例6 对比例1
总药量(μg) 544.218 557.253 551.24 566.312 568.73
组织药量(μg) 120.464 131.856 83.45 117.082 35.66
转载率(％) 22.135 23.662 15.139 20.674 6.27
由表2可以看出，实施例1、实施例2、实施例5及实施例6制备的药物球囊扩张导管的转载率至少为15.139％，远高于对比例1的经过一次卷绕的药物球囊扩张导管的转载率，说明经过二次卷绕，能够大大提高药物球囊扩张导管的转载率，这是因为球囊经过第一次卷绕后，折翼间的夹角为药物涂覆留下涂药空间，药物能够均匀的涂覆到折翼卷绕后的球囊表面，并且保证第二次卷绕时由于第一次卷绕的弧度作用，已经粘附有药物的各翼只会发生相对较小的形变，减少药物涂层的脱落，有更多的药物被球囊各翼包裹，避免输送过程血液的直接冲刷，从而使更多的药物能够被输送到球扩位置，并被转载到血管组织上。
(三)体内转载率测试
将实施例1和对比例1以及对比例2的药物球囊扩张导管进行动物体内组织转载率实验。
具体方法为：对约3月大、重约30kg的猪通过标准血管造影术经右股动脉穿刺，先用装有不锈钢裸支架的球囊，将支架输送至冠脉位置后，膨胀，然后收缩并撤回，留下不锈钢支架用于做取样标记；然后取药物球囊样品经导引导管输送至动物冠脉，在距离标记支架5mm位置充盈球囊，充盈时间45s，过扩比(球囊扩张直径与血管直径之比)1.10～1.20，然后收缩球囊并撤回，30min后解剖取样，采用甲醇进行组织提取，使用HPLC(日本岛津LC-20A高效液相色谱仪，色谱柱：Aglilent ZOBAX SB-C18 4.6×250mm，5um，流动相：甲醇:乙腈:水＝230:360:410，柱温：30℃，检测波长：227nm(紫外检测器)，流速：1.0mL/min)检测血管组织中的药物含量。表3表示的是实施例1、对比例1以及对比例2的药物球囊扩张导管的体内组织转载率测试结果(药物球囊扩张导管上的总药量、转载到血管组织上的药量以及转转率)。
表3
  实施例1 对比例1 对比例2
总药量(μg) 544.218 568.73 480.42
组织药量(μg) 82.786 33.465 24.372
转载率(％) 15.212 5.88 5.073
从表3中可知，经过二次卷绕的实施例1为的药物球囊扩张导管的转载率远高于对比例1和对比例2，说明二次卷绕工艺可以提高药物与球囊表面的粘结力，以及增强药物本身的强度，避免血液的过分冲刷，保证了药物球囊扩张导管将更多的药物输送到病变血管部位，从而提高了药物球囊扩张导管的转载率。
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对本发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。

Claims (9)

  1. 一种药物球囊扩张导管的制备方法，其特征在于，包括如下步骤：
    将球囊进行折叠，形成n个折翼，卷绕每个所述折翼至所述折翼形成弧形结构，且使相邻两个所述折翼所在的弧线的中点的切线形成的锐角为30°～75°，得到折翼卷绕球囊，所述n为大于或者等于2的整数；
    在所述折翼卷绕球囊的外表面上涂覆药物溶液，干燥，得到粘附有药物的折翼卷绕球囊；
    使用柔性材料包裹所述粘附有药物的折翼卷绕球囊，再对每个所述折翼进行卷绕，去除所述柔性材料，灭菌，得到所述药物球囊扩充导管。
  2. 根据权利要求1所述的药物球囊扩张导管的制备方法，其特征在于，所述n为3、4、5或6。
  3. 根据权利要求1所述的药物球囊扩张导管的制备方法，其特征在于，在将所述球囊进行折叠的步骤之前，还包括对所述球囊进行醇化处理或等离子处理。
  4. 根据权利要求1所述的药物球囊扩张导管的制备方法，其特征在于，所述药物溶液包括活性药物、水溶性添加剂及溶剂，所述活性药物的浓度为0.1～30mg/mL，所述水溶性添加剂的浓度为0.1～15mg/mL；其中，所述活性药物为用于治疗血管再狭窄的抗内膜增生药物、抗凝血药物、抗血小板粘附药物、抗感染药物、抗菌药物或抗肿瘤药物，所述水溶性添加剂为含有极性基团的有机物。
  5. 根据权利要求4所述的药物球囊扩张导管的制备方法，其特征在于，所述药物球囊扩充导管的球囊的外表面上的活性药物的密度为0.1～10μg/mm2。
  6. 根据权利要求4所述的药物球囊扩张导管的制备方法，其特征在于，所述水溶性添加剂选自阿魏酸钠、L-苯丙氨酸、苯甲酸盐、蛋氨酸、脯氨酸、赖氨酸、亮氨酸、羟丙基-β-环糊精、山梨醇、L-缬氨酸、烟酰胺、乙酰胺、葡甲胺、L-异亮氨酸、葡萄糖、麦芽糖、吐温80、甘露醇、卵磷脂、色氨酸、L-苏氨酸、水杨酸、对氨基水杨酸钠、肝素钠、维生素C、聚乙二醇、聚赖氨酸、透 明质酸钠、泊洛沙姆、聚乙烯基吡罗烷酮、聚乙烯醇、聚氧化乙烯、聚丙烯酸酯及聚丙烯酰胺中的至少一种。
  7. 根据权利要求1所述的药物球囊扩张导管的制备方法，其特征在于，在去除所述柔性材料的步骤之后，所述灭菌的步骤之前，还包括在所述折翼卷绕球囊的外表面再次涂覆所述药物溶液并干燥的步骤。
  8. 根据权利要求1所述的药物球囊扩张导管的制备方法，其特征在于，得到所述折翼卷绕球囊的步骤具体为：于0～60℃，向所述球囊内施加1～50psi的压力使所述球囊充盈，接着对所述球囊的外表面施力进行折叠，以形成所述折翼；再于0～60℃，对所述球囊施加0～-50psi的压力，再将每个所述折翼卷绕2s～30min。
  9. 一种折翼卷绕球囊，其特征在于，所述折翼卷绕球囊包括n个弧形折翼，所述n为大于或者等于2的整数，相邻两个所述折翼所在的弧线的中点的切线形成的锐角为30°～75°。
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CN106237330A (zh) * 2016-07-27 2016-12-21 杭州唯强医疗科技有限公司 用于动脉血管病变扩张载药球囊的复配药物及载药球囊
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CN109481826A (zh) * 2018-11-05 2019-03-19 南京友德邦医疗科技有限公司 一种药物涂层球囊导管及其制备方法
CN112933301B (zh) * 2019-11-26 2023-01-24 上海微创医疗器械（集团）有限公司 载药植入医疗器械及其制备方法
CN114098899B (zh) * 2021-11-04 2023-11-03 杭州天路医疗器械有限公司 非封闭式球囊的冲击波导管及其制备工艺、定向送药方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009135125A2 (en) * 2008-05-01 2009-11-05 Bayer Schering Pharma Ag Catheter balloon drug adherence techniques and methods
CN101687066A (zh) * 2007-01-21 2010-03-31 汉莫提克股份有限公司 治疗体通道狭窄和预防危险的再狭窄的医学产品
WO2011061295A1 (en) * 2009-11-19 2011-05-26 Blue Medical Devices Bv Narrow profile composition-releasing expandable medical balloon catheter
US20130066268A1 (en) * 2006-02-09 2013-03-14 B. Braun Melsungen Ag Coating Method for a Folded Balloon

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130066268A1 (en) * 2006-02-09 2013-03-14 B. Braun Melsungen Ag Coating Method for a Folded Balloon
CN101687066A (zh) * 2007-01-21 2010-03-31 汉莫提克股份有限公司 治疗体通道狭窄和预防危险的再狭窄的医学产品
WO2009135125A2 (en) * 2008-05-01 2009-11-05 Bayer Schering Pharma Ag Catheter balloon drug adherence techniques and methods
WO2011061295A1 (en) * 2009-11-19 2011-05-26 Blue Medical Devices Bv Narrow profile composition-releasing expandable medical balloon catheter

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106075703A (zh) * 2016-07-27 2016-11-09 杭州唯强医疗科技有限公司 载药球囊及其载药球囊的制造方法
CN106237330A (zh) * 2016-07-27 2016-12-21 杭州唯强医疗科技有限公司 用于动脉血管病变扩张载药球囊的复配药物及载药球囊
WO2018019055A1 (zh) * 2016-07-27 2018-02-01 杭州唯强医疗科技有限公司 用于动脉血管病变扩张载药球囊的复配药物及载药球囊
CN108295361A (zh) * 2018-02-23 2018-07-20 北京东方金荣超声电器有限公司 一种药物球囊涂药设备
CN108295361B (zh) * 2018-02-23 2023-10-03 北京东方金荣超声电器有限公司 一种药物球囊涂药设备

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