WO2020244388A1 - Surface-drug-loading inflatable balloon for vertebroplasty and preparation method therefor - Google Patents

Surface-drug-loading inflatable balloon for vertebroplasty and preparation method therefor Download PDF

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Publication number
WO2020244388A1
WO2020244388A1 PCT/CN2020/091478 CN2020091478W WO2020244388A1 WO 2020244388 A1 WO2020244388 A1 WO 2020244388A1 CN 2020091478 W CN2020091478 W CN 2020091478W WO 2020244388 A1 WO2020244388 A1 WO 2020244388A1
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WIPO (PCT)
Prior art keywords
drug
coating
balloon
vertebroplasty
loaded
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PCT/CN2020/091478
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French (fr)
Chinese (zh)
Inventor
张海军
孙刚
田振凡
侯文博
周超
尹玉霞
鲁手涛
刘光
Original Assignee
山东百多安医疗器械股份有限公司
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Publication of WO2020244388A1 publication Critical patent/WO2020244388A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/56—Surgical instruments or methods for treatment of bones or joints; Devices specially adapted therefor
    • A61B17/58—Surgical instruments or methods for treatment of bones or joints; Devices specially adapted therefor for osteosynthesis, e.g. bone plates, screws, setting implements or the like
    • A61B17/88—Osteosynthesis instruments; Methods or means for implanting or extracting internal or external fixation devices
    • A61B17/8802—Equipment for handling bone cement or other fluid fillers
    • A61B17/8805—Equipment for handling bone cement or other fluid fillers for introducing fluid filler into bone or extracting it
    • A61B17/8816—Equipment for handling bone cement or other fluid fillers for introducing fluid filler into bone or extracting it characterised by the conduit, e.g. tube, along which fluid flows into the body or by conduit connections
    • 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
    • A61M25/0021—Catheters; Hollow probes characterised by the form of the tubing
    • 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
    • A61M25/0043—Catheters; Hollow probes characterised by structural features
    • 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
    • A61M25/1027—Making of 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
    • A61M29/00—Dilators with or without means for introducing media, e.g. remedies
    • A61M29/02—Dilators made of swellable material
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/56—Surgical instruments or methods for treatment of bones or joints; Devices specially adapted therefor
    • A61B2017/564—Methods for bone or joint treatment
    • 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
    • A61M2025/0008—Catheters; Hollow probes having visible markings on its surface, i.e. visible to the naked eye, for any purpose, e.g. insertion depth markers, rotational markers or identification of type
    • 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
    • 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
    • A61M2210/00—Anatomical parts of the body
    • A61M2210/10—Trunk
    • A61M2210/1003—Spinal column

Definitions

  • the invention relates to an expansion balloon for vertebroplasty, in particular to a vertebroplasty expansion balloon with a drug on its surface and a preparation method thereof, and belongs to the technical field of medical devices for percutaneous vertebroplasty.
  • Bone cement is prone to leak and diffuse during injection, damaging nerves, veins or other tissues; after a period of support, the bone cement is not closely connected with the original vertebral body tissues and easily prolapses out of the original position; caused by osteoporosis Decreased bone density, bone loss, and increased bone fragility are prone to re-fractures and secondary fractures.
  • the balloon used in percutaneous vertebroplasty or percutaneous kyphoplasty uses polyethylene, polyethylene terephthalate, nylon, nylon elastomer (Pebax), polyurethane, polyether Made of polyurethane and other materials, the surface of the balloon is smooth, which can only achieve the function of expanding the body to form a cavity, which cannot solve the above-mentioned shortcomings.
  • Patent CN107088259A discloses a drug balloon structure with flaps, which is 360° loaded with drugs, and the surface of the balloon in the flaps can also contact blood vessels when the balloon is filled to release drugs.
  • Patent CN108853690A discloses a design of a membrane-sealed drug storage balloon. The surface of the balloon is directly pressed out of the surface texture, the surface is sprayed with drugs, and then the film is used to seal it. When the balloon is filled in the blood vessel, the film is ruptured to release the drug .
  • the above balloons are used in blood vessels and are designed for the special use environment of blood vessels. Although these balloons carry drugs on their surfaces, they are administered through contact with the drugs and blood vessels. The drugs cannot be left in the affected area for a long time. To the purpose of sustained release.
  • Patent CN107596455A uses a degradable polymer mesh balloon to wrap bone cement, and realizes the antibacterial properties of the material by adding nano-ZnO.
  • the defect of this patent is: the balloon cannot expand and raise the vertebral body to form bone cement infusion The cavity is unable to squeeze the loose vertebral body tissues and compact, so the effect of restoring the height of the vertebral body is poor; and the mesh balloon has not been loaded with drugs, which cannot treat the cause of osteoporosis, and the incidence of secondary fractures is high.
  • Patent CN106726019A discloses a minimally invasive fusion cage with nano-bioglass coating through the intervertebral foramen.
  • the minimally invasive cage uses cobalt-chromium alloy wires to achieve flexibility and mechanical support, and the nano-bioglass coating is attached to the surface to increase its biological phase.
  • Capacitive used in the treatment of lumbar vertebral instability during lumbar interbody fusion under intervertebral foraminal endoscope. This patent has different application fields and does not realize the function of forming bone cement to fill the cavity and load medicine.
  • the functions of the currently disclosed balloons are relatively simple, and there is no ball that can meet the multiple functions of preventing bone cement dislocation, ensuring the continuous action of drugs, increasing bone density, and reducing the probability of fractures caused by osteoporosis.
  • the capsule is open.
  • the present invention provides a drug-loaded vertebroplasty expansion balloon, the expansion balloon surface attached There is a drug-loaded film, which can be retained in the body after the balloon is withdrawn to form a shell that wraps the bone cement, which not only plays a role in effectively releasing the drug to the desired site, improves the efficiency of the drug, but also prevents
  • the role of bone cement from the position and multi-faceted function improves the postoperative effect of percutaneous vertebroplasty and percutaneous kyphoplasty, and is especially suitable for the treatment of osteoporosis and related compression fractures.
  • the present invention also provides a method for preparing the vertebroplasty expansion balloon with a drug on the surface, which is simple to operate, easy to implement, and convenient for industrial production.
  • the present invention provides a vertebroplasty and dilatation balloon with a drug on its surface.
  • the vertebroplasty and dilatation balloon with a drug on the surface includes a balloon body, and a drug-loading membrane is attached to the surface of the balloon body.
  • At least two layers of drug-carrying coatings are composed, wherein the first drug-carrying coating directly in contact with the balloon body is formed by electrostatic spinning.
  • the balloon body of the present invention is attached with a drug-loaded film on the surface.
  • the drug-loaded film expands with the balloon body when the balloon body is pressurized and expanded.
  • the balloon body is retracted and compressed, due to the stress and friction between the vertebral body Separated from the balloon, it still maintains the shape of the balloon body when it is inflated, and is left in the affected area in close contact with the vertebral body tissue, so that the bone cement can be injected into the cavity wrapped by the drug-loaded membrane, which is equivalent to a shell of the bone cement , Wrap the bone cement to prevent its leakage.
  • the number of layers of the drug-loaded coating can be selected and adjusted according to actual needs such as the type of drug required, the amount of drug loaded, etc., at least two layers, preferably 2-5 layers, such as 2 layers, 3 layers, 4 floors, 5 floors.
  • other drug-carrying coatings can be formed by electrospinning, spraying, leaching or brushing, etc., for example, other layers are sprayed, It is formed by one of leaching, brushing, and electrostatic spinning, or each layer is formed by a different formation method, or part of the drug-loaded coating is formed in the same way and part is formed in a different way.
  • a layer of drug-loaded coating in the present invention means that the composition and formation method of the drug-loaded coating layer are exactly the same, and the same formation method is used but different components cannot be counted as the same layer.
  • the same composition is used but the formation method is used. Differences cannot be counted as the same layer.
  • the composition and the formation method are the same, even if the drug-loaded coating is formed through multiple operations, it is counted as the same layer. For example, in order to meet the film drug loading or thickness requirements, the coating formed by multiple spray-drying methods is counted as the same layer.
  • the drug-loaded film adopts an electrospinning-spraying method, or an electrospinning-extraction method, or an electrospinning-brushing method, or an electrospinning-spraying-dipping method.
  • the method of extraction, or the method of electrospinning-extraction-spraying, or the method of electrospinning-spraying-extraction-brushing, or the method of electrospinning-spraying-electrospinning-extraction, or electrospinning Silk-spraying-electrospinning-spraying, or electrospinning-extraction-electrospinning-extraction and other different methods are formed.
  • the two adjacent drug-carrying coatings adopt two different formation methods, a and b; the formation method a refers to electrospinning, and the formation method b refers to It can be formed by spraying, leaching or brushing.
  • the drug-loaded film adopts the method of electrospinning-spraying, or electrospinning-spraying-electrospinning-spraying, or electrospinning-extraction-electrospinning-extraction, or electrospinning -Spray-electrospinning-extraction and other different ways to form.
  • the number of layers of the drug-loaded coating is two, and the second drug-loaded coating is formed by spraying, leaching or brushing.
  • the drug-loaded film adopts an electrostatic spinning-spraying method, or an electrostatic spinning-extraction method, or an electrostatic spinning-painting method.
  • each layer of drug-loaded coating can be adjusted according to different reasons such as drug-loaded amount, type and quantity of drugs, use requirements, etc., and the thickness of each drug-loaded coating is about 0.05-0.2 mm.
  • the surface of the drug-loaded film is preferably a non-smooth structure to increase friction with surrounding tissues.
  • the surface of the drug-loaded film is distributed with protrusions or/and grooves, protrusions or / And grooves are preferably evenly distributed on the surface of the drug-loaded film, and the shape of the protrusions or/and grooves can be selected at will, and can be at least one of wavy, zigzag, spiral, needle, rod, figure, etc.
  • the convex shape of the figure may be at least one of a circle, an ellipse, a regular polygon, an irregular polygon, and an irregular figure.
  • the height or depth of the protrusions or/and grooves can be adjusted as required, and is generally 0.01 to 0.1 mm.
  • the vertebroplasty expansion balloon with the drug on the surface of the present invention expands and expands under pressure, and then retracts and withdraws from the body.
  • the drug-loaded membrane is due to the stress between the vertebral body It is separated from the balloon by friction and maintains the expanded and expanded shape of the balloon body.
  • the drug-loaded membrane can wrap the bone cement to prevent its leakage and avoid damage to the surrounding tissues.
  • the protrusions or/and grooves can increase the friction between the bone cement and the vertebral body, which is more conducive to the separation of the drug-loaded membrane from the balloon body, and can also prevent the bone cement wrapped by it from coming out of the original position.
  • the protrusions Or/and the groove can increase the specific surface area of the drug-loaded film and increase the drug-loading amount.
  • the protrusions or/and grooves on the surface of the drug-loading film are composed of protrusions or/and grooves on each layer of the drug-loading coating, and the surface of at least one drug-loading coating is provided with protrusions or/and Grooves, that is, protrusions or/and grooves can be provided on each layer, or only part of the drug-loaded coating, and the shape of the protrusions or/and grooves is consistent with the above description.
  • the surface of the first layer of drug-loaded coating is provided with protrusions or/and grooves, which can increase the load of the subsequent drug-loaded coating, increase the amount of drug loaded, and adjust the protrusions or/and grooves.
  • the height or depth of the groove can make the protrusions or/and grooves of the first drug-loaded coating still protrude or dent on the outer surface of the drug-loaded film.
  • other drug-loaded coatings can also be provided with protrusions or/and grooves to further increase the drug loading or friction .
  • protrusions or/and grooves on the drug-loaded coating or the drug-loaded film can be realized by any technology that is feasible in the prior art, such as etching, engraving, spraying, pressing, and laser groove technology.
  • the drug-carrying membrane is provided with through holes that can penetrate each layer of the drug-carrying coating, and the size of the through holes is millimeter-level.
  • the bone cement When the bone cement is injected into the cavity formed by the drug-loaded film, the bone cement can seep out through the through holes in the drug-loaded film in a small amount before it is solidified, forming a structure similar to the convex shape, which can interact with the convexity on the drug-loading film. Plays the same role.
  • the balloon body of the present invention is an expanding balloon frequently used in percutaneous vertebroplasty or percutaneous kyphoplasty, and can also be referred to as an inflatable balloon or an inflatable balloon. It can be purchased directly from the market, or it can be prepared by itself according to the methods disclosed in the prior art.
  • the expansion balloon uses one of polyethylene (PE), polyethylene terephthalate (PET), polyamide (PA), nylon elastomer (Pebax), polyurethane (PU) and other materials or Various made.
  • PE polyethylene
  • PET polyethylene terephthalate
  • PA polyamide
  • Pebax nylon elastomer
  • PU polyurethane
  • the drug-loaded coating formed by electrospinning contains drugs and degradable polymer materials. After electrospinning, the drug is fused with the degradable polymer material and is not easy to release. The degradable polymer material degrades. It is released slowly during the process, which plays a role of slow release.
  • the drug-loaded coating formed by other methods such as spraying, leaching or brushing contains drugs without degradable polymer materials, and the drugs can be released quickly. Electrospinning, spraying, leaching or brushing can be performed using conventional procedures reported in the prior art.
  • each drug-loaded coating layer may contain one or more drugs, and the drug in each drug-loaded coating layer may be the same or different; the drug-loaded amount in each drug-loaded coating layer may be the same, It can also be different.
  • the drug may be one or more of drugs that inhibit bone resorption, drugs that promote bone formation, analgesics, anesthetics, etc.; the drugs that inhibit bone resorption include bisphosphonates, and the drugs that promote bone formation include parathyroid At least one of gland hormone, prostaglandin E2, fluoride, strontium salt, etc.
  • the analgesic drug includes arginine aspirin
  • the anesthetic drug includes at least one of procaine and lidocaine.
  • the degradable polymer material is polylactic acid (PLA), polylactic acid-glycolic acid copolymer (PLGA), chitosan, sodium alginate, polyethylene glycol (PEG), polyglycolide (PGA) ), polycaprolactone (PCL), polyaspartic acid (PASP), sodium carboxymethyl cellulose (CMC), hydroxypropyl methyl cellulose (INN), polyvinyl alcohol (PVA), polyether, etc. At least one of them.
  • the performance parameters of degradable polymer materials are required to be: viscosity 0.1-0.5dl/g, weight average molecular weight 20000-100000.
  • the viscosity requirements of the electrospinning solution can be met, and the drug-loaded membrane can be more conducive to the detachment from the balloon body after the balloon body is expanded and retracted, and is more conducive to the formation of the drug film A cavity that can hold bone cement.
  • the drug-loading amount of the drug-loaded coating formed by the electrospinning method is 1-300 mg/cm 2 .
  • the drug loading amount of the drug-loaded coating formed by spraying, leaching or brushing is 1 to 500 mg/cm 2 .
  • the present invention also provides a method for preparing a vertebroplasty and dilatable balloon with a drug on its surface, the method comprising the following steps:
  • the electrospinning solution in addition to drugs and polymer degradable materials, also contains other components required for electrospinning. These components can be selected according to the contents disclosed in the prior art . The conditions of electrospinning are adjusted according to the required film thickness, drug loading, etc.
  • the solvent can be any solvent that can be used in the human body and can dissolve drugs.
  • water is preferred for water-soluble drugs, and suitable solvents are selected for non-water-soluble drugs according to the properties of different drugs. It can be one type or multiple types.
  • the above preparation method further includes the step of forming protrusions or grooves on at least one layer of the drug-loaded coating.
  • the above preparation method further includes the step of forming a through hole on the drug-carrying film.
  • the invention discloses a vertebroplasty expansion balloon with a drug on its surface, which comprises a balloon body, and a drug-loading membrane is attached on the surface of the balloon body.
  • the drug-loaded vertebroplasty balloon can be used to restore the height of the vertebral body in minimally invasive surgery such as kyphoplasty, form and maintain a bone cement perfusion cavity, release drugs locally, and reduce secondary fractures and re-fractures.
  • the present invention is provided with a drug-carrying membrane on the surface of the balloon body.
  • the drug-loaded membrane separates from the balloon due to the stress and friction between the vertebral body, temporarily supports the shape of the vertebral body, and stays in the affected area in close contact with the vertebral body tissue, providing a cavity and package for the filled bone cement. Prevent the bone cement from spreading out to other tissues, and avoid serious complications such as nerve and dural sac injury.
  • the drug-loading film of the present invention is composed of multiple drug-loading coatings. Through different formation methods of the drug-loading coating, the drug-loading film can not only release the drug quickly when placed in the body, but also stay in the affected area for a longer time. Sustained release, better drug utilization.
  • the drug-loaded membrane of the present invention can quickly and slowly release drugs locally to achieve the effects of inhibiting bone resorption, promoting bone formation or pain relief, and can further alleviate bone loss and improve bone density during postoperative repair. Better postoperative results of osteoporotic vertebral fractures and reduce the incidence of secondary fractures.
  • the drug contained in the drug-loaded film of the present invention can enter the blood circulation under the blood operation of the vertebral body, thereby realizing systemic drug administration, solving the problem of low gastrointestinal absorption and utilization of oral drugs, and improving the utilization rate of drugs, thereby increasing The amount of bone tissue per unit volume of the patient reduces osteoporosis.
  • the drug-loaded membrane of the present invention can be provided with structures such as protrusions, depressions, through holes, etc., on the one hand, it can increase the friction between the bone cement and the vertebral body, prevent the bone cement from coming out of the original position, and on the other hand, increase the drug loading
  • the specific surface area of the membrane increases the drug loading.
  • Figure 1 is a schematic diagram of the structure of the vertebroplasty and dilatation balloon with a drug on the surface of the present invention; among them, 1. the vertebroplasty and dilatation balloon with a drug on the surface, 2. the balloon body, 3, the first drug-loaded coating, and 4 , The second layer of drug-loaded coating, 5 is a balloon catheter;
  • Figure 2 Schematic diagram of the use of a vertebroplasty balloon with a drug on the surface in percutaneous kyphoplasty, left: before treatment, right: surface with drug The vertebroplasty and expansion balloon is compressed and expanded to restore the height of the vertebral body;
  • Figure 3 is a schematic diagram of the use state of the vertebroplasty balloon with medicine on the surface, left: pressurized and expanded; right: decompression and withdrawal;
  • Figure 4 is a schematic diagram of the bone cement filled with a drug-loaded film wrapped in the affected area
  • Fig. 5 is a schematic structural diagram of a protruding drug-loaded membrane; wherein, 5, a balloon catheter, and 6, a spiral protrusion extending along the axial direction of the balloon.
  • Fig. 6 is a schematic diagram of a drug-loaded membrane with a through hole wrapping the bone cement; wherein, 7, the drug-loaded membrane with a through hole, and 8, the bone cement passes through the through hole to form a protrusion.
  • a vertebroplasty and expansion balloon with a drug on the surface (referred to as a vertebroplasty and expansion balloon).
  • the vertebroplasty and expansion balloon with a drug on the surface includes a balloon body, and a drug-loaded membrane is attached to the surface of the balloon body.
  • the drug-loading film is composed of at least two drug-loading coatings, wherein the first drug-loading coating is in direct contact with the balloon body, and the other drug-loading coatings are sequentially attached to the upper drug-loading coating on.
  • Figure 1 is a schematic structural diagram of a vertebroplasty expansion balloon with two drug-loaded coatings, including the balloon body 2, the first drug-loaded coating 3 and the second drug-loaded coating 4, the first drug-loaded coating The layer 3 directly contacts the balloon body 2, and the second drug-loaded coating 4 directly contacts the first drug-loaded coating 3.
  • the balloon body is an expandable balloon, also called an inflatable balloon, an inflatable balloon, or a balloon for short.
  • the balloon body can be made of any one of polyethylene (PE), polyethylene terephthalate (PET), polyamide (PA), nylon elastomer (Pebax), polyurethane (PU) and other materials production.
  • the drug-carrying coating of the first layer is formed by electrospinning
  • the drug-carrying coating of the other layers is formed by electrospinning, spraying, leaching or brushing.
  • the thickness of the drug-loaded film formed by electrospinning is 0.05-0.2 mm, for example, 0.05 mm, 0.1 mm, 0.15 mm, 0.2 mm.
  • the drug-loading coating formed by electrostatic spinning contains drugs and degradable polymer materials, and the drug-loading coating formed by other methods contains drugs but not degradable polymer materials. Electrospinning, spraying, leaching or brushing can be carried out in the manner disclosed in the prior art.
  • each drug-loaded coating layer contains one or more drugs, and the drugs in each drug-loaded coating layer may be the same or different.
  • the drug may be at least one of bone resorption inhibiting drugs, bone formation promoting drugs, analgesic drugs, anesthetics, etc.; the bone resorption inhibiting drugs include bisphosphonates, and the bone formation promoting drugs include parathyroid hormone , Prostaglandin E2, fluoride, strontium salt, etc., the analgesic drug includes arginine aspirin, and the anesthetic drug includes at least one of procaine and lidocaine.
  • the drug loading amount of the drug-loaded coating formed by the electrospinning method is 1 ⁇ 300mg/cm 2 , this drug loading amount can be adjusted according to different drugs and different drug requirements, such as 1-20mg/cm 2 , 30-50mg / cm 2, 60-90mg / cm 2, 100-200mg / cm 2, 200-300mg / cm 2.
  • the drug loading of the drug-loaded coating formed by spraying, leaching or brushing is 1 ⁇ 500mg/cm 2 , this drug loading can be adjusted according to different drugs and different drug requirements, such as 1-20mg/ cm 2, 30-50mg / cm 2, 60-90mg / cm 2, 100-200mg / cm 2, 200-300mg / cm 2, 300-400mg / cm 2, 400-500mg / cm 2.
  • the degradable polymer material is polylactic acid (PLA), polylactic acid-glycolic acid copolymer (PLGA), chitosan, sodium alginate, polyethylene glycol (PEG), polyglycolide (PGA) ), polycaprolactone (PCL), polyaspartic acid (PASP), sodium carboxymethyl cellulose (CMC), hydroxypropyl methyl cellulose (INN), polyvinyl alcohol (PVA), polyether At least one of: the viscosity of the degradable polymer material is 0.1-0.5dl/g, and the weight average molecular weight is 20000-100000.
  • the number of layers of the drug-loaded coating is at least two, such as 2, 3, 4, 5, 6, 7 etc., preferably 2-5 layers.
  • the formation or preparation methods of the two adjacent drug-carrying coatings can be the same or different.
  • the other layers are formed by spraying, leaching, brushing, electrostatic spinning, or each layer is formed by Different formation methods are used, or some drug-loaded coatings adopt the same formation method and some use different formation methods.
  • the last layer of drug-loaded coating is not formed by electrospinning.
  • the two adjacent drug-carrying coatings adopt two different formation methods, a and b; the formation method a refers to electrospinning, and the formation method b refers to spraying, leaching or brushing.
  • the drug-loaded film adopts the method of electrospinning-spraying, or electrospinning-spraying-electrospinning-spraying, or electrospinning-extraction-electrospinning-extraction, or electrospinning -Spray-electrospinning-extraction and other different ways to form.
  • the number of layers of the drug-loading coating is two, and the second drug-loading coating is formed by spraying, leaching or brushing, for example, the drug-loading film is formed by electrospinning-spraying, or It is formed by electrospinning-leaching, or electrospinning-brushing.
  • FIG. 2 The use of the above-mentioned drug-loaded vertebroplasty and dilatation balloon is shown in Figure 2.
  • the vertebroplasty and dilatation balloon with the drug on the surface is inserted into the desired part through the expansion sleeve, as shown in Figure 3. Pressurize to inflate to restore the height of the vertebral body, and then decompress and withdraw.
  • Figure 4 after the balloon is decompressed and withdrawn, the drug-loaded membrane on the balloon surface separates from the balloon and remains in the vertebral body. The cavity is used to wrap the bone cement injected later.
  • a vertebroplasty and dilatation balloon (referred to as a vertebroplasty and dilatation balloon) loaded with a drug on its surface has the same structure as in Example 1.
  • the surface of the drug-loaded membrane is a non-smooth structure, and the surface is distributed with
  • the protrusions or/and grooves, the protrusions or/and grooves are preferably evenly distributed on the surface of the drug-loaded film, and the shape of the protrusions or/and grooves can be any shape that can increase the specific surface area or/and friction, such as waves Shapes, zigzags, spirals, needles, rods, graph shapes, etc.
  • the graph may be at least one of a circle, an ellipse, a regular polygon, an irregular polygon, an irregular graph, and the like.
  • rod-shaped protrusions are uniformly distributed on the surface of the drug-loaded membrane.
  • the surface of the drug-loaded membrane has evenly distributed spiral protrusions extending along the axial direction of the
  • the protrusions or/and grooves on the surface of the drug-loaded film are composed of protrusions or/and grooves on the drug-loaded coating, and at least the first layer of the drug-loaded coating is provided with protrusions or/and recesses.
  • Grooves that is, protrusions or/and grooves can be provided on each layer, or only part of the drug-loaded coating, and the shape of the protrusions or/and grooves is consistent with the above description.
  • the protrusions or/and grooves are formed by etching, engraving, blowing, pressing, etc., and the height or depth of the protrusions or/and grooves is 0.01-0.1mm, such as 0.01mm, 0.02mm, 0.03mm, 0.05mm, 0.08mm, 0.1mm.
  • the surface of the first layer of drug-loaded coating is provided with protrusions or/and grooves, which can increase the load of the subsequent drug-loaded coating, increase the amount of drug loaded, and adjust the protrusions or/and grooves. Or/and the height or depth of the groove can make the protrusions or/and grooves of the first drug-loaded coating still protrude or dent on the outer surface of the drug-loaded film. More preferably, on the basis that the first drug-loaded coating is provided with protrusions or/and grooves, other drug-loaded coatings may also be provided with protrusions or/and grooves to further increase the drug loading or friction force.
  • a vertebroplasty and dilatation balloon (referred to as a vertebroplasty and dilatation balloon) loaded with a drug on its surface has the same structure as that of Embodiment 1 or 2. Further, the drug-loaded membrane is also provided with a penetrating The size of the through hole of the drug-loaded coating layer is millimeter level. As shown in Figure 6, when the bone cement is injected into the cavity formed by the drug-loaded membrane, the bone cement can seep out a small amount through the through holes on the drug-loaded membrane before it is solidified, forming a protruding structure similar to The same effect as the bumps on the drug-loaded film.
  • Electrospinning to make the first drug-carrying coating fill the balloon of the balloon catheter at a nominal pressure and ground it, add the above mixed solution to the syringe of the electrospinning equipment, and set the electrospinning parameters as: speed 0.12ml/h, distance 30cm, negative pressure -0.14kV, high voltage 0.67kV, using electrospinning technology to form a drug-loaded coating on the surface of the balloon with a thickness of 0.2mm;
  • Spraying to make the second drug-carrying coating spray the bisphosphonate solution on the surface of the first drug-carrying coating at a dose of 1 to 500 mg of effective drug in the area of 1 cm 2 balloon;
  • Electrospinning to make the first drug-carrying coating fill the balloon of the balloon catheter at a nominal pressure and ground it, add the above mixed solution to the syringe of the electrospinning equipment, and set the electrospinning parameters as: speed 0.12ml/h, distance 30cm, negative pressure -0.14kV, high voltage 0.67kV, using electrospinning technology to form a drug-loaded coating on the surface of the balloon with a thickness of 0.2mm;
  • Spraying to make the second drug-carrying coating spray the bisphosphonate solution on the surface of the first drug-carrying coating at a dose of 1 to 500 mg of effective drug in the area of 1 cm 2 balloon;
  • Electrospinning to make the first drug-carrying coating fill the balloon of the balloon catheter at a nominal pressure and ground it, add the above mixed solution to the syringe of the electrospinning equipment, and set the electrospinning parameters as: speed 0.12ml/h, distance 30cm, negative pressure -0.14kV, high voltage 0.67kV, using electrospinning technology to form a drug-loaded coating on the surface of the balloon with a thickness of 0.2mm;
  • Spraying to make the second drug-carrying coating spray the bisphosphonate solution on the surface of the first drug-carrying coating at a dose of 1 to 500 mg of effective drug in the area of 1 cm 2 balloon;
  • Electrospinning to make the first drug-carrying coating fill the balloon of the balloon catheter at a nominal pressure and ground it, add the above mixed solution to the syringe of the electrospinning equipment, and set the electrospinning parameters as: speed 0.12ml/h, distance 30cm, negative pressure -0.14kV, high voltage 0.67kV, using electrospinning technology to form a drug-loaded coating on the surface of the balloon with a thickness of 0.2mm;
  • Spraying to make the second drug-loading coating spray the lidocaine solution on the surface of the first drug-loading coating at a dose of 1 to 500 mg of effective drug in the area of 1 cm 2 balloon;
  • Drying The temperature of the oven is controlled at 50 ⁇ 80°C, and the vacuum drying is 30min;
  • Electrospinning to make the first drug-carrying coating fill the balloon of the balloon catheter at a nominal pressure and ground it, add the above mixed solution to the syringe of the electrospinning equipment, and set the electrospinning parameters as: speed 0.12ml/h, distance 30cm, negative pressure -0.14kV, high voltage 0.67kV, using electrospinning technology to form a drug-loaded coating on the surface of the balloon with a thickness of 0.2mm;
  • Preparation of the second drug-carrying coating by spraying spray the bisphosphonate solution on the surface of the first drug-carrying coating at a dose of 1 to 500 mg of effective drug in the area of 1 cm 2 balloon;
  • Drying The temperature of the oven is controlled at 50 ⁇ 80°C, and the vacuum drying is 30min;
  • Electrospinning to make the third drug-carrying coating make the third drug-carrying coating on the surface of the second drug-carrying coating, add the mixed solution of step 7 above into the syringe of the electrospinning equipment, and set the electrostatic Spinning parameters are: speed 0.12ml/h, distance 30 cm, negative pressure -0.14kV, high pressure 0.67kV, and the resulting drug-loaded coating thickness is 0.2mm;
  • Preparation of the fourth drug-loaded coating by spraying spray the strontium ranelate solution on the surface of the third drug-loading coating at a dose of 1 to 500 mg of effective drug in the area of 1 cm 2 balloon;
  • Drying The temperature of the oven is controlled at 50 ⁇ 80°C, and the vacuum drying is 30min;
  • Electrospinning to make the first drug-carrying coating fill the balloon of the balloon catheter at a nominal pressure and ground it, add the above mixed solution to the syringe of the electrospinning equipment, and set the electrospinning parameters as: speed 0.12ml/h, distance 30cm, negative pressure -0.14kV, high voltage 0.67kV, using electrospinning technology to form a drug-loaded coating on the surface of the balloon with a thickness of 0.2mm;
  • Spraying to make the second drug-carrying coating spray the bisphosphonate solution on the surface of the first drug-carrying coating at a dose of 1 to 500 mg of effective drug in the area of 1 cm 2 balloon;
  • Drying The temperature of the oven is controlled at 50 ⁇ 80°C, and the vacuum drying is 30min;
  • Electrospinning to make the third drug-carrying coating make the third drug-carrying coating on the surface of the second drug-carrying coating, add the mixed solution of step 7 above into the syringe of the electrospinning equipment, and set the electrostatic Spinning parameters are: speed 0.12ml/h, distance 30cm, negative pressure -0.14kV, high pressure 0.67kV, and the resulting drug-loaded coating thickness is 0.2mm;
  • the fourth layer of drug-loading coating is made by spraying: spray the calcitonin solution on the surface of the third layer of drug-loading film according to the dose of 1 to 500 mg of effective drug in the area of 1cm 2 balloon;
  • Drying The temperature of the oven is controlled at 50 ⁇ 80°C, and the vacuum drying is 30min;
  • Electrospinning to make the first drug-carrying coating fill the balloon of the balloon catheter at a nominal pressure and ground it, add the above mixed solution to the syringe of the electrospinning equipment, and set the electrospinning parameters as: speed 0.12ml/h, distance 30cm, negative pressure -0.14kV, high voltage 0.67kV, using electrospinning technology to form a drug-loaded coating on the surface of the balloon with a thickness of 0.2mm;
  • a picosecond UV laser is used to engrave a spiral-shaped convex pattern extending along the axial direction of the balloon, the convex height is 0.05mm, and the spacing is 2mm;
  • Spraying to make the second drug-carrying coating spray the bisphosphonate solution on the surface of the first drug-carrying coating at a dose of 1 to 500 mg of effective drug in the area of 1 cm 2 balloon;
  • Electrospinning to make the first drug-carrying coating fill the balloon of the balloon catheter at a nominal pressure and ground it, add the above mixed solution to the syringe of the electrospinning equipment, and set the electrospinning parameters as: speed 0.12ml/h, distance 30cm, negative pressure -0.14kV, high voltage 0.67kV, using electrospinning technology to form a drug-loaded coating on the surface of the balloon with a thickness of 0.2mm;
  • a picosecond UV laser is used to engrave a cilia-like convex pattern with a diameter of 0.01mm and a spacing of 0.05mm;
  • Spraying to make the second drug-carrying coating spray the bisphosphonate solution on the surface of the first drug-carrying coating at a dose of 1 to 500 mg of effective drug in the area of 1 cm 2 balloon;

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Abstract

Disclosed are a surface-drug-loading inflatable balloon for vertebroplasty and a preparation method therefor, wherein same comprises a balloon body and a drug-loading film attached to the surface of the balloon body. The drug-loading film consists of at least two drug-loading coating layers, and the first drug-loading coating layer directly in contact with the balloon body is formed by means of electrospinning. In the present invention, the surface of the balloon body is provided with the drug-loading film, and the drug-loading film consists of a plurality of drug-loading coating layers. The drug-loading film can be retained in the body after the balloon is withdrawn and forms an outer shell enclosing bone cement, playing the role of effectively releasing the drug at the desired sites, improving the efficiency of the drug, and also preventing the bone cement from leaving the positions thereof. Due to multiple functions, the inflatable balloon improves postoperative effects of percutaneous vertebroplasty and percutaneous kyphoplasty, and is especially suitable for the treatment of osteoporosis and related compression fractures.

Description

一种表面载药的椎体成形扩张球囊及其制备方法Vertebroplasty and expansion balloon loaded with medicine on surface and preparation method thereof 技术领域Technical field
本发明涉及一种椎体成形术用扩张球囊，具体涉及一种表面载药的椎体成形扩张球囊及其制备方法，属于经皮椎体成形术用医疗器械技术领域。The invention relates to an expansion balloon for vertebroplasty, in particular to a vertebroplasty expansion balloon with a drug on its surface and a preparation method thereof, and belongs to the technical field of medical devices for percutaneous vertebroplasty.
背景技术Background technique
随着社会老龄化现象的加剧，骨质疏松症成为危害老年人健康的一种常见疾病。骨质疏松造成的骨折愈合过程缓慢，再次骨折的风险大，患者的生活质量受到明显的影响。在1984年，法国医生首先使用了经皮椎体成形术(percutaneous vertebroplasty,PVP)、经皮注射骨水泥甲基丙烯酸甲酯(polymethyl-methacrylate,PMMA)来增加脊柱稳定性，缓解患者疼痛，防止椎体进一步塌陷。后来此项技术传到美国，在此基础上发展出了经皮椎体后凸成形术(percutaneous kyphoplasty，PKP)，使用扩张球囊在椎体内膨胀，形成填充骨水泥的空腔，增强椎体的强度和稳定性，还能减少对神经的压迫和刺激，缓解患者的疼痛，提高患者术后的生活质量。With the intensification of social aging, osteoporosis has become a common disease that endangers the health of the elderly. The fracture healing process caused by osteoporosis is slow, the risk of fracture again is high, and the patient's quality of life is significantly affected. In 1984, French doctors first used percutaneous vertebroplasty (PVP) and percutaneous injection of bone cement methyl methacrylate (PMMA) to increase spinal stability, relieve patient pain, and prevent The vertebral body collapses further. Later, this technology was introduced to the United States, and on this basis, a percutaneous kyphoplasty (PKP) was developed, which uses an expansion balloon to expand in the vertebral body to form a cavity filled with bone cement to strengthen the vertebral body. The strength and stability of the body can also reduce the compression and stimulation of nerves, relieve the pain of the patient, and improve the quality of life of the patient after surgery.
但是经过多年的发展，经皮椎体后凸成形术仍有一些不足。例如：骨水泥在注射时容易发生渗漏弥散，损伤神经、静脉或其他组织；骨水泥在支撑一段时间后，与原有的椎体组织连接不紧密，易脱出原位；骨质疏松症引起骨密度降低、骨量丢失和骨脆性增加，容易发生再次骨折和继发骨折。而目前在经皮椎体成形术或经皮椎体后凸成形术中使用的球囊采用聚乙烯、聚对苯二甲酸乙二醇酯、尼龙、尼龙弹性体(Pebax)、聚氨酯、聚醚聚氨酯等材料制成，球囊表面光滑，仅能实现体内膨胀形成空腔的作用，对于上述不足无法解决。However, after years of development, percutaneous kyphoplasty still has some shortcomings. For example: Bone cement is prone to leak and diffuse during injection, damaging nerves, veins or other tissues; after a period of support, the bone cement is not closely connected with the original vertebral body tissues and easily prolapses out of the original position; caused by osteoporosis Decreased bone density, bone loss, and increased bone fragility are prone to re-fractures and secondary fractures. At present, the balloon used in percutaneous vertebroplasty or percutaneous kyphoplasty uses polyethylene, polyethylene terephthalate, nylon, nylon elastomer (Pebax), polyurethane, polyether Made of polyurethane and other materials, the surface of the balloon is smooth, which can only achieve the function of expanding the body to form a cavity, which cannot solve the above-mentioned shortcomings.
除了经皮椎体成形术外，还有一些疾病治疗领域需要用到扩张球囊，最常用的是冠心病等疾病的介入治疗领域。在冠心病等疾病的介入治疗中，需要使用药物洗脱球囊作用于血管中，以起到减少血管狭窄的作用。例如2004年，
Figure PCTCN2020091478-appb-000001
Please药物球囊首次将碘普罗胺与紫杉醇附着于球囊表面，应用于人体支架内再狭窄的治疗。后来2017年Kang-Ju Lee等研究发现，通过采用吹塑工艺给药物球囊表面制成微型纹理，使球囊与血管获得更大的接触面积，可以提高所负载药物的利用度。类似的，中国专利CN107088259A公开了一种具有折翼的药物球囊结构，其360°载药，在球囊充盈时折翼内的球囊表面也能接触血管进而释放药物。专利CN108853690A公开了一种膜封储药球囊的设计，直接将球囊表面压出表面纹理，表面喷涂药物，再使用覆膜将其封闭，当球囊在血管中充盈时覆膜破裂释放药物。 In addition to percutaneous vertebroplasty, there are also some disease treatment fields that require expansion balloons. The most commonly used is the interventional treatment of coronary heart disease and other diseases. In the interventional treatment of coronary heart disease and other diseases, it is necessary to use drug-eluting balloons to act in the blood vessels to reduce vascular stenosis. For example, in 2004,
Figure PCTCN2020091478-appb-000001
Please drug balloon attaches iopromide and paclitaxel to the surface of the balloon for the first time for the treatment of restenosis in a human stent. Later in 2017, a study by Kang-Ju Lee et al. found that by using a blow molding process to make a micro-texture on the surface of the drug balloon, the balloon and the blood vessel can obtain a larger contact area, which can improve the utilization of the loaded drug. Similarly, Chinese patent CN107088259A discloses a drug balloon structure with flaps, which is 360° loaded with drugs, and the surface of the balloon in the flaps can also contact blood vessels when the balloon is filled to release drugs. Patent CN108853690A discloses a design of a membrane-sealed drug storage balloon. The surface of the balloon is directly pressed out of the surface texture, the surface is sprayed with drugs, and then the film is used to seal it. When the balloon is filled in the blood vessel, the film is ruptured to release the drug .
以上球囊均是使用在血管中、针对血管的特殊使用环境设计的，这些球囊虽然表面载药，但是都是通过与药物与血管的接触实现给药，药物无法长时间的留置在患处起到持续释放的目的。The above balloons are used in blood vessels and are designed for the special use environment of blood vessels. Although these balloons carry drugs on their surfaces, they are administered through contact with the drugs and blood vessels. The drugs cannot be left in the affected area for a long time. To the purpose of sustained release.
中国专利CN107596455A使用一种可降解高分子网状球囊来对骨水泥进行包裹，通过 加入纳米ZnO来实现材料的抗菌性，该专利的缺陷是：球囊无法扩张抬高椎体形成骨水泥灌注空腔，无法将疏松的椎体组织挤压密实，因而恢复椎体高度方面效果较差；而且该网状球囊没有实现载药，无法治疗骨质疏松病因，继发骨折的发生率较高。专利CN106726019A公开了一种经椎间孔纳米生物玻璃涂层微创融合器，该微创融合器使用钴铬合金丝实现伸缩性和力学支撑，将纳米生物玻璃涂层附于表面增加其生物相容性，应用于椎间孔镜下腰椎间融合术中治疗腰椎不稳。该专利应用领域不同，没有实现形成骨水泥填充空腔和载药的功能。Chinese patent CN107596455A uses a degradable polymer mesh balloon to wrap bone cement, and realizes the antibacterial properties of the material by adding nano-ZnO. The defect of this patent is: the balloon cannot expand and raise the vertebral body to form bone cement infusion The cavity is unable to squeeze the loose vertebral body tissues and compact, so the effect of restoring the height of the vertebral body is poor; and the mesh balloon has not been loaded with drugs, which cannot treat the cause of osteoporosis, and the incidence of secondary fractures is high. . Patent CN106726019A discloses a minimally invasive fusion cage with nano-bioglass coating through the intervertebral foramen. The minimally invasive cage uses cobalt-chromium alloy wires to achieve flexibility and mechanical support, and the nano-bioglass coating is attached to the surface to increase its biological phase. Capacitive, used in the treatment of lumbar vertebral instability during lumbar interbody fusion under intervertebral foraminal endoscope. This patent has different application fields and does not realize the function of forming bone cement to fill the cavity and load medicine.
由此来看，目前公开的球囊作用均比较单一，尚没有一种能够满足防止骨水泥脱位、保证药物持续作用、提高骨密度、减少骨质疏松导致的骨折发生概率等多种功能的球囊公开。From this point of view, the functions of the currently disclosed balloons are relatively simple, and there is no ball that can meet the multiple functions of preventing bone cement dislocation, ensuring the continuous action of drugs, increasing bone density, and reducing the probability of fractures caused by osteoporosis. The capsule is open.
发明内容Summary of the invention
针对现今经皮椎体成形术或经皮椎体后凸成形术中使用的球囊作用单一的不足，本发明提供了一种表面载药的椎体成形扩张球囊，该扩张球囊表面附有载药膜，载药膜在球囊撤出后能够保留在体内，形成包裹骨水泥的外壳，既起到了向所需部位有效释放药物的作用，提高了药物的作用效率，又起到了防止骨水泥脱离位置的作用，功能多面，提高了经皮椎体成形术和经皮椎体后凸成形术的术后效果，尤其适合于骨质疏松症以及相关压缩性骨折的治疗。In view of the single function of the balloon used in percutaneous vertebroplasty or percutaneous kyphoplasty, the present invention provides a drug-loaded vertebroplasty expansion balloon, the expansion balloon surface attached There is a drug-loaded film, which can be retained in the body after the balloon is withdrawn to form a shell that wraps the bone cement, which not only plays a role in effectively releasing the drug to the desired site, improves the efficiency of the drug, but also prevents The role of bone cement from the position and multi-faceted function improves the postoperative effect of percutaneous vertebroplasty and percutaneous kyphoplasty, and is especially suitable for the treatment of osteoporosis and related compression fractures.
本发明还提供了一种表面载药的椎体成形扩张球囊的制备方法，该方法操作简单、易于实施，便于工业化生产。The present invention also provides a method for preparing the vertebroplasty expansion balloon with a drug on the surface, which is simple to operate, easy to implement, and convenient for industrial production.
本发明具体技术方案如下：The specific technical scheme of the present invention is as follows:
本发明提供了一种表面载药的椎体成形扩张球囊，该表面载药的椎体成形扩张球囊包括球囊本体，在球囊本体表面附有载药膜，所述载药膜由至少两层的载药涂层组成，其中，与球囊本体直接接触的第一层载药涂层通过静电纺丝形成。The present invention provides a vertebroplasty and dilatation balloon with a drug on its surface. The vertebroplasty and dilatation balloon with a drug on the surface includes a balloon body, and a drug-loading membrane is attached to the surface of the balloon body. At least two layers of drug-carrying coatings are composed, wherein the first drug-carrying coating directly in contact with the balloon body is formed by electrostatic spinning.
本发明球囊本体表面附有载药膜，该载药膜在球囊本体加压膨胀时随球囊本体一起膨胀，当球囊本体撤压缩回时由于和椎体间的应力和摩擦力作用与球囊分离，仍然维持在球囊本体膨胀时的形状，留置在患处与椎体组织紧密接触，这样骨水泥可以注入载药膜包裹的空腔中，载药膜相当于骨水泥的一个外壳，包裹住骨水泥防止其外泄。The balloon body of the present invention is attached with a drug-loaded film on the surface. The drug-loaded film expands with the balloon body when the balloon body is pressurized and expanded. When the balloon body is retracted and compressed, due to the stress and friction between the vertebral body Separated from the balloon, it still maintains the shape of the balloon body when it is inflated, and is left in the affected area in close contact with the vertebral body tissue, so that the bone cement can be injected into the cavity wrapped by the drug-loaded membrane, which is equivalent to a shell of the bone cement , Wrap the bone cement to prevent its leakage.
进一步的，所述载药涂层的层数根据所需药物种类、载药量等实际需要可以进行选择和调整，最少为两层，优选的为2-5层，例如2层、3层、4层、5层。除了第一层载药涂层采用静电纺丝的形式形成外，其他的载药涂层可以采用静电纺丝、喷涂、浸提或刷涂等任意一种方式形成，例如其他层均采用喷涂、浸提、刷涂、静电纺丝中的一种方式形成，或者每层都采用不同的形成方式形成，或者部分载药涂层采用相同的形成方式部分采用不同的形成方式。但因为静电纺丝法形成的药物涂层的药物释放缓慢，而喷涂、浸提、刷涂等方式形成的药物涂层的药物释放迅速，因此优选采用静电纺丝和喷涂、浸提、刷涂这三种中的一种或 多种结合使用的方式来形成，以使载药膜中的药物能够部分快速释放、部分缓慢释放，既满足立即给药的目的，又能实现长期缓释给药的目的。优选的，最后一层载药涂层不采用静电纺丝方式形成。本发明中所指的一层载药涂层，意思是该层载药涂层的成分和形成方式完全一样，采用相同的形成方式但是成分不同不能算作同一层，采用相同的成分但是形成方式不同也不能算作同一层。当成分和形成方式相同时，即使通过多次操作形成载药涂层那也算作同一层，例如为了满足薄膜载药量或厚度要求，采用多次喷涂-干燥的方式形成的涂层算作采用喷涂方式形成的同一层载药涂层。Further, the number of layers of the drug-loaded coating can be selected and adjusted according to actual needs such as the type of drug required, the amount of drug loaded, etc., at least two layers, preferably 2-5 layers, such as 2 layers, 3 layers, 4 floors, 5 floors. Except for the first layer of drug-carrying coating formed by electrospinning, other drug-carrying coatings can be formed by electrospinning, spraying, leaching or brushing, etc., for example, other layers are sprayed, It is formed by one of leaching, brushing, and electrostatic spinning, or each layer is formed by a different formation method, or part of the drug-loaded coating is formed in the same way and part is formed in a different way. However, because the drug release of the drug coating formed by the electrospinning method is slow, and the drug release of the drug coating formed by spraying, leaching, and brushing is rapid, it is preferable to use electrospinning, spraying, leaching, and brushing. One or more of these three methods are used in combination to form, so that the drug in the drug-loaded film can be partly released quickly and partly slowly, which not only meets the purpose of immediate administration, but also achieves long-term sustained release administration the goal of. Preferably, the last layer of drug-loaded coating is not formed by electrospinning. A layer of drug-loaded coating in the present invention means that the composition and formation method of the drug-loaded coating layer are exactly the same, and the same formation method is used but different components cannot be counted as the same layer. The same composition is used but the formation method is used. Differences cannot be counted as the same layer. When the composition and the formation method are the same, even if the drug-loaded coating is formed through multiple operations, it is counted as the same layer. For example, in order to meet the film drug loading or thickness requirements, the coating formed by multiple spray-drying methods is counted as the same layer. The same layer of drug-carrying coating formed by spraying.
在本发明某一具体实施方式中，载药膜采用静电纺丝-喷涂的方式、或者静电纺丝-浸提的方式、或者静电纺丝-涂刷的方式、或者静电纺丝-喷涂-浸提的方式、或者静电纺丝-浸提-喷涂的方式、或者静电纺丝-喷涂-浸提-刷涂的方式、或者静电纺丝-喷涂-静电纺丝-浸提的方式、或者静电纺丝-喷涂-静电纺丝-喷涂的方式、或者静电纺丝-浸提-静电纺丝-浸提的方式等多种不同的方式形成。In a specific embodiment of the present invention, the drug-loaded film adopts an electrospinning-spraying method, or an electrospinning-extraction method, or an electrospinning-brushing method, or an electrospinning-spraying-dipping method. The method of extraction, or the method of electrospinning-extraction-spraying, or the method of electrospinning-spraying-extraction-brushing, or the method of electrospinning-spraying-electrospinning-extraction, or electrospinning Silk-spraying-electrospinning-spraying, or electrospinning-extraction-electrospinning-extraction and other different methods are formed.
在本发明某一具体实施方式中，相邻的两层载药涂层采用a和b两种不同的形成方式；所述a形成方式指的是静电纺丝方式形成，b形成方式指的是喷涂、浸提或刷涂中的任意一种方式形成。例如，载药膜采用静电纺丝-喷涂的方式、或者静电纺丝-喷涂-静电纺丝-喷涂的方式、或者静电纺丝-浸提-静电纺丝-浸提的方式、或者静电纺丝-喷涂-静电纺丝-浸提的方式等多种不同的方式形成。In a specific embodiment of the present invention, the two adjacent drug-carrying coatings adopt two different formation methods, a and b; the formation method a refers to electrospinning, and the formation method b refers to It can be formed by spraying, leaching or brushing. For example, the drug-loaded film adopts the method of electrospinning-spraying, or electrospinning-spraying-electrospinning-spraying, or electrospinning-extraction-electrospinning-extraction, or electrospinning -Spray-electrospinning-extraction and other different ways to form.
优选的，载药涂层的层数为2层，第二层载药涂层通过喷涂、浸提或刷涂中的任意一种的方式形成。例如载药膜采用静电纺丝-喷涂的方式，或者静电纺丝-浸提的方式，或者静电纺丝-涂刷的方式。Preferably, the number of layers of the drug-loaded coating is two, and the second drug-loaded coating is formed by spraying, leaching or brushing. For example, the drug-loaded film adopts an electrostatic spinning-spraying method, or an electrostatic spinning-extraction method, or an electrostatic spinning-painting method.
进一步的，各层载药涂层的厚度可以根据载药量、药物的种类和数量、使用要求等不同原因进行调整，每层载药涂层的厚度大约为0.05-0.2mm。Further, the thickness of each layer of drug-loaded coating can be adjusted according to different reasons such as drug-loaded amount, type and quantity of drugs, use requirements, etc., and the thickness of each drug-loaded coating is about 0.05-0.2 mm.
在本发明某一具体实施方式中，所述载药膜的表面优选为非光滑结构，以增加与周围组织的摩擦力，载药膜的表面分布有凸起或/和凹槽，凸起或/和凹槽优选均匀分布在载药膜表面，凸起或/和凹槽的形状可以随意选择，可以是波浪状、锯齿状、螺旋状、针状、棒状、图形状等中的至少一种，所述图形状凸起可以是圆形、椭圆形、正多边形、非正多边形、不规则图形等中的至少一种。凸起或/和凹槽的高度或深度可以根据需要进行调整，一般为0.01～0.1mm。本发明表面载药的椎体成形扩张球囊在加压下扩张膨胀，然后收压撤出体内，在球囊本体由扩张膨胀状态变为收缩状态时，载药膜由于和椎体间的应力和摩擦力作用与球囊分离，维持球囊本体膨胀扩张的形状，进一步骨水泥注入后载药膜可以包裹住骨水泥，起到防止其泄露、避免损伤周围组织的作用，载药膜表面的凸起或/和凹槽可以增加骨水泥与椎体之间的摩擦力，更利于载药膜与球囊本体的脱离，同时也可以防止其包裹的骨水泥脱出原位，另一 方面凸起或/和凹槽可以增大载药膜的比表面积，提高载药量。In a specific embodiment of the present invention, the surface of the drug-loaded film is preferably a non-smooth structure to increase friction with surrounding tissues. The surface of the drug-loaded film is distributed with protrusions or/and grooves, protrusions or / And grooves are preferably evenly distributed on the surface of the drug-loaded film, and the shape of the protrusions or/and grooves can be selected at will, and can be at least one of wavy, zigzag, spiral, needle, rod, figure, etc. The convex shape of the figure may be at least one of a circle, an ellipse, a regular polygon, an irregular polygon, and an irregular figure. The height or depth of the protrusions or/and grooves can be adjusted as required, and is generally 0.01 to 0.1 mm. The vertebroplasty expansion balloon with the drug on the surface of the present invention expands and expands under pressure, and then retracts and withdraws from the body. When the balloon body changes from the expanded and expanded state to the contracted state, the drug-loaded membrane is due to the stress between the vertebral body It is separated from the balloon by friction and maintains the expanded and expanded shape of the balloon body. After further bone cement is injected, the drug-loaded membrane can wrap the bone cement to prevent its leakage and avoid damage to the surrounding tissues. The protrusions or/and grooves can increase the friction between the bone cement and the vertebral body, which is more conducive to the separation of the drug-loaded membrane from the balloon body, and can also prevent the bone cement wrapped by it from coming out of the original position. On the other hand, the protrusions Or/and the groove can increase the specific surface area of the drug-loaded film and increase the drug-loading amount.
进一步的，载药膜表面的凸起或/和凹槽由各层载药涂层上的凸起或/和凹槽构成，在至少一层载药涂层的表面设有凸起或/和凹槽，即凸起或/和凹槽可以设置于每一层上，也可以仅设置于部分载药涂层上，凸起或/和凹槽的形状与上面描述一致。优选的，第一层载药涂层表面设有凸起或/和凹槽，该凸起或/和凹槽可以提高后续载药涂层的负载量，提高载药量，并且通过调整凸起或/和凹槽的高度或深度可以使第一层载药涂层的凸起或/和凹槽仍然在载药膜的外表面突出或凹陷。优选的，在第一次载药涂层设有凸起或/和凹槽的基础上，其他载药涂层上也可以设有凸起或/和凹槽，进一步增加载药量或摩擦力。Further, the protrusions or/and grooves on the surface of the drug-loading film are composed of protrusions or/and grooves on each layer of the drug-loading coating, and the surface of at least one drug-loading coating is provided with protrusions or/and Grooves, that is, protrusions or/and grooves can be provided on each layer, or only part of the drug-loaded coating, and the shape of the protrusions or/and grooves is consistent with the above description. Preferably, the surface of the first layer of drug-loaded coating is provided with protrusions or/and grooves, which can increase the load of the subsequent drug-loaded coating, increase the amount of drug loaded, and adjust the protrusions or/and grooves. Or/and the height or depth of the groove can make the protrusions or/and grooves of the first drug-loaded coating still protrude or dent on the outer surface of the drug-loaded film. Preferably, on the basis that the first drug-loaded coating is provided with protrusions or/and grooves, other drug-loaded coatings can also be provided with protrusions or/and grooves to further increase the drug loading or friction .
进一步的，载药涂层或载药膜上的凸起或/和凹槽可以采用现有技术中可行的任意技术实现，例如刻蚀、雕刻、喷吹、压制、激光刻槽技术等。Further, the protrusions or/and grooves on the drug-loaded coating or the drug-loaded film can be realized by any technology that is feasible in the prior art, such as etching, engraving, spraying, pressing, and laser groove technology.
在本发明某一具体实施方式中，所述载药膜上设有能够穿透各层载药涂层的通孔，通孔的尺寸为毫米级。在骨水泥注入载药膜形成的空腔中时，骨水泥在未凝固之前可以通过载药膜上的通孔少量渗出，形成类似于凸起状结构，起到与载药膜上的凸起一样的作用。In a specific embodiment of the present invention, the drug-carrying membrane is provided with through holes that can penetrate each layer of the drug-carrying coating, and the size of the through holes is millimeter-level. When the bone cement is injected into the cavity formed by the drug-loaded film, the bone cement can seep out through the through holes in the drug-loaded film in a small amount before it is solidified, forming a structure similar to the convex shape, which can interact with the convexity on the drug-loading film. Plays the same role.
进一步的，本发明所述的球囊本体为现今经皮椎体成形术或经皮椎体后凸成形术中经常使用的扩张球囊，也可以称为可膨胀球囊或可膨胀性球囊，其可以直接从市场上购买得到，也可以按照现有技术公开的方法自行制备。一般的，扩张球囊采用聚乙烯(PE)、聚对苯二甲酸乙二醇酯(PET)、聚酰胺(PA)、尼龙弹性体(Pebax)、聚氨酯(PU)等材料中的一种或多种制成。当加压时，该球囊本体能膨胀，压缩周围组织，在撤压后回缩，形成一个可注入骨水泥的空腔。Further, the balloon body of the present invention is an expanding balloon frequently used in percutaneous vertebroplasty or percutaneous kyphoplasty, and can also be referred to as an inflatable balloon or an inflatable balloon. It can be purchased directly from the market, or it can be prepared by itself according to the methods disclosed in the prior art. Generally, the expansion balloon uses one of polyethylene (PE), polyethylene terephthalate (PET), polyamide (PA), nylon elastomer (Pebax), polyurethane (PU) and other materials or Various made. When pressurized, the balloon body can expand, compress the surrounding tissue, and retract after the pressure is withdrawn to form a cavity into which bone cement can be injected.
进一步的，通过静电纺丝形成的载药涂层中含有药物和可降解高分子材料，药物经过静电纺丝后与可降解高分子材料融合为一体，不容易释放，在可降解高分子材料降解过程中缓慢释放，起到了缓释的作用。通过其他喷涂、浸提或刷涂等方式形成的载药涂层中含有药物不含可降解高分子材料，药物可以快速释放。静电纺丝、喷涂、浸提或刷涂可以采用现有技术中报道的常规步骤进行操作。Further, the drug-loaded coating formed by electrospinning contains drugs and degradable polymer materials. After electrospinning, the drug is fused with the degradable polymer material and is not easy to release. The degradable polymer material degrades. It is released slowly during the process, which plays a role of slow release. The drug-loaded coating formed by other methods such as spraying, leaching or brushing contains drugs without degradable polymer materials, and the drugs can be released quickly. Electrospinning, spraying, leaching or brushing can be performed using conventional procedures reported in the prior art.
进一步的，每层载药涂层中可以含着一种或多种药物，各层载药涂层中的药物可以相同，也可以不同；每层载药涂层中的载药量可以相同，也可以不同。所述药物可以为抑制骨吸收药物、促进骨形成药物、止痛药物、***物等中的一种或多种；所述抑制骨吸收药物包括双膦酸盐，所述促进骨形成药物包括甲状旁腺激素、***素E2、氟化物、锶盐等中的至少一种，所述止痛药物包括精氨酸阿司匹林，所述***物包括普鲁卡因、利多卡因等中的至少一种。Further, each drug-loaded coating layer may contain one or more drugs, and the drug in each drug-loaded coating layer may be the same or different; the drug-loaded amount in each drug-loaded coating layer may be the same, It can also be different. The drug may be one or more of drugs that inhibit bone resorption, drugs that promote bone formation, analgesics, anesthetics, etc.; the drugs that inhibit bone resorption include bisphosphonates, and the drugs that promote bone formation include parathyroid At least one of gland hormone, prostaglandin E2, fluoride, strontium salt, etc., the analgesic drug includes arginine aspirin, and the anesthetic drug includes at least one of procaine and lidocaine.
进一步的，所述可降解高分子材料为聚乳酸(PLA)、聚乳酸-羟基乙酸共聚物(PLGA)、壳聚糖、海藻酸钠、聚乙二醇(PEG)、聚乙交酯(PGA)、聚己内酯(PCL)、聚天冬氨酸(PASP)、 羧甲基纤维素钠(CMC)、羟丙基甲基纤维素(INN)、聚乙烯醇(PVA)、聚醚等中的至少一种。可降解高分子材料的性能参数要求为：粘度0.1-0.5dl/g，重均分子量20000-100000。通过本发明可降解高分子材料的选择，既可以满足静电纺丝液粘度的要求，又可以使载药膜在球囊本体膨胀回缩后更利于与球囊本体的脱离，更利于药膜形成一个能够容纳骨水泥的空腔。Further, the degradable polymer material is polylactic acid (PLA), polylactic acid-glycolic acid copolymer (PLGA), chitosan, sodium alginate, polyethylene glycol (PEG), polyglycolide (PGA) ), polycaprolactone (PCL), polyaspartic acid (PASP), sodium carboxymethyl cellulose (CMC), hydroxypropyl methyl cellulose (INN), polyvinyl alcohol (PVA), polyether, etc. At least one of them. The performance parameters of degradable polymer materials are required to be: viscosity 0.1-0.5dl/g, weight average molecular weight 20000-100000. Through the selection of the degradable polymer material of the present invention, the viscosity requirements of the electrospinning solution can be met, and the drug-loaded membrane can be more conducive to the detachment from the balloon body after the balloon body is expanded and retracted, and is more conducive to the formation of the drug film A cavity that can hold bone cement.
进一步的，采用静电纺丝法形成的载药涂层的载药量为1～300mg/cm 2。 Further, the drug-loading amount of the drug-loaded coating formed by the electrospinning method is 1-300 mg/cm 2 .
采用喷涂、浸提或刷涂形成的载药涂层的载药量为1～500mg/cm 2。 The drug loading amount of the drug-loaded coating formed by spraying, leaching or brushing is 1 to 500 mg/cm 2 .
进一步的，本发明还提供了一种表面载药的椎体成形扩张球囊的制备方法，该方法包括以下步骤：Furthermore, the present invention also provides a method for preparing a vertebroplasty and dilatable balloon with a drug on its surface, the method comprising the following steps:
(1)将药物、高分子可降解材料配成静电纺丝液，在球囊本体表面进行静电纺丝形成薄膜，静电纺丝后干燥，得到第一层载药涂层；(1) Prepare an electrospinning solution with drugs and polymer degradable materials, electrospin on the surface of the balloon body to form a film, and dry after electrospinning to obtain the first drug-carrying coating;
(2)配制含有药物和高分子可降解材料的静电纺丝液或配制药物和溶剂的药物溶液，选择静电纺丝、喷涂、浸提或刷涂方式形成各层载药涂层，最终得到表面载药的椎体成形扩张球囊。(2) Prepare the electrospinning solution containing drugs and polymer degradable materials or prepare drug and solvent drug solutions, choose electrospinning, spraying, leaching or brushing methods to form each layer of drug-carrying coatings, and finally obtain the surface The drug-loaded vertebroplasty expands the balloon.
进一步的，步骤(1)中，所述静电纺丝液中除了药物、高分子可降解材料外，还含有静电纺丝所需的其他成分，这些成分可以按照现有技术中公开的内容进行选择。静电纺丝的条件根据所需薄膜的厚度、载药量等进行调整。Further, in step (1), in addition to drugs and polymer degradable materials, the electrospinning solution also contains other components required for electrospinning. These components can be selected according to the contents disclosed in the prior art . The conditions of electrospinning are adjusted according to the required film thickness, drug loading, etc.
进一步的，步骤(2)中，所述溶剂可以是任意可用于人体、能够溶解药物的溶剂，例如水溶性药物优先选用水为溶剂，非水溶性药物根据不同药物的性质选择合适的溶剂，溶剂可以是一种，也可以是多种。Furthermore, in step (2), the solvent can be any solvent that can be used in the human body and can dissolve drugs. For example, water is preferred for water-soluble drugs, and suitable solvents are selected for non-water-soluble drugs according to the properties of different drugs. It can be one type or multiple types.
进一步的，上述制备方法中，还包括在至少一层的载药涂层上形成凸起或凹槽的步骤。Further, in the above preparation method, it further includes the step of forming protrusions or grooves on at least one layer of the drug-loaded coating.
进一步的，上述制备方法中，还包括在载药膜上形成通孔的步骤。Further, in the above preparation method, it further includes the step of forming a through hole on the drug-carrying film.
本发明公开了一种表面载药的椎体成形扩张球囊，包括球囊本体，在球囊本体表面附有载药膜。该表面载药的椎体成形扩张球囊可应用于椎体后凸成形等微创手术中恢复椎体高度，形成和保持骨水泥灌注腔，局部释放药物，减少继发骨折和再次骨折，具有以下有益效果：The invention discloses a vertebroplasty expansion balloon with a drug on its surface, which comprises a balloon body, and a drug-loading membrane is attached on the surface of the balloon body. The drug-loaded vertebroplasty balloon can be used to restore the height of the vertebral body in minimally invasive surgery such as kyphoplasty, form and maintain a bone cement perfusion cavity, release drugs locally, and reduce secondary fractures and re-fractures. The following beneficial effects:
1、本发明在球囊本体表面设置载药膜，在球囊本体加压膨胀时，疏松的椎体组织由于压力作用被挤压紧实，减轻了局部骨质疏松的情况；在球囊减压脱离时，载药膜由于和椎体间的应力和摩擦力作用与球囊分离，暂时支撑椎体形状，留置在患处与椎体组织紧密接触，为填充的骨水泥提供空腔和包裹，防止骨水泥弥散外溢到其他组织，避免引起神经、硬膜囊损伤等严重并发症。1. The present invention is provided with a drug-carrying membrane on the surface of the balloon body. When the balloon body is pressurized and expanded, the loose vertebral body tissue is squeezed and compacted due to the pressure, which reduces local osteoporosis; During pressure detachment, the drug-loaded membrane separates from the balloon due to the stress and friction between the vertebral body, temporarily supports the shape of the vertebral body, and stays in the affected area in close contact with the vertebral body tissue, providing a cavity and package for the filled bone cement. Prevent the bone cement from spreading out to other tissues, and avoid serious complications such as nerve and dural sac injury.
2、本发明载药膜由多层的载药涂层构成，通过载药涂层的不同形成方式，载药膜不仅可以在置入体内时快速释放药物，还能留置在患处更长时间的缓释，获得更好的药物利用率。2. The drug-loading film of the present invention is composed of multiple drug-loading coatings. Through different formation methods of the drug-loading coating, the drug-loading film can not only release the drug quickly when placed in the body, but also stay in the affected area for a longer time. Sustained release, better drug utilization.
3、本发明载药膜能快速和缓慢的在局部释放药物，以达到抑制骨吸收、促进骨形成或 止痛的效果，在术后修复过程中可以进一步的缓解骨质流失、提高骨密度，获得更好的骨质疏松性椎体骨折的术后效果，减少继发骨折的发生率。3. The drug-loaded membrane of the present invention can quickly and slowly release drugs locally to achieve the effects of inhibiting bone resorption, promoting bone formation or pain relief, and can further alleviate bone loss and improve bone density during postoperative repair. Better postoperative results of osteoporotic vertebral fractures and reduce the incidence of secondary fractures.
4、本发明载药膜所载药物能在椎体内血运作用下进入血液循环，从而实现全身用药，解决了口服用药肠胃吸收利用度低的问题，并且还能提高药物利用率，进而增加患者单位体积内骨组织量，减轻骨质疏松症。4. The drug contained in the drug-loaded film of the present invention can enter the blood circulation under the blood operation of the vertebral body, thereby realizing systemic drug administration, solving the problem of low gastrointestinal absorption and utilization of oral drugs, and improving the utilization rate of drugs, thereby increasing The amount of bone tissue per unit volume of the patient reduces osteoporosis.
5、本发明载药膜上可以设置凸起、凹陷、通孔等结构，一方面可以增大骨水泥与椎体之间的摩擦力，防止骨水泥脱出原位，另一方面增大载药膜的比表面积，提高载药量。5. The drug-loaded membrane of the present invention can be provided with structures such as protrusions, depressions, through holes, etc., on the one hand, it can increase the friction between the bone cement and the vertebral body, prevent the bone cement from coming out of the original position, and on the other hand, increase the drug loading The specific surface area of the membrane increases the drug loading.
附图说明Description of the drawings
图1本发明表面载药的椎体成形扩张球囊的结构示意图；其中，1、表面载药的椎体成形扩张球囊，2、球囊本体，3、第一层载药涂层，4、第二层载药涂层，5为球囊导管；图2经皮椎体后凸成形术中表面载药的椎体成形扩张球囊的使用示意图，左：治疗前，右：表面载药的椎体成形扩张球囊加压膨胀恢复椎体高度；Figure 1 is a schematic diagram of the structure of the vertebroplasty and dilatation balloon with a drug on the surface of the present invention; among them, 1. the vertebroplasty and dilatation balloon with a drug on the surface, 2. the balloon body, 3, the first drug-loaded coating, and 4 , The second layer of drug-loaded coating, 5 is a balloon catheter; Figure 2 Schematic diagram of the use of a vertebroplasty balloon with a drug on the surface in percutaneous kyphoplasty, left: before treatment, right: surface with drug The vertebroplasty and expansion balloon is compressed and expanded to restore the height of the vertebral body;
图3表面载药的椎体成形扩张球囊使用状态示意图，左：加压膨胀；右：减压撤出；Figure 3 is a schematic diagram of the use state of the vertebroplasty balloon with medicine on the surface, left: pressurized and expanded; right: decompression and withdrawal;
图4留置在患处的载药膜包裹填充的骨水泥的示意图；Figure 4 is a schematic diagram of the bone cement filled with a drug-loaded film wrapped in the affected area;
图5具有凸起的载药膜的结构示意图；其中，5、球囊导管，6、螺旋形的沿球囊轴向延伸的凸起。Fig. 5 is a schematic structural diagram of a protruding drug-loaded membrane; wherein, 5, a balloon catheter, and 6, a spiral protrusion extending along the axial direction of the balloon.
图6具有通孔的载药膜包裹骨水泥的示意图；其中，7、具有通孔的载药膜，8、骨水泥穿过通孔形成凸起。Fig. 6 is a schematic diagram of a drug-loaded membrane with a through hole wrapping the bone cement; wherein, 7, the drug-loaded membrane with a through hole, and 8, the bone cement passes through the through hole to form a protrusion.
具体实施方式Detailed ways
下面对本发明的具体实施例进行详细的说明，但本发明的实施例不限于此。The specific embodiments of the present invention will be described in detail below, but the embodiments of the present invention are not limited thereto.
下述实施例中，如无特别说明，各原料均从市场中购买得到。In the following examples, unless otherwise specified, all raw materials are purchased from the market.
实施例1Example 1
一种表面载药的椎体成形扩张球囊(简称椎体成形扩张球囊)，该表面载药的椎体成形扩张球囊包括球囊本体，在球囊本体表面附有载药膜，所述载药膜由至少两层的载药涂层组成，其中，与球囊本体直接接触的为第一层载药涂层，其他层载药涂层依次附着在上一层的载药涂层上。图1为2层载药涂层的椎体成形扩张球囊的结构示意图，包括球囊本体2、第一层载药涂层3和第二层载药涂层4，第一层载药涂层3直接与球囊本体2接触，第二层载药涂层4直接与第一层载药涂层3接触。A vertebroplasty and expansion balloon with a drug on the surface (referred to as a vertebroplasty and expansion balloon). The vertebroplasty and expansion balloon with a drug on the surface includes a balloon body, and a drug-loaded membrane is attached to the surface of the balloon body. The drug-loading film is composed of at least two drug-loading coatings, wherein the first drug-loading coating is in direct contact with the balloon body, and the other drug-loading coatings are sequentially attached to the upper drug-loading coating on. Figure 1 is a schematic structural diagram of a vertebroplasty expansion balloon with two drug-loaded coatings, including the balloon body 2, the first drug-loaded coating 3 and the second drug-loaded coating 4, the first drug-loaded coating The layer 3 directly contacts the balloon body 2, and the second drug-loaded coating 4 directly contacts the first drug-loaded coating 3.
进一步的，所述球囊本体为扩张球囊，又叫可膨胀球囊、可膨胀性球囊，简称球囊，当球囊本体由扩张膨胀状态变为收缩状态时，大部分载药膜与球囊本体脱离。球囊本体可以采用用聚乙烯(PE)、聚对苯二甲酸乙二醇酯(PET)、聚酰胺(PA)、尼龙弹性体(Pebax)、聚氨酯(PU)等材料中的任意一种材料制成。Further, the balloon body is an expandable balloon, also called an inflatable balloon, an inflatable balloon, or a balloon for short. When the balloon body changes from an expanded state to a contracted state, most of the drug-loaded membrane and The balloon body is detached. The balloon body can be made of any one of polyethylene (PE), polyethylene terephthalate (PET), polyamide (PA), nylon elastomer (Pebax), polyurethane (PU) and other materials production.
进一步的，第一层的载药涂层通过静电纺丝形成，其他层的载药涂层通过静电纺丝、喷涂、浸提或刷涂的方式形成。优选的，通过静电纺丝形成的载药膜的厚度为0.05-0.2mm，例如0.05mm、0.1mm、0.15mm、0.2mm。通过静电纺丝形成的载药涂层中含有药物和可降解高分子材料，通过其他方式形成的载药涂层中含有药物但不含可降解高分子材料。静电纺丝、喷涂、浸提或刷涂采用现有技术中公开的方式进行即可。Further, the drug-carrying coating of the first layer is formed by electrospinning, and the drug-carrying coating of the other layers is formed by electrospinning, spraying, leaching or brushing. Preferably, the thickness of the drug-loaded film formed by electrospinning is 0.05-0.2 mm, for example, 0.05 mm, 0.1 mm, 0.15 mm, 0.2 mm. The drug-loading coating formed by electrostatic spinning contains drugs and degradable polymer materials, and the drug-loading coating formed by other methods contains drugs but not degradable polymer materials. Electrospinning, spraying, leaching or brushing can be carried out in the manner disclosed in the prior art.
进一步的，每层载药涂层中含着一种或多种药物，各层载药涂层中的药物可以相同，也可以不同。所述药物可以为抑制骨吸收药物、促进骨形成药物、止痛药物、***物等中的至少一种；所述抑制骨吸收药物包括双膦酸盐，所述促进骨形成药物包括甲状旁腺激素、***素E2、氟化物、锶盐等中的至少一种，所述止痛药物包括精氨酸阿司匹林，所述***物包括普鲁卡因、利多卡因等中的至少一种。采用静电纺丝法形成的载药涂层的载药量为1～300mg/cm 2，这一载药量可以根据不同的药物、不同的药物需求量进行调整，例如1-20mg/cm 2、30-50mg/cm 2、60-90mg/cm 2、100-200mg/cm 2、200-300mg/cm 2。采用喷涂、浸提或刷涂形成的载药涂层的载药量为1～500mg/cm 2，这一载药量可以根据不同的药物、不同的药物需求量进行调整，例如1-20mg/cm 2、30-50mg/cm 2、60-90mg/cm 2、100-200mg/cm 2、200-300mg/cm 2、300-400mg/cm 2、400-500mg/cm 2。 Further, each drug-loaded coating layer contains one or more drugs, and the drugs in each drug-loaded coating layer may be the same or different. The drug may be at least one of bone resorption inhibiting drugs, bone formation promoting drugs, analgesic drugs, anesthetics, etc.; the bone resorption inhibiting drugs include bisphosphonates, and the bone formation promoting drugs include parathyroid hormone , Prostaglandin E2, fluoride, strontium salt, etc., the analgesic drug includes arginine aspirin, and the anesthetic drug includes at least one of procaine and lidocaine. The drug loading amount of the drug-loaded coating formed by the electrospinning method is 1～300mg/cm 2 , this drug loading amount can be adjusted according to different drugs and different drug requirements, such as 1-20mg/cm 2 , 30-50mg / cm 2, 60-90mg / cm 2, 100-200mg / cm 2, 200-300mg / cm 2. The drug loading of the drug-loaded coating formed by spraying, leaching or brushing is 1～500mg/cm 2 , this drug loading can be adjusted according to different drugs and different drug requirements, such as 1-20mg/ cm 2, 30-50mg / cm 2, 60-90mg / cm 2, 100-200mg / cm 2, 200-300mg / cm 2, 300-400mg / cm 2, 400-500mg / cm 2.
进一步的，所述可降解高分子材料为聚乳酸(PLA)、聚乳酸-羟基乙酸共聚物(PLGA)、壳聚糖、海藻酸钠、聚乙二醇(PEG)、聚乙交酯(PGA)、聚己内酯(PCL)、聚天冬氨酸(PASP)、羧甲基纤维素钠(CMC)、羟丙基甲基纤维素(INN)、聚乙烯醇(PVA)、聚醚中的至少一种；可降解高分子材料的粘度为0.1-0.5dl/g，重均分子量为20000-100000。Further, the degradable polymer material is polylactic acid (PLA), polylactic acid-glycolic acid copolymer (PLGA), chitosan, sodium alginate, polyethylene glycol (PEG), polyglycolide (PGA) ), polycaprolactone (PCL), polyaspartic acid (PASP), sodium carboxymethyl cellulose (CMC), hydroxypropyl methyl cellulose (INN), polyvinyl alcohol (PVA), polyether At least one of: the viscosity of the degradable polymer material is 0.1-0.5dl/g, and the weight average molecular weight is 20000-100000.
进一步的，载药涂层的层数至少两层，例如2层、3层、4层、5层、6层、7层等，优选为2-5层。相邻的两层载药涂层的形成方式或制备方式可以相同，也可以不同，例如其他层均采用喷涂、浸提、刷涂、静电纺丝中的一种方式形成，或者每层都采用不同的形成方式形成，或者部分载药涂层采用相同的形成方式部分采用不同的形成方式。但因为静电纺丝法形成的药物涂层的药物释放缓慢，而喷涂、浸提、刷涂等方式形成的药物涂层的药物释放迅速，因此优选采用静电纺丝和喷涂、浸提、刷涂这三种中的一种或多种结合使用的方式来形成，以使载药膜中的药物能够部分快速释放、部分缓慢释放，既满足立即给药的目的，又能实现长期缓释给药的目的。优选的，最后一层载药涂层不采用静电纺丝方式形成。Further, the number of layers of the drug-loaded coating is at least two, such as 2, 3, 4, 5, 6, 7 etc., preferably 2-5 layers. The formation or preparation methods of the two adjacent drug-carrying coatings can be the same or different. For example, the other layers are formed by spraying, leaching, brushing, electrostatic spinning, or each layer is formed by Different formation methods are used, or some drug-loaded coatings adopt the same formation method and some use different formation methods. However, because the drug release of the drug coating formed by the electrospinning method is slow, and the drug release of the drug coating formed by spraying, leaching, and brushing is rapid, it is preferable to use electrospinning, spraying, leaching, and brushing. One or more of these three methods are used in combination to form, so that the drug in the drug-loaded film can be partly released quickly and partly slowly, which not only meets the purpose of immediate administration, but also achieves long-term sustained release administration the goal of. Preferably, the last layer of drug-loaded coating is not formed by electrospinning.
优选的，相邻的两层载药涂层采用a和b两种不同的形成方式；所述a形成方式指的是静电纺丝方式形成，b形成方式指的是喷涂、浸提或刷涂中的任意一种方式形成。例如，载药膜采用静电纺丝-喷涂的方式、或者静电纺丝-喷涂-静电纺丝-喷涂的方式、或者静电纺丝-浸提-静电纺丝-浸提的方式、或者静电纺丝-喷涂-静电纺丝-浸提的方式等多种不同的方式形成。Preferably, the two adjacent drug-carrying coatings adopt two different formation methods, a and b; the formation method a refers to electrospinning, and the formation method b refers to spraying, leaching or brushing. Formed in any of the ways. For example, the drug-loaded film adopts the method of electrospinning-spraying, or electrospinning-spraying-electrospinning-spraying, or electrospinning-extraction-electrospinning-extraction, or electrospinning -Spray-electrospinning-extraction and other different ways to form.
优选的，所述载药涂层的层数为两层，第二层载药涂层通过喷涂、浸提或刷涂的方式形成，例如载药膜采用静电纺丝-喷涂的方式形成，或者静电纺丝-浸提的方式形成，或者静电纺丝-涂刷的方式形成。Preferably, the number of layers of the drug-loading coating is two, and the second drug-loading coating is formed by spraying, leaching or brushing, for example, the drug-loading film is formed by electrospinning-spraying, or It is formed by electrospinning-leaching, or electrospinning-brushing.
上述表面载药的椎体成形扩张球囊的使用方式如图2所示，将表面载药的椎体成形扩张球囊经扩张套管放入所需部位，如图3所示，将球囊加压使其膨胀，恢复椎体高度，然后减压撤出，如图4所示，球囊减压撤出后，球囊表面的载药膜与球囊脱离，留在椎体中形成空腔，包裹后期注入的骨水泥。The use of the above-mentioned drug-loaded vertebroplasty and dilatation balloon is shown in Figure 2. The vertebroplasty and dilatation balloon with the drug on the surface is inserted into the desired part through the expansion sleeve, as shown in Figure 3. Pressurize to inflate to restore the height of the vertebral body, and then decompress and withdraw. As shown in Figure 4, after the balloon is decompressed and withdrawn, the drug-loaded membrane on the balloon surface separates from the balloon and remains in the vertebral body. The cavity is used to wrap the bone cement injected later.
实施例2Example 2
一种表面载药的椎体成形扩张球囊(简称椎体成形扩张球囊)，其具有与实施例1相同的结构，进一步的，其载药膜的表面为非光滑结构，其表面分布有凸起或/和凹槽，凸起或/和凹槽优选均匀分布在载药膜表面，凸起或/和凹槽的形状可以是任意能够增加比表面积或/和摩擦力的形状，例如波浪状、锯齿状、螺旋状、针状、棒状、图形状等，所述图形可以是圆形、椭圆形、正多边形、非正多边形、不规则图形等中的至少一种。如图3所示，载药膜表面均匀分布有棒状凸起，如图5所述，载药膜表面均匀分布有螺旋形的沿球囊轴向延伸的凸起。A vertebroplasty and dilatation balloon (referred to as a vertebroplasty and dilatation balloon) loaded with a drug on its surface has the same structure as in Example 1. Further, the surface of the drug-loaded membrane is a non-smooth structure, and the surface is distributed with The protrusions or/and grooves, the protrusions or/and grooves are preferably evenly distributed on the surface of the drug-loaded film, and the shape of the protrusions or/and grooves can be any shape that can increase the specific surface area or/and friction, such as waves Shapes, zigzags, spirals, needles, rods, graph shapes, etc., the graph may be at least one of a circle, an ellipse, a regular polygon, an irregular polygon, an irregular graph, and the like. As shown in Figure 3, rod-shaped protrusions are uniformly distributed on the surface of the drug-loaded membrane. As shown in Figure 5, the surface of the drug-loaded membrane has evenly distributed spiral protrusions extending along the axial direction of the balloon.
进一步的，载药膜表面的凸起或/和凹槽由载药涂层上的凸起或/和凹槽构成，在至少第一层载药涂层的表面设有凸起或/和凹槽，即凸起或/和凹槽可以设置于每一层上，也可以仅设置于部分载药涂层上，凸起或/和凹槽的形状与上面描述一致。Further, the protrusions or/and grooves on the surface of the drug-loaded film are composed of protrusions or/and grooves on the drug-loaded coating, and at least the first layer of the drug-loaded coating is provided with protrusions or/and recesses. Grooves, that is, protrusions or/and grooves can be provided on each layer, or only part of the drug-loaded coating, and the shape of the protrusions or/and grooves is consistent with the above description.
进一步的，所述凸起或/和凹槽采用刻蚀、雕刻、喷吹、压制等方式形成，凸起或/和凹槽的高度或深度为0.01～0.1mm，例如0.01mm、0.02mm、0.03mm、0.05mm、0.08mm、0.1mm。Further, the protrusions or/and grooves are formed by etching, engraving, blowing, pressing, etc., and the height or depth of the protrusions or/and grooves is 0.01-0.1mm, such as 0.01mm, 0.02mm, 0.03mm, 0.05mm, 0.08mm, 0.1mm.
优选的，第一层载药涂层表面设有凸起或/和凹槽，该凸起或/和凹槽可以提高后续载药涂层的负载量，提高载药量，并且通过调整凸起或/和凹槽的高度或深度可以使第一层载药涂层的凸起或/和凹槽仍然在载药膜的外表面突出或凹陷。更优选的，在第一次载药涂层设有凸起或/和凹槽的基础上，其他载药涂层上也可以设有凸起或/和凹槽，进一步增加载药量或摩擦力。Preferably, the surface of the first layer of drug-loaded coating is provided with protrusions or/and grooves, which can increase the load of the subsequent drug-loaded coating, increase the amount of drug loaded, and adjust the protrusions or/and grooves. Or/and the height or depth of the groove can make the protrusions or/and grooves of the first drug-loaded coating still protrude or dent on the outer surface of the drug-loaded film. More preferably, on the basis that the first drug-loaded coating is provided with protrusions or/and grooves, other drug-loaded coatings may also be provided with protrusions or/and grooves to further increase the drug loading or friction force.
实施例3Example 3
一种表面载药的椎体成形扩张球囊(简称椎体成形扩张球囊)，其具有与实施例1或2相同的结构，进一步的，所述载药膜上还设有能够穿透各层载药涂层的通孔，通孔的尺寸为毫米级。如图6所示，在骨水泥注入载药膜形成的空腔中时，骨水泥在未凝固之前可以通过载药膜上的通孔少量渗出，形成类似于凸起状结构，起到与载药膜上的凸起一样的作用。A vertebroplasty and dilatation balloon (referred to as a vertebroplasty and dilatation balloon) loaded with a drug on its surface has the same structure as that of Embodiment 1 or 2. Further, the drug-loaded membrane is also provided with a penetrating The size of the through hole of the drug-loaded coating layer is millimeter level. As shown in Figure 6, when the bone cement is injected into the cavity formed by the drug-loaded membrane, the bone cement can seep out a small amount through the through holes on the drug-loaded membrane before it is solidified, forming a protruding structure similar to The same effect as the bumps on the drug-loaded film.
实施例4Example 4
1、准备FG1010型扩张球囊；1. Prepare FG1010 dilation balloon;
2、称取1.3g PLGA、1.5ml二甲基甲酰胺、1.5ml四氢呋喃和0.1g双膦酸盐混合，常温下磁 力搅拌均匀，得混合溶液；2. Weigh 1.3g of PLGA, 1.5ml of dimethylformamide, 1.5ml of tetrahydrofuran and 0.1g of bisphosphonate and mix them with magnetic stirring at room temperature to obtain a mixed solution;
3、静电纺丝制作第一层载药涂层：将球囊导管的球囊以标称压力充盈后接地，将上述混合溶液加入静电纺丝设备的注射器中，设置静电纺丝参数为：速度0.12ml/h，距离30cm，负压-0.14kV，高压0.67kV，使用静电纺丝技术在球囊表面形成载药涂层，厚度为0.2mm；3. Electrospinning to make the first drug-carrying coating: fill the balloon of the balloon catheter at a nominal pressure and ground it, add the above mixed solution to the syringe of the electrospinning equipment, and set the electrospinning parameters as: speed 0.12ml/h, distance 30cm, negative pressure -0.14kV, high voltage 0.67kV, using electrospinning technology to form a drug-loaded coating on the surface of the balloon with a thickness of 0.2mm;
4、干燥：烘箱控制温度为50～80℃，真空干燥30min；4. Drying: The temperature of the oven is controlled at 50～80℃, and the vacuum drying is 30min;
5、喷涂制作第二层载药涂层：将双膦酸盐溶液按照1cm 2球囊面积1～500mg有效药物的剂量，喷涂于第一层载药涂层表面； 5. Spraying to make the second drug-carrying coating: spray the bisphosphonate solution on the surface of the first drug-carrying coating at a dose of 1 to 500 mg of effective drug in the area of 1 cm 2 balloon;
6、再次干燥：烘箱控制温度为50～80℃，真空干燥30min；6. Dry again: control the temperature of the oven at 50～80℃, dry in vacuum for 30min;
7、排除球囊内的气体,进行卷片，制成表面载药的椎体成形扩张球囊。7. Exhaust the gas in the balloon and roll the sheet to form a vertebroplasty expansion balloon with a drug on the surface.
实施例5Example 5
1、准备FG1010型扩张球囊；1. Prepare FG1010 dilation balloon;
2、称取1.3g PLGA、1.5ml二甲基甲酰胺、1.5ml四氢呋喃和0.1g双膦酸盐混合，常温下磁力搅拌均匀，得混合溶液；2. Weigh 1.3g of PLGA, 1.5ml of dimethylformamide, 1.5ml of tetrahydrofuran and 0.1g of bisphosphonate and mix them with magnetic stirring at room temperature to obtain a mixed solution;
3、静电纺丝制作第一层载药涂层：将球囊导管的球囊以标称压力充盈后接地，将上述混合溶液加入静电纺丝设备的注射器中，设置静电纺丝参数为：速度0.12ml/h，距离30cm，负压-0.14kV，高压0.67kV，使用静电纺丝技术在球囊表面形成载药涂层，厚度为0.2mm；3. Electrospinning to make the first drug-carrying coating: fill the balloon of the balloon catheter at a nominal pressure and ground it, add the above mixed solution to the syringe of the electrospinning equipment, and set the electrospinning parameters as: speed 0.12ml/h, distance 30cm, negative pressure -0.14kV, high voltage 0.67kV, using electrospinning technology to form a drug-loaded coating on the surface of the balloon with a thickness of 0.2mm;
4、在第一层载药涂层表面使用皮秒紫外激光器雕刻出锯齿状的凸起图案，设置锯齿凸起高度为0.05mm，锯齿形状的间距为1mm；4. Use picosecond UV laser to engrave the zigzag convex pattern on the surface of the first drug-loaded coating, set the zigzag convex height to 0.05mm, and the zigzag shape spacing to 1mm;
5、干燥：烘箱控制温度为50～80℃，真空干燥30min；5. Drying: The temperature of the oven is controlled at 50～80℃, and the vacuum drying is 30min;
6、喷涂制作第二层载药涂层：将双膦酸盐溶液按照1cm 2球囊面积1～500mg有效药物的剂量，喷涂于第一层载药涂层表面； 6. Spraying to make the second drug-carrying coating: spray the bisphosphonate solution on the surface of the first drug-carrying coating at a dose of 1 to 500 mg of effective drug in the area of 1 cm 2 balloon;
7、再次干燥：烘箱控制温度为50～80℃，真空干燥30min；7. Re-drying: the temperature of the oven is controlled at 50～80℃, and the vacuum drying is 30min;
8、排除球囊内的气体,进行卷片，制成表面载药的椎体成形扩张球囊。8. Exhaust the gas in the balloon and roll the sheet to make a vertebroplasty expansion balloon with a drug on the surface.
实施例6Example 6
1、准备FG1010型扩张球囊；1. Prepare FG1010 dilation balloon;
2、称取1.3g PLGA、1.5ml二甲基甲酰胺、1.5ml四氢呋喃和0.1g双膦酸盐混合，常温下磁力搅拌均匀，得混合溶液；2. Weigh 1.3g of PLGA, 1.5ml of dimethylformamide, 1.5ml of tetrahydrofuran and 0.1g of bisphosphonate and mix them with magnetic stirring at room temperature to obtain a mixed solution;
3、静电纺丝制作第一层载药涂层：将球囊导管的球囊以标称压力充盈后接地，将上述混合溶液加入静电纺丝设备的注射器中，设置静电纺丝参数为：速度0.12ml/h，距离30cm，负压-0.14kV，高压0.67kV，使用静电纺丝技术在球囊表面形成载药涂层，厚度为0.2mm；3. Electrospinning to make the first drug-carrying coating: fill the balloon of the balloon catheter at a nominal pressure and ground it, add the above mixed solution to the syringe of the electrospinning equipment, and set the electrospinning parameters as: speed 0.12ml/h, distance 30cm, negative pressure -0.14kV, high voltage 0.67kV, using electrospinning technology to form a drug-loaded coating on the surface of the balloon with a thickness of 0.2mm;
4、在第一层载药涂层表面使用皮秒紫外激光器雕刻出微孔，设置微孔直径为1mm，微孔圆心的间距为5mm；4. Use a picosecond ultraviolet laser to carve micro-holes on the surface of the first drug-loaded coating, set the diameter of the micro-holes to 1mm, and the spacing of the micro-hole centers to 5mm;
5、干燥：烘箱控制温度为50～80℃，真空干燥30min；5. Drying: The temperature of the oven is controlled at 50～80℃, and the vacuum drying is 30min;
6、喷涂制作第二层载药涂层：将双膦酸盐溶液按照1cm 2球囊面积1～500mg有效药物的剂量，喷涂于第一层载药涂层表面； 6. Spraying to make the second drug-carrying coating: spray the bisphosphonate solution on the surface of the first drug-carrying coating at a dose of 1 to 500 mg of effective drug in the area of 1 cm 2 balloon;
7、再次干燥：烘箱控制温度为50～80℃，真空干燥30min；7. Re-drying: the temperature of the oven is controlled at 50～80℃, and the vacuum drying is 30min;
8、排除球囊内的气体,进行卷片，制成表面载药的椎体成形扩张球囊。8. Exhaust the gas in the balloon and roll the sheet to make a vertebroplasty expansion balloon with a drug on the surface.
实施例7Example 7
1、准备FG1010型扩张球囊；1. Prepare FG1010 dilation balloon;
2、称取1.3g PLGA、1.5ml二甲基甲酰胺、1.5ml四氢呋喃和0.1g双膦酸盐混合，常温下磁力搅拌均匀，得混合溶液；2. Weigh 1.3g of PLGA, 1.5ml of dimethylformamide, 1.5ml of tetrahydrofuran and 0.1g of bisphosphonate and mix them with magnetic stirring at room temperature to obtain a mixed solution;
3、静电纺丝制作第一层载药涂层：将球囊导管的球囊以标称压力充盈后接地，将上述混合溶液加入静电纺丝设备的注射器中，设置静电纺丝参数为：速度0.12ml/h，距离30cm，负压-0.14kV，高压0.67kV，使用静电纺丝技术在球囊表面形成载药涂层，厚度为0.2mm；3. Electrospinning to make the first drug-carrying coating: fill the balloon of the balloon catheter at a nominal pressure and ground it, add the above mixed solution to the syringe of the electrospinning equipment, and set the electrospinning parameters as: speed 0.12ml/h, distance 30cm, negative pressure -0.14kV, high voltage 0.67kV, using electrospinning technology to form a drug-loaded coating on the surface of the balloon with a thickness of 0.2mm;
4、干燥：烘箱控制温度为50～80℃，真空干燥30min；4. Drying: The temperature of the oven is controlled at 50～80℃, and the vacuum drying is 30min;
5、喷涂制作第二层载药涂层：将利多卡因溶液按照1cm 2球囊面积1～500mg有效药物的剂量，喷涂于第一层载药涂层表面； 5. Spraying to make the second drug-loading coating: spray the lidocaine solution on the surface of the first drug-loading coating at a dose of 1 to 500 mg of effective drug in the area of 1 cm 2 balloon;
6、干燥：烘箱控制温度为50～80℃，真空干燥30min；6. Drying: The temperature of the oven is controlled at 50～80℃, and the vacuum drying is 30min;
7、排除球囊内的气体,进行卷片，制成表面载药的椎体成形扩张球囊。7. Exhaust the gas in the balloon and roll the sheet to form a vertebroplasty expansion balloon with a drug on the surface.
实施例8Example 8
1、准备FG1010型扩张球囊；1. Prepare FG1010 dilation balloon;
2、称取1.3g PLGA、1.5ml二甲基甲酰胺、1.5ml四氢呋喃和0.1g双膦酸盐混合，常温下磁力搅拌均匀，得混合溶液；2. Weigh 1.3g of PLGA, 1.5ml of dimethylformamide, 1.5ml of tetrahydrofuran and 0.1g of bisphosphonate and mix them with magnetic stirring at room temperature to obtain a mixed solution;
3、静电纺丝制作第一层载药涂层：将球囊导管的球囊以标称压力充盈后接地，将上述混合溶液加入静电纺丝设备的注射器中，设置静电纺丝参数为：速度0.12ml/h，距离30cm，负压-0.14kV，高压0.67kV，使用静电纺丝技术在球囊表面形成载药涂层，厚度为0.2mm；3. Electrospinning to make the first drug-carrying coating: fill the balloon of the balloon catheter at a nominal pressure and ground it, add the above mixed solution to the syringe of the electrospinning equipment, and set the electrospinning parameters as: speed 0.12ml/h, distance 30cm, negative pressure -0.14kV, high voltage 0.67kV, using electrospinning technology to form a drug-loaded coating on the surface of the balloon with a thickness of 0.2mm;
4、干燥：烘箱控制温度为50～80℃，真空干燥30min；4. Drying: The temperature of the oven is controlled at 50～80℃, and the vacuum drying is 30min;
5、喷涂制备第二层载药涂层：将双膦酸盐溶液按照1cm 2球囊面积1～500mg有效药物的剂量，喷涂于第一层载药涂层表面； 5. Preparation of the second drug-carrying coating by spraying: spray the bisphosphonate solution on the surface of the first drug-carrying coating at a dose of 1 to 500 mg of effective drug in the area of 1 cm 2 balloon;
6、干燥：烘箱控制温度为50～80℃，真空干燥30min；6. Drying: The temperature of the oven is controlled at 50～80℃, and the vacuum drying is 30min;
7、称取1.3g PLGA与1.5ml二甲基甲酰胺、1.5ml四氢呋喃、0.1g雷尼酸锶混合，常温下磁力搅拌均匀，得混合溶液；7. Weigh 1.3g of PLGA, 1.5ml of dimethylformamide, 1.5ml of tetrahydrofuran, and 0.1g of strontium ranelate and mix them with magnetic stirring at room temperature to obtain a mixed solution;
8、静电纺丝制作第三层载药涂层：在第二层载药涂层表面制作第三层载药涂层，将上述步骤7的混合溶液加入静电纺丝设备的注射器中，设置静电纺丝参数为：速度0.12ml/h，距离30 cm，负压-0.14kV，高压0.67kV，所得载药涂层厚度为0.2mm；8. Electrospinning to make the third drug-carrying coating: make the third drug-carrying coating on the surface of the second drug-carrying coating, add the mixed solution of step 7 above into the syringe of the electrospinning equipment, and set the electrostatic Spinning parameters are: speed 0.12ml/h, distance 30 cm, negative pressure -0.14kV, high pressure 0.67kV, and the resulting drug-loaded coating thickness is 0.2mm;
9、干燥：烘箱控制温度为50～80℃，真空干燥30min；9. Drying: The temperature of the oven is controlled at 50～80℃, and the vacuum drying is 30min;
10、喷涂制作第四层载药涂层：将雷尼酸锶溶液按照1cm 2球囊面积1～500mg有效药物的剂量，喷涂于第三层载药涂层表面； 10. Preparation of the fourth drug-loaded coating by spraying: spray the strontium ranelate solution on the surface of the third drug-loading coating at a dose of 1 to 500 mg of effective drug in the area of 1 cm 2 balloon;
11、干燥：烘箱控制温度为50～80℃，真空干燥30min；11. Drying: The temperature of the oven is controlled at 50～80℃, and the vacuum drying is 30min;
12、排除球囊内的气体,进行卷片，制成表面载药的椎体成形扩张球囊。12. Exhaust the gas in the balloon and roll the sheet to form a vertebroplasty expansion balloon with a drug on the surface.
实施例9Example 9
1、准备FG1010型扩张球囊，1. Prepare FG1010 dilation balloon,
2、称取1.3g PLGA、1.5ml二甲基甲酰胺、1.5ml四氢呋喃和0.1g双膦酸盐混合，常温下磁力搅拌均匀，得混合溶液；2. Weigh 1.3g of PLGA, 1.5ml of dimethylformamide, 1.5ml of tetrahydrofuran and 0.1g of bisphosphonate and mix them with magnetic stirring at room temperature to obtain a mixed solution;
3、静电纺丝制作第一层载药涂层：将球囊导管的球囊以标称压力充盈后接地，将上述混合溶液加入静电纺丝设备的注射器中，设置静电纺丝参数为：速度0.12ml/h，距离30cm，负压-0.14kV，高压0.67kV，使用静电纺丝技术在球囊表面形成载药涂层，厚度为0.2mm；3. Electrospinning to make the first drug-carrying coating: fill the balloon of the balloon catheter at a nominal pressure and ground it, add the above mixed solution to the syringe of the electrospinning equipment, and set the electrospinning parameters as: speed 0.12ml/h, distance 30cm, negative pressure -0.14kV, high voltage 0.67kV, using electrospinning technology to form a drug-loaded coating on the surface of the balloon with a thickness of 0.2mm;
4、干燥：烘箱控制温度为50～80℃，真空干燥30min；4. Drying: The temperature of the oven is controlled at 50～80℃, and the vacuum drying is 30min;
5、喷涂制作第二层载药涂层：将双膦酸盐溶液按照1cm 2球囊面积1～500mg有效药物的剂量，喷涂于第一层载药涂层表面； 5. Spraying to make the second drug-carrying coating: spray the bisphosphonate solution on the surface of the first drug-carrying coating at a dose of 1 to 500 mg of effective drug in the area of 1 cm 2 balloon;
6、干燥：烘箱控制温度为50～80℃，真空干燥30min；6. Drying: The temperature of the oven is controlled at 50～80℃, and the vacuum drying is 30min;
7、称取1.3g PLGA与1.5ml二甲基甲酰胺、1.5ml四氢呋喃、0.1g降钙素混合，常温下磁力搅拌均匀，得混合溶液；7. Weigh 1.3g of PLGA, 1.5ml of dimethylformamide, 1.5ml of tetrahydrofuran, and 0.1g of calcitonin and mix them with magnetic stirring at room temperature to obtain a mixed solution;
8、静电纺丝制作第三层载药涂层：在第二层载药涂层表面制作第三层载药涂层，将上述步骤7的混合溶液加入静电纺丝设备的注射器中，设置静电纺丝参数为：速度0.12ml/h，距离30cm，负压-0.14kV，高压0.67kV，所得载药涂层厚度为0.2mm；8. Electrospinning to make the third drug-carrying coating: make the third drug-carrying coating on the surface of the second drug-carrying coating, add the mixed solution of step 7 above into the syringe of the electrospinning equipment, and set the electrostatic Spinning parameters are: speed 0.12ml/h, distance 30cm, negative pressure -0.14kV, high pressure 0.67kV, and the resulting drug-loaded coating thickness is 0.2mm;
9、干燥：烘箱控制温度为50～80℃，真空干燥30min；9. Drying: The temperature of the oven is controlled at 50～80℃, and the vacuum drying is 30min;
10、喷涂制作第四层载药涂层：将降钙素溶液按照1cm 2球囊面积1～500mg有效药物的剂量，喷涂于第三层载药薄膜表面； 10. The fourth layer of drug-loading coating is made by spraying: spray the calcitonin solution on the surface of the third layer of drug-loading film according to the dose of 1 to 500 mg of effective drug in the area of 1cm 2 balloon;
11、干燥：烘箱控制温度为50～80℃，真空干燥30min；11. Drying: The temperature of the oven is controlled at 50～80℃, and the vacuum drying is 30min;
12、排除球囊内的气体,进行卷片，制成表面载药的椎体成形扩张球囊。12. Exhaust the gas in the balloon and roll the sheet to form a vertebroplasty expansion balloon with a drug on the surface.
实施例10Example 10
1、准备FG1010型扩张球囊；1. Prepare FG1010 dilation balloon;
2、称取1.3g PLGA、1.5ml二甲基甲酰胺、1.5ml四氢呋喃和0.1g双膦酸盐混合，常温下磁力搅拌均匀，得混合溶液；2. Weigh 1.3g of PLGA, 1.5ml of dimethylformamide, 1.5ml of tetrahydrofuran and 0.1g of bisphosphonate and mix them with magnetic stirring at room temperature to obtain a mixed solution;
3、静电纺丝制作第一层载药涂层：将球囊导管的球囊以标称压力充盈后接地，将上述混合溶 液加入静电纺丝设备的注射器中，设置静电纺丝参数为：速度0.12ml/h，距离30cm，负压-0.14kV，高压0.67kV，使用静电纺丝技术在球囊表面形成载药涂层，厚度为0.2mm；3. Electrospinning to make the first drug-carrying coating: fill the balloon of the balloon catheter at a nominal pressure and ground it, add the above mixed solution to the syringe of the electrospinning equipment, and set the electrospinning parameters as: speed 0.12ml/h, distance 30cm, negative pressure -0.14kV, high voltage 0.67kV, using electrospinning technology to form a drug-loaded coating on the surface of the balloon with a thickness of 0.2mm;
4、在第一层载药涂层表面使用皮秒紫外激光器雕刻出螺旋形的沿球囊轴向延伸的凸起图案，凸起高度为0.05mm，间距为2mm；4. On the surface of the first drug-loaded coating, a picosecond UV laser is used to engrave a spiral-shaped convex pattern extending along the axial direction of the balloon, the convex height is 0.05mm, and the spacing is 2mm;
5、干燥：烘箱控制温度为50～80℃，真空干燥30min；5. Drying: The temperature of the oven is controlled at 50～80℃, and the vacuum drying is 30min;
6、喷涂制作第二层载药涂层：将双膦酸盐溶液按照1cm 2球囊面积1～500mg有效药物的剂量，喷涂于第一层载药涂层表面； 6. Spraying to make the second drug-carrying coating: spray the bisphosphonate solution on the surface of the first drug-carrying coating at a dose of 1 to 500 mg of effective drug in the area of 1 cm 2 balloon;
7、再次干燥：烘箱控制温度为50～80℃，真空干燥30min；7. Re-drying: the temperature of the oven is controlled at 50～80℃, and the vacuum drying is 30min;
8、排除球囊内的气体,进行卷片，制成表面载药的椎体成形扩张球囊，该表面载药的椎体成形扩张球囊的结构示意图如图5所示，表面具有螺旋形的沿球囊轴向延伸的凸起。8. Exhaust the gas in the balloon and roll the sheet to form a vertebroplasty expansion balloon loaded with medicine on the surface. The schematic diagram of the structure of the vertebroplasty expansion balloon loaded with medicine on the surface is shown in Figure 5, and the surface has a spiral shape. The protrusions extending axially along the balloon.
实施例11Example 11
1、准备FG1010型扩张球囊；1. Prepare FG1010 dilation balloon;
2、称取1.3g PLGA、1.5ml二甲基甲酰胺、1.5ml四氢呋喃和0.1g双膦酸盐混合，常温下磁力搅拌均匀，得混合溶液；2. Weigh 1.3g of PLGA, 1.5ml of dimethylformamide, 1.5ml of tetrahydrofuran and 0.1g of bisphosphonate and mix them with magnetic stirring at room temperature to obtain a mixed solution;
3、静电纺丝制作第一层载药涂层：将球囊导管的球囊以标称压力充盈后接地，将上述混合溶液加入静电纺丝设备的注射器中，设置静电纺丝参数为：速度0.12ml/h，距离30cm，负压-0.14kV，高压0.67kV，使用静电纺丝技术在球囊表面形成载药涂层，厚度为0.2mm；3. Electrospinning to make the first drug-carrying coating: fill the balloon of the balloon catheter at a nominal pressure and ground it, add the above mixed solution to the syringe of the electrospinning equipment, and set the electrospinning parameters as: speed 0.12ml/h, distance 30cm, negative pressure -0.14kV, high voltage 0.67kV, using electrospinning technology to form a drug-loaded coating on the surface of the balloon with a thickness of 0.2mm;
4、在第一层载药涂层表面使用皮秒紫外激光器雕刻出纤毛状凸起图案，纤毛直径为0.01mm，间距为0.05mm；4. On the surface of the first drug-loaded coating, a picosecond UV laser is used to engrave a cilia-like convex pattern with a diameter of 0.01mm and a spacing of 0.05mm;
5、干燥：烘箱控制温度为50～80℃，真空干燥30min；5. Drying: The temperature of the oven is controlled at 50～80℃, and the vacuum drying is 30min;
6、喷涂制作第二层载药涂层：将双膦酸盐溶液按照1cm 2球囊面积1～500mg有效药物的剂量，喷涂于第一层载药涂层表面； 6. Spraying to make the second drug-carrying coating: spray the bisphosphonate solution on the surface of the first drug-carrying coating at a dose of 1 to 500 mg of effective drug in the area of 1 cm 2 balloon;
7、再次干燥：烘箱控制温度为50～80℃，真空干燥30min；7. Re-drying: the temperature of the oven is controlled at 50～80℃, and the vacuum drying is 30min;
8、排除球囊内的气体,进行卷片，制成表面载药的椎体成形扩张球囊。8. Exhaust the gas in the balloon and roll the sheet to make a vertebroplasty expansion balloon with a drug on the surface.

Claims (15)

  1. 一种表面载药的椎体成形扩张球囊，包括球囊本体，其特征是：在球囊本体表面附有载药膜，所述载药膜由至少两层的载药涂层组成，其中，与球囊本体直接接触的第一层载药涂层通过静电纺丝形成。A vertebroplasty expansion balloon with a drug on its surface, comprising a balloon body, characterized in that a drug-loading film is attached to the surface of the balloon body, and the drug-loading film is composed of at least two drug-loading coatings, wherein , The first drug-carrying coating directly in contact with the balloon body is formed by electrospinning.
  2. 根据权利要求1所述的椎体成形扩张球囊，其特征是：除第一层载药涂层外，其他层的载药涂层通过静电纺丝、喷涂、浸提或刷涂的方式形成。The vertebroplasty and expansion balloon according to claim 1, characterized in that in addition to the first layer of drug-carrying coating, other drug-carrying coatings are formed by electrospinning, spraying, leaching or brushing. .
  3. 根据权利要求1或2所述的椎体成形扩张球囊，其特征是：相邻的两层载药涂层采用a和b两种不同的形成方式；所述a形成方式指的是静电纺丝方式形成，b形成方式指的是喷涂、浸提或刷涂中的任意一种方式形成。The vertebroplasty expansion balloon according to claim 1 or 2, characterized in that: the two adjacent layers of drug-carrying coatings adopt two different formation methods a and b; the formation method a refers to electrospinning Formed by silk, and b-formed means any one of spraying, leaching or brushing.
  4. 根据权利要求1、2或3所述的椎体成形扩张球囊，其特征是：所述载药涂层的层数为2-5层。The vertebroplasty expansion balloon according to claim 1, 2 or 3, wherein the number of layers of the drug-loaded coating is 2-5.
  5. 根据权利要求1、2或4所述的椎体成形扩张球囊，其特征是：所述载药涂层的层数为两层，第二层载药涂层通过喷涂、浸提或刷涂的方式形成。The vertebroplasty expansion balloon according to claim 1, 2 or 4, characterized in that: the number of layers of the drug-loading coating is two, and the second drug-loading coating is sprayed, leached or brushed. Way to form.
  6. 根据权利要求1-5中任一项所述的椎体成形扩张球囊，其特征是：通过静电纺丝形成的载药涂层中含有药物和可降解高分子材料；通过其他方式形成的载药涂层中含有药物，不含可降解高分子材料；每层载药涂层中含有一种或多种药物。The vertebroplasty expansion balloon according to any one of claims 1 to 5, wherein the drug-carrying coating formed by electrospinning contains a drug and a degradable polymer material; the carrier formed by other means The drug coating contains drugs and does not contain degradable polymer materials; each drug-loading coating contains one or more drugs.
  7. 根据权利要求6所述的椎体成形扩张球囊，其特征是：所述药物为抑制骨吸收药物、促进骨形成药物、止痛药物、***物中的至少一种；优选的，所述抑制骨吸收药物包括双膦酸盐，所述促进骨形成药物包括甲状旁腺激素、***素E2、氟化物和锶盐中的至少一种，所述止痛药物包括精氨酸阿司匹林，所述***物包括普鲁卡因和利多卡因中的至少一种。The vertebroplasty and expansion balloon according to claim 6, wherein the medicine is at least one of bone resorption inhibiting medicine, bone formation promoting medicine, analgesic medicine, and anesthetic medicine; preferably, the bone inhibiting medicine The absorption drug includes a bisphosphonate, the bone formation drug includes at least one of parathyroid hormone, prostaglandin E2, fluoride, and strontium salt, the analgesic drug includes arginine aspirin, and the anesthetic drug includes At least one of procaine and lidocaine.
  8. 根据权利要求6所述的椎体成形扩张球囊，其特征是：所述可降解高分子材料为聚乳酸、聚乳酸-羟基乙酸共聚物、壳聚糖、海藻酸钠、聚乙二醇、聚乙交酯、聚己内酯、聚天冬氨酸、羧甲基纤维素钠、羟丙基甲基纤维素、聚乙烯醇、聚醚中的至少一种；优选的，所述可降解高分子材料的粘度为0.1-0.5dl/g，重均分子量为20000-100000。The vertebroplasty and expansion balloon according to claim 6, wherein the degradable polymer material is polylactic acid, polylactic acid-glycolic acid copolymer, chitosan, sodium alginate, polyethylene glycol, At least one of polyglycolide, polycaprolactone, polyaspartic acid, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, polyvinyl alcohol, and polyether; preferably, the degradable The viscosity of the polymer material is 0.1-0.5dl/g, and the weight average molecular weight is 20000-100000.
  9. 根据权利要求1-8中任一项所述的椎体成形扩张球囊，其特征是：采用静电纺丝法形成的载药涂层的载药量为1～300mg/cm 2；采用喷涂、浸提或刷涂形成的载药涂层的载药量为1～500mg/cm 2。 The vertebroplasty expansion balloon according to any one of claims 1-8, characterized in that: the drug-loading coating formed by the electrospinning method has a drug-loading amount of 1 to 300 mg/cm 2 ; The drug-loading coating formed by leaching or brushing has a drug-loading amount of 1-500 mg/cm 2 .
  10. 根据权利要求1-9中任一项所述的椎体成形扩张球囊，其特征是：载药膜的 表面为非光滑结构，其表面分布有凸起或/和凹槽；The vertebroplasty and expansion balloon according to any one of claims 1-9, wherein the surface of the drug-loaded membrane is a non-smooth structure, and the surface is distributed with protrusions or/and grooves;
    优选的，凸起或/和凹槽均匀分布在载药膜表面；Preferably, the protrusions or/and grooves are evenly distributed on the surface of the drug-loaded film;
    优选的，凸起或/和凹槽的形状为波浪状、锯齿状、螺旋状、针状、棒状和图形状中的至少一种，所述图形状凸起为圆形、椭圆形、正多边形、非正多边形和不规则图形中的至少一种；Preferably, the shape of the protrusions or/and grooves is at least one of wavy, zigzag, spiral, needle, rod, and figure shapes, and the figure-shaped projections are round, elliptical, and regular polygon. , At least one of irregular polygons and irregular graphics;
    优选的，凸起或/和凹槽的高度或深度为0.01～0.1mm。Preferably, the height or depth of the protrusion or/and groove is 0.01-0.1 mm.
  11. 根据权利要求10所述的椎体成形扩张球囊，其特征是：至少第一载药涂层的表面设有凸起或/和凹槽，载药膜表面的凸起或/和凹槽由各层载药涂层上的凸起或/和凹槽构成。The vertebroplasty expansion balloon according to claim 10, characterized in that: at least the surface of the first drug-loaded coating is provided with protrusions or/and grooves, and the protrusions or/and grooves on the surface of the drug-loaded film are formed by The protrusions or/and grooves on each layer of the drug-carrying coating are formed.
  12. 根据权利要求1-11中任一项所述的椎体成形扩张球囊，其特征是：所述载药膜上设有能够穿透各层载药涂层的通孔；优选的，通孔的尺寸为毫米级。The vertebroplasty expansion balloon according to any one of claims 1-11, characterized in that: the drug-loaded membrane is provided with a through hole that can penetrate each layer of the drug-loaded coating; preferably, the through hole The size is millimeter level.
  13. 根据权利要求1-12中任一项所述的椎体成形扩张球囊，其特征是：各层载药涂层的厚度为0.05-0.2mm。The vertebroplasty and expansion balloon according to any one of claims 1-12, wherein the thickness of each layer of drug-carrying coating is 0.05-0.2 mm.
  14. 一种权利要求1或2所述的表面载药的椎体成形扩张球囊的制备方法，其特征是：A method for preparing a drug-loaded vertebroplasty and dilatation balloon as claimed in claim 1 or 2, characterized in that:
    (1)将药物、高分子可降解材料配成静电纺丝液，在球囊本体表面进行静电纺丝形成薄膜，静电纺丝后干燥，得到第一层载药涂层；(1) Prepare an electrospinning solution with drugs and polymer degradable materials, electrospin on the surface of the balloon body to form a film, and dry after electrospinning to obtain the first drug-carrying coating;
    (2)配制含有药物和高分子可降解材料的静电纺丝液，或者配制药物和溶剂的药物溶液，选择静电纺丝、喷涂、浸提或刷涂方式形成各层载药涂层，最终得到表面载药的椎体成形扩张球囊。(2) Prepare the electrospinning solution containing drugs and polymer degradable materials, or prepare the drug solution of drugs and solvents, choose electrospinning, spraying, extraction or brushing to form each layer of drug-carrying coating, and finally obtain The vertebroplasty balloon with a drug on the surface.
  15. 根据权利要求14所述的制备方法，其特征是：还包括以下a或/b步骤：The preparation method according to claim 14, characterized in that it further comprises the following steps a or /b:
    a.在至少一层的载药涂层上形成凸起或凹槽的步骤；a step of forming protrusions or grooves on at least one layer of drug-loaded coating;
    b.在载药膜上形成通孔的步骤。b. The step of forming a through hole on the drug-loaded film.
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