WO2024060540A1 - 一种载药球囊及其制备方法 - Google Patents

一种载药球囊及其制备方法 Download PDF

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Publication number
WO2024060540A1
WO2024060540A1 PCT/CN2023/082108 CN2023082108W WO2024060540A1 WO 2024060540 A1 WO2024060540 A1 WO 2024060540A1 CN 2023082108 W CN2023082108 W CN 2023082108W WO 2024060540 A1 WO2024060540 A1 WO 2024060540A1
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Prior art keywords
drug
loaded
release
balloon
sustained
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PCT/CN2023/082108
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English (en)
French (fr)
Inventor
王利伟
黄君仪
张志军
李斌
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广东博迈医疗科技股份有限公司
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Priority to US18/414,450 priority Critical patent/US20240148943A1/en
Publication of WO2024060540A1 publication Critical patent/WO2024060540A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/08—Materials for coatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/04—Macromolecular materials
    • A61L29/049—Mixtures of macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/08—Materials for coatings
    • A61L29/085—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A61L29/148—Materials at least partially resorbable by the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A61L29/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/216—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with other specific functional groups, e.g. aldehydes, ketones, phenols, quaternary phosphonium groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/602—Type of release, e.g. controlled, sustained, slow
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/606—Coatings
    • A61L2300/608—Coatings having two or more layers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/62—Encapsulated active agents, e.g. emulsified droplets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/63—Crystals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2420/00—Materials or methods for coatings medical devices
    • A61L2420/02—Methods for coating medical devices
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2420/00—Materials or methods for coatings medical devices
    • A61L2420/06—Coatings containing a mixture of two or more compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2420/00—Materials or methods for coatings medical devices
    • A61L2420/08—Coatings comprising two or more layers

Definitions

  • the present application relates to the technical field of medical devices, and more specifically to a drug-loaded balloon and a preparation method thereof.
  • Percutaneous transluminal angioplasty has become a common option for the treatment of coronary and peripheral artery disease.
  • the balloon catheter enters the diseased site through the artery.
  • the balloon applies mechanical force to the diseased blood vessel to compress the diseased plaque tissue against the artery wall, expand the blood vessel lumen, and help restore blood flux.
  • the balloon is then withdrawn from the blood vessel, and the drug-loaded balloon mechanically dilates the narrowed vascular passage and rapidly releases therapeutic drugs to the blood vessel wall to achieve local administration.
  • Drug-loaded balloons are a new treatment method based on the concept of intervention rather than implantation.
  • drug-loaded balloons avoid the need for superimposed stents when used for in-stent restenosis and reduce the need for permanent It can reduce the metal cage effect brought by permanent stent implantation to blood vessels; shorten the use time of dual antiplatelet drugs and reduce the complications caused by them; it also has the advantages of strong operability and is more conducive to the treatment of small vessel lesions.
  • drug-loaded balloons and drug-eluting stents deliver drugs to diseased blood vessels.
  • Active drugs in drug-eluting stents usually use polymers as carriers.
  • the composition of the polymer/active drug coating determines the drug release mechanism and release kinetics after stent implantation.
  • the stent is implanted and retained in the target blood vessel, and the possibility of drug migration to other locations in the body is low.
  • the single-sided drug-coated stent near the blood vessel wall limits the drug coating to the closely adhering vessel wall and Between the outer surfaces of the stent, the active drug can be slowly released and dissolved. This is not the case with drug-loaded balloons.
  • the balloon only contacts the blood vessel wall for a short time.
  • the required active drug dose needs to be released to the diseased blood vessel. After the balloon is withdrawn from the blood vessel, the active drug does not remain in situ similar to that provided by the eluting stent.
  • the above-mentioned application method of drug-loaded balloons makes it impossible to have a stable polymer coating system, so the delivery and use are The loss of active drug during the process cannot be ignored.
  • drug-coated balloons that have been approved and drug-loaded balloons in research literature basically have much higher device drug loading doses than corresponding drug-eluting stents, such as the active drug purple in the SSED P180011 drug-eluting stent.
  • the alcohol dose is even less than one-tenth that of the drug-loaded balloon SSED P190019.
  • sirolimus a drug that is generally recognized for its safety and effectiveness in the field of coronary drug-loaded stents, as the active component of drug-loaded balloons.
  • sirolimus due to differences in its molecular structure and physical and chemical properties from paclitaxel, sirolimus has lower lipophilicity and is more difficult to transfer to the blood vessel wall. Overcoming this issue also makes developing sirolimus balloon coatings more challenging.
  • the purpose of this application is to provide a drug-loaded balloon and a preparation method thereof, which can provide a sufficient initial loading drug dose to the lesion site, provide a controllable long-acting therapeutic drug to the lesion site, and improve Overall vascular drug release rates.
  • this application discloses a drug-loaded balloon, which includes a balloon body and a drug-loaded coating coated on the outer surface of the balloon body.
  • the drug-loaded coating includes at least two types of drug-loaded balloons with different drug release kinetics.
  • a second drug-loaded coating composed of free unbound forms of active drugs dispersed among the controllable sustained-release drugs in the first drug-loaded coating and coupled to the balloon body ;
  • the first drug-loaded coating and the second drug-loaded coating are both non-hydrophilic compositions.
  • the drug-loaded balloon of the present application is coated with a non-hydrophilic material on the outer surface of the balloon body.
  • the drug-loaded coating is also set to contain active drugs in free, unbound forms. It can provide sufficient initial loading drug dose for blood vessels that may be damaged due to instantaneous expansion during angioplasty.
  • this application also provides a method for preparing a drug-loaded balloon, including the steps:
  • Figure 1 shows a schematic structural diagram of the drug-loaded balloon of the present application.
  • Figure 2 shows the results of the in vitro simulation test of the product of this application.
  • This application provides a drug-loaded balloon, including a balloon body 101 and a drug-loaded coating 102 coated on the outer surface of the balloon body 101.
  • the drug-loaded coating 102 has a non-hydrophilic structure, and Drug Loaded Coating 102 It includes a first drug-loaded coating and a second drug-loaded coating 1023; the first drug-loaded coating includes at least two controllable sustained-release drugs, and each controllable sustained-release drug has different drug release kinetics; the second The drug-loaded coating 1023 includes active drugs in free unbound form, and can be dispersed between different controllable sustained-release drugs in the first drug-loaded coating, and can couple each controllable sustained-release drug to the balloon body. 101 on.
  • the first drug-loaded coating includes a first controllable sustained-release drug 1021 and a second controllable sustained-release drug 1022.
  • the sustained-release drug 1021 and the second controllable sustained-release drug 1022 have different drug release kinetics.
  • the first controllable sustained-release drug 1021 has a faster drug release rate
  • the second controllable sustained-release drug 1022 has a slower drug release rate.
  • Drug release kinetics but not limited thereto.
  • the first controllable sustained-release drug 1021 and the second controllable sustained-release drug 1022 have different drug release kinetics, and the drug release rate can be adjusted through different combinations, so that the drug-loaded balloon can target the vascular restenosis cascade reaction.
  • Bioactive drugs are provided to the treatment site at different stages to provide controllable long-acting treatment drugs to the diseased site and improve the overall vascular drug release rate.
  • the non-hydrophilic structure involved in this application includes structures that do not contain water solubility, structures that do not contain hydrophilic molecules, and structures that do not contain amphiphilic molecules.
  • the first drug-loaded coating and the second drug-loaded coating of the present application have a non-hydrophilic structure, that is to say, the controlled sustained-release drug has a non-hydrophilic structure, and the free unbound form of the active drug has a non-hydrophilic structure. sexual structure.
  • controllable sustained-release drug uses a polymer as a carrier to embed the drug to form drug-loaded microparticles, and the polymer is biocompatible and biodegradable.
  • the polymer is a non-hydrophilic degradable polymer.
  • the polymer is selected from at least one of polylactic acid, polyglycolic acid and its copolymers, and polydioxanone. More preferably, polylactic acid or lactic acid-glycolic acid copolymer is an amorphous or partially crystalline polymer.
  • the method of using polymers as carriers to entrap drugs to form drug-loaded microparticles can be prepared by any applicable existing polymer-embedded drug technology, such as microfluidic technology, membrane emulsification technology, etc.
  • any applicable existing polymer-embedded drug technology such as microfluidic technology, membrane emulsification technology, etc.
  • controlled sustained-release drug refers to a drug whose sustained-release rate is controllable.
  • the sustained release rate of the drug can be controlled by drug release kinetics, and different drug release kinetics have different drug release rates.
  • Controllable sustained-release drugs with different drug release kinetics can slowly release active drugs at different rates to provide the required therapeutic drugs for the middle and late stages of the vascular restenosis cascade reaction, thereby avoiding the explosive release and extinction of drugs.
  • the controllable sustained-release drug has different drug release kinetics.
  • the adjustment method includes at least one of the following: using different polymer types to adjust, using different polymer molecular weights to adjust, controlling different ratios of polymer and drug, and controlling different ratios of surface area and volume of drug-loaded particles, but not limited to this.
  • the specific different release kinetics of the controlled sustained-release drug are adjusted by changing the ratio of polymer and drug.
  • the drug loading in the controlled sustained-release drug is not less than 30% of the weight of the sustained-release drug, preferably 30-45%, and the controlled sustained-release drug has a faster drug release rate; the drug loading in the controlled sustained-release drug is less than 30% of the weight of the sustained-release drug, preferably 10-25%, and the controlled sustained-release drug has a slower drug release rate.
  • the first drug-loaded coating includes a first controllable sustained-release drug and a second controllable sustained-release drug.
  • the first controllable sustained-release drug has a faster drug release rate
  • the second controllable sustained-release drug has a faster drug release rate.
  • Controlled sustained-release drugs have relatively slow drug release kinetics.
  • the drug-loaded coating includes 10%-30% of the first controllable sustained-release drug, 20%-50% of the a second controlled release drug, and 20%-50% of the free unbound bioactive drug.
  • the release kinetics of the first controllable sustained-release drug and the second controllable sustained-release drug are controlled by changing the ratio of the polymer and the drug, wherein the drug loading amount of the first controllable sustained-release drug is Not less than 30% of the weight of the first controllable sustained-release drug, preferably 30-45%, more preferably 35-45%, and the drug loading amount of the second controllable sustained-release drug is lower than that of the second controllable sustained-release drug. 30% of the weight of the controlled sustained-release drug, preferably 10-20%.
  • the total drug dose of the drug-loaded coating in the drug-loaded balloon can be 0.5 ⁇ g/mm 2 to 4 ⁇ g/mm 2 based on the effective surface area of the balloon, preferably 0.8 ⁇ g/mm 2 to 1.5 ⁇ g. /mm 2 .
  • the free non-bound active drug is considered to be the only bioactive drug in terms of pharmacokinetics.
  • the second drug-loaded coating of the present application can provide a sufficient initial loading drug dose to the blood vessels that may be damaged by instantaneous expansion during percutaneous transluminal angioplasty by using the free non-bound active drug.
  • the free non-bound active drug is bonded to the balloon body in the form of loose drug particles rather than dense drug films, dispersed between the controlled sustained-release drugs in the first drug-loaded coating and coupled to the balloon body.
  • the formation form of the free non-bound active drug can include but is not limited to being dissolved in the coating liquid in the form of pure drugs or added to the coating liquid in the form of particles.
  • the coating liquid includes but is not limited to a dispersion liquid
  • the dispersion liquid should be a non-solvent for the polymer used to ensure the stability of the drug-loaded particles in the dispersion liquid, and should not have the ability to dissolve the active drug in the drug-loaded particles to ensure the stability of the active drug in the drug-loaded particles.
  • the dispersion liquid can be a single solvent or a mixture of multiple mutually soluble solvents, and the solvent includes but is not limited to methanol, ethanol, isopropanol, n-hexane, heptane, petroleum ether, water, ethyl acetate, and acetone.
  • the method of adding the particles to the coating liquid may include but is not limited to preparation by grinding, solvent/non-solvent precipitation, and emulsified solvent evaporation.
  • the drug-loaded coating may be formed by spraying, droplet coating, or dipping on the surface of the balloon body.
  • the drug-loaded coating may be formed by spraying on the balloon body using mature ultrasonic atomization spraying technology.
  • the content of free non-bound bioactive drugs in the balloon drug-loaded coating is 0%-60% of the total drug loading, preferably 20%-50%.
  • the drug or active drug referred to in this application is sirolimus, also known as rapamycin, but it is not limited to this. Of course, it can also be paclitaxel as the unique pharmaceutical ingredient or drug. One of the ingredients can be selected according to the different physical and chemical properties of the drug.
  • the first drug-loaded coating includes at least two controllable sustained-release sirolimus with different drug release kinetics, and the second drug-loaded coating includes free unbound form of sirolimus. Rolimus, on the one hand, is clinically safer and more effective; on the other hand, it solves the problem of difficulty in transferring sirolimus to the blood vessel wall due to its low lipophilicity.
  • the release kinetics of controlled sustained-release drugs can be controlled by changing the ratio of polymer and drug.
  • the drug takes sirolimus as an example, as follows:
  • Preparation solution 3 Provide 1wt% PVA aqueous solution
  • the release kinetics of controlled sustained-release drugs can be controlled by changing the ratio of polymers and drugs.
  • the drug takes sirolimus as an example, as follows:
  • Preparation solution 3 Provide 1wt% PVA aqueous solution
  • the balloon body is inflated and not pressurized
  • Example 2 The drug-loaded microspheres prepared in Example 1, the drug-loaded microspheres prepared in Example 2, and the drug particles prepared in Example 3 were prepared for suspension spraying at a weight ratio of 20%, 40%, and 40%. liquid; the suspension is filled into a syringe, and an electromagnetic field is applied inside or outside the syringe for magnetic stirring; the uniformly stirred suspension is ultrasonically atomized and sprayed on the outer surface of the rotating inflatable balloon body;
  • the drug-loaded balloon prepared in Example 4 was subjected to in vitro simulation testing as follows:
  • Fresh porcine coronary vessels were provided and flushed with physiological saline several times to remove excess fat, connective tissue and fascia. Cut the blood vessel to an appropriate length and connect it to the distal outlet of the ASTM F2394-07 curvature model blood vessel simulation channel.
  • the proximal entrance of the vascular simulation channel is connected to the 37°C physiological saline pipeline with a three-way valve, and the physiological saline flow is controlled by a peristaltic pump at 50 ml/min.
  • the simulated vascular channel is pre-flushed with 37°C physiological saline.
  • the balloon enters from the proximal end of the simulated blood vessel channel, reaches the blood vessel through the simulated channel within 60 ⁇ 10 seconds, pressurizes to 8 atm, maintains for 60 seconds, and releases the drug-loaded coating to the blood vessel.
  • the released balloon is withdrawn along the simulated vascular channel after applying negative pressure; the simulated channel includes the pig vascular channel and is flushed with 37°C physiological saline for 1 hour, with a flow rate of 50ml/min.
  • the test results are shown in Figure 2.
  • the drug-loaded coating of the balloon has a drug-loading dose of 1.3 ⁇ g/mm 2.
  • the drug loss of the balloon through the simulated vascular channel was 25.6%, indicating that the drug-loaded coating in the drug-loaded balloon of the present application has superior drug release rate and anti-erosion ability.
  • the drug-loaded balloon prepared in Example 4 was tested for insoluble particles, as follows:
  • Freshly harvested pig coronary vessels were flushed with physiological saline several times to remove excess fat, connective tissue and fascia. Cut the blood vessel to an appropriate length and connect it to the distal outlet of the ASTM F2394-07 curvature model blood vessel simulation channel.
  • the proximal entrance of the vascular simulation channel is connected to the 37°C physiological saline pipeline with a three-way valve, and the physiological saline flow is controlled by a peristaltic pump at 50 ml/min.
  • the simulated vascular channel is pre-flushed with 37°C physiological saline.
  • the balloon enters from the proximal end of the simulated blood vessel channel, reaches the blood vessel through the simulated channel within 60 ⁇ 10 seconds, pressurizes to 8 atm, maintains for 60 seconds, and releases the drug-loaded coating to the blood vessel. , the released balloon is decompressed and withdrawn along the simulated vascular channel; the simulated channel including the porcine vascular access is flushed with 37°C physiological saline for 1 hour, with a flow rate of 50ml/min.

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  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

一种载药球囊及其制备方法，载药球囊包括球囊本体及载药涂层，载药涂层包括至少两种具有不同药物释放动力学的可控缓释药物的第一载药涂层；及分散于第一载药涂层中的各可控缓释药物之间并将它们偶联在球囊本体的自由非结合形式的活性药物组成的第二载药涂层；第一载药涂层和第二载药涂层均为非亲水性组成。该载药球囊能够向病变部位提供足够的初始负荷药物剂量，多个可控缓释药物具有不同的药物释放动力学，能避免药物爆发式释放与澌灭，还可通过不同的组合方式调整药物释放速率，使得载药球囊能够针对血管再狭窄级联反应的不同阶段向治疗部位提供生物活性药物，实现向病变部位提供可调控的长效治疗药物，提高总体血管药物释放率。

Description

一种载药球囊及其制备方法 技术领域
本申请涉及医疗器械技术领域，更具体地涉及一种载药球囊及其制备方法。
背景技术
经皮腔内血管成形术已经成为一种常见的用于治疗冠状动脉和外周动脉疾病的选择。球囊导管经由动脉进入病变部位，球囊在充压过程中向病变血管施以机械力将病变斑块组织压缩到动脉壁上，扩大血管腔道从而帮助恢复血液通量。之后将球囊从血管中撤出，而载药球囊则在机械扩张狭窄血管通路的同时具有向所在血管壁快速释放治疗性药物以达到局部给药的目的。载药球囊作为一种介入而非植入概念下产生的新型治疗手段，与常规使用的药物洗脱支架相比，避免了在应用于支架内再狭窄病症时的支架叠加置入，减少永久性支架植入给血管带来的金属笼效应；缩短双联抗血小板药物的使用时间从而减少其带来的并发症；同时具有可操作性强，更利于处理小血管病变等优势。
载药球囊和药物洗脱支架在向病变血管给药的方式上也存在着区别。药物洗脱支架中活性药物通常由聚合物作为载体，该聚合物/活性药物涂层的组成决定了支架植入后的药物释放机理和释放动力学。支架被植入并保留在目标血管内，药物向体内其它位置迁移的可能性较低，尤其是近血管腔壁的单面药物涂层支架更是将药物涂层局限于紧贴的血管壁和支架外表面之间，活性药物可以缓慢释放溶解。载药球囊则不然，球囊仅与血管壁接触很短的时间，在球囊扩张的几分钟甚至数十秒内，需要向病变血管释放所需的活性药物剂量。球囊撤出血管后，活性药物也不具有类似洗脱支架所提供的原位保留方式。另外载药球囊的上述应用方式使其无法具有稳定的聚合物涂层体系，因此输送和使用过 程中的活性药物损失也不容忽视。基于以上因素，已经获批药物涂层球囊及研究文献中的载药球囊基本上器械载药剂量远高于相应的药物洗脱支架，如SSED P180011药物洗脱支架中的活性药物紫衫醇剂量甚至低于载药球囊SSED P190019的十分之一。
绝大多数已经批准用于临床的载药球囊均为基于紫杉醇为活性药物，大量的临床研究也为使用药物涂层球囊DCB的安全性和可行性提供了证据支持。然而Katsanos医生等根据大量临床数据进行了系统的分析统计，其结果发表于Journal of the American Heart Association，得出在下肢股腘动脉使用紫杉醇为活性药物的球囊和支架，死亡风险提高；相关研究认为流失在人体中的紫杉醇晶体颗粒仍然存在安全隐患。
越来越多的研究开始使用西罗莫司这一安全有效性在冠脉载药支架领域被普遍认可的药物作为载药球囊的活性组分。然而介于其分子结构和物化性质与紫杉醇的区别，西罗莫司具有较低的亲脂性，向血管壁转移比较困难。克服这个问题也使开发西罗莫司球囊涂层更具挑战性。
申请内容
为了克服现有技术的缺陷，本申请的目的是提供一种载药球囊及其制备方法，能够向病变部位提供足够的初始负荷药物剂量，向病变部位提供可调控的长效治疗药物，提高总体血管药物释放率。
为了实现上述目的，本申请公开了一种载药球囊，包括球囊本体及涂覆在球囊本体外表面的载药涂层，所述载药涂层包括至少两种具有不同药物释放动力学的可控缓释药物的第一载药涂层；
及分散于所述第一载药涂层中的各所述可控缓释药物之间并将它们偶联在所述球囊本体的自由非结合形式的活性药物组成的第二载药涂层；
所述第一载药涂层和所述第二载药涂层均为非亲水性组成。
与现有技术相比，本申请的载药球囊通过在球囊本体外表面涂覆非亲水性 结构的载药涂层，从而保证载药涂层的亲脂性，以保证药物向血管壁的转载能力和药物在血管内壁的滞留能力；同时设置第一载药涂层包括至少2种可控缓释药物，且每个可控缓释药物具有不同的药物释放动力学，从而避免药物爆发式释放与澌灭，且可通过不同的组合方式调整药物释放速率，使得载药球囊能够针对血管再狭窄级联反应的不同阶段向治疗部位提供生物活性药物，实现向病变部位提供可调控的长效治疗药物，提高总体血管药物释放率；载药涂层还设置含有自由非结合形式的活性药物，能提供血管成形术中因瞬间扩张可能受损的血管所需要足量的初始负荷药物剂量。
相应地，本申请还提供一种载药球囊的制备方法，包括步骤：
(1)提供球囊本体；
(2)制备至少2种可控缓释药物，且控制每个可控缓释药物具有不同的药物释放动力学；
(3)制备自由非结合形式的活性药物；
(4)将可控缓释药物与自由非结合形式的活性药物以一定比例制成悬浮喷涂液；
(5)将悬浮喷涂液涂覆在球囊本体表面。
附图说明
图1展示本申请载药球囊的结构示意图。
图2展示本申请产品体外模拟测试的结果。
具体实施方式
为详细说明本申请的技术内容、构造特征、所实现目的及效果，以下结合实施方式并配合附图详予说明。
请参考图1，本申请提供一种载药球囊，包括球囊本体101和涂覆在球囊本体101外表面的载药涂层102，载药涂层102为非亲水性结构，且载药涂层102 包括第一载药涂层和第二载药涂层1023；第一载药涂层包括至少2种可控缓释药物，且每个可控缓释药物具有不同的药物释放动力学；第二载药涂层1023包括自由非结合形式的活性药物，且能分散在第一载药涂层中不同的可控缓释药物之间，并能将各可控缓释药物偶联在球囊本体101上。
示例地，以第一载药涂层包括2种可控缓释药物为例，第一载药涂层包括第一可控缓释药物1021和第二可控缓释药物1022，第一可控缓释药物1021和第二可控缓释药物1022具有不同的药物释放动力学，比如第一可控缓释药物1021具有较快的药物释放速率，第二可控缓释药物1022具有较缓慢的药物释放动力学，但不限于此。第一可控缓释药物1021和第二可控缓释药物1022具有不同的药物释放动力学，可通过不同的组合方式调整药物释放速率，使得载药球囊能够针对血管再狭窄级联反应的不同阶段向治疗部位提供生物活性药物，实现向病变部位提供可调控的长效治疗药物，提高总体血管药物释放率。
需要理解的是，本申请涉及的非亲水性结构包括不含水溶性的结构，还包括不含亲水分子结构，也包括不含双亲分子结构。本申请的第一载药涂层和第二载药涂层为非亲水性结构，也就是说可控缓释药物为非亲水性结构，及自由非结合形式的活性药物为非亲水性结构。通过采用非亲水性结构的载药涂层，从而保证载药涂层的亲脂性，提高药物向血管壁的转载能力，同时也提高了药物在血管内壁的抗血流冲刷能力或滞留能力。
在一较佳实施例中，所述可控缓释药物为以聚合物作为载体包埋药物形成载药微粒，所述聚合物具有生物相容性和可生物降解。优选地，聚合物为非亲水可降解聚合物。进一步地，聚合物选自聚乳酸、聚乙醇酸及其共聚物、聚二恶烷酮中的至少一种。更为优选地，聚乳酸或乳酸-乙醇酸共聚物为无定形或部分结晶态的聚合物。值得一提的是，对于以聚合物作为载体包埋药物形成载药微粒的方式可借由任何适用的现有聚合物包埋药物技术制备，比如微流控技术，膜乳化技术等，在此不进行具体阐述。
需要理解的是，本申请涉及的可控缓释药物是指药物的缓释速率可控，能 够通过药物释放动力学来控制药物的缓释速率，不同的药物释放动力学具有不同的药物释放速率。具有不同药物释放动力学的可控缓释药物能够以不同速率缓慢释放活性药物的载药涂层为血管再狭窄级联反应的中期和后期提供所需治疗药物，从而避免药物爆发式释放与澌灭。因此，通过调控药物释放动力学能实现针对血管再狭窄级联反应的不同阶段向治疗部位提供生物活性药物，还能实现使活性药物在短暂扩张时长内(一般为30-180秒)向病变血管进行快速药物释放转载。值得一提的是，可通过一定手段来实现不同的药物释放动力学，在本申请中，可控缓释药物具有不同的药物释放动力学的调节方式包括以下至少一种：采用不同的聚合物种类调节、采用不同的聚合物分子量调节、控制聚合物与药物的不同比例调节、控制载药微粒的表面积与体积的不同比例调节，但不以此为限。优选地，通过改变聚合物和药物的比例来调控可控缓释药物的具体不同的释放动力学。示例地，可控缓释药物中载药量不低于该可缓释药物重量的30％，优选为30-45％，该可控缓释药物具有较快的药物释放速率；可控缓释药物中载药量低于该可缓释药物重量的30％，优选为10-25％，该可控缓释药物具有较缓慢的药物释放速率。
在一较佳实施例中，所述第一载药涂层包括第一可控缓释药物和第二可控缓释药物，第一可控缓释药物具有较快的药物释放速率，第二可控缓释药物具有较缓慢的药物释放动力学，按重量百分数计，所述载药涂层包括10％-30％的所述第一可控缓释药物、20％-50％的所述第二可控缓释药物，及20％-50％的所述自由非结合生物活性药物。在本实施例中，通过改变聚合物和药物比例来调控第一可控缓释药物和第二可控缓释药物的释放动力学，其中，所述第一可控缓释药物中载药量不低于所述第一可控缓释药物重量的30％，优选为30-45％，更优选为35-45％，所述第二可控缓释药物中载药量低于所述第二可控缓释药物重量的30％，优选为10-20％。更进一步地，载药球囊中载药涂层的总药物剂量可以是按照球囊有效表面积为计量标准的0.5μg/mm2至4μg/mm2，优选地，0.8μg/mm2至1.5μg/mm2。
需要理解的是，自由非结合形式的活性药物，在药物动力学上，其被认为是唯一的生物活性药。本申请第二载药涂层通过采用自由非结合形式的活性药物能给经皮腔内血管成形术中因瞬间扩张可能受损伤的血管提供足量的初始负荷药物剂量。进一步地，自由非结合形式的活性药物是以松散药物微粒而非致密药膜接合在球囊本体上，分散于第一载药涂层中的各可控缓释药物之间并将它们偶联在球囊本体。值得一提的是，自由非结合形式的活性药物的形成形式可以包括但不限于以纯药形式溶解于涂层液体中或以微粒形式添加于涂层液体中。其中，涂层液体包含但不限于分散液，分散液应是所使用聚合物的非溶剂，以保证载药微粒在分散液中的稳定性，还应不具有溶出载药微粒中的活性药物的能力，保证活性药物在载药微粒中的稳定性。有的实施例中，分散液可以是一种单一溶剂或多种可互溶溶剂的混合物，溶剂包括但不限于甲醇、乙醇、异丙醇、正己烷、庚烷、石油醚、水、乙酸乙酯、丙酮。其中，以微粒形式添加于涂层液体中的形成方式可以包括但不限于通过研磨法、溶剂/非溶剂沉淀法、乳化溶剂蒸发法制备。其中，可以采用喷涂法，微滴法，浸渍法涂覆于球囊本体表面形成载药涂层，优选地，以成熟的超声雾化喷涂技术喷涂于球囊本体成为均匀牢固的载药涂层。更进一步地，球囊载药涂层中的自由非结合生物活性药物含量为总载药量的0％-60％，优选的20％-50％。
在一较佳实施例中，本申请所称的药物或活性药物为西罗莫司，又名雷帕霉素，但不限于此，当然也可以是紫杉醇，作为其中独有的药物成分或药物成分之一，可根据药物不同的理化性能进行选择。有的实施例中，所述第一载药涂层包括至少2种具有不同的药物释放动力学的可控缓释西罗莫司，所述第二载药涂层包括自由非结合形式的西罗莫司，一方面西罗莫司在临床上更安全有效，另一方面，解决了西罗莫司由于具有较低的亲脂性而存在的向血管壁转移困难问题。
以下通过具体实施例进一步来说明本申请载药球囊的制备方法，但不以此 为限。
实施例1
较快药物释放动力学的可控缓释药物的制备，通过改变聚合物和药物的比例来调控可控缓释药物的释放动力学，药物以西罗莫司为例，具体如下：
(1)制备溶液1：提供300mg聚合物(PLGA)及将200mg西罗莫斯溶解于10ml二氯甲烷，待用；
(2)制备溶液2：提供2wt％PVA水溶液；
(3)制备溶液3：提供1wt％PVA水溶液；
(4)将2ml溶液1加入6ml溶液2中，10,000RPM高速匀化1分钟制成乳液1；
(5)再将乳液1加入45ml溶液3中，10,000RPM高速匀化3分钟成乳液2；
(6)将乳液2于室温下磁力搅拌至少6小时除溶剂二氯甲烷后冷藏(4-10℃)60分钟；
(7)离心分离并多次以去离子冰水洗涤微球；
(8)将微球悬浮于5ml去离子水，冻干保存待用。
实施例2
较缓慢药物释放动力学的可控缓释药物的制备，通过改变聚合物和药物比例来调控可控缓释药物的释放动力学，药物以西罗莫司为例，具体如下：
(1)制备溶液1：提供300mg聚合物(PLGA)及将60mg西罗莫斯溶解于10ml二氯甲烷，待用；
(2)制备溶液2：提供2wt％PVA水溶液；
(3)制备溶液3：提供1wt％PVA水溶液；
(4)将2ml溶液1加入6ml溶液2中，10,000RPM高速匀化1分钟制成乳液1；
(5)再将乳液1加入45ml溶液3中，10,000RPM高速匀化3分钟成乳液2；
(6)将乳液2于室温下磁力搅拌至少6小时除溶剂二氯甲烷后冷藏(4-10℃)60分钟；
(7)离心分离并多次以去离子冰水洗涤微球；
(8)将微球悬浮于5ml去离子水，冻干保存待用。
实施例3
自由非结合形式的活性药物的制备，活性药物以西罗莫司为例，具体如下：
(1)制备12mg/ml的西罗莫斯甲醇溶液；
(2)100ml烧杯中加入60ml去离子水置于低温控制超声水浴中超声；
(3)西罗莫斯甲醇溶液以1：12的体积比用注射泵小流量(0.2ml/min)滴加入去离子水中；
(4)注射完成后，继续保持超声10分钟；
(5)离心分离并以去离子冰水洗涤后冻干备用。
实施例4
载药球囊的制备：
(1)球囊本体充气，不加压；
(2)将实施例1制得的载药微球、实施例2制得的载药微球和实施例3制得的药物微粒以20％、40％、40％的重量比例制成悬浮喷涂液；悬浮液充入注射器，注射器内或注射器外施以电磁场进行磁力搅拌；搅拌均匀的悬浮液超声雾化喷涂于旋转的充气球囊本体外表面；
(3)喷涂后的球囊干燥，折叠，放入保护套管后环氧乙烷灭菌。
实施例5
对实施例4制得的载药球囊进行体外模拟测试，如下：
提供新鲜猪冠脉血管，并以生理盐水多次冲洗，去除多余脂肪，结缔组织和筋膜。将血管剪至适当长度后与ASTM F2394-07曲度模型血管模拟通道远端出口相连接。血管模拟通道近端入口处以三通阀连接37℃生理食盐水管道，生理盐水流量由蠕动泵控制在50ml/min.模拟血管通道预先以37℃生理食盐水冲刷。
去除载药球囊保护套管，球囊从模拟血管通道近端进入，在60±10秒的时间内通过模拟通道到达血管处，加压到8atm，保持60秒，向血管释放载药涂层，释放后的球囊抽负压后沿模拟血管通道撤回；模拟通道包括猪血管通路以37℃生理盐水冲刷1小时，流量为50ml/min.
测试结果如图2所示，该球囊的载药涂层载药剂量为1.3μg/mm2，以猪冠脉为模型，模拟术后1小时冲刷，血管剩余载药达到289.2ng/mg；球囊通过模拟血管通道的药物损失则为25.6％，说明本申请的载药球囊中载药涂层具有优越的药物释放率与抗冲刷能力。
实施例6
对实施例4制得的载药球囊进行不溶微粒测试，如下：
将新鲜收获猪冠脉血管以生理盐水多次冲洗，去除多余脂肪，结缔组织和筋膜。将血管剪至适当长度后与ASTM F2394-07曲度模型血管模拟通道远端出口相连接。血管模拟通道近端入口处以三通阀连接37℃生理食盐水管道，生理盐水流量由蠕动泵控制在50ml/min.模拟血管通道预先以37℃生理食盐水冲刷。
去除载药球囊保护套管，球囊从模拟血管通道近端进入，在60±10秒的时间内通过模拟通道到达血管处，加压到8atm，保持60秒，向血管释放载药涂层，释放后的球囊卸压沿模拟血管通道撤回；模拟通道包括猪血管通路以37℃生理盐水冲刷1小时，流量为50ml/min.
在血管远端收集自冲刷开始至120秒共计100ml液体，光阻法测量不溶微 粒计数，结果见表1。从表1结果可见，本申请技术制备的载药球囊，模拟使用产生的不溶微粒计数较低，尤其是没有大于或等于100μm的微粒生成。
表1不溶微粒测试结果
以上所揭露的仅为本申请的优选实施例而已，当然不能以此来限定本申请之权利范围，因此依本申请专利范围所作的等同变化，仍属本申请所涵盖的范围。

Claims (10)

  1. 一种载药球囊，其特征在于，包括球囊本体及涂覆在所述球囊本体外表面的载药涂层，所述载药涂层包括至少两种具有不同药物释放动力学的可控缓释药物的第一载药涂层；
    及分散于所述第一载药涂层中的各所述可控缓释药物之间并将它们偶联在所述球囊本体的自由非结合形式的活性药物组成的第二载药涂层；
    所述第一载药涂层和所述第二载药涂层均为非亲水性组成。
  2. 如权利要求1所述的载药球囊，其特征在于，所述可控缓释药物为以聚合物作为载体包埋药物形成载药微粒，所述聚合物具有生物相容性和可生物降解。
  3. 如权利要求2所述的载药球囊，其特征在于，所述聚合物选自聚乳酸、聚乙醇酸及其共聚物、聚二恶烷酮中的至少一种。
  4. 如权利要求2所述的载药球囊，其特征在于，所述可控缓释药物具有不同的药物释放动力学的调节方式包括以下至少一种：
    采用不同的聚合物种类调节、采用不同的聚合物分子量调节、控制聚合物与药物的不同比例调节、控制载药微粒的表面积与体积的不同比例调节。
  5. 如权利要求2所述的载药球囊，其特征在于，所述第一载药涂层包括第一可控缓释药物和第二可控缓释药物，所述第一可控缓释药物中载药量不低于所述第一可控缓释药物重量的30％，所述第二可控缓释药物中载药量低于所述第二可控缓释药物重量的30％。
  6. 如权利要求5所述的载药球囊，其特征在于，所述第一可控缓释药物中载 药量占所述第一可控缓释药物重量的30-45％，所述第二可控缓释药物中载药量占所述第二可控缓释药物重量的10-20％。
  7. 如权利要求5所述的载药球囊，其特征在于，按重量百分数计，所述载药涂层包括10％-30％的所述第一可控缓释药物、20％-50％的所述第二可控缓释药物，及20％-50％的所述自由非结合生物活性药物。
  8. 如权利要求1所述的载药球囊，其特征在于，所述自由非结合形式的活性药物是以松散药物微粒而非致密药膜接合在所述球囊本体上，分散于所述第一载药涂层中的各所述可控缓释药物之间并将它们偶联在所述球囊本体。
  9. 如权利要求1所述的载药球囊，其特征在于，所述第一载药涂层包括至少2种可控缓释西罗莫司，所述第二载药涂层包括自由非结合形式的西罗莫司。
  10. 一种如权利要求1-9任一项所述的载药球囊的制备方法，其特征在于，包括步骤：
    (1)提供球囊本体；
    (2)制备至少2种可控缓释药物，且控制每个可控缓释药物具有不同的药物释放动力学；
    (3)制备自由非结合形式的活性药物；
    (4)将可控缓释药物与自由非结合形式的活性药物以一定比例制成悬浮喷涂液；
    (5)将悬浮喷涂液涂覆在球囊本体表面。
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