WO2021129279A1 - 载药植入医疗器械及其制备方法 - Google Patents

载药植入医疗器械及其制备方法 Download PDF

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Publication number
WO2021129279A1
WO2021129279A1 PCT/CN2020/131333 CN2020131333W WO2021129279A1 WO 2021129279 A1 WO2021129279 A1 WO 2021129279A1 CN 2020131333 W CN2020131333 W CN 2020131333W WO 2021129279 A1 WO2021129279 A1 WO 2021129279A1
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drug
nanocrystalline
microporous membrane
loaded
medical device
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PCT/CN2020/131333
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English (en)
French (fr)
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李猛
李俊菲
王钰富
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上海微创医疗器械（集团）有限公司
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Priority to EP20904609.3A priority Critical patent/EP4070825A4/en
Priority to US17/789,028 priority patent/US20230044992A1/en
Publication of WO2021129279A1 publication Critical patent/WO2021129279A1/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
    • A61L29/14—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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
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    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00—Catheters; Hollow probes
    • A61M25/10—Balloon catheters
    • A61M25/1027—Making of balloon catheters
    • A61M25/1029—Production methods of the balloon members, e.g. blow-moulding, extruding, deposition or by wrapping a plurality of layers of balloon material around a mandril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
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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
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
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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
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
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    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • 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
    • 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
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    • 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
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    • A61M25/00—Catheters; Hollow probes
    • A61M25/10—Balloon catheters
    • A61M25/1027—Making of balloon catheters
    • A61M25/1029—Production methods of the balloon members, e.g. blow-moulding, extruding, deposition or by wrapping a plurality of layers of balloon material around a mandril
    • A61M2025/1031—Surface processing of balloon members, e.g. coating or deposition; Mounting additional parts onto the balloon member's surface
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    • 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
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    • A61M25/00—Catheters; Hollow probes
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    • A61M2025/1043—Balloon catheters with special features or adapted for special applications
    • A61M2025/1075—Balloon catheters with special features or adapted for special applications having a balloon composed of several layers, e.g. by coating or embedding
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    • 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
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    • A61M2025/1043—Balloon catheters with special features or adapted for special applications
    • A61M2025/1086—Balloon catheters with special features or adapted for special applications having a special balloon surface topography, e.g. pores, protuberances, spikes or grooves
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    • A61M25/00—Catheters; Hollow probes
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    • A61M25/104—Balloon catheters used for angioplasty

Definitions

  • This application relates to the technical field of medical devices, in particular to a drug-carrying implanted medical device and a preparation method thereof.
  • the coating drug inhibits the proliferation of smooth muscle cells, it also inhibits the regeneration of endothelial cells, leading to a delay in the process of vascular endothelialization after stent implantation; (3)
  • the drug-eluting stent is in the stent It is difficult to adapt to restenosis, small vessel disease and bifurcation disease.
  • due to the need to take a long time of double antibodies it also limits the application to patients who are prone to bleeding.
  • the drug-coated balloon came into being.
  • the emergence of the drug-coated balloon provides a new option for the treatment of the above-mentioned conditions, and provides a long-term prognosis for the interventional treatment of coronary heart disease. Come new hope.
  • the drug-coated balloon is uniformly coated with anti-proliferative drugs on the surface, and then delivered to the diseased location to release the drug within a short expansion time (30s to 60s) to inhibit the proliferation of vascular smooth muscle cells. Its advantages such as no implantation, no risk of thrombosis, and fast treatment effect make it attract more and more people's attention.
  • the antiproliferative drugs on the surface of the drug-coated balloon are mainly amorphous and crystalline. It has been found that when the drug in the drug coating of the drug balloon is in an amorphous form, the drug coating is more uniform, the particles formed during the drug release process are also smaller, the risk of embolism is less, and it has a higher safety. Amorphous drugs have very poor retention effects in tissues. Usually, the tissue concentration has fallen below the therapeutic concentration in less than a week, and it is difficult to effectively inhibit the proliferation of vascular smooth muscle cells.
  • the crystalline drug has an excellent sustained-release effect and a long tissue retention time, the surface uniformity of the drug coating has also become poor, and it is easier to form larger-sized particles, which is likely to cause terminal embolism.
  • large-sized crystalline drugs may cause high local drug concentration, bring toxic side effects, and have great risks.
  • a medicine-carrying implanted medical device and a preparation method thereof.
  • a medicine-loaded implanted medical device includes a device body, a microporous film fixed on the device body, and a nanocrystalline drug loaded on the surface of the microporous film.
  • the surface of the microporous film and the nanocrystalline drug are both charged, and the charge on the surface of the microporous film is the same as that of the nanocrystalline drug.
  • the microporous membrane is formed of at least one of the following materials: nylon, polyvinylidene fluoride, mixed cellulose, polytetrafluoroethylene, polypropylene, polyethersulfone or glass fiber.
  • the porosity of the microporous membrane is 40% to 90%.
  • the pore size of the microporous membrane is 0.02 ⁇ m to 0.8 ⁇ m.
  • the thickness of the microporous membrane is 1 ⁇ m to 200 ⁇ m.
  • the drug-loaded implanted medical device further includes a stabilizer adsorbed on the surface of the nanocrystalline drug, and the mass of the stabilizer is 0.2% to 20% of the total mass of the nanocrystalline drug. %.
  • the stabilizer is selected from: poloxamer, polyvinylpyrrolidone (PVP), Tween, hydroxypropyl methylcellulose (HPMC), dextran, sodium lauryl sulfate One or more of (SDS), sodium carboxymethyl cellulose and polyvinyl alcohol (PVA).
  • the nanocrystalline drug is an anti-proliferative drug.
  • the particle size of the nanocrystalline drug is 20 nm to 300 nm.
  • the morphology of the nanocrystalline drug is spherical, rod-shaped, worm-shaped or disc-shaped.
  • the mass percentage of the crystalline medicine is 70%-100%.
  • the device body is a balloon.
  • a method for preparing a medicine-loaded implanted medical device includes:
  • microporous membrane loaded with the nanocrystalline drug is fixed to the device body.
  • the nanocrystalline drug is loaded on the microporous membrane by means of mechanical filtration.
  • a laser welding method is used to fix the microporous membrane loaded with the nanocrystalline drug on the device body.
  • loading the nanocrystalline drug on the microporous membrane includes:
  • one of the first solvent and the second solvent is an organic solvent miscible with water, and the other is water.
  • the above-mentioned drug-loaded implanted medical devices innovatively adopt a microporous film to load nanocrystalline drugs, and the nanocrystalline drugs are firmly loaded on the microporous film, and they are not easy to fall off during transportation. After reaching the target lesion, the nanocrystalline drug is re-dissolved and dispersed due to the expansion effect of the device itself and the dissolution effect of the blood, which improves the utilization rate of the drug.
  • the microporous membrane is loaded with nanocrystalline drugs.
  • the drug loading can be greatly increased, avoiding the use of a large number of excipients, carriers, etc., and improving safety;
  • the size of the crystalline drug avoids the risk of embolism and toxic side effects; it can also effectively increase the content of the crystalline drug in the nanocrystalline drug, thereby improving the sustained release effect and prolonging the retention time of the tissue.
  • Fig. 1 is a schematic diagram of a medicine-loaded implanted medical device according to an embodiment.
  • Figure 2 shows the morphology of a microporous membrane made of nylon magnified 10 thousand times under an electron microscope.
  • Figure 3 shows the morphology of a microporous membrane made of PTFE magnified 5 thousand times under an electron microscope.
  • Figure 4 shows the morphology of the microporous membrane made of PVDF magnified 10 thousand times under the electron microscope.
  • Fig. 5 is a flowchart of a preparation method of a medicine-loaded implanted medical device according to an embodiment.
  • FIG. 6 is a diagram of the size distribution of the nanocrystalline drug prepared in Example 1.
  • FIG. 7 is the XRD pattern of the nanocrystalline drug prepared in Example 1.
  • a medicine-loaded implanted medical device 10 which includes a device body 100, a microporous membrane 200 fixed on the device body 100, and a nanoporous membrane 200 loaded on the microporous membrane 200.
  • Crystal drug 300 is provided.
  • the above-mentioned drug-loaded implanted medical device 10 can be used in vivo or in vitro, can be used for a short time, or can be permanently implanted for a long time.
  • the above-mentioned medical devices may provide medical treatment and/or diagnosis for arrhythmia, heart failure, valvular disease, vascular disease, diabetes, neurological diseases and disorders, plastic surgery, neurosurgery, oncology, ophthalmology, and ENT surgery Of equipment.
  • the medical devices involved in this application include but are not limited to the following devices: stents, stent grafts, anastomotic connectors, synthetic patches, leads, electrodes, needles, wires, catheters, sensors, surgical instruments, angioplasty balls, wound drainage tubes , Shunt, tube, infusion sleeve, urethral cannula, pellet, implant, blood oxygenation generator, pump, vascular graft, embedded intervention kit (vascular access port), heart valves, annuloplasty rings, sutures, surgical clips, surgical nails, pacemakers, implantable defibrillators, neurostimulators, orthopedic instruments, cerebrospinal fluid shunt tubes, implantable Medicine pumps, vertebral cages, artificial intervertebral discs, replacement instruments for nucleus pulposus, ear tubes, intraocular lenses and any tubes used in interventional surgery.
  • the stents include, but are not limited to, coronary vascular stents, peripheral vascular stents, intracranial vascular stents, urethral stents, and esophageal stents.
  • the above-mentioned drug-loaded implanted medical device is a drug-coated balloon, that is, the device body is a balloon.
  • the microporous membrane 200 refers to a membrane with a network structure containing micropores, and the pore diameter of the micropores can be adjusted according to the particle size of the nanocrystalline drug. In this way, the size of the nanocrystalline drug loaded on the microporous membrane can be adjusted by selecting a microporous membrane with a suitable pore size.
  • the particle size of the nanocrystalline drug 300 is greater than or equal to the pore size of the microporous membrane 200, so that the nanocrystalline drug 300 can be loaded on the microporous membrane 200 more conveniently through mechanical filtration.
  • the pore size of the microporous membrane 200 is 0.02 ⁇ m to 0.8 ⁇ m. Further, the pore size of the microporous membrane 200 may be 0.1 ⁇ m to 0.5 ⁇ m. Further, the pore size of the microporous membrane 200 may be 0.1 ⁇ m to 0.3 ⁇ m.
  • the porosity of the microporous membrane 200 is 40% to 90%. The porosity refers to the percentage of the pore volume in the material to the total volume of the material in its natural state.
  • the thickness of the microporous membrane 200 is 1 ⁇ m to 200 ⁇ m. Further, the thickness of the microporous membrane 200 may be 1 ⁇ m-50 ⁇ m.
  • the microporous membrane 200 may be formed of one or more of the following materials: nylon, polyvinylidene fluoride, mixed cellulose, polytetrafluoroethylene, polypropylene, polyethersulfone, or glass fiber.
  • the microporous membrane 200 is formed of a nylon material (such as nylon 66, etc.), which can improve the loading efficiency and at the same time facilitate the nanocrystalline drug 300 to be firmly supported on the microporous membrane 200.
  • Fig. 2 shows the morphology of the microporous membrane 200 made of nylon magnified 10 thousand times under the electron microscope.
  • Fig. 3 shows the morphology of the microporous membrane 200 made of PTFE magnified 5 thousand times under the electron microscope.
  • Fig. 4 shows the morphology of the microporous membrane 200 made of PVDF magnified 10 thousand times under the electron microscope. It can be seen from FIG. 2 to FIG. 4 that the above-mentioned microporous film 200 has a relatively high porosity and the pores are uniformly formed, which is suitable for loading the nanocrystalline drug 300. It is understandable that the material and type of the microporous membrane 200 are not limited to this, and other membranes with higher porosity can also be used, such as nylon transfer membranes for protein and nucleic acid transfer and detection.
  • the nanocrystalline medicine 300 can be loaded on the side of the microporous membrane 200 away from the device body 100.
  • the surface of the microporous film 200 and the nanocrystalline drug 300 are both charged, and the charge on the surface of the microporous film 200 is the same as that of the nanocrystalline drug 300. In this way, the use of the charge repulsion effect can greatly promote the release of the nanocrystalline drug 300, the utilization rate of the drug is high, and the required drug dose is low.
  • the nanocrystalline drug 300 refers to a nano-sized (less than 1000 nm) drug crystal. It can be understood that the nanocrystalline drug 300 may include partially crystalline drugs and non-crystalline drugs. In one embodiment, in the nanocrystalline medicine 300, the mass percentage of the crystalline medicine may be 0%-100%, and the mass percentage may be 70%-100%.
  • the drug loading of the nanocrystalline drug 300 is 1% to 99%, and further, the drug loading may be 50% to 100%.
  • the particle size of the nanocrystalline drug 300 is 1 nm to 1000 nm, and further, the particle size may be 3 nm to 300 nm. Further, the particle size of the nanocrystalline medicine 300 may be 20 nm to 300 nm, and further, the particle size may be 50 nm to 250 nm.
  • the shape of the nanocrystalline drug 300 may be spherical, rod-shaped, worm-shaped, or disc-shaped.
  • the drug-loaded implanted medical device 10 may further include a stabilizer adsorbed on the surface of the nanocrystalline drug 300.
  • the mass of the stabilizer is 0.2%-20% of the total mass of the nanocrystalline drug.
  • the stabilizer is selected from poloxamer, polyvinylpyrrolidone (PVP), Tween, hydroxypropyl methylcellulose (HPMC), dextran, sodium dodecyl sulfate (SDS), carboxylate At least one of sodium methyl cellulose and polyvinyl alcohol (PVA).
  • PVP polyvinylpyrrolidone
  • HPMC hydroxypropyl methylcellulose
  • SDS sodium dodecyl sulfate
  • PVA polyvinyl alcohol
  • the nanocrystalline medicine 300 can be selected according to actual needs.
  • the nanocrystalline drug 300 may be an anti-proliferative, anti-inflammatory, anti-inflammatory, anti-proliferative, antibacterial, anti-tumor, anti-mitotic, anti-cell, cytotoxic, anti-osteoporosis drug, Anti-angiogenic, anti-restenosis, microtubule-inhibiting, anti-metastasis, or anti-thrombotic drugs.
  • Nanocrystalline drug 300 includes but is not limited to dexamethasone, prednisolone, corticosterone, budesonide, estrogen, sulfasalazine and salicylic acid, acemethacin, aescin, aminopterin, anti Mycotoxins, arsenic trioxide, aristolochic acid, aspirin, ominine, ginkgo phenol, rapamycin and its derivatives (including zotamus, everolimus, biomus, 7-O-nor Kirapamycin, temsirolimus, desfolimus, etc.), endostatin, angiostatin, angiopeptin, monoclonal antibodies that can block the proliferation of smooth muscle cells, levofloxacin, paclitaxel, docetaxel, hydroxyxi Tonoline, vinblastine, vincristine, adriamycin, 5-fluorouracil, cisplatin, thymidine kinase inhibitor
  • the nanocrystalline drug 300 is an anti-proliferative drug.
  • the nanocrystalline drug 300 may be paclitaxel, a paclitaxel derivative, rapamycin, or a rapamycin derivative.
  • the rapamycin derivative may be Everolimus or Zotarolimus.
  • the above-mentioned drug-loaded implanted medical device 10 innovatively uses a microporous film 200 to load the nanocrystalline drug 300, so that the nanocrystalline drug 300 is firmly loaded on the microporous film 200 to ensure that the nanocrystalline drug 300 is not easy to transport during transportation. Fall off from the microporous membrane 200.
  • the nanocrystalline drug 300 reaches the target lesion, due to the expansion effect of the drug-loaded implanted medical device 10 and the dissolving effect of the blood, the nanocrystalline drug 300 can be re-dissolved and dispersed, thereby improving the utilization rate of the drug.
  • the microporous membrane 200 is loaded with a nanocrystalline drug 300, compared with the traditional core-shell structured nanomedicine, the drug loading can be greatly increased, avoiding the use of a large number of excipients, carriers, etc., and improving safety. Further, it can be beneficial to reduce the size of the nanocrystalline drug 300, and avoid the risk of embolism and toxic side effects. Further, the content of the crystalline drug in the nanocrystalline drug 300 can also be effectively increased, thereby improving the sustained release effect and prolonging the tissue residence time.
  • a method for preparing a medicine-loaded implanted medical device includes:
  • Step S101 providing a microporous membrane.
  • step S101 the selection of the microporous membrane is as described above, and will not be repeated here.
  • Step S102 loading the nanocrystalline drug on the microporous membrane.
  • the nanocrystalline drug is loaded on the microporous membrane by means of mechanical filtration.
  • the mechanical filtration method is simple and quick to operate, can abandon the expensive and time-consuming ultrasonic spraying procedures commonly used in the industry, can simplify large-scale preparation, and has great industrial prospects.
  • the mechanical filtration method can tightly combine the nanocrystalline drug with the microporous membrane, so that the nanocrystalline drug is firmly combined with the microporous membrane during the delivery process, and is not easy to fall off from the microporous membrane.
  • step S102 includes: step (a), dissolving the drug in the first solvent to obtain a drug solution, and suspending the stabilizer in the second solvent to obtain a stabilizer suspension.
  • the first solvent and the second solvent can be selected according to the types of drugs and stabilizers.
  • the first solvent is an organic solvent that is miscible with water, and the second solvent is water. Of course, the reverse is also possible.
  • the concentration of the drug solution is 20 mg/mL to 60 mg/mL; the concentration of the stabilizer in the stabilizer suspension is 0.05% to 0.3%.
  • step (b) under stirring conditions, the drug solution is added to the stabilizer suspension to obtain a mixed solution.
  • the drug solution is slowly added to the stabilizer suspension, and the reverse solvent principle is used to make the drug gradually precipitate out.
  • the drug will adsorb a small amount of stabilizer on the surface while the drug is precipitated, which can effectively avoid the agglomeration between the nanoparticles, which is beneficial to the formation of small-diameter precipitation particles, and at the same time It is also conducive to the formation of crystalline drugs.
  • step (b) it is possible to form the particle morphology of pure nano-medicine particles adsorbing a small amount of stabilizer, which not only has higher stability, but also has more advantages than traditional core-shell structured nano-medicine.
  • the high drug loading can also avoid the addition of a large amount of carrier and auxiliary materials at the same time, reducing toxic and side effects.
  • step (c) the mixed solution is sonicated, then dialyzed and concentrated to prepare a nanocrystalline drug suspension.
  • Ultrasounding the mixed solution can not only facilitate the formation of small-particle nanocrystalline drugs, but also facilitate the transformation of amorphous drugs to crystalline drugs, increase the proportion of crystalline drugs in nanocrystalline drugs, and thereby improve drug-loaded implanted medical devices The sustained-release effect.
  • probe-type ultrasound also called ultrasonic cell pulverizer
  • water bath ultrasound also called ultrasonic cleaner
  • the ultrasound time can be adjusted as needed. In one embodiment, the ultrasound time is 15 minutes to 30 minutes.
  • the mixed solution can be put into a dialysis bag for dialysis, and the water is changed at intervals to prepare a nanocrystalline drug suspension. Finally, the prepared nanocrystalline drug suspension is concentrated for use.
  • step (d) the nanocrystalline drug in the nanocrystalline drug suspension is loaded on the microporous membrane and dried.
  • the nanocrystalline drug is loaded on one surface of the microporous film, and the other surface of the microporous film that is not loaded with the nanocrystalline drug is attached to the device body to facilitate the fixation of the microporous film.
  • the microporous membrane can be fixed on the filter mold first, and then an appropriate amount of the above-mentioned nanocrystalline drug suspension can be drawn with a syringe or other equipment, and injected onto the microporous membrane to load the nanocrystalline drug Put it on the microporous membrane and dry it.
  • Step S103 fixing the microporous membrane loaded with the nanocrystalline drug to the device body.
  • step S103 the microporous membrane loaded with nanocrystalline drugs can be fixed to the device body by laser welding, so as to improve the bonding firmness between the microporous membrane and the device body and prevent the microporous membrane from slipping off. And this method is relatively simple and suitable for mass production.
  • the above-mentioned nanocrystalline drug is a pure drug crystal, only a small amount of stabilizer is adsorbed on the surface, and the drug loading can be close to 100% at the highest.
  • the above-mentioned nanocrystalline drugs can greatly increase the content of crystalline drugs, so that they have excellent sustained-release effects, long tissue retention time, and nano-sized nano-sized drugs. Crystal drugs can avoid the risk of embolism and side effects, and are safe and effective.
  • nanocrystalline drugs are loaded on the surface of the microporous membrane, which is firm and stable, and is firm and not easy to fall off during the transportation process. After reaching the target lesion, the nanocrystalline drug is re-dissolved and dispersed due to the action of the device itself and the dissolving action of the blood.
  • the microporous film and the nanocrystalline drug can also be charged with the same charge, so that based on the charge repulsion between the microporous film and the nanocrystalline drug, the release of the nanocrystalline drug can be further improved, and further Improve drug utilization and reduce the required drug dosage.
  • the concentration of nanocrystalline drug suspension and the pore size of the microporous membrane can be adjusted according to the needs, and then the target drug loading can be adjusted; the appropriate microporous membrane can also be selected according to the needs to achieve nanometer The particle size of the crystalline drug can be adjusted; the microporous membrane and the nanocrystalline drug with appropriate charges can be selected according to the needs, so as to use the charge effect to realize the control of the release rate of the nanocrystalline drug particles.
  • Poloxamer 188 is fully dissolved in pure water to obtain a poloxamer aqueous solution with a concentration of 0.15% (w/v). Rapamycin was dissolved in acetone to obtain a acetone solution of rapamycin with a concentration of 40 mg/mL. Take the above-mentioned rapamycin acetone solution and slowly add it to the above-mentioned poloxamer aqueous solution under stirring to obtain a mixed solution. Subsequently, the mixed solution was transferred to an ultrasonic cell pulverizer and sonicated for 20 minutes. After sonication, it was put into a dialysis bag for 12 hours and the water was changed every 2 hours to prepare a nanocrystalline drug suspension.
  • the prepared nanocrystalline drug suspension is concentrated for use.
  • the size and surface charge of the nanocrystalline drugs were characterized using the Malvern ZS90 test.
  • the drug loading of nanocrystalline drugs was calculated by high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • XRPD X-ray powder diffraction
  • nylon microporous membrane with a negative surface charge and a pore size of 0.22 ⁇ m Take a piece of nylon microporous membrane with a negative surface charge and a pore size of 0.22 ⁇ m, clamp it on the filter mold, use a syringe to extract the nanocrystalline drug suspension with a suitable concentration, load it on the nylon microporous membrane, and dry it overnight in a vacuum. Subsequently, the nylon microporous membrane loaded with nanocrystalline drugs is tightly welded to the surface of the ordinary balloon by laser welding, and sterilized with ethylene oxide, to obtain the drug-loaded implanted medical device (that is, the drug-coated balloon ).
  • the polyvinylpyrrolidone K30 is fully dissolved in pure water to obtain an aqueous solution of polyvinylpyrrolidone with a concentration of 0.15% (w/v). Rapamycin was dissolved in acetone to obtain a acetone solution of rapamycin with a concentration of 40 mg/mL. Take the above-mentioned rapamycin acetone solution and slowly add it to the above-mentioned aqueous solution of polyvinylpyrrolidone under stirring to obtain a mixed solution. Subsequently, the mixed solution was transferred to an ultrasonic cell pulverizer and sonicated for 20 minutes.
  • nanocrystalline drug suspension After sonication, it was put into a dialysis bag for 12 hours and the water was changed every 2 hours to prepare a nanocrystalline drug suspension. Subsequently, the prepared nanocrystalline drug suspension is concentrated for use. The size and surface charge of the nanocrystalline drugs were characterized using the Malvern ZS90 test. The drug loading of nanocrystalline drugs was calculated by high performance liquid chromatography (HPLC). The crystal form of the nanocrystalline drug is detected by X-ray powder diffraction (XRPD).
  • nylon microporous membrane with a negative surface charge and a pore size of 0.22 ⁇ m Take a piece of nylon microporous membrane with a negative surface charge and a pore size of 0.22 ⁇ m, clamp it on the filter mold, use a syringe to extract the nanocrystalline drug suspension with a suitable concentration, load it on the nylon microporous membrane, and dry it overnight in a vacuum. Subsequently, the nylon microporous membrane loaded with nanocrystalline drugs is tightly welded to the surface of the ordinary balloon by laser welding, and sterilized with ethylene oxide, to obtain the drug-loaded implanted medical device (that is, the drug-coated balloon ).
  • Tween 80 Take Tween 80 and fully dissolve it in pure water to obtain a Tween aqueous solution with a concentration of 0.15% (w/v). Rapamycin was dissolved in acetone to obtain a acetone solution of rapamycin with a concentration of 40 mg/mL. Take the above-mentioned rapamycin acetone solution and slowly add it to the above-mentioned Tween aqueous solution under stirring to obtain a mixed solution. Subsequently, the mixed solution was transferred to an ultrasonic cell pulverizer and sonicated for 20 minutes. After the sonication was completed, it was put into a dialysis bag for 12 hours and the water was changed every 2 hours to prepare a nanocrystalline drug suspension.
  • the prepared nanocrystalline drug suspension is concentrated for use.
  • the size and surface charge of the nanocrystalline drugs were characterized using the Malvern ZS90 test.
  • the drug loading of nanocrystalline drugs was calculated by high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • XRPD X-ray powder diffraction
  • nylon microporous membrane with a negative surface charge and a pore size of 0.22 ⁇ m Take a piece of nylon microporous membrane with a negative surface charge and a pore size of 0.22 ⁇ m, clamp it on the filter mold, use a syringe to extract the nanocrystalline drug suspension with a suitable concentration, load it on the nylon microporous membrane, and dry it overnight in a vacuum. Subsequently.
  • the nylon microporous membrane loaded with nanocrystalline drugs is tightly welded on the surface of the ordinary balloon by laser welding, and sterilized with ethylene oxide to obtain the drug-loaded implanted medical device (ie, the drug-coated balloon).
  • the prepared nanocrystalline drug suspension is concentrated for use.
  • the size and surface charge of the nanocrystalline drugs were characterized using the Malvern ZS90 test.
  • the drug loading of nanocrystalline drugs was calculated by high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • XRPD X-ray powder diffraction
  • nylon microporous membrane with a negative surface charge and a pore size of 0.22 ⁇ m Take a piece of nylon microporous membrane with a negative surface charge and a pore size of 0.22 ⁇ m, clamp it on the filter mold, use a syringe to extract the nanocrystalline drug suspension with a suitable concentration, load it on the nylon microporous membrane, and dry it overnight in a vacuum. Subsequently, the nylon microporous membrane loaded with nanocrystalline drugs is tightly welded to the surface of the ordinary balloon by laser welding, and sterilized with ethylene oxide, to obtain the drug-loaded implanted medical device (that is, the drug-coated balloon ).
  • Poloxamer 188 is fully dissolved in pure water to obtain a poloxamer aqueous solution with a concentration of 0.15% (w/v).
  • Everolimus was dissolved in acetone to obtain everolimus acetone solution with a concentration of 50 mg/mL.
  • the mixed solution was transferred to an ultrasonic cell pulverizer and sonicated for 20 minutes. After the sonication was completed, it was put into a dialysis bag for 12 hours and the water was changed every 2 hours to prepare a nanocrystalline drug suspension. Subsequently, the prepared nanocrystalline drug suspension is concentrated for use.
  • the size and surface charge of the nanocrystalline drugs were characterized using the Malvern ZS90 test.
  • the drug loading of nanocrystalline drugs was calculated by high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • XRPD X-ray powder diffraction
  • nylon microporous membrane with a negative surface charge and a pore size of 0.22 ⁇ m Take a piece of nylon microporous membrane with a negative surface charge and a pore size of 0.22 ⁇ m, clamp it on the filter mold, use a syringe to extract the nanocrystalline drug suspension with a suitable concentration, load it on the nylon microporous membrane, and dry it overnight in a vacuum. Subsequently, the nylon microporous membrane loaded with nanocrystalline drugs is tightly welded to the surface of the ordinary balloon by laser welding, and sterilized with ethylene oxide, to obtain the drug-loaded implanted medical device (that is, the drug-coated balloon ).
  • the hydroxypropyltrimethylammonium chloride chitosan is fully dissolved in pure water to obtain an aqueous solution of hydroxypropyltrimethylammonium chloride chitosan with a concentration of 0.15% (w/v).
  • Rapamycin was dissolved in acetone to obtain a acetone solution of rapamycin with a concentration of 40 mg/mL.
  • the above-mentioned rapamycin acetone solution is slowly added to the above-mentioned hydroxypropyltrimethylammonium chloride chitosan aqueous solution under stirring to obtain a mixed solution.
  • the mixed solution was transferred to a water-bath ultrasound for 20 minutes, and after the ultrasound was completed, it was put into a dialysis bag for dialysis for 12 hours, and the water was changed every 2 hours to prepare a nanocrystalline drug suspension.
  • the prepared nanocrystalline drug suspension is concentrated for use.
  • the size and surface charge of the nanocrystalline drugs were characterized using the Malvern ZS90 test.
  • the drug loading of nanocrystalline drugs was calculated by high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • the crystal form of the nanocrystalline drug is detected by X-ray powder diffraction (XRPD).
  • nylon microporous membrane with a positive surface charge and a pore size of 0.22 ⁇ m Take a piece of nylon microporous membrane with a positive surface charge and a pore size of 0.22 ⁇ m, clamp it on the filter mold, use a syringe to extract the nanocrystalline drug suspension with a suitable concentration, load it on the nylon microporous membrane, and dry it overnight in a vacuum. Subsequently, the nylon microporous membrane loaded with nanocrystalline drugs is tightly welded to the surface of the ordinary balloon by laser welding, and sterilized with ethylene oxide, to obtain the drug-loaded implanted medical device (that is, the drug-coated balloon ).
  • Poloxamer 407 was fully dissolved in pure water to obtain a poloxamer aqueous solution with a concentration of 0.15% (w/v). Rapamycin was dissolved in acetone to obtain a acetone solution of rapamycin with a concentration of 40 mg/mL. Take the above-mentioned rapamycin acetone solution and slowly add it to the above-mentioned poloxamer aqueous solution under stirring to obtain a mixed solution. Subsequently, the mixed solution was transferred to an ultrasonic cell pulverizer and sonicated for 20 minutes. After sonication, it was put into a dialysis bag for 12 hours and the water was changed every 2 hours to prepare a nanocrystalline drug suspension.
  • the prepared nanocrystalline drug suspension is concentrated for use.
  • the size and surface charge of the nanocrystalline drugs were characterized using the Malvern ZS90 test.
  • the drug loading of nanocrystalline drugs was calculated by high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • XRPD X-ray powder diffraction
  • nylon microporous membrane with a negative surface charge and a pore size of 0.22 ⁇ m Take a piece of nylon microporous membrane with a negative surface charge and a pore size of 0.22 ⁇ m, clamp it on the filter mold, use a syringe to extract the nanocrystalline drug suspension with a suitable concentration, load it on the nylon microporous membrane, and dry it overnight in a vacuum. Subsequently, the nylon microporous membrane loaded with the nanocrystalline drug is sutured on the surface of the cobalt-chromium alloy stent by suture, and sterilized with ethylene oxide to obtain the drug-loaded implanted medical device (ie, the drug-containing stent-covered stent).
  • the drug-loaded implanted medical device ie, the drug-containing stent-covered stent.
  • the nanocrystalline drug suspension prepared in Example 1 was sprayed on the surface of a common balloon (non-welded nylon microporous membrane) by ultrasonic spraying, dried overnight, and sterilized with ethylene oxide to obtain a drug-coated balloon .
  • Particle size photon correlation spectroscopy
  • the instrument is Malvern Zetasizer Nano ZS90 polydispersity index: photon correlation spectroscopy
  • the instrument is Malvern Zetasizer Nano ZS90 Surface charge: photon correlation spectroscopy
  • the instrument is Malvern Zetasizer Nano ZS90;
  • the nanocrystalline drugs of Example 1 to Example 8 all have a smaller particle size, and the particle size distribution is relatively uniform, and the drug loading is relatively high.
  • the nanocrystalline drugs of Example 1 to Example 5, Example 7 and Example 8 are all negatively charged, so they can work together with the negatively charged microporous membrane to promote the crystalline drug on the drug-coated balloon Release.
  • the nanocrystalline drug of Example 6 is positively charged, so that it can work together with the positively charged microporous membrane to promote the release of the crystalline drug on the drug-coated balloon.
  • FIG. 6 is a diagram showing the size distribution of the nanocrystalline drug prepared in Example 1, and FIG. 6 shows the XRD pattern of the nanocrystalline drug prepared in Example 1. It can be seen from Fig. 6 and Fig. 7 that the nanocrystalline drug of Example 1 not only has a smaller particle size, but also has a higher content of crystalline drug, which is beneficial to the sustained release effect of the drug-coated balloon.
  • Example 1 To Conveying loss% Example 1 4% Example 2 3% Example 3 6% Example 4 4% Example 5 5% Example 6 6% Example 7 7% Example 8 5% Comparative example 1 28%
  • Example 1 349.2 ⁇ 97ng/mg 4%
  • Example 2 417.8 ⁇ 128ng/mg 3%
  • Example 3 477.1 ⁇ 62ng/mg 6%
  • Example 4 560.4 ⁇ 96ng/mg 8%
  • Example 5 305.3 ⁇ 143ng/mg 6%
  • Example 6 644.3 ⁇ 115ng/mg 4%
  • Example 7 211.8 ⁇ 152ng/mg twenty two%
  • Example 8 368.8 ⁇ 71ng/mg 7% Comparative example 1 102.3 ⁇ 52ng/mg 17%
  • Example 7 It can be seen from Table 3 that the tissue concentrations of Examples 1 to 6 and Example 8 are all higher, and the amount of drug residue on the balloon surface is lower, which is significantly better than Comparative Example 1. In addition, it was found that the final balloon surface of Example 7 had a relatively high drug residue, indicating that the drug-loaded implanted medical device of the present application can release drugs more effectively when there is a charge repulsion effect in the tissue, and can achieve the target tissue concentration and drug utilization rate. Higher.
  • Example 7 It can be seen from Table 4 that the coated balloons of Examples 1 to 8 exhibit excellent sustained-release effects, which are significantly better than those of Comparative Example 1, and the sustained-release effects of Examples 1 to 6 and Example 8 The sustained release effect is better than that of Example 7. It shows that the drug-loaded implanted medical device of the present application has a better sustained-release effect, and when the charge of the nanocrystalline drug is the same as that of the microporous membrane, it has a better sustained-release effect.

Abstract

提供了一种载药植入医疗器械及其制备方法。载药植入医疗器械(10)包括器械本体(100)、固定在器械本体(100)上的微孔膜(200)和负载在微孔膜(200)上的纳米晶药物(300)。

Description

载药植入医疗器械及其制备方法
相关申请的交叉引用
本申请要求于2019年12月27日提交中国专利局、申请号为2019113805552、申请名称为“载药植入医疗器械及其制备方法”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本申请涉及医疗器械技术领域，特别涉及载药植入医疗器械及其制备方法。
背景技术
随着社会经济的发展，国民生活方式发生了深刻的变化。尤其是人口老龄化及城镇化进程的加速，中国心血管病危险因素流行趋势明显，导致了心血管病的发病人数持续增加。因此，关于心血管疾病的预防和治疗越来越成为全球医生共同关注的焦点。
自上世纪70年代以来，通过介入类医疗器械治疗各种心血管疾病变得越来越常见。并先后经历了单纯球囊扩张(PTCA)、裸金属支架(BMS)、药物洗脱支架(DES)三个里程碑式的快速发展。尤其是药物洗脱支架的出现，在治疗血管狭窄方面取得极大的成功，显示了DES在治疗狭窄方面的潜力。然而药物洗脱支架仍然具有以下问题：(1)仍然具有5％左右的再狭窄率，随着PCI手术量持续增加，该问题越来越不可忽视；(2)药物洗脱支架多聚物涂层基质可诱发炎症反应、延缓伤口愈合、涂层药物在抑制平滑肌细胞增殖的同时，也抑制内皮细胞的再生，导致支架植入后血管内皮化过程延迟；(3)药物洗脱支架在支架内再狭窄、小血管病变和分叉病变难以适应，同时由于需要服用较长时间的双抗，也限制了对易出血的病患的应用。在这种情况下，药物涂层球囊(Drug Coating Balloon，DCB)应运而生，药物涂层球囊的出现为上述情况的处理提供了新的选择，为冠心病介入治疗的远期预后带来新的希望。药物涂层球囊是在表面均匀的涂覆抗增生药物，然后输送至病变位置后在短暂的扩张时间内(30s～60s)释放药物，抑制血管平滑肌细胞的增生。其介入不植入、无血栓风险和治疗效果快等优点使其越来越受到人们的关注。
药物涂层球囊表面的抗增生药物主要为无定形态和结晶态。人们发现当药物球囊的药物涂层中药物以无定形态存在时，药物涂层较均匀，药物释放过程中形成的微粒也较小，栓塞的风险较小，具有较高的安全性，但是无定形的药物在组织中滞留效果很差，通常不到一周组织浓度已经降到治疗浓度以下，难以有效的抑制血管平滑肌细胞的增生。另一方 面，虽然结晶态的药物具有极佳的缓释效果，组织滞留时间长，但药物涂层表面均一性也变得很差，也更容易形成较大尺寸的微粒，容易造成末端栓塞，且很大尺寸的结晶药物可能导致局部药物浓度很高，带来毒副作用，风险极大。
发明内容
根据本申请的多个实施例，提供一种载药植入医疗器械及其制备方法。
一种载药植入医疗器械，包括器械本体、固定在所述器械本体上的微孔膜和负载在所述微孔膜的表面上的纳米晶药物。
在其中一实施例中，所述微孔膜的表面及所述纳米晶药物均带有电荷，且所述微孔膜的表面所带电荷和所述纳米晶药物所带电荷的类型相同。
在其中一实施例中，所述微孔膜由以下材料中的至少一种形成：尼龙、聚偏氟乙烯、混合纤维素、聚四氟乙烯、聚丙烯、聚醚砜或玻璃纤维。
在其中一实施例中，所述微孔膜的孔隙率为40％～90％。
在其中一实施例中，所述微孔膜的孔径为0.02μm～0.8μm。
在其中一实施例中，所述微孔膜的厚度为1μm～200μm。
在其中一实施例中，所述载药植入医疗器械还包括吸附在所述纳米晶药物的表面的稳定剂，所述稳定剂的质量为所述纳米晶药物的总质量的0.2％～20％。
在其中一实施例中，所述稳定剂选自：泊洛沙姆、聚乙烯吡咯烷酮(PVP)、吐温、羟丙基甲基纤维素(HPMC)、葡聚糖、十二烷基硫酸钠(SDS)、羧甲基纤维素钠和聚乙烯醇(PVA)中的一种或多种。
在其中一实施例中，所述纳米晶药物为抗增生药物。
在其中一实施例中，所述纳米晶药物的粒径为20nm～300nm。
在其中一实施例中，所述纳米晶药物的形貌为球形、棒状、蠕虫状或圆盘状。
在其中一实施例中，在所述纳米晶药物中，结晶型药物的质量百分比为70％～100％。
在其中一实施例中，所述器械本体为球囊。
一种制备载药植入医疗器械的方法，包括：
提供微孔膜；
将纳米晶药物负载在所述微孔膜上；以及
将负载有所述纳米晶药物的所述微孔膜固定到所述器械本体上。
在其中一实施例中，采用机械过滤的方式将所述纳米晶药物负载在所述微孔膜上。
在其中一实施例中，采用激光焊接的方法将负载有所述纳米晶药物的所述微孔膜固定在所述器械本体上。
在其中一实施例中，将纳米晶药物负载在所述微孔膜上包括：
将药物溶解在第一溶剂中，得到药物溶液；
将稳定剂悬浮在第二溶剂中，得到稳定剂悬浮液；
在搅拌的条件下，将所述药物溶液加入所述稳定剂悬浮液中，得到混合液；
将所述混合液进行超声，然后进行透析，浓缩，制得纳米晶药物悬浮液；以及
将所述纳米晶药物悬浮液中的纳米晶药物负载到所述微孔膜上，干燥；
其中，第一溶剂和第二溶剂二者中的一个为与水互溶的有机溶剂，另一个为水。
上述载药植入医疗器械创新性地采用微孔膜负载纳米晶药物的方式，将纳米晶药物牢固地负载在微孔膜上，在运输过程中不易脱落。当到达靶病变后，由于器械自身扩展作用和血液的溶解作用使纳米晶药物重新溶解分散，提高药物利用率。且该微孔膜上负载了纳米晶药物，相比于传统的核-壳结构的纳米药物，可以大幅度地提高载药量，避免大量辅料载体等的使用，提高安全性；有利于缩小纳米晶药物的尺寸，避免栓塞的风险和毒副作用；还可以有效地提高纳米晶药物中结晶型药物的含量，进而提高缓释效果，延长组织滞留时间。
附图说明
为了更清楚地说明本申请实施例或现有技术中的技术方案，下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本申请的一些实施例，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他实施例的附图。
图1为根据一实施方式的载药植入医疗器械的示意图。
图2示出了由尼龙制成的微孔膜在电镜下放大10千倍的形貌。
图3示出了由PTFE制成的微孔膜在电镜下放大5千倍的形貌。
图4示出了由PVDF制成的微孔膜在电镜下放大10千倍的形貌。
图5是根据一实施方式的载药植入医疗器械的制备方法的流程图。
图6是由实施例1制备得到的纳米晶药物的尺寸分布的示图。
图7是由实施例1制备得到的纳米晶药物的XRD图谱。
具体实施方式
为了便于理解本申请，下面将对本申请进行更全面的描述，并给出了本申请的较佳实施例。但是，本申请可以以许多不同的形式来实现，并不限于本文所描述的实施例。相反地，提供这些实施例的目的是使对本申请的公开内容的理解更加透彻全面。
除非另有定义，本文所使用的所有的技术和科学术语与属于本申请的技术领域的技术人员通常理解的含义相同。本文中在本申请的说明书中所使用的术语只是为了描述具体的实施例的目的，不是旨在于限制本申请。本文所使用的术语“和/或”包括一个或多个相关的所列项目的任意的和所有的组合。
如图1所示，根据一个实施例，提供了一种载药植入医疗器械10，其包括器械本体100、固定在器械本体100上的微孔膜200和负载在微孔膜200上的纳米晶药物300。
可以理解，上述载药植入医疗器械10可以在体内使用，也可以在体外使用，可以短期使用，也可以长期永久性植入。此外，上述医疗器械可以是为心律失调、心力衰竭、瓣膜性疾病、血管病、糖尿病、神经疾病和失调症、整型外科、神经外科、肿瘤学、眼科学和ENT手术提供医疗和/或诊断的器械。本申请所涉及的医疗器械包括但不限于以下设备：支架、支架移植物、吻合连接器、合成贴片、引线、电极、针、导线、导管、传感器、手术仪器、血管成形球、创口引流管、分流管(shunt)、管子、输液套简(infusion sleeve)、尿道插管、小球、植入物、血液充氧发生器、泵、脉管移植物、埋入式介入药盒(vascular access port)、心瓣膜、瓣环成形术环、缝合线、手术夹、手术钉、起博器、可植入去纤颤器、神经刺激器、整型外科器械、脑脊髓液分流管、可植入药泵、椎笼、人造椎间盘、髓核的替代器械、耳管、眼内晶状体和在介入手术中使用的任何管。其中，支架包括但不限于，冠脉血管支架、外周血管支架、颅内血管支架、尿道支架、食道支架。在本实施例中，上述载药植入医疗器械为药物涂层球囊，即器械本体为球囊。
在一实施例中，微孔膜200是指含有微孔的网状结构的膜，微孔的孔径可以根据纳米晶药物的粒径进行调节。如此可以通过选择合适孔径的微孔膜，实现对微孔膜上负载的纳米晶药物尺寸的调节。
在一实施例中，纳米晶药物300的粒径大于或等于微孔膜200的孔径，如此可以更方便地通过机械过滤的方式将纳米晶药物300负载在微孔膜200上。在一实施例中，微孔膜200的孔径为0.02μm～0.8μm。进一步地，微孔膜200的孔径可以为0.1μm～0.5μm。进一步地，微孔膜200的孔径可以为0.1μm～0.3μm。在一实施例中，微孔膜200的孔隙率为40％～90％。所述的孔隙率是指材料中孔隙体积与材料在自然状态下总体积的百分比。在一实施例中，微孔膜200的厚度为1μm～200μm。进一步地，微孔膜200的厚度可以为1μm～50μm。
在一实施例中，微孔膜200可由以下材料中的一种或多形成：尼龙、聚偏氟乙烯、混合纤维素、聚四氟乙烯、聚丙烯、聚醚砜或玻璃纤维。在一实施例中，微孔膜200由尼龙材料(例如尼龙66等)形成如此可提高负载效率，同时有利于纳米晶药物300牢固地负载在微孔膜200上。
图2示出了由尼龙制成的微孔膜200在电镜下放大10千倍的形貌。图3示出了由PTFE制成的微孔膜200在电镜下放大5千倍的形貌。图4示出了由PVDF制成的微孔膜200在电镜下放大10千倍的形貌。从图2至图4可以看出，上述微孔膜200具有较高的孔隙率，且孔隙均匀地形成，适宜用于负载纳米晶药物300。可理解的是，微孔膜200的材料、类型并不仅限于此，也可使用其他具有较高孔隙率的薄膜，例如用于蛋白质和核酸的转移和检测的尼龙转印膜等。
纳米晶药物300可负载在微孔膜200的远离器械本体100的一侧。在一实施例中，微孔膜200的表面及纳米晶药物300均带有电荷，且微孔膜200表面所带电荷和纳米结晶药物300所带电荷的类型相同。如此，利用电荷排斥作用，可大大促进纳米晶药物300的释放，药物利用率高，所需的药物剂量低。
在一实施例中，纳米晶药物300是指纳米尺寸(小于1000nm)的药物晶体。可以理解的是，纳米晶药物300可以包含部分结晶型药物和非结晶型药物。在一实施例中，在纳米晶药物300中，结晶型药物的质量百分比可为0％～100％，质量百分比为70％～100％。
在一实施例中，纳米晶药物300的载药量为1％～99％，进一步地，载药量可以为50％～100％。
在一实施例中，纳米晶药物300的粒径为1nm～1000nm，进一步地，粒径可以为3nm～300nm。进一步地，纳米晶药物300的粒径可以为20nm～300nm，进一步地，粒径可以为50nm～250nm。
在一实施例中，纳米晶药物300的形貌可以为球形、棒状、蠕虫状或圆盘状。
在一实施例中，载药植入医疗器械10还可包括吸附在纳米晶药物300的表面的稳定剂。在一实施例中，稳定剂的质量为纳米晶药物的总质量的0.2％～20％。通过使在纳米晶药物300的表面吸附少量稳定剂，可增加纳米晶药物300的稳定性，同时可以避免纳米颗粒团聚等现象的发生，从而有利于更小尺寸的纳米晶药物300的形成。此外，相比于传统的核-壳结构的纳米药物，上述纳米晶药物300能够大幅度提高载药量(其载药量最高可接近100％)，且更方便调节纳米晶药物的粒径。一实施例中，稳定剂选自泊洛沙姆、聚乙烯吡咯烷酮(PVP)、吐温、羟丙基甲基纤维素(HPMC)、葡聚糖、十二烷基硫酸钠(SDS)、羧甲基纤维素钠和聚乙烯醇(PVA)中的至少一种。
纳米晶药物300可以根据实际需求进行选择。例如，纳米晶药物300可以是抗增殖的、抗炎的、消炎的、抗增生的、抗菌的、抗肿瘤的、抗有丝分裂的、抑制细胞的、具有细胞毒的、抗骨质疏松症药物、抗血管生成的、抗再狭窄的、抑制微管的、抗转移的或者抗血栓的药物。纳米晶药物300包括但不限于地塞米松、泼尼松龙、皮质酮、布地奈德、雌激素、柳氮磺吡啶和氨水杨酸、阿西美辛、七叶皂苷、氨基蝶呤、抗霉菌素、三氧化二 砷、马兜铃酸、阿司匹林、小糪碱，银杏酚，雷帕霉素及其衍生物(包括佐他莫司、依维莫司、比欧莫斯、7-O-去甲基雷帕霉素、替西罗莫司、地磷莫司等)，内皮他汀、血管他汀、血管肽素、能够阻断平滑肌细胞增殖的单克隆抗体、左氧氟沙星、紫杉醇，多西紫杉醇，羟基喜树碱、长春花碱、长春新碱、阿霉素、5-氟尿嘧啶、顺铂、胸苷激酶抑制剂抗生素(特别是放线菌素-D)、激素、抗体治癌药物、双膦酸盐、选择性雌激素受体调节剂、雷尼酸锶、环孢霉素A、环孢霉素C、布雷菲德菌素A。
在一实施例中，纳米晶药物300为抗增生药物。进一步地，纳米晶药物300可以为紫杉醇、紫杉醇衍生物、雷帕霉素或雷帕霉素衍生物。在一实施例中，雷帕霉素衍生物可以为依维莫司(Everolimus)、佐他莫司(Zotarolimus)。
上述载药植入医疗器械10创新性地采用微孔膜200来负载纳米晶药物300，从而将纳米晶药物300牢固地负载在微孔膜200上，以保证纳米晶药物300在运输过程中不易从微孔膜200上脱落。当纳米晶药物300到达靶病变后，由于载药植入医疗器械10自身的扩展作用和血液的溶解作用，可使纳米晶药物300重新溶解分散，提高药物利用率。另外，由于该微孔膜200上负载的为纳米晶药物300，因此相比于传统的核-壳结构的纳米药物，可以大幅度地提高载药量，避免大量辅料载体等的使用，提高了安全性。进一步地，可有利于缩小纳米晶药物300的尺寸，避免栓塞的风险和毒副作用。进一步地，还可以有效地提高纳米晶药物300中结晶型药物的含量，进而提高缓释效果，延长组织滞留时间。
参照图5，一实施例的制备载药植入医疗器械的方法，包括：
步骤S101，提供微孔膜。
在步骤S101中，微孔膜的选择如上所述，在此不再进行赘述。
步骤S102，将纳米晶药物负载在微孔膜上。
在一实施例中，采用机械过滤的方式将纳米晶药物负载在微孔膜上。机械过滤的方式操作简单快捷，可摒弃行业内常用的昂贵且耗时的超声喷涂程序，可简化大规模的制备，极具工业化前景。且该机械过滤的方式可以使纳米晶药物和微孔膜紧密结合，从而使得纳米晶药物在输送过程中与微孔膜牢固结合，不易从微孔膜脱落。
在一实施例中，步骤S102包括：步骤(a)，将药物溶解在第一溶剂中，得到药物溶液，将稳定剂悬浮在第二溶剂中，得到稳定剂悬浮液。可以根据药物和稳定剂的种类来选择第一溶剂和第二溶剂。在一实施例中，第一溶剂为与水互溶的有机溶剂，第二溶剂为水。当然，反之亦可。进一步地，药物溶液的浓度为20mg/mL～60mg/mL；稳定剂悬浮液中稳定剂的浓度为0.05％～0.3％。步骤(b)，在搅拌的条件下，将药物溶液加入稳定剂悬浮液中，得到混合液。将药物溶液缓慢加入稳定剂悬浮液中，利用反向溶剂原理，使得药物逐渐沉淀析出。而且，由于悬浮液中稳定剂的存在，会使得药物在沉淀析出的同时在其 表面上吸附少量的稳定剂，从而可以有效地避免纳米颗粒之间的团聚，有利形成小粒径沉淀颗粒，同时也有利于结晶型药物的形成。
此外，通过采用步骤(b)中的方法，可以形成纯纳米药物颗粒吸附少量稳定剂的颗粒形貌，这不仅具有较高的稳定性，且相比于传统的核-壳结构纳米药物具有更高的载药量，也可以同时避免大量载体辅料等的添加，降低毒副作用。
步骤(c)，将混合液进行超声，然后进行透析，浓缩，制得纳米晶药物悬浮液。
将混合液进行超声，不仅能够有利于小颗粒纳米晶药物的形成，也有利于无定型药物向结晶型药物的转变，提高纳米晶药物中结晶型药物的比例，进而提高载药植入医疗器械的缓释效果。
步骤(c)中可以采用探头式超声(也称超声波细胞粉碎机)或水浴超声(也称超声波清洗器)进行超声。超声时间可以根据需要进行调节。在一实施例中，超声时间为15min～30min。超声之后，可以将混合液装入透析袋中进行透析，每隔一段时间换一次水，从而制备得到纳米晶药物悬浮液。最后，将制备得到的纳米晶药物悬浮液浓缩备用。
步骤(d)，将纳米晶药物悬浮液中的纳米晶药物负载到微孔膜上，干燥。
在一实施例中，在微孔膜的一个表面负载纳米晶药物，使微孔膜的未负载有纳米晶药物的另一表面与器械本体贴合，以利于微孔膜的固定。进一步地，在步骤(d)中，可先将微孔膜固定在过滤模具上，然后利用注射器等设备抽取合适量的上述纳米晶药物悬浮液，注射至微孔膜上，使纳米晶药物负载到微孔膜上，干燥即可。
步骤S103，将负载有纳米晶药物的微孔膜固定到器械本体上。
在步骤S103中，可以采用激光焊接的方式将负载有纳米晶药物的微孔膜固定器械本体上，以提高微孔膜与器械本体之间的结合牢固度，避免微孔膜滑落。且该方式较为简便，适宜大批量生产。
上述制备载药植入医疗器械的方法具有以下优点：
(1)创新性地将纳米技术和结晶技术相结合，可以获得较小尺寸的纳米晶药物，降低栓塞和毒副作用。而且，上述纳米晶药物是纯的药物晶体，仅表面吸附少量稳定剂，载药量最高可接近100％。不同于传统的载体包覆药物的核-壳结构纳米药物，上述纳米晶药物可以大幅度提高结晶型药物的含量，使其具有极佳的缓释效果，组织滞留时间长，且纳米尺寸的纳米晶药物又可以避免栓塞的风险和毒副作用，安全有效。
(2)创新性的采用微孔膜，将纳米晶药物负载于微孔膜表面，牢固稳定，在输送过程中牢固不易脱落。当到达靶病变后，由于器械自身作用和血液的溶解作用使纳米晶药物重新溶解分散。另外，还可以使微孔膜和纳米晶药物带相同的电荷，如此在微孔膜和纳米晶药物之间的电荷排斥作用的基础上，能够更进一步地提高纳米晶药物的释放，进而更进 一步提高药物利用率，降低所需的药物剂量。
(3)可调节性较高，例如：可以根据需要调整纳米晶药物悬浮液的浓度以及微孔膜的孔径，进而调节目标载药量；也可以根据需要选择合适的微孔膜，以实现纳米晶药物粒径调节；可以根据需要选择合适电荷的微孔膜和纳米晶药物，以利用电荷作用，实现对纳米晶药物颗粒的释放速率的控制。
下面列举具体实施例对本申请进行说明。
实施例1
取泊洛沙姆188充分溶于纯水中，得到浓度为0.15％(w/v)的泊洛沙姆水溶液。雷帕霉素溶于丙酮中，得到浓度为40mg/mL的雷帕霉素丙酮溶液。取上述的雷帕霉素丙酮溶液在搅拌下缓慢加入上述的泊洛沙姆水溶液中，得到混合液。随后，将混合液转移到超声波细胞粉碎机下超声20min，超声完毕后，将其装入透析袋中透析12h，每隔2h换一次水，从而制备得到纳米晶药物悬浮液。随后，将制备得到的纳米晶药物悬浮液浓缩备用。纳米晶药物的尺寸和表面电荷使用Malvern ZS90测试来表征。纳米晶药物的载药量通过高效液相色谱(HPLC)来计算。纳米晶药物的晶型通过X-射线粉末衍射(XRPD)来检测。
取一片表面电荷为负、孔径为0.22μm的尼龙微孔膜，夹在过滤模具上，使用注射器抽取上述浓度合适的纳米晶药物悬浮液，使其负载于尼龙微孔膜，真空干燥过夜。随后，通过激光焊接方式将负载有纳米晶药物的尼龙微孔膜紧密地焊接在普通球囊表面，用环氧乙烷进行灭菌，即得载药植入医疗器械(即药物涂层球囊)。
实施例2
取聚乙烯吡咯烷酮K30充分溶于纯水中，得到浓度为0.15％(w/v)的聚乙烯吡咯烷酮水溶液。雷帕霉素溶于丙酮中，得到浓度为40mg/mL的雷帕霉素丙酮溶液。取上述的雷帕霉素丙酮溶液在搅拌下缓慢加入上述的聚乙烯吡咯烷酮水溶液中，得到混合溶液。随后，将混合溶液转移到超声波细胞粉碎机下超声20min，超声完毕后，将其装入透析袋中透析12h，每隔2h换一次水，从而制备得到纳米晶药物悬浮液。随后，将制备得到的纳米晶药物悬浮液浓缩备用。纳米晶药物的尺寸和表面电荷使用Malvern ZS90测试来表征。纳米晶药物的载药量通过高效液相色谱(HPLC)来计算。纳米晶药物的晶型通过X-射线粉末衍射(XRPD)来检测。
取一片表面电荷为负、孔径为0.22μm的尼龙微孔膜，夹在过滤模具上，使用注射器抽取上述浓度合适的纳米晶药物悬浮液，使其负载于尼龙微孔膜，真空干燥过夜。随后，通过激光焊接方式将负载有纳米晶药物的尼龙微孔膜紧密地焊接在普通球囊表面，用环氧 乙烷进行灭菌，即得载药植入医疗器械(即药物涂层球囊)。
实施例3
取吐温80充分溶于纯水中，得到浓度为0.15％(w/v)的吐温水溶液。雷帕霉素溶于丙酮中，得到浓度为40mg/mL的雷帕霉素丙酮溶液。取上述的雷帕霉素丙酮溶液在搅拌下缓慢加入上述的吐温水溶液中，得到混合溶液。随后，将混合溶液转移到超声波细胞粉碎机下超声20min，超声完毕后，将其装入透析袋中透析12h，每隔2h换一次水，从而制备得到纳米晶药物悬浮液。随后，将制备得到的纳米晶药物悬浮液浓缩备用。纳米晶药物的尺寸和表面电荷使用Malvern ZS90测试来表征。纳米晶药物的载药量通过高效液相色谱(HPLC)来计算。纳米晶药物的晶型通过X-射线粉末衍射(XRPD)来检测。
取一片表面电荷为负、孔径为0.22μm的尼龙微孔膜，夹在过滤模具上，使用注射器抽取上述浓度合适的纳米晶药物悬浮液，使其负载于尼龙微孔膜，真空干燥过夜。随后。通过激光焊接方式将负载有纳米晶药物的尼龙微孔膜紧密地焊接在普通球囊表面，用环氧乙烷进行灭菌，即得载药植入医疗器械(即药物涂层球囊)。
实施例4
取HPMC E5充分溶于纯水中，得到浓度为0.15％(w/v)的HPMC E5水溶液。雷帕霉素溶于丙酮中，浓度为40mg/mL。取上述的雷帕霉素丙酮溶液在搅拌下缓慢加入上述的HPMC E5水溶液中，得到混合溶液。随后，将混合液转移到超声波细胞粉碎机下超声20min，超声完毕后，将其装入透析袋中透析12h，每隔2h换一次水，从而制备得到纳米晶药物悬浮液。随后，将制备得到的纳米晶药物悬浮液浓缩备用。纳米晶药物的尺寸和表面电荷使用Malvern ZS90测试来表征。纳米晶药物的载药量通过高效液相色谱(HPLC)来计算。纳米晶药物的晶型通过X-射线粉末衍射(XRPD)来检测。
取一片表面电荷为负、孔径为0.22μm的尼龙微孔膜，夹在过滤模具上，使用注射器抽取上述浓度合适的纳米晶药物悬浮液，使其负载于尼龙微孔膜，真空干燥过夜。随后，通过激光焊接方式将负载有纳米晶药物的尼龙微孔膜紧密地焊接在普通球囊表面，用环氧乙烷进行灭菌，即得载药植入医疗器械(即药物涂层球囊)。
实施例5
取泊洛沙姆188充分溶于纯水中，得到浓度为0.15％(w/v)的泊洛沙姆水溶液。依维莫司溶于丙酮中，得到浓度为50mg/mL的依维莫司丙酮溶液。取上述的依维莫司丙酮溶液在搅拌下缓慢加入上述的泊洛沙姆水溶液中，得到混合溶液。随后，将混合液转移到 超声波细胞粉碎机下超声20min，超声完毕后，将其装入透析袋中透析12h，每隔2h换一次水，从而制备得到纳米晶药物悬浮液。随后，将制备得到的纳米晶药物悬浮液浓缩备用。纳米晶药物的尺寸和表面电荷使用Malvern ZS90测试来表征。纳米晶药物的载药量通过高效液相色谱(HPLC)来计算。纳米晶药物的晶型通过X-射线粉末衍射(XRPD)来检测。
取一片表面电荷为负、孔径为0.22μm的尼龙微孔膜，夹在过滤模具上，使用注射器抽取上述浓度合适的纳米晶药物悬浮液，使其负载于尼龙微孔膜，真空干燥过夜。随后，通过激光焊接方式将负载有纳米晶药物的尼龙微孔膜紧密地焊接在普通球囊表面，用环氧乙烷进行灭菌，即得载药植入医疗器械(即药物涂层球囊)。
实施例6
取羟丙基三甲基氯化铵壳聚糖充分溶于纯水中，得到浓度为0.15％(w/v)的羟丙基三甲基氯化铵壳聚糖水溶液。雷帕霉素溶于丙酮中，得到浓度为40mg/mL的雷帕霉素丙酮溶液。取上述的雷帕霉素丙酮溶液在搅拌下缓慢加入上述的羟丙基三甲基氯化铵壳聚糖水溶液中，得到混合液。随后，将混合液转移到水浴型超声中超声20min，超声完毕后，将其装入透析袋中透析12h，每隔2h换一次水，从而制备得到纳米晶药物悬浮液。随后，将制备得到的纳米晶药物悬浮液浓缩备用。纳米晶药物的尺寸和表面电荷使用Malvern ZS90测试来表征。纳米晶药物的载药量通过高效液相色谱(HPLC)来计算。纳米晶药物的晶型通过X-射线粉末衍射(XRPD)来检测。
取一片表面电荷为正、孔径为0.22μm的尼龙微孔膜，夹在过滤模具上，使用注射器抽取上述浓度合适的纳米晶药物悬浮液，使其负载于尼龙微孔膜，真空干燥过夜。随后，通过激光焊接方式将负载有纳米晶药物的尼龙微孔膜紧密地焊接在普通球囊表面，用环氧乙烷进行灭菌，即得载药植入医疗器械(即药物涂层球囊)。
实施例7
取一片不带电荷(中性)、孔径为0.22μm的尼龙微孔膜，夹在过滤模具上，使用注射器抽取上述实施例1制备的浓度合适的纳米晶药物悬浮液，使其负载于尼龙微孔膜，真空干燥过夜。随后，通过激光焊接方式将负载有纳米晶药物的尼龙微孔膜紧密地焊接在普通球囊表面，用环氧乙烷进行灭菌，即得载药植入医疗器械(即药物涂层球囊)。
实施例8
取泊洛沙姆407充分溶于纯水中，得到浓度为0.15％(w/v)的泊洛沙姆水溶液。雷 帕霉素溶于丙酮中，得到浓度为40mg/mL的雷帕霉素丙酮溶液。取上述的雷帕霉素丙酮溶液在搅拌下缓慢加入上述的泊洛沙姆水溶液中，得到混合液。随后，将混合液转移到超声波细胞粉碎机下超声20min，超声完毕后，将其装入透析袋中透析12h，每隔2h换一次水，从而制备得到纳米晶药物悬浮液。随后，将制备得到的纳米晶药物悬浮液浓缩备用。纳米晶药物的尺寸和表面电荷使用Malvern ZS90测试来表征。纳米晶药物的载药量通过高效液相色谱(HPLC)来计算。纳米晶药物的晶型通过X-射线粉末衍射(XRPD)来检测。
取一片表面电荷为负、孔径为0.22μm的尼龙微孔膜，夹在过滤模具上，使用注射器抽取上述浓度合适的纳米晶药物悬浮液，使其负载于尼龙微孔膜，真空干燥过夜。随后，通过缝合方式将负载有纳米晶药物的尼龙微孔膜缝合在钴铬合金支架表面，用环氧乙烷进行灭菌，即得载药植入医疗器械(即含药覆膜支架)。
对比例1
取实施例1中制备的纳米晶药物悬浮液通过超声喷涂方式喷涂在普通球囊(不焊接尼龙微孔膜)表面，干燥过夜，用环氧乙烷进行灭菌，即得药物涂层球囊。
性能表征
对实施例1至实施例8以及对比例1的负载在微孔膜上的制备得到纳米晶药物悬浮液进行表征，测试结果如表1所示。
测试方法：
粒径：光子相关光谱法，仪器为马尔文Zetasizer Nano ZS90多分散性指数：光子相关光谱法，仪器为马尔文Zetasizer Nano ZS90表面电荷：光子相关光谱法，仪器为马尔文Zetasizer Nano ZS90；
载药量：高效液相色谱(HPLC)，型号安捷伦1100；
表1
Figure PCTCN2020131333-appb-000001
Figure PCTCN2020131333-appb-000002
从表1可以看出，实施例1至实施例8的纳米晶药物均具有较小的粒径，且粒径大小分布较为均匀，载药量较高。而且，实施例1至实施例5与实施例7和实施例8的纳米晶药物均带负电荷，如此可以和带负电荷的微孔膜共同作用，促进药物涂层球囊的上的结晶药物的释放。实施例6的纳米晶药物带正电荷，如此可以和带正电荷的微孔膜共同作用，促进药物涂层球囊的上的结晶药物的释放。
另外，图6为表示由实施例1制备得到的纳米晶药物的尺寸分布的示图，图6表示由实施例1制备得到的纳米晶药物的XRD图谱。从图6和图7可以看出，实施例1的纳米晶药物不仅具有较小的粒径，且结晶型药物含量较高，有利于药物涂层球囊的缓释作用。
输送损失测试
将上述实施例中制备的药物球囊插入体外血管模型中，控制达到靶标的时间为60s，不扩张药物球囊，随后取出药物球囊。使用高效液相色谱(HPLC)测试球囊表面的药物残留，计算输送过程的药物损失率，测试结果如表2所示。
表2
  输送损失％
实施例1 4％
实施例2 3％
实施例3 6％
实施例4 4％
实施例5 5％
实施例6 6％
实施例7 7％
实施例8 5％
对比例1 28％
从表2可以看出，实施例1至实施例8的输送损失率均较低，且明显低于对比例1，说明本申请的载药植入医疗器械上的结晶型药物与微孔膜结合较为牢固。
组织吸收测试
取离体的猪动脉血管段，保持37℃恒温。取灭菌的裸球囊扩张猪动脉血管1min，6atm，随后泄压取出。将上述不同实施例制备的药物球囊置入扩张过的猪动脉血管，扩张1min，6atm，随后泄压取出。立即使用PBS冲洗3次，每次使用1mL的PBS。然后，通过气相色谱-质谱联用仪(GC-MS)测试组织药物浓度，同时使用HPLC测试球囊表面残留的药量，测试结果如表3所示。
表3
  组织浓度(ng/mg) 球囊表面药物残留％
实施例1 349.2±97ng/mg 4％
实施例2 417.8±128ng/mg 3％
实施例3 477.1±62ng/mg 6％
实施例4 560.4±96ng/mg 8％
实施例5 305.3±143ng/mg 6％
实施例6 644.3±115ng/mg 4％
实施例7 211.8±152ng/mg 22％
实施例8 368.8±71ng/mg 7％
对比例1 102.3±52ng/mg 17％
从表3可以看出，实施例1至实施例6与实施例8的组织浓度均较高，球囊表面药物残留量较低，且明显优于对比例1。此外，发现实施例7最终的球囊表面药物残留较高，说明本申请的载药植入医疗器械在组织中存在电荷排斥作用时能够更有效地释放药物，能够达到目标组织浓度，药物利用率较高。
组织滞留时间测试
取离体的猪动脉血管段，保持37℃恒温。取灭菌的裸球囊扩张猪动脉血管1min，6atm，随后泄压取出。将上述不同实施例制备的药物球囊置入扩张过的猪动脉血管，扩张1min，6atm，随后泄压取出。立即使用PBS冲洗3次，每次使用1mL的PBS。然后，将其放置在培养基中培养，分别培养7天和28天，每个时间点3个重复样，样品取样后使用气相色谱-质谱联用仪(GC-MS)测试组织药物浓度，测试结果如表4。
表4
Figure PCTCN2020131333-appb-000003
Figure PCTCN2020131333-appb-000004
BQL：低于检测限
从表4可以看出，实施例1至实施例8的涂层球囊表现出优异的缓释效果，明显优于对比例1，且实施例1至实施例6以及实施例8的缓释效果优于实施例7的缓释效果。说明本申请的载药植入医疗器械具有较优的缓释作用，且当纳米晶药物的电荷和微孔膜电荷的类型相同时，具有更优的缓释效果。
以上所述实施例的各技术特征可以进行任意的组合，为使描述简洁，未对上述实施例中的各个技术特征所有可能的组合都进行描述，然而，只要这些技术特征的组合不存在矛盾，都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本申请的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对申请专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本申请构思的前提下，还可以做出若干变形和改进，这些都属于本申请的保护范围。因此，本申请专利的保护范围应以所附权利要求为准。

Claims (17)

  1. 一种载药植入医疗器械，包括器械本体、固定在所述器械本体上的微孔膜和负载在所述微孔膜的表面上的纳米晶药物。
  2. 根据权利要求1所述的载药植入医疗器械，其特征在于，所述微孔膜的所述表面及所述纳米晶药物均带有电荷，且所述微孔膜的所述表面所带电荷和所述纳米晶药物所带电荷的类型相同。
  3. 根据权利要求1所述的载药植入医疗器械，其特征在于，所述微孔膜由以下材料中的至少一种形成：尼龙、聚偏氟乙烯、混合纤维素、聚四氟乙烯、聚丙烯、聚醚砜或玻璃纤维。
  4. 根据权利要求1所述的载药植入医疗器械，其特征在于，所述微孔膜的孔隙率为40％～90％。
  5. 根据权利要1所述的载药植入医疗器械，其特征在于，所述微孔膜的孔径为0.02μm～0.8μm。
  6. 根据权利要求1所述的载药植入医疗器械，其特征在于，所述微孔膜的厚度为1μm～200μm。
  7. 根据权利要求1-所述的载药植入医疗器械，还包括吸附在所述纳米晶药物的表面的稳定剂，所述稳定剂的质量为所述纳米晶药物的总质量的0.2％～20％。
  8. 根据权利要求7所述的载药植入医疗器械，其特征在于，所述稳定剂选自：泊洛沙姆、聚乙烯吡咯烷酮、吐温、羟丙基甲基纤维素、葡聚糖、十二烷基硫酸钠、羧甲基纤维素钠和聚乙烯醇中的至少一种。
  9. 根据权利要求7所述的载药植入医疗器械，其特征在于，所述纳米晶药物为抗增生药物。
  10. 根据权利要求1所述的载药植入医疗器械，其特征在于，所述纳米晶药物的粒径为20nm-300nm。
  11. 根据权利要求1所述的载药植入医疗器械，其特征在于，所述纳米晶药物的形貌为球形、棒状、蠕虫状或圆盘状。
  12. 根据权利要求1所述的载药植入医疗器械，其特征在于，在所述纳米晶药物中，结晶型药物的质量百分比为70％～100％。
  13. 根据权利要求1所述的载药植入医疗器械，其特征在于，所述器械本体为球囊。
  14. 一种制备载药植入医疗器械的方法，包括：
    提供微孔膜；
    将纳米晶药物负载在所述微孔膜上；以及
    将负载有所述纳米晶药物的所述微孔膜固定到器械本体上。
  15. 根据权利要求14所述的方法，其特征在于，采用机械过滤的方式将所述纳米晶药物负载在所述微孔膜上。
  16. 根据权利要求14所述的方法，其特征在于，采用激光焊接的方法将负载有所述纳米晶药物的所述微孔膜固定在所述器械本体上。
  17. 根据权利要求14所述的方法，其特征在于，将纳米晶药物负载在所述微孔膜上包括：
    将药物溶解在第一溶剂中，得到药物溶液；
    将稳定剂悬浮在第二溶剂中，得到稳定剂悬浮液；
    在搅拌的条件下，将所述药物溶液加入所述稳定剂悬浮液中，得到混合液；
    将所述混合液进行超声，然后进行透析，浓缩，制得纳米晶药物悬浮液；以及
    将所述纳米晶药物悬浮液中的纳米晶药物负载到所述微孔膜上，干燥；
    其中，所述第一溶剂和所述第二溶剂二者中的其中之一为与水互溶的有机溶剂，另一为水。
PCT/CN2020/131333 2019-12-27 2020-11-25 载药植入医疗器械及其制备方法 WO2021129279A1 (zh)

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