WO2020134541A1 - 药物洗脱器械及其制备方法 - Google Patents

药物洗脱器械及其制备方法 Download PDF

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Publication number
WO2020134541A1
WO2020134541A1 PCT/CN2019/114698 CN2019114698W WO2020134541A1 WO 2020134541 A1 WO2020134541 A1 WO 2020134541A1 CN 2019114698 W CN2019114698 W CN 2019114698W WO 2020134541 A1 WO2020134541 A1 WO 2020134541A1
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WIPO (PCT)
Prior art keywords
drug
wall
solvent
substrate
coating
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PCT/CN2019/114698
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English (en)
French (fr)
Inventor
陈丽萍
林文娇
张万谦
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元心科技(深圳)有限公司
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Priority to JP2021537057A priority Critical patent/JP7350862B2/ja
Priority to EP19902886.1A priority patent/EP3903740A4/en
Priority to AU2019414923A priority patent/AU2019414923A1/en
Priority to KR1020217023651A priority patent/KR102647631B1/ko
Priority to US17/418,409 priority patent/US20220062015A1/en
Publication of WO2020134541A1 publication Critical patent/WO2020134541A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/0077—Special surfaces of prostheses, e.g. for improving ingrowth
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • A61L31/02—Inorganic materials
    • A61L31/022—Metals or alloys
    • 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
    • A61L31/04—Macromolecular materials
    • A61L31/048—Macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
    • 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
    • A61L31/08—Materials for coatings
    • A61L31/082—Inorganic materials
    • A61L31/088—Other specific inorganic materials not covered by A61L31/084 or A61L31/086
    • 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
    • A61L31/146—Porous materials, e.g. foams or sponges
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/0077—Special surfaces of prostheses, e.g. for improving ingrowth
    • A61F2002/009—Special surfaces of prostheses, e.g. for improving ingrowth for hindering or preventing attachment of biological tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2240/00—Manufacturing or designing of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2240/001—Designing or manufacturing processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2250/00—Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2250/0058—Additional features; Implant or prostheses properties not otherwise provided for
    • A61F2250/0067—Means for introducing or releasing pharmaceutical products into 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
    • 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

Definitions

  • the invention relates to the field of interventional medical devices, in particular to a drug eluting device and a preparation method thereof.
  • a vascular stent is an intravascular implant that is expandable. After being implanted in a diseased blood vessel site, it can play the role of radial support, enabling blood flow reconstruction.
  • the drug-eluting stent is generally coated with a drug coating on the surface of the bare stent base, and the drug coating contains an active drug, which inhibits the occurrence of blood vessel restenosis through the release of the active drug.
  • a drug-eluting stent When a drug-eluting stent is implanted in a blood vessel, only the outer wall and the side wall of the stent come into contact with the blood vessel wall.
  • the active drugs released from the outer wall and the side wall of the stent will enter the blood vessel wall to inhibit the intimal hyperplasia of the blood vessel wall and prevent blood vessel recurrence.
  • the stenosis effect, and the active drugs on the inner wall of the stent can not inhibit the intimal hyperplasia, but will be released into the blood, circulate to the whole body, and have side effects on other organs.
  • active drugs on the inner wall of the stent will also inhibit endothelialization of the stent, thereby increasing the risk of thrombosis.
  • the current drug eluting stents are only provided with a drug coating on the outer wall and the side wall of the stent, and there is no drug coating on the inner wall of the stent and no other coatings.
  • the stent rod will deform significantly from the compressed state to the expanded state, and the coating on the stent will also be significantly deformed, so the outer wall and the side wall are coated
  • peeling between the coating and the stent base may occur.
  • the coating is incomplete, the risk of peeling of the coating is exacerbated, which may cause the coating to fall off the substrate into the blood, thereby increasing the risk of embolism and thrombosis.
  • a drug eluting device includes a base and a drug coating provided on the base, the base has an outer wall, a side wall and an inner wall, the drug coating contains an active drug and a drug carrier, and the active drug is dispersed In the drug carrier, the drug coating coats the outer wall, the side wall and the inner wall of the substrate, and the content of the active drug on the outer wall and the side wall is greater than that on the inner wall Or, the active drug is only distributed on the outer wall and the side wall, and the inner wall does not contain the active drug.
  • At least a part of the area of the drug coating layer on the inner wall is a pore structure.
  • the porosity of the pore structure is 5% to 60%.
  • the content of the active drug is 0.5-6 micrograms per square millimeter.
  • the drug carrier is a degradable polymer
  • the degradable polymer is selected from at least one of degradable polyester and degradable acid anhydride.
  • the thickness of the drug coating is 2-20 microns.
  • the thickness of the portion of the drug coating on the outer wall and the thickness of the portion of the drug coating on the side wall are both greater than the thickness of the drug coating on the inner wall thickness of.
  • the material of the substrate is pure iron or iron alloy.
  • the drug eluting device further includes a zinc-containing protective layer, the zinc-containing protective layer is disposed on the substrate, the zinc-containing protective layer covers at least the inner wall of the substrate, and the The zinc-containing protective layer is covered by the drug coating.
  • the coverage of the zinc-containing protective layer on the substrate is 20-100%.
  • a method for preparing a drug eluting device includes the following steps:
  • the base having an outer wall, a side wall and an inner wall;
  • the solvent is in contact with a portion of the drug coating located on the inner wall to partially or completely dissolve the active drug in the portion of the drug coating located on the inner wall
  • the drug carrier is insoluble in the solvent
  • the step of removing the solvent from the substrate includes:
  • the adsorbent material adsorbed with the solvent is brought into contact with the inner wall of the base body to partially or completely dissolve the active drug of the part of the drug coating located on the inner wall in the solvent, and the drug carrier Insoluble in the solvent, and then remove the adsorbent material.
  • the adsorbent material is nylon material, polypropylene, polytetrafluoroethylene material, rubber material or fiber material.
  • the contact time between the adsorbent material adsorbed with the solvent and the inner wall of the substrate is 10s-20min.
  • the adsorbent material adsorbed with the solvent is contacted with the inner wall of the substrate to partially or completely dissolve the active drug in the portion of the drug coating on the inner wall.
  • the solvent and the drug carrier is insoluble in the solvent, and then the step of removing the adsorbent material includes:
  • a mandrel is provided, the adsorbent material is coated on the outer surface of the mandrel, and then the mandrel covered with the adsorbent material is extended into the interior of the base body, and the The adsorbent material adsorbs the solvent, and the adsorbent material is brought into contact with the inner wall of the substrate, so that the active drug part of the drug coating located on the inner wall is partially dissolved or completely dissolved in the solvent, and then Removing the adsorbent material and the mandrel from the substrate; or,
  • the mandrel or the base is in a rotating state.
  • the solvent is in contact with a portion of the drug coating located on the inner wall to partially or completely dissolve the active drug in the portion of the drug coating located on the inner wall In the solvent, and the drug carrier is insoluble in the solvent, and after the step of removing the solvent from the matrix, the active drug content of the matrix is reduced by up to 50%.
  • the distribution of the active drug in the drug coating is such that the content of the active drug on the outer wall and the side wall is greater than the content on the inner wall or the active drug is only distributed on the outer wall and the side wall, While the part of the drug coating on the inner wall does not contain active drugs, the drug coating covers the outer wall, the side walls and the inner wall of the substrate, that is, the drug coating is a complete and continuous coating, so that when expanding, the drug coating The layer is not easily separated from the substrate and falls off the substrate. Therefore, the inner wall of the drug eluting device does not contain active drugs or the content of the active drugs on the inner wall is small, and the drug eluting device is not prone to the phenomenon of coating falling off.
  • FIG. 1 is a schematic cross-sectional structure diagram of a drug eluting device according to an embodiment
  • FIG. 2 is a schematic cross-sectional structure diagram of a drug eluting device according to another embodiment
  • FIG. 3 is a schematic cross-sectional structure diagram of a drug eluting device according to another embodiment
  • FIG. 4 is a schematic diagram of a cross-sectional structure of a drug eluting device according to another embodiment.
  • a drug eluting device includes a base 100 and a drug coating 200 provided on the base 100.
  • the base body 100 is a hollow lumen structure.
  • the base 100 has an outer wall 110, a side wall 120, and an inner wall 130.
  • the substrate 100 is made of a bioabsorbable material.
  • the base 100 is made of iron, iron-based alloy, magnesium, magnesium-based alloy, or absorbable polymer material.
  • the base 100 is made of an iron-based alloy having a carbon content of not higher than 2.11 wt.% or the base 100 is made of pure iron.
  • the base 100 is made of a material that is not bioabsorbable.
  • the base 100 is made of a material such as nickel-titanium alloy, cobalt-chromium alloy, or stainless steel.
  • the drug coating 200 is coated on the outer wall 110, the side wall 120, and the inner wall 130 of the substrate 100, that is, the drug coating 200 is a complete and continuous coating, and all surfaces of the substrate 100 are covered by the drug coating 200.
  • the drug coating 200 contains an active drug 210 and a drug carrier (not shown).
  • the active drug 210 is unevenly dispersed in the drug carrier, that is, the distribution of the active drug 210 in the drug coating 200 is non-uniformly distributed.
  • the content of active drug 210 on both the outer wall 110 and the side wall 120 is greater than the content on the inner wall 130.
  • the content per unit area of the active drug 210 on the outer wall 110 and the content per unit area of the active drug 210 on the side wall 120 are greater than the content per unit area of the active drug 210 on the inner wall 130.
  • the active drug 210 is only distributed on the portion of the drug coating 200 on the outer wall 110 and the side wall 120, and the part of the drug coating 200 on the inner wall 130 does not contain the active drug 210.
  • the distribution of the active drug 210 in the drug coating 200 is such that the content of the active drug 210 on the outer wall 110 and the side wall 120 is greater than the content on the inner wall 130 or the active drug 210 only Distributed on the outer wall 110 and the side wall 120, while the inner wall 130 does not contain the active drug 210, the drug coating 200 is coated on the outer wall 110, the side wall 120 and the inner wall 130 of the substrate 100, that is, the drug coating 200 is complete,
  • the continuous coating makes it difficult for the drug coating 200 to separate from the substrate 100 and detach from the substrate 100 during expansion. Therefore, the inner wall 130 of the above drug eluting device does not contain the active drug 210 or the content of the active drug 210 on the inner wall 130 is small, and the drug eluting device is not prone to the phenomenon of coating falling off.
  • the inner wall 130 of the base 100 does not contain the active drug 210 or the content of the active drug 210 on the inner wall 130 is low, it is advantageous for the rapid endothelialization of the drug-eluting device and reduces the risk of thrombosis. In addition, it is beneficial to reduce the drugs released into the blood, thereby reducing the toxic and side effects on other organs, and improving the safety of clinical use.
  • the active drug 210 is selected from cell growth inhibitors, corticosteroids, prostacyclin, antibiotics, cell proliferation inhibitors, immunosuppressants, anti-inflammatory agents, anti-inflammatory agents, anti-angiogenic drugs, anti-restenosis At least one of drugs, antithrombotic drugs, antisensitizing drugs, and antitumor drugs.
  • the drug that inhibits angiogenesis is selected from at least one of paclitaxel, rapamycin, and derivatives of rapamycin.
  • the antiplatelet drug is cilostazol.
  • the antithrombotic drug is heparin.
  • the anti-inflammatory drug is dexamethasone.
  • the anti-sensitizing drug is selected from at least one of calcium gluconate, chlorpheniramine and cortisone.
  • the content of the active drug 210 in the drug coating 200 is 0.5 ⁇ g/mm 2 to 6 ⁇ g/mm 2 .
  • the content of active drug 210 is 0.5 ⁇ g / mm 2 ⁇ 6 ⁇ g / mm 2 is an average of the active drug in the drug coating layer 210 200 outer wall 110, side wall 120 and inner wall 130 of the content.
  • the drug carrier is a degradable polymer.
  • the active drug 210 is dispersed in the degradable polymer, and the release of the active drug 210 is controlled by the degradable polymer to prevent the active drug 210 from bursting and most of it being lost in the blood.
  • the degradable polymer is selected from at least one of degradable polyester and degradable acid anhydride.
  • the degradable polyester is selected from polylactic acid, polyglycolic acid, polysuccinate, poly( ⁇ -hydroxybutyrate), polycaprolactone, polyethylene glycol adipate, polyvalerate, At least one of polyhydroxyalkyl alcohol ester and poly(malate).
  • the degradable polyester is a copolymer of at least two of the monomers forming the aforementioned degradable polyester-based polymer.
  • the degradable polyanhydride is selected from at least one of poly 1,3-bis(p-carboxyphenoxy)propane-sebacic acid, polyerucic acid dimer-sebacic acid, and polyfumaric acid-sebacic anhydride.
  • the degradation of the above-mentioned degradable polyester and degradable polyanhydride will create a local slightly acidic environment around the substrate 100, which is beneficial to accelerate the later corrosion of the substrate 100.
  • At least a part of the portion of the drug coating 200 on the inner wall 130 has a pore structure. Due to the pore structure, in the early stage of implantation, when the degradable polymer in the drug coating 200 degrades, fewer degradation products are generated, and the degradation products can diffuse more freely with body fluids, so that they do not aggregate locally and cause localization. The pH value is too low, so as to avoid the phenomenon that the corrodible or degradable substrate 100 locally accelerates the corrosion or degradation obviously.
  • the porosity of the pore structure of the portion of the inner wall 130 of the drug coating 200 is 5% to 60%, to ensure that the degradation products of the degradable polymer diffuse out as soon as possible, to avoid the corrodible or degradable matrix 100 Too fast corrosion or too fast degradation.
  • the thickness of the drug coating 200 is 2-20 microns.
  • the thickness of the drug coating 200 refers to the average of the thickness of the portion of the drug coating 200 located on the outer wall 110, the thickness of the portion located on the side wall 120, and the thickness of the portion located on the inner wall 130.
  • the degradable polymerization is ensured
  • the amount of the substance is sufficient to match the degradation rate of the drug coating 200 with the corrosion or degradation rate of the corrodible or degradable substrate 100, so that after the repair of the lesion is completed, there is still enough degradable polymer residue , So that the degradation products of the remaining degradable polymer accelerate the corrosion or degradation of the matrix 100, thereby reducing the risk of long-term clinical use.
  • the thickness of the portion of the drug coating 200 on the outer wall 110 and the thickness of the portion of the drug coating 200 on the side wall 120 are both greater than the thickness of the portion of the drug coating 200 on the inner wall 130.
  • the thickness of the portion of the drug coating 200 on the outer wall 110 is greater than the thickness of the portion of the drug coating 200 on the inner wall 130, which is beneficial to increase the effective drug loading, To meet the needs of treatment.
  • the drug eluting device when the material of the base 100 is pure iron or iron alloy, the drug eluting device further includes a zinc-containing protective layer 300.
  • the zinc-containing protective layer 300 is disposed on the substrate 100, and the zinc-containing protective layer 300 is covered by the drug coating 200.
  • the zinc-containing protective layer 300 contains pure zinc, a zinc alloy, and/or a zinc-containing compound.
  • the zinc-containing protective layer 300 covers at least the inner wall 130 of the base 100.
  • the zinc-containing protective layer 300 covers at least the inner wall 130 of the substrate 100 means that the zinc-containing protective layer 300 completely covers the surface of the substrate 100, that is, the zinc-containing protective layer completely covers the outer wall 110, the side walls 120, and the inner wall of the substrate 100 130, as shown in Figure 3.
  • the zinc-containing protective layer 300 covers at least the inner wall 130 of the substrate 100 means that the zinc-containing protective layer 300 only covers the inner wall 130 of the substrate 100; or, the zinc-containing protective layer 300 completely covers the inner wall 130 of the substrate 100, including The zinc protective layer 300 only partially covers the sidewall 120 of the substrate, and the zinc-containing protective layer 300 does not completely cover the outer wall 110 of the substrate 100; or, the zinc-containing protective layer 300 completely covers the inner wall 130 and the sidewall 120 of the substrate 100, and contains zinc The protective layer 300 only partially covers the outer wall 110 of the base 100; alternatively, the zinc-containing protective layer 300 completely covers the inner wall 130 and the side wall 120 of the base 100, and the zinc-containing protective layer does not cover the outer wall 110 of the base 100 at all.
  • the zinc-containing protective layer 300 only covers the inner wall 130 of the base 100 means that the zinc-containing protective layer 300 completely covers the inner wall 130 of the base 100, or the zinc-containing protective layer 300 only partially covers the inner wall 130 of the base 100, and the outer wall of the base 100 110 and the side wall 120 are not covered by the zinc-containing protective layer 300 at all.
  • the zinc-containing protective layer 300 when the zinc-containing protective layer 300 is prepared on the substrate 100, some areas of the zinc-containing protective layer 300 on the substrate 100 may be discontinuous, for example, there are leaky plating areas As a result, certain regions of the zinc-containing protective layer 300 on the substrate 100 are discontinuous.
  • the zinc-containing protective layer 300 only covers the inner wall 130 of the substrate 100, but some areas of the zinc-containing protective layer 300 are discontinuous.
  • the zinc-containing protective layer 300 is located on the outer wall 110, the side wall 120, and the inner wall 130 of the base 100, and at least the portion of the zinc-containing protective layer 300 located on the outer wall 110, the portion located on the side wall 120, and the portion located on the inner wall 130 Some areas are discontinuous.
  • the zinc-containing protective layer 300 is located on the inner wall 130 of the substrate 100, and the zinc-containing protective layer 300 only partially covers the sidewall 120 of the substrate 100, and the zinc-containing protective layer 300 does not completely cover the outer wall 110 of the substrate 100, and, At least part of the part of the zinc protective layer 300 on the inner wall 130 and the part on the side wall 120 is discontinuous.
  • the zinc-containing protective layer 300 is located on the inner wall 130 and the side wall 120 of the substrate 100, and the zinc-containing protective layer 300 only partially covers the outer wall 110 of the substrate 100 or the zinc-containing protective layer 300 does not cover the outer wall 110 of the substrate 100 at all, and contains At least part of the zinc protective layer 300 located on the inner wall 130, the sidewall 120 and the outer wall 110 is discontinuous.
  • the zinc-containing protective layer 300 can better protect the substrate 100.
  • the zinc-containing protective layer 300 covers at least the inner wall 130 of the base 100. After the drug eluting device is implanted in the blood vessel, the outer wall 110 of the base 100 is in contact with the blood vessel wall, and the inner wall 130 of the base 100 is always in contact with the blood flow and is always washed by the blood flow.
  • the zinc-containing protective layer 300 At least covering the inner wall 130 of the base 100 can prevent the corrodible base 100 from prematurely corroding.
  • the coverage of the zinc-containing protective layer 300 on the substrate 100 is 20 to 100%, so that the zinc-containing protective layer 300 can protect the corrodible substrate 100 at an early stage and prevent the corrodible substrate 100 from being premature. While corroding, it can not affect the corrosion rate of the substrate 100 in the late stage. If the inner wall 130 of the base 100 does not contain zinc, it may corrode earlier and cause thrombogenicity. Therefore, the zinc-containing protective layer 300 is required to cover at least the inner wall 130 of the base 100.
  • the outer wall 110 of the base 100 since the outer wall 110 of the base 100 is not in contact with blood, in order to improve the corrosion rate of the entire base 100, the outer wall 110 of the base 100 may not be covered by the zinc-containing protective layer 300 or the outer wall 110 is only partially covered by the zinc-containing protective layer 300.
  • At least a portion of the outer wall 110 of the base 100 is not covered by the zinc-containing protective layer 300.
  • the thickness of the portion of the drug coating 200 located on the outer wall 110 of the base 100 is large.
  • the zinc-containing protective layer 300 can better protect the substrate 100 and avoid premature corrosion of the substrate 100, at least a part of the outer wall 110 of the substrate 100 is not covered by the zinc-containing protective layer 300, which is beneficial to the later from the outer wall 110 Start to accelerate the corrosion of the substrate 100 and shorten the corrosion cycle.
  • the above drug eluting device avoids the excessive release of active drug 210 from the direction of the inner wall 130 of the substrate 100 directly into the blood through the complete, continuous, asymmetric drug-loaded drug coating 200, causing toxic and side effects, and is beneficial to the endothelium
  • the cells crawl on the inner wall 130 of the substrate 100, while effectively preventing the drug coating 200 from falling off during expansion.
  • the base 100 is made of an iron-based alloy with a carbon content of not higher than 2.11 wt.% or made of pure iron, and the content of the active drug 210 in the drug coating 200 is 0.5 ⁇ g/mm 2 to 6 ⁇ g /mm 2 , the thickness of the drug coating 200 is 2-20 microns, and the porosity of the pore structure of the portion of the drug coating 200 located on the inner wall 130 is 5%-60%, so that the release of the active drug 210 and the corrodible matrix The corrosion of 100 is matched so that the release period of the active drug 210 is consistent with the repair period of the implantation site.
  • the corrodible matrix 100 maintains sufficient radial support; after the repair is completed, the active drug 210 It has been completely released. At this time, the degradable polymer has not been completely degraded, so it can continue to degrade and maintain the local slightly acidic environment around the substrate 100, so that the corrodible substrate 100 can quickly corrode, thereby reducing the long-term clinical risk.
  • the base 100 of the drug eluting device is made of an iron-based alloy with a carbon content not higher than 2.11 wt.% or made of pure iron, and the content of the active drug 210 in the drug coating 200 is 0.5 ⁇ g/mm 2 to 6 ⁇ g/mm 2 , the thickness of the drug coating 200 is 2 to 20 micrometers, and the base 100 is provided with a zinc-containing protective layer 300 covering at least the inner wall 100 of the base 100, which can also delay the time of starting corrosion of the base 100,
  • the release of the active drug 210 is matched with the corrosion of the corrodible base 100, so that the release period of the active drug 210 is consistent with the repair period of the implantation site, and during the repair period, the corrodible base 100 maintains sufficient radial Supporting force; and after the repair is completed, the corrodible substrate 100 corrodes rapidly, thereby reducing the long-term clinical risk.
  • the base 100 of the drug eluting device is made of an iron-based alloy with a carbon content not higher than 2.11 wt.% or made of pure iron, and the content of the active drug 210 in the drug coating 200 is 0.5 ⁇ g/mm 2 to 6 ⁇ g /mm 2 , the thickness of the drug coating 200 is 2 to 20 microns, the porosity of the pore structure of the portion of the drug coating 200 located on the inner wall 130 is 5% to 60%, and the substrate 100 is provided with at least one covering the substrate 100
  • the zinc-containing protective layer 300 of the inner wall 100 can further ensure that the release of the active drug 210 matches the corrosion of the corrodible substrate 100, so that the release period of the active drug 210 is consistent with the repair period of the implantation site.
  • the erodible substrate 100 maintains sufficient radial support; after the repair is completed, the erodible substrate 100 corrodes rapidly, thereby reducing long-term clinical risks.
  • the drug eluting device may be applied to various parts.
  • the drug eluting device is a cardiovascular stent, a cerebrovascular stent, a peripheral vascular stent, a biliary stent, an esophageal stent, an airway stent, an orthopedic implant, and so on.
  • Step 110 Provide a base, the base having an outer wall, a side wall, and an inner wall.
  • the base body is a hollow lumen structure.
  • Step 120 A solution containing an active drug and a drug carrier is applied on a substrate to form a drug coating.
  • the active drug is dispersed in the drug carrier, and the drug coating covers the outer wall, side walls, and inner wall of the substrate.
  • the active drug and drug carrier are dissolved in a solvent to prepare a solution containing the active drug and drug carrier.
  • the drug carrier is a degradable polymer
  • the active drug and the degradable polymer are dissolved in a solvent, fully dissolved and stirred uniformly to obtain a solution containing the active drug and the drug carrier.
  • the active drug and the degradable polymer are separately dissolved in different solvents to prepare a solution containing the active drug and a solution containing the drug carrier, and then the solution containing the active drug and the solution containing the drug carrier are mixed to obtain the active drug and Mixture of drug carriers.
  • the solution containing the active drug and the drug carrier is applied on the substrate to form a drug coating by spraying, leaching, dipping or rolling.
  • the drug coating coats the outer wall, side wall and inner wall of the substrate.
  • the drug coating has a single-layer structure, the active drug is dispersed in the drug carrier, and the active drug is unevenly dispersed in the drug carrier.
  • the concentration of the active drug and the concentration of the drug carrier are selected according to need, and there is no specific limit.
  • Step 130 Use the solvent to contact the part of the drug coating on the inner wall, so that the active drug on the part of the drug coating on the inner wall is partially dissolved or completely dissolved in the solvent, and the drug carrier is insoluble in the solvent and moves away from the substrate In addition to solvent.
  • the adsorbent material adsorbed with the solvent is brought into contact with the inner wall of the substrate to dissolve or completely dissolve the active drug in the portion of the drug coating on the inner wall, and the drug carrier is insoluble in the solvent, and then The adsorbent material is removed, thereby removing the solvent from the substrate.
  • the active drug on the inner wall of the above drug coating is partially dissolved or completely dissolved in the solvent, and the drug carrier is not soluble in the solvent. It is not necessarily required that the drug carrier cannot be completely dissolved in the solvent, but Refers to the same solvent, the solubility of the active drug and the drug carrier is quite different, or the drug carrier dissolves in the solvent at a slower rate, when the solvent is in contact with the part of the drug coating on the inner wall Within a period of time, the active drug can be quickly dissolved in the solvent, and the amount of the drug carrier dissolved in the solvent is minimal, and the continuity of the portion of the drug coating on the inner wall will not be disrupted.
  • the solvent is methanol, ethanol, propanol, isopropanol, acetonitrile or ethyl acetate.
  • the adsorptive material is nylon material, polypropylene, polytetrafluoroethylene material, polyurethane material, rubber material or fiber material, for example, non-woven fabric absorbent cotton made of polypropylene material.
  • the above-mentioned adsorptive materials not only have adsorptivity and can absorb solvents, but also will not pollute the substrate during the contact with the substrate. It can be understood that, in addition to the materials listed above, any adsorbent material capable of adsorbing a solvent and not polluting the substrate can be used.
  • the adsorbent material adsorbed with the solvent is brought into contact with the inner wall of the substrate, so that the active drug part of the drug coating on the inner wall is partially dissolved or completely dissolved in the solvent, and the drug carrier is insoluble in the solvent, so that the drug coating is on the inner wall Part of the active drug is removed at least partially, and at the same time, at least part of the area of the drug coating on the inner wall becomes a pore structure with a suitable porosity.
  • the adsorbent material adsorbed with the solvent and the matrix The inner wall contact time is 10s ⁇ 20min.
  • the adsorbent material adsorbed with the solvent is brought into contact with the inner wall of the substrate to dissolve or completely dissolve the active drug in the portion of the drug coating on the inner wall, and then remove the adsorbent material
  • the steps include: providing a mandrel, covering the outer surface of the mandrel with an adsorbent material, and then extending the mandrel covered with the adsorbent material into the interior of the substrate, and allowing the adsorbent material to adsorb the solvent, which will adsorb the solvent
  • the adsorbent material is in contact with the inner wall of the substrate to partially or completely dissolve the active drug in the portion of the drug coating on the inner wall, and then the adsorbent material and the mandrel are removed from the substrate.
  • a mandrel is provided, the adsorbent material is coated on the outer surface of the mandrel, the adsorbent material adsorbs the solvent, and then the mandrel coated with the adsorbent material is extended into the interior of the base body , And make the adsorbent material contact with the inner wall of the substrate, so that the active drug part of the drug coating located on the inner wall is partially dissolved or completely dissolved in the solvent, and then the adsorbent material and the mandrel are removed from the substrate.
  • the mandrel is cylindrical to fit the base of the lumen structure.
  • the material of the mandrel is not limited as long as it can support the adsorbent material.
  • the cylindrical mandrel can also be directly made of an adsorbent material.
  • the mandrel adsorbed with the solvent is then extended into the matrix and contacted with the inner wall of the matrix to dissolve the active drug on the inner wall of the drug coating in the solvent, and then The mandrel is removed from the base.
  • the mandrel is extended into the base body, and the mandrel is absorbed into the solvent and contacted with the inner wall of the base body to dissolve the active drug on the inner wall portion of the drug coating in the solvent, and then the mandrel is removed from the base body.
  • the mandrel is rotating. Or, in another embodiment, the mandrel remains fixed while the base body is in a rotating state.
  • the absorbent material adsorbed with the solvent is directly wiped on the inner wall of the substrate to dissolve or completely dissolve the active drug in the part of the drug coating on the inner wall, and the drug carrier is insoluble in the solvent , And then remove the adsorbent material.
  • the corresponding operation can be repeated multiple times to ensure that the drug coating is located on the inner wall
  • the active drug on the inner wall of the substrate is reduced as much as possible or the active drug on the inner wall of the substrate is completely removed. It can be predicted that during the contact of the material adsorbed with the solvent with the inner wall of the substrate, part of the side walls of the substrate may be contacted at the same time, so that part of the drug on the side walls of the substrate close to the inner wall is also reduced.
  • the preparation method of the drug eluting device described above first prepares a continuous drug coating covering the outer wall, the side walls and the inner wall of the substrate, and then at least partially removes the active drug on the inner wall portion of the drug coating.
  • the active drug content of the drug eluting device obtained after step 130 is reduced by up to 50% compared to the active drug content of the semi-finished product obtained after step 120.
  • a drying step is further included to evaporate the solvent of the drug coating as soon as possible.
  • desiccant, ventilation, vacuum, etc. can be used for drying. In other embodiments, it can also be dried naturally.
  • the preparation method of the above drug eluting device utilizes the obvious difference in the solubility of the active drug and the drug carrier in the same solvent to prepare a complete and continuous drug coating that completely covers the outer wall, inner wall and side wall of the substrate, and realizes the drug coating
  • the content of the active drug in the layer on the outer wall and the side wall is greater than the content on the inner wall; or the active drug is only distributed on the outer wall and the side wall, and the inner wall does not contain the active drug. Therefore, it is beneficial to improve the safety of clinical use.
  • the preparation method of the drug eluting device is simple in process and has low requirements on equipment.
  • the method before preparing the drug coating, the method further includes preparing a zinc-containing protective layer attached to the substrate.
  • the zinc-containing protective layer can be prepared by electroplating, spraying, dipping, brushing, electrospinning, etc.
  • Endothelialization speed test The drug-eluting device is implanted into the rabbit iliac artery. After a certain period of time, the blood vessel where the drug-eluting device is located is taken out, soaked with glutaraldehyde (such as 6h), dried, and then cut along the axial direction. Gold spraying, SEM measurement and observation of drug-eluting device endothelial coverage. When the coverage reaches more than 95% of the area, it indicates that the drug-eluting device has completed endothelialization.
  • glutaraldehyde such as 6h
  • Corrosion rate test of absorbable drug-eluting devices in the body can be characterized by the mass loss of drug-eluting devices. For example, after implanting an absorbable drug-eluting device into a rabbit for a certain period of time, the drug-eluting device and surrounding tissues are taken out, and the drug-eluting device is ultrasonically cleaned with a tartaric acid solution (eg, mass fraction 3%).
  • a tartaric acid solution eg, mass fraction 3%
  • the mass of the drug-eluting device is M1
  • the mass of the bare bare stent of the drug-eluting device is M 0
  • the mass loss of the drug-eluting device is (M 0 -M 1 )/M 0 .
  • Corrosion start of drug-eluting devices means that the mass loss of the device is 5-10%.
  • Characterization of the asymmetric effect of the active drug content of the drug-eluting device it can be characterized by Raman spectroscopy.
  • the specific characterization method is: using the Raman spectrometer of Thermo Fisher Scientific at a wavelength of 532 nm to apply the drug Raman spectroscopy analysis was performed on the outer wall and inner wall of the layer.
  • the outer wall showed the characteristic peak of the active drug, but the inner wall did not, it means that the outer wall had the active drug and the inner wall did not have the active drug; when the outer wall part had the characteristic peak intensity
  • it is higher than the inner wall it means that the active drug content in the inner wall is less than that in the outer wall.
  • the test method of the drug loading capacity of the drug eluting device before and after removing the active drug on the inner wall is: soaking the drug eluting device in a certain volume of acetonitrile to ensure that the acetonitrile is fully submerged in the drug eluting device, ultrasound for a certain time (eg 30min ), using Agilent 1260 liquid chromatography to test the amount of drug in the solution, the device parameter is ultraviolet wavelength 278nm, the mobile phase is acetonitrile and water ratio is 65:35, the pump flow rate is 1mL/min.
  • the active drug content on the stent can also be expressed by the drug content per unit area: M 1 /S, where S is the surface area of the stent rod mm 2 .
  • Coating thickness test The prepared drug-eluting device is subjected to gold spraying, resin embedding, and grinding sample treatment. Observe and measure the dimensions of each cross-section under the scanning electron microscope, and take the typical cross-section. The drug coating of each cross-section The inner wall, the outer wall and the side wall of each are taken to be the thickness of the coating in the middle of each direction, and the average value of each thickness is taken as the thickness of the drug coating.
  • Porosity of the pore structure of the portion of the drug coating on the inner wall the percentage of the volume of the pores of the drug coating on the inner wall and the total volume of the drug coating on the inner wall. Due to the small amount of drug coating, the conventional porosity test method is not precise enough, so the SEM method is used for rough evaluation.
  • the specific operation method is: brittlely break the drug eluting device in the axial direction, spray gold, observe the coating of the inner wall of each stent rod, select at least 3 axial sections, and select at least 5 2*2 ⁇ m areas for each section to take pictures Then, use statistical software to uniformly calculate the ratio of pore area to the area of the selected area, and take 15 average values of the ratio as the porosity.
  • the drug-eluting stent is used as an example to further elaborate on the above-mentioned drug-eluting device and its preparation method.
  • the concentration of PDLLA and sirolimus are 6mg/mL
  • the solvent is acetone
  • the mixed solution is coated on the outer wall, side wall and inner wall of the base of the 30008 standard stent, After drying, a drug coating is formed on the outer wall, side wall and inner wall of the substrate.
  • the base material is pure iron.
  • the sirolimus content of this batch of stents was measured to be 2.0 ⁇ g/mm 2 .
  • the mandrel made of porous nylon material penetrates the inner wall of the stent base, and then the mandrel is fully adsorbed with ethanol. After the ethanol is fully adsorbed, the mandrel expands and contacts the portion of the drug coating on the inner wall for 2 minutes, and then removes the Mandrel and dry the bracket sufficiently.
  • the final sirolimus content of the batch of stents was measured to be 1.5 ⁇ g/mm 2 , which was 25% less than the amount of stents before solvent adsorption.
  • the thickness of the drug coating was measured to be 5 ⁇ m.
  • Tests with a Raman spectrometer showed that the drug content of the drug coating on the inner wall of the substrate was smaller than that on the outer wall.
  • the porosity of the portion of the drug coating located on the inner wall of the substrate was measured to be 35%.
  • the results of the peeling experiment showed that the stent was pushed and expanded to the burst pressure by simulation, and the coating was complete.
  • the multiple stents prepared in this batch were implanted into the iliac arteries of multiple rabbits, and samples were taken at different time periods. The test found that the stent was completely endothelialized after 2 months of implantation; after 3 months of implantation, the quality of the stent was lost by 25 %; one year after implantation, the mass loss of the stent is 50%.
  • the concentrations of PDLLA and sirolimus are 4mg/mL and 6mg/mL, respectively, and the solvent is acetone.
  • the mixed solution is coated on the outer wall and side wall of the stent base of 30008 size And the inner wall, after drying to form a drug coating covering the outer wall, side wall and inner wall of the substrate.
  • the base material is pure iron.
  • the sirolimus content of the batch of stents was measured to be 2.5 ⁇ g/mm 2 , the porous nylon material was coated on the surface of the cylindrical mandrel, and the mandrel was penetrated through the inner wall of the stent base, and then made porous The nylon material fully adsorbed ethanol, and after the ethanol was fully adsorbed, the porous nylon material expanded and contacted the drug-coated portion of the inner wall for 10 minutes, and then the mandrel was taken out and the stent was sufficiently dried.
  • the final sirolimus content of the batch of stents was measured to be 1.5 ⁇ g/mm 2 , which was 40% less than the amount of stents before solvent adsorption.
  • the thickness of the drug coating was measured to be 5 ⁇ m.
  • Tests with a Raman spectrometer showed that the part of the drug coating located on the inner wall of the substrate contains no drug.
  • the porosity of the portion of the drug coating located on the inner wall of the substrate was measured to be 55%.
  • the results of the peeling experiment showed that the stent was pushed and expanded to the burst pressure by simulation, and the coating was complete.
  • the multiple stents prepared in this batch were implanted into the iliac arteries of multiple rabbits respectively, and samples were taken at different time periods. The test found that the stents were completely endothelialized after 1.5 months of implantation; after 3 months of implantation, the stent mass lost 20% ; One year after implantation, the mass loss of the stent is 50%.
  • the mixed solution is coated on the outer wall, side wall and The inner wall, after drying, forms a drug coating covering the outer wall, side wall and inner wall of the substrate.
  • the base material is pure iron.
  • a zinc-containing protective layer is provided on the substrate. The zinc-containing protective layer covers a part of the outer wall, all the side walls and the inner wall of the substrate. The coverage of the zinc-containing protective layer is 90%. The material of the zinc-containing protective layer is pure zinc.
  • the drug coating covers the surface of the zinc-containing protective layer.
  • the sirolimus content of this batch of stents was measured to be 2.0 ⁇ g/mm 2 .
  • the porous polystyrene material is coated on the surface of the stainless steel mandrel, and the mandrel is penetrated through the inner wall of the support base, so that the porous polystyrene material fully absorbs ethanol. After the ethanol is fully absorbed, the porous polystyrene material expands The part of the drug coating on the inner wall was contacted for 2 minutes, and then the mandrel was taken out, and the stent was sufficiently dried.
  • the final sirolimus content of the batch of stents was measured to be 1.5 ⁇ g/mm 2 , which was 25% less than the amount of stents before solvent adsorption.
  • the thickness of the drug coating was measured to be 4 ⁇ m.
  • Tests with a Raman spectrometer showed that the part of the drug coating located on the inner wall of the substrate had less drug content than the outer wall.
  • the porosity of the portion of the drug coating located on the inner wall of the substrate was measured to be 45%.
  • the results of the peeling experiment showed that the stent was pushed and expanded to the burst pressure by simulation, and the coating was complete.
  • the multiple stents prepared in this batch were implanted into the iliac arteries of multiple rabbits, and samples were taken at different time periods. The test found that the stent was completely endothelialized after 2 months of implantation; after 3 months of implantation, the stent started to corrode; One year after implantation, the mass loss of the stent was 40%.
  • the material of the substrate is an iron-based alloy with a carbon content not higher than 2.11wt.%.
  • the substrate is provided with a zinc-containing protective layer.
  • the zinc-containing protective layer only covers the entire surface of the sidewall and the inner wall of the substrate, and the outer wall is not covered with zinc.
  • the coverage of the zinc-containing protective layer on the substrate is 70%, and the material of the zinc-containing protective layer is pure zinc.
  • the drug coating covers the surface of the zinc-containing protective layer.
  • the sirolimus content of this batch of stents was measured to be 5 ⁇ g/mm 2 .
  • the porous polystyrene material is coated on the surface of the stainless steel mandrel, and the mandrel is penetrated through the inner wall of the support base to make the porous polystyrene material fully absorb methanol. After the methanol is fully absorbed, the porous polystyrene material expands and collides with The part of the drug coating located on the inner wall was contacted for 10 seconds, and then the mandrel was taken out, and the stent was sufficiently dried.
  • the final sirolimus content of this batch of stents was measured to be 4.5 ⁇ g/mm 2 , which was 10% less than the amount of stents before solvent adsorption.
  • the thickness of the drug coating was measured to be 8 ⁇ m.
  • Tests with a Raman spectrometer showed that the drug content of the portion of the drug coating located on the inner wall of the substrate is less than that of the portion located on the outer wall.
  • the porosity of the portion of the drug coating located on the inner wall of the substrate was measured to be 15%.
  • the results of the peeling experiment showed that the stent was pushed and expanded to the burst pressure by simulation, and the coating was complete.
  • the multiple stents prepared in this batch were implanted into the iliac arteries of multiple rabbits, and samples were taken at different time periods. The test found that the stent was completely endothelialized after 2.5 months of implantation; after 3 months of implantation, the stent started to corrode; One year after implantation, the mass loss of the stent was 50%.
  • the material of the substrate is an iron-based alloy with a carbon content not higher than 2.11wt.%.
  • the substrate is provided with a zinc-containing protective layer.
  • the zinc-containing protective layer covers the outer wall, side walls, and inner wall of the substrate.
  • the zinc-containing protective layer is on the substrate. The coverage rate is 100%, the drug coating covers the surface of the zinc-containing protective layer, and the drug coating simultaneously covers the outer wall, side wall, and inner wall of the substrate.
  • the material of the zinc-containing protective layer is pure zinc.
  • the sirolimus content of this batch of stents was measured to be 10 ⁇ g/mm 2 .
  • Spread the sponge rod dipped in acetonitrile on the inner wall of the substrate wipe the inner wall of the substrate evenly, and repeat it.
  • the contact time of the sponge rod dipped in acetonitrile and the inner wall of the branch is 20 minutes, so that the sponge rod dipped in acetonitrile can absorb the drug coating
  • the portion of sirolimus located on the inner wall is fully dried.
  • the final sirolimus content of the batch of stents was measured to be 6 ⁇ g/mm 2 , which was 40% less than the amount of stents before solvent adsorption.
  • the thickness of the drug coating was measured to be 15 ⁇ m.
  • Tests with a Raman spectrometer showed that the part of the drug coating located on the inner wall of the substrate contains no drug.
  • the porosity of the portion of the drug coating located on the inner wall of the substrate was measured to be 60%.
  • the results of the peeling experiment showed that the stent was pushed and expanded to the burst pressure by simulation, and the coating was complete.
  • the multiple stents prepared in this batch were implanted into the iliac arteries of multiple rabbits respectively, and samples were taken at different time periods. The test found that the stent was completely endothelialized after 2 months of implantation; after 3 months of implantation, the stent did not initiate corrosion; One year after implantation, the mass loss of the stent was 65%.
  • the solvent is chloroform.
  • the mixed solution is evenly sprayed on the outer wall, side wall and inner wall of the base of the stent with a diameter of 30008.
  • a drug coating is formed on the outer wall, side wall and inner wall of the substrate.
  • the base material is pure iron.
  • the substrate is provided with a zinc-containing protective layer.
  • the zinc-containing protective layer covers all inner walls and a part of the side walls of the substrate.
  • the coverage of the zinc-containing protective layer on the substrate is 60%.
  • the material of the zinc-containing protective layer is pure zinc.
  • the drug coating covers the surface of the zinc-containing protective layer.
  • the paclitaxel content of this batch of scaffolds was measured to be 1 ⁇ g/mm 2 .
  • a dust-free cloth dipped in ethyl acetate was brought into contact with the inner wall of the substrate for a contact time of 8 minutes to allow ethyl acetate to absorb the drug on the inner wall of the drug coating, and the stent was sufficiently dried.
  • the final paclitaxel content of this batch of stents was measured to be 0.95 ⁇ g/mm 2 , which was 5% less than the amount of stents before solvent adsorption.
  • the thickness of the drug coating was measured to be 10 ⁇ m.
  • Tests with a Raman spectrometer showed that the drug content of the portion of the drug coating located on the inner wall of the substrate is less than that of the portion located on the outer wall.
  • the porosity of the portion of the drug coating located on the inner wall of the substrate was measured to be 5%.
  • the results of the peeling experiment showed that the stent was pushed and expanded to the burst pressure by simulation, and the coating was complete.
  • the multiple stents prepared in this batch were implanted into the iliac arteries of multiple rabbits, and samples were taken at different time periods. The test found that the stent was completely endothelialized after 2 months of implantation; after 3 months of implantation, the stent started to corrode; One year after implantation, the mass loss of the stent was 65%.
  • the base material is pure iron.
  • the content of the sirolimus derivative of this batch of stents was measured to be 0.8 ⁇ g/mm 2 .
  • the polypropylene non-woven fabric dipped in isopropyl alcohol was brought into contact with the inner wall of the substrate for a contact time of 5 minutes, so that the isopropyl alcohol adsorbed the drug on the inner wall of the drug coating, and the stent was sufficiently dried.
  • the final sirolimus derivative content of this batch of stents was measured to be 0.5 ⁇ g/mm 2 , which was 38% less than the amount of stents before solvent adsorption.
  • the thickness of the drug coating was measured to be 2 ⁇ m.
  • Tests with a Raman spectrometer showed that the part of the drug coating located on the inner wall of the substrate contains no drug.
  • the porosity of the portion of the drug coating located on the inner wall of the substrate was measured to be 50%.
  • the results of the peeling experiment showed that the stent was pushed and expanded to the burst pressure by simulation, and the coating was complete.
  • the multiple stents prepared in this batch were implanted into the iliac arteries of multiple rabbits respectively, and samples were taken at different time intervals. The test found that the stent was completely endothelialized after 1 month of implantation; after 3 months of implantation, the mass loss of the stent was 15%; after 1 year of implantation, the mass loss of the stent is 40%.
  • a crystalline PLLA solution with a concentration of 5 mg/mL, and a mixed solution of 5 mg/mL PLLA and 1 mg/mL sirolimus.
  • the solvent is chloroform.
  • the outer wall, the side wall and the inner wall of the substrate form a primer coating on the outer wall, the side wall and the inner wall of the substrate.
  • the mixed solution of PLLA and sirolimus is uniformly sprayed on the surface of the stent to form a drug-carrying coating, and the drug-carrying coating covers the bottom layer, wherein the material of the substrate is pure iron.
  • the substrate is provided with a zinc-containing protective layer, and the zinc layer covers the surfaces of the outer wall, the side walls, and the inner wall of the substrate at the same time.
  • the coverage of the zinc-containing protective layer on the substrate is 100%, and the material of the zinc-containing protective layer is pure zinc.
  • the drug coating covers the surface of the zinc-containing protective layer.
  • the sirolimus content of this batch of stents was measured to be 4 ⁇ g/mm 2 .
  • the polypropylene non-woven fabric dipped in acetonitrile was brought into contact with the inner wall of the substrate for a contact time of 15 minutes, so that the acetonitrile adsorbed the drug on the inner wall of the drug coating, and the stent was sufficiently dried.
  • the final sirolimus content of this batch of stents was measured to be 3.2 ⁇ g/mm 2 , which was 20% less than the amount of stents before solvent adsorption.
  • the thickness of the drug coating was measured to be 20 ⁇ m.
  • Tests with a Raman spectrometer showed that the drug content of the part of the drug coating located on the inner wall of the substrate was smaller than that of the part located on the outer wall.
  • the porosity of the portion of the drug coating located on the inner wall of the substrate was measured to be 10%.
  • the results of the peeling experiment showed that the stent was pushed and expanded to the burst pressure by simulation, and the coating was complete.
  • the multiple stents prepared in this batch were implanted into the iliac arteries of multiple rabbits, and samples were taken at different time periods. The test found that the stent was completely endothelialized after 2.5 months of implantation; after 3 months of implantation, the stent started to corrode; One year after implantation, the mass loss of the stent was 70%.
  • the solvent is ethyl acetate.
  • the mixed solution is evenly sprayed on the outer wall, side wall and inner wall of the stent base of 30008 size.
  • a package is formed Covered with a matrix drug coating.
  • the material of the substrate is an iron-based alloy with a carbon content not higher than 2.11wt.%.
  • the substrate is provided with a zinc-containing protective layer.
  • the zinc-containing protective layer only covers most of the inner wall surface of the substrate.
  • the zinc-containing protective layer is on the substrate.
  • the coverage rate is 20%, and the material of the zinc-containing protective layer is pure zinc.
  • the drug coating covers the surface of the zinc-containing protective layer.
  • the sirolimus content of this batch of stents was measured to be 4 ⁇ g/mm 2 .
  • the contact time of the sponge rod dipped in propanol and the inner wall of the branch is 15 minutes to make the sponge rod dipped in propanol adsorb
  • the drug-coated portion of sirolimus on the inner wall fully dried the stent.
  • the final sirolimus content of the batch of stents was measured to be 2 ⁇ g/mm 2 , which was 50% less than the amount of stents before solvent adsorption.
  • the thickness of the drug coating was measured to be 7 ⁇ m.
  • Tests with a Raman spectrometer showed that the drug content of the portion of the drug coating located on the inner wall of the substrate is less than that of the portion located on the outer wall.
  • the porosity of the portion of the drug coating located on the inner wall of the substrate was measured to be 60%.
  • the results of the peeling experiment showed that the stent was pushed and expanded to the burst pressure by simulation, and the coating was complete.
  • the multiple stents prepared in this batch were implanted into the iliac arteries of multiple rabbits, and samples were taken at different time periods. The test found that the stent was completely endothelialized after 1 month of implantation; after 3 months of implantation, the stent started to corrode; One year after implantation, the mass loss of the stent was 50%.
  • the base material is pure iron.
  • the sirolimus on the batch of stents was measured to be 1.5 ⁇ g/mm 2 , and the coating thickness was 5 ⁇ m.
  • Tests with a Raman spectrometer showed that the outer wall and the side wall of the substrate contained drugs, and the inner wall was free of drugs.
  • the peeling experiment showed that the stent was pushed and expanded to burst pressure by simulation, and the coating was obviously damaged and warped, and a large area of coating and The phenomenon of matrix peeling.
  • the multiple stents prepared in this batch were implanted into the iliac arteries of multiple rabbits, and samples were taken at different time periods. The test found that the stent was completely endothelialized after 1.5 months of implantation; after 3 months of implantation, the mass loss of the stent was 15%; after 1 year of implantation, the mass loss of the stent is 40%.
  • the base material is pure iron.
  • the sirolimus on the batch of stents was measured to be 2.5 ⁇ g/mm 2 , and the coating thickness was 5 ⁇ m.
  • Tests with a Raman spectrometer showed that the drug content of the drug coating located on the inner wall of the substrate was not significantly different from the drug content located on the outer wall.
  • the results of the peeling experiment showed that the stent was pushed and expanded to the burst pressure by simulation, and the coating was complete.
  • the multiple stents prepared in this batch were implanted into the iliac arteries of multiple rabbits, and samples were taken at different time periods. The test found that after 3 months of implantation, the stent was completely endothelialized and the mass loss of the stent was 28%; 1 year after implantation After that, the mass loss of the stent is 50%.

Abstract

一种药物洗脱器械及其制备方法，其中，药物洗脱器械包括基体（100）和设置于基体（100）上的药物涂层（200），基体（100）具有外壁（110）、侧壁（120）和内壁（130），药物涂层（200）中含有活性药物（210）和药物载体，活性药物（210）分散于药物载体中，药物涂层（200）包覆于基体（100）的外壁（110）、侧壁（120）和内壁（130）上，且活性药物（210）在外壁（110）和侧壁（120）上的含量均大于在内壁（130）上的含量；或者，活性药物（210）仅分布在外壁（110）和侧壁（120）上，内壁（130）不含有活性药物（210）。该药物洗脱器械不易发生涂层脱落的现象。

Description

药物洗脱器械及其制备方法 技术领域
本发明涉及介入式医疗器械领域，特别是涉及一种药物洗脱器械及其制备方法。
背景技术
血管支架是一种血管内植入物，具有可膨胀性，植入病变血管部位后，能够起到径向支撑的作用，使得血运重建。药物洗脱支架一般是在裸支架基体的表面涂覆药物涂层，药物涂层中含有活性药物，通过活性药物的释放，抑制血管再狭窄的发生。
当将药物洗脱支架植入血管中后，只有支架的外壁和侧壁与血管壁接触，支架外壁和侧壁释放出来的活性药物会进入血管壁起到抑制血管壁内膜增生、预防血管再狭窄的作用，而支架的内壁的活性药物则无法起到抑制内膜增生的作用，反而会被释放进入血液，循环至全身，对其他器官起到副作用。另外，支架的内壁的活性药物还会抑制支架内皮化，从而增加血栓形成的风险。
为了解决上述问题，目前现有的药物洗脱支架仅在支架的外壁和侧壁上设置药物涂层，支架的内壁上没有药物涂层，亦没有其他涂层。
然而，对于球囊扩张的支架而言，支架从压握状态到扩张状态，支架杆会发生明显的变形，而支架上的涂层同样会发生明显变形，因此对于外壁和侧壁上设有涂层，内壁上不设有涂层的支架，当支架扩张的时候，可能会发生涂层与支架基体间的剥离。当涂层不完整时，会加剧涂层剥离的风险，从而可能会导致涂层从基体上脱落入血液中，从而增大栓塞和血栓风险。
发明内容
基于此，有必要提供一种内壁上不含有活性药物或内壁上的活性药物的含量较少的药物洗脱器械，且该药物洗脱器械不易发生涂层脱落的现象。
一种药物洗脱器械，包括基体和设置于所述基体上的药物涂层，所述基体具有外壁、侧壁和内壁，所述药物涂层中含有活性药物和药物载体，所述活性药物分散于所述药物载体中，所述药物涂层包覆于所述基体的外壁、侧壁和内壁上，且所述活性药物在所述外壁和所述侧壁上的含量均大于在所述内壁上的含量；或者，所述活性药物仅分布在所述外壁和侧壁上，所述内壁不含有所述活性药物。
在其中一个实施例中，所述药物涂层的位于所述内壁的部分至少有部分区域为孔隙结构。
在其中一个实施例中，所述孔隙结构的孔隙率为5％～60％。
在其中一个实施例中，所述药物涂层中，所述活性药物的含量为0.5～6微克/平方毫米。
在其中一个实施例中，所述药物载体为可降解聚合物，所述可降解聚合物选自可降解聚酯和可降解酸酐中的至少一种。
在其中一个实施例中，所述药物涂层的厚度为2～20微米。
在其中一个实施例中，所述药物涂层的位于所述外壁的部分的厚度和所述药物涂层的位于所述侧壁的部分的厚度均大于所述药物涂层的位于所述内壁部分的厚度。
在其中一个实施例中，所述基体的材料为纯铁或铁合金。
在其中一个实施例中，所述药物洗脱器械还包括含锌保护层，所述含锌保护层设置于所述基体上，所述含锌保护层至少覆盖所述基体的内壁，且所述含锌保护层被所述药物涂层所覆盖。
在其中一个实施例中，所述含锌保护层在所述基体上的覆盖率为20～100％。
一种药物洗脱器械的制备方法，包括如下步骤：
提供基体，所述基体具有外壁、侧壁和内壁；
将含有活性药物和药物载体的溶液施加在所述基体上形成药物涂层，所述活性药物分散于所述药物载体中，所述药物涂层覆盖于所述基体的外壁、侧壁和内壁上；及，
用溶剂与所述药物涂层的位于所述内壁的部分接触，使所述药物涂层的位于所述内壁的部分的活性药物部分溶解或完全溶解于所述溶剂中，且所述药物载体不溶于所述溶剂中，并从所述基体上移除所述溶剂。
在其中一个实施例中，所述用溶剂与所述药物涂层的位于所述内壁的部分接触，使所述药物涂层的位于所述内壁的部分的活性药物部分溶解或完全溶解于所述溶剂中，且所述药物载体不溶于所述溶剂中，并从所述基体上移除所述溶剂的步骤包括：
将吸附有所述溶剂的吸附性材料与所述基体的内壁接触，使所述药物涂层的位于所述内壁的部分的活性药物部分溶解或完全溶解于所述溶剂中，且所述药物载体不溶于所述溶剂中，然后移除所述吸附性材料。
在其中一个实施例中，所述吸附性材料为尼龙材料、聚丙烯、聚四氟乙烯材料、橡胶类材料或纤维类材料。
在其中一个实施例中，所述将吸附有所述溶剂的吸附性材料与所述基体的内壁接触的时间为10s～20min。
在其中一个实施例中，所述将吸附有所述溶剂的吸附性材料与所述基体的内壁接触，使所述药物涂层的位于所述内壁的部分的活性药物部分溶解或完全溶解于所述溶剂中，且所述药物载体不溶于所述溶剂中，然后移除所述吸附性材料的步骤包括：
提供芯轴，将所述吸附性材料包覆于所述芯轴的外表面上，然后将包覆有所述吸附性材料的所述芯轴伸入所述基体的内部，并使所述吸附性材料吸附所述溶剂，将所述吸附性材料与所述基体的内壁接触，以使所述药物涂层的位于所述内壁的部分的活性药物部分溶解或完全溶解于所述溶剂中，然后将所述吸附性材料和所述芯轴从所述基体上移除；或者，
提供芯轴，将所述吸附性材料包覆于所述芯轴的外表面上，使所述吸附性材料吸附所述溶剂，然后将包覆有所述吸附性材料的所述芯轴伸入所述基体的内部，并使所述吸附性材料与所述基体的内壁接触，以使所述活性药物的位于所述内壁的部分的活性药物部分溶解或完全溶解于所述溶剂中，然后将所述吸附性材料和所述芯轴从所述基体上移除；或者，
提供由所述吸附性材料制成的芯轴，使所述芯轴吸附所述溶剂，然后将所述吸附有所述溶剂的芯轴伸入所述基体的内部，并使所述芯轴与所述基体的内壁接触，以使所述药物涂层的位于所述内壁的部分的活性药物部分溶解或完全溶解于所述溶剂中，然后将所述芯轴从所述基体上移除；或者，
提供由所述吸附性材料制成的芯轴，将所述芯轴伸入所述基体的内部，使所述芯轴吸附所述溶剂，并使所述芯轴与所述基体的内壁接触，以使所述药物涂层的位于所述内壁的部分的活性药物部分溶解或完全溶解于所述溶剂中，然后将所述芯轴从所述基体上移除；或者，
将吸附有所述溶剂的吸附性材料在所述基体的内壁上擦拭，以使所述药物涂层的位于所述内壁的部分的活性药物部分溶解或完全溶解于所述溶剂中，然后将所述吸附性材料从所述基体上移除。
在其中一个实施例中，所述吸附有所述溶剂的吸附性材料与所述基体的内壁接触的过程中，所述芯轴或所述基体处于旋转状态。
在其中一个实施例中，所述用溶剂与所述药物涂层的位于所述内壁的部分接触，使所述药物涂层的位于所述内壁的部分的活性药物部分溶解或完全溶解于所述溶剂中，且所述药物载体不溶于所述溶剂中，并从所述基体上移除所述溶剂的步骤后，所述基体的活性药物的含量减少最多达50％。
上述药物洗脱器械的药物涂层，在使药物涂层中活性药物的分布满足活性药物在外壁和侧壁上的含量均大于在内壁上的含量或活性药物仅分布在外壁和侧壁上，药物涂层位于内壁的部分不含有活性药物的同时，药物涂层包覆于基体的外壁、侧壁和内壁上，即药物涂层为完整的、连续的涂层，使得在扩张时，药物涂层不易与基体发生分离而从基体上脱落。因此，上述药物洗脱器械内壁上不含有活性药物或内壁上的活性药物的含量较少，且该药物洗脱器械不易发生涂层脱落的现象。
附图说明
图1为一实施方式的药物洗脱器械的截面结构示意图；
图2为另一实施方式的药物洗脱器械的截面结构示意图；
图3为另一实施方式的药物洗脱器械的截面结构示意图；
图4为另一实施方式的药物洗脱器械的截面结构示意图。
具体实施方式
为使本发明的上述目的、特征和优点能够更加明显易懂，下面结合附图对本发明的具体实施方式做详细的说明。在下面的描述中阐述了很多具体细节以便于充分理解本发明。但是本发明能够以很多不同于在此描述的其它方式来实施，本领域技术人员可以在不违背本发明内涵的情况下做类似改进，因此本发明不受下面公开的具体实施的限制。
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发明的技术领域的技术人员通常理解的含义相同。本文中在本发明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，不是旨在于限制本发明。
请参阅图1，一实施方式的药物洗脱器械，包括基体100和设置于基体100上的药物涂层200。
基体100为镂空的管腔结构。基体100具有外壁110、侧壁120和内壁130。
在一实施方式中，基体100由生物可吸收的材料的制成。例如，基体100由铁、铁基合金、镁、镁基合金或可吸收的高分子材料等材料制成。在一实施方式中，基体100由碳含量不高于2.11wt.％的铁基合金制成或基体100由纯铁制成。
在其他实施方式中，基体100由生物不可吸收的材料制成。例如，基体100由镍钛合金、钴铬合金或不锈钢等材料制成。
药物涂层200包覆于基体100的外壁110、侧壁120和内壁130上，即药物涂层200为完整的、连续的涂层，基体100的所有表面均被药物涂层200所覆盖。
药物涂层200中含有活性药物210和药物载体(图未示)，活性药物210非均匀地分散于药物载体中，即活性药物210在药物涂层200中的分布为非均匀分布。在一实施方式中，如图1所示，活性药物210在外壁110和侧壁120上的含量均大于在内壁130上的含量。具体地，活性药物210在外壁110上的单位面积的含量和活性药物210在侧壁120上的单位面积的含量均大于活性药物 210在内壁130上的单位面积的含量。
在另一实施方式中，如图2，活性药物210仅分布在药物涂层200的位于外壁110和侧壁120的部分上，药物涂层200的位于内壁130的部分不含有活性药物210。
上述药物洗脱器械的药物涂层200，在使药物涂层200中活性药物210的分布满足活性药物210在外壁110和侧壁120上的含量均大于在内壁130上的含量或活性药物210仅分布在外壁110和侧壁120上，内壁130不含有活性药物210的同时，药物涂层200包覆于基体100的外壁110、侧壁120和内壁130上，即药物涂层200为完整的、连续的涂层，使得在扩张时，药物涂层200不易与基体100发生分离而从基体100上脱落。因此，上述药物洗脱器械的内壁130上不含有活性药物210或内壁130上的活性药物210的含量较少，且该药物洗脱器械不易发生涂层脱落的现象。
因此，由于基体100的内壁130上不含有活性药物210或内壁130上的活性药物210的含量较低，有利于该药物洗脱器械快速内皮化，降低了血栓形成风险。并且，有利于减少释放入血液中的药物，从而降低了对其他器官的毒副作用，提高了临床使用安全。
在一实施方式中，活性药物210选自细胞生长抑制剂、类皮质激素、前列腺环素、抗生素、细胞增殖抑制剂、免疫抑制剂、抗炎剂、消炎剂、抗血管生成药物、抗再狭窄药物、抗血栓形成药物、抗致敏药物及抗肿瘤药物中的至少一种。在一实施方式中，抑制血管增生的药物选自紫杉醇、雷帕霉素及雷帕霉素其衍生物中的至少一种。抗血小板类药物为西洛他唑。抗血栓类药物为肝素。抗炎症反应的药物为地塞米松。抗致敏药物选自葡萄糖酸钙、扑尔敏及可的松的至少一种。
在一实施方式中，药物涂层200中，活性药物210的含量为0.5μg/mm 2～6μg/mm 2。需要说明的是，活性药物210的含量为0.5μg/mm 2～6μg/mm 2是指活性药物210在药物涂层200的外壁110、侧壁120和内壁130上含量的平均值。
在一实施方式中，药物载体为可降解聚合物。活性药物210分散于可降解聚合物中，通过可降解聚合物控制活性药物210的释放，避免活性药物210爆释而大部分流失于血液中。
在一实施方式中，可降解聚合物选自可降解聚酯和可降解酸酐中的至少一种。其中，可降解聚酯选自聚乳酸、聚乙醇酸、聚丁二酸酯、聚(β-羟基丁酸酯)、聚已内酯、聚己二酸乙二醇酯、聚戊酸酯、聚羟基烷基醇酯及聚(苹果酸酯)中的至少一种。或者，可降解聚酯为形成前述可降解聚酯类聚合物的单体中的至少两种的共聚物。可降解聚酸酐选自聚1,3-双(对羧基苯氧基)丙烷-癸二酸、聚芥酸二聚体-癸二酸及聚富马酸-癸二酸酐中的至少一种。
上述可降解聚酯和可降解聚酸酐的降解会在基体100的周围产生局部微酸性环境，有利于加速基体100后期的腐蚀。
在一实施方式中，药物涂层200的位于内壁130的部分至少有部分区域为孔隙结构。由于该孔隙结构，在植入的早期，当药物涂层200中的可降解聚合物降解时，产生的降解产物较少，降解产物能够随体液比较自由地扩散，不至于在局部聚集而导致局部的pH值过低，从而避免可腐蚀或可降解的基体100的局部明显加速腐蚀或降解的现象。
在一实施方式中，药物涂层200的位于内壁130的部分的孔隙结构的孔隙率为5％～60％，保证可降解聚合物的降解产物尽快地扩散出去，避免可腐蚀或 可降解的基体100过快腐蚀或过快降解。
在一实施方式中，药物涂层200的厚度为2～20微米。药物涂层200的厚度指是药物涂层200的位于外壁110的部分的厚度、位于侧壁120的部分的厚度和位于内壁130部分的厚度的平均值。
通过使药物涂层200同时覆盖基体100的外壁110、侧壁120和内壁130，且合理地设置药物涂层200的厚度和控制药物涂层200中可降解聚合物的量，在保证可降解聚合物的量足够多，以使药物涂层200的降解速率和可腐蚀或可降解的基体100的腐蚀或降解速率相匹配，使得在完成病变部位的修复后，仍然有足够的可降解聚合物残留，以使残留的可降解聚合物的降解产物加速基体100的腐蚀或降解，从而降低远期临床使用风险。
在一实施方式中，药物涂层200的位于外壁110的部分的厚度和药物涂层200的位于侧壁120的部分的厚度均大于药物涂层200的位于内壁130部分的厚度。当将药物洗脱器械植入体内后，基体100的外壁110为与血管壁直接接触的一侧，位于外壁110上的活性药物210可控地释放并渗透入血管的内膜中而发挥较好的疗效。因此，在避免药物涂层200的局部厚度过大的前提下，药物涂层200的位于外壁110的部分的厚度大于药物涂层200的位于内壁130部分的厚度，有利于提高有效载药量，以满足治疗的需求。
请参阅图3，在一实施方式中，当基体100的材料为纯铁或铁合金时，药物洗脱器械还包括含锌保护层300。含锌保护层300设置于基体100上，且含锌保护层300被药物涂层200所覆盖。含锌保护层300中含有纯锌、锌合金和/或含锌化合物。通过在基体上100上设置含锌保护层300，以保护基体100，延缓可腐蚀的基体100的腐蚀，保持基体100在早期的径向支撑性能。
含锌保护层300至少覆盖基体100的内壁130。
在一实施方式中，含锌保护层300至少覆盖基体100的内壁130是指含锌保护层300完全覆盖基体100的表面，即含锌保护层完全覆盖基体100的外壁110、侧壁120和内壁130，如图3所示。
在另一实施方式中，含锌保护层300至少覆盖基体100的内壁130是指含锌保护层300仅覆盖基体100的内壁130；或者，含锌保护层300完全覆盖基体100的内壁130，含锌保护层300仅部分覆盖基体的侧壁120，且含锌保护层300完全不覆盖基体100的外壁110；或者，含锌保护层300完全覆盖基体100的内壁130和侧壁120，且含锌保护层300仅部分覆盖基体100的外壁110；或者，含锌保护层300完全覆盖基体100的内壁130和侧壁120，且含锌保护层完全不覆盖基体100的外壁110。其中，含锌保护层300仅覆盖基体100的内壁130是指含锌保护层300完全覆盖基体100的内壁130，或者含锌保护层300仅部分覆盖基体100的内壁130，并且，基体100的外壁110和侧壁120完全没有被含锌保护层300所覆盖。
需要说明的是，由于工艺控制的原因，在基体100上制备含锌保护层300时，可能存在含锌保护层300的位于基体100上的某些区域为非连续的，例如，存在漏镀区域而导致含锌保护层300的位于基体100上的某些区域为非连续的。例如，含锌保护层300仅覆盖基体100的内壁130上，但含锌保护层300的某些区域为非连续的。又如，含锌保护层300位于基体100的外壁110、侧壁120和内壁130上，且含锌保护层300的位于外壁110的部分、位于侧壁120的部分及位于内壁130的部分中至少有部分区域为非连续的。又如，含锌保护层300位于基体100的内壁130上，且含锌保护层300仅部分覆盖基体100的侧壁120，且含锌保护层300完全不覆盖基体100的外壁110，并且，含锌保护层300的位 于内壁130上的部分及位于侧壁120上的部分中至少有部分区域为非连续的。或者，含锌保护层300位于基体100的内壁130和侧壁120上，且含锌保护层300仅部分覆盖基体100的外壁110或含锌保护层300完全不覆盖基体100的外壁110，且含锌保护层300位于内壁130上的部分、位于侧壁120上的部分及位于外壁110的部分中至少有部分区域为非连续的。
无论含锌保护层300在基体100上如何分布，即便含锌保护层300的部分区域为非连续的，含锌保护层300亦能较好地保护基体100。
含锌保护层300至少覆盖基体100的内壁130。在将药物洗脱器械植入血管中后，基体100的外壁110与血管壁抵接，而基体100的内壁130时时处于与血流接触的状态，时时被血流所冲刷，含锌保护层300至少覆盖基体100的内壁130，能够较好地避免可腐蚀的基体100过早地腐蚀。
在一实施方式中，含锌保护层300在基体100上的覆盖率为20～100％，以在满足含锌保护层300能够在早期保护可腐蚀的基体100，避免可腐蚀的基体100过早腐蚀的同时，又能不影响基体100晚期的腐蚀速率。如果基体100的内壁130上不含有锌，可能会较早腐蚀，引起血栓源性，因此要求含锌保护层300至少覆盖基体100的内壁130。并且，由于基体100的外壁110不与血液接触，为了提高基体100整体的腐蚀速率，基体100的外壁110可以不被含锌保护层300所覆盖或外壁110仅部分被含锌保护层300覆盖。
在一实施方式中，如图4所示，基体100的外壁110的至少部分区域没有被含锌保护层300所覆盖。为了提高基体100的有效载药量，药物涂层200的位于基体100的外壁110的部分的厚度较大。在满足含锌保护层300能够较好地保护基体100，避免基体100过早腐蚀的前提下，基体100的外壁110的至少部分区域没有被含锌保护层300所覆盖，有利于后期从外壁110开始加快对基体100的腐蚀，缩短腐蚀周期。
上述药物洗脱器械通过完整的、连续的、不对称载药的药物涂层200避免了过多的活性药物210从基体100的内壁130方向直接向血液中释放，引起毒副作用，且有利于内皮细胞在基体100的内壁130上爬覆，同时有效地避免在扩张时药物涂层200的脱落。并且，在一实施方式中，基体100由碳含量不高于2.11wt.％的铁基合金或由纯铁制成，药物涂层200中的活性药物210的含量为0.5μg/mm 2～6μg/mm 2，药物涂层200的厚度为2～20微米，药物涂层200的位于内壁130的部分的孔隙结构的孔隙率为5％～60％，使得活性药物210的释放与可腐蚀的基体100的腐蚀相匹配，以使活性药物210的释放周期内与植入部位的修复期一致，在修复期内，可腐蚀的基体100保持足够的径向支撑力；而修复完成后，活性药物210已经完全释放，此时可降解聚合物还没有完全降解，因而能够继续降解而使基体100周围的保持局部微酸性环境，以使可腐蚀的基体100快速腐蚀，从而降低远期临床风险。
在一实施方式中，药物洗脱器械的基体100由碳含量不高于2.11wt.％的铁基合金或由纯铁制成，药物涂层200中的活性药物210的含量为0.5μg/mm 2～6μg/mm 2，药物涂层200的厚度为2～20微米，且基体100上设有至少覆盖基体100的内壁100的含锌保护层300，亦能够延缓基体100的启动腐蚀的时间，使得活性药物210的释放与可腐蚀的基体100的腐蚀相匹配，以使活性药物210的释放周期内与植入部位的修复期一致，在修复期内，可腐蚀的基体100保持足够的径向支撑力；而修复完成后，可腐蚀的基体100快速腐蚀，从而降低远期临床风险。
进一步地，药物洗脱器械的基体100由碳含量不高于2.11wt.％的铁基合金 或由纯铁制成，药物涂层200中的活性药物210的含量为0.5μg/mm 2～6μg/mm 2，药物涂层200的厚度为2～20微米，药物涂层200的位于内壁130的部分的孔隙结构的孔隙率为5％～60％，且基体100上设有至少覆盖基体100的内壁100的含锌保护层300，能够进一步保障活性药物210的释放与可腐蚀的基体100的腐蚀相匹配，以使活性药物210的释放周期内与植入部位的修复期一致，在修复期内，可腐蚀的基体100保持足够的径向支撑力；而修复完成后，可腐蚀的基体100快速腐蚀，从而降低远期临床风险。
上述药物洗脱器械可以为应用于各个部位的器械。例如，上述药物洗脱器械为心血管支架、脑血管支架、外周血管支架、胆道支架、食道支架、气道支架或骨科植入物等等。
一实施方式的药物洗脱器械的制备方法，包括如下步骤：
步骤110：提供基体，基体具有外壁、侧壁和内壁。
基体为镂空的管腔结构。
步骤120：将含有活性药物和药物载体的溶液施加在基体上形成药物涂层，所述活性药物分散于所述药物载体中，药物涂层包覆盖于基体的外壁、侧壁和内壁上。
将活性药物和药物载体溶解于溶剂中，配制含有活性药物和药物载体的溶液。在一实施方式中，当药物载体为可降解聚合物时，将活性药物和可降解聚合物溶解于溶剂中，充分溶解并搅拌均匀后得到含有活性药物和药物载体的溶液。或者，将活性药物和可降解聚合物分别溶解于不同的溶剂中分别配制得到含有活性药物的溶液和含有药物载体的溶液，然后将含有活性药物的溶液和含有药物载体的溶液混合得到活性药物和药物载体的混合液。
在一实施方式中，采用喷涂、浸提、蘸取或辊压等方式将含有活性药物和药物载体的溶液施加在基体上形成药物涂层。药物涂层包覆于基体的外壁、侧壁和内壁上。该实施方式中，药物涂层为单层结构，活性药物分散于药物载体中，且活性药物非均匀地分散于药物载体中。
需要说明的是，含有活性药物和药物载体的溶液中，活性药物的浓度和药物载体的浓度根据需要选择，没有具体限制。
还需要说明的是，上述步骤可以重复多次，以获得需要的药物涂层的厚度。
步骤130：用溶剂与药物涂层的位于内壁的部分接触，使药物涂层的位于内壁的部分的活性药物部分溶解或完全溶解于溶剂中，且药物载体不溶于溶剂中，并从基体上移除溶剂。
在一实施方式中，将吸附有溶剂的吸附性材料与基体的内壁接触，使药物涂层的位于内壁的部分的活性药物部分溶解或完全溶解于溶剂中，且药物载体不溶于溶剂中，然后移除吸附性材料，从而从基体上移除该溶剂。
需要说明的是，上述的药物涂层的位于内壁的部分的活性药物部分溶解或完全溶解于溶剂中，且药物载体不溶于溶剂中，不一定要求药物载体完全不能溶解于该溶剂中，而是指就同一溶剂而言，其对活性药物和药物载体的溶解性差异较大，或者，药物载体在该溶剂中的溶解速度较慢，在该溶剂与药物涂层的位于内壁上的部分接触的时间内，活性药物能够快速地溶解于该溶剂中，而药物载体溶解于该溶剂中的量微乎其微，不会破坏药物涂层的位于内壁的部分的连续性。
在一实施方式中，溶剂为甲醇、乙醇、丙醇、异丙醇、乙腈或乙酸乙酯。
在一实施方式中，吸附性材料为尼龙材料、聚丙烯，聚四氟乙烯材料、聚氨酯类材料、橡胶类材料或纤维类材料，具体例如聚丙烯材料制备的无纺布吸 附棉。
上述吸附性材料不仅具有吸附性，能够吸附溶剂，而且在与基体接触的过程中，不会对基体产生污染。可以理解，除了上述列举的材料，任何能够吸附溶剂且不会对基体产生污染的吸附性材料均可应用。
将吸附有溶剂的吸附性材料与基体的内壁接触，使药物涂层的位于内壁的部分的活性药物部分溶解或完全溶解于溶剂中，且药物载体不溶于溶剂中，使得药物涂层的位于内壁的部分的活性药物至少部分被移除，同时，使得药物涂层的位于内壁的部分至少有部分区域变成孔隙结构，具有合适的孔隙率。为了保证能够移除一定量的活性药物，同时保证药物涂层的位于内壁的部分的孔隙结构的孔隙率为5％～60％，在一实施方式中，将吸附有溶剂的吸附性材料与基体的内壁接触的时间为10s～20min。
具体地，在一实施方式中，将吸附有溶剂吸附性材料与基体的内壁接触，使药物涂层的位于内壁的部分的活性药物部分溶解或完全溶解于溶剂中，然后移除吸附性材料的步骤包括：提供芯轴，将吸附性材料包覆于芯轴的外表面上，然后将包覆有吸附性材料的芯轴伸入基体的内部，并使吸附性材料吸附溶剂，将吸附有溶剂的吸附性材料与基体的内壁接触，以使药物涂层的位于内壁的部分的活性药物部分溶解或完全溶解于溶剂中，然后将吸附性材料和芯轴从基体上移除。
或者，在另一实施方式中，提供芯轴，将吸附性材料包覆于芯轴的外表面上，使吸附性材料吸附溶剂，然后将包覆有吸附性材料的芯轴伸入基体的内部，并使吸附性材料与基体的内壁接触，以使药物涂层的位于内壁的部分的活性药物部分溶解或完全溶解于溶剂中，然后将吸附性材料和芯轴从基体上移除。
芯轴为圆柱形，以和管腔结构的基体相适配。在将吸附性材料包覆于芯轴的外表面上的实施方式中，芯轴的材料不限，只要能够支撑吸附性材料即可。
在另外的实施方式中，也可以直接采用吸附性材料制成圆柱形的芯轴，这种方式无需在芯轴的表面上再额外地包覆吸附性材料，直接用芯轴吸附能够溶解活性药物而难溶或不溶药物载体的溶剂，然后将吸附有该溶剂的芯轴伸入基体中并与基体的内壁接触，以使药物涂层的位于内壁的部分的活性药物溶解于溶剂中，然后将芯轴从基体上移除。或者，将芯轴伸入基体，并使芯轴吸附溶剂并与基体的内壁接触，以使药物涂层的位于内壁的部分的活性药物溶解于溶剂中，然后将芯轴从基体上移除。
需要说明的是，无论是将吸附性材料包覆于芯轴上还是使用吸附性材料制成芯轴，在将活性药物从基体的内壁上移除或减少基体的内壁上的活性药物的操作中，芯轴处于旋转状态。或者，在另一实施方式中，芯轴保持固定，而基体处于旋转状态。
在另一方式中，直接将吸附有溶剂的吸附性材料在基体的内壁上擦拭，使药物涂层的位于内壁的部分的活性药物部分溶解或完全溶解于溶剂中，且药物载体不溶于溶剂中，然后移除吸附性材料。
还需要说明的是，无论是采用上述何种方式将活性药物从基体的内壁上移除或减少基体的内壁上的活性药物，相应的操作可以重复多次，以在保证药物涂层的位于内壁的部分为连续的涂层的前提下，尽可能多地减少基体的内壁上的活性药物或完全除去基体的内壁上的活性药物。可以预估的是，在吸附有溶剂的材料与基体的内壁接触过程中，可能同时会接触部分基体的侧壁，从而使得基体的侧壁靠近内壁的部分药物也减少。
上述药物洗脱器械的制备方法先制备覆盖基体的外壁、侧壁和内壁的连续 的药物涂层，然后再至少部分地除去药物涂层的位于内壁的部分的活性药物。完成步骤130之后所得到的药物洗脱器械的活性药物的含量比步骤120之后得到的半成品的活性药物的含量减少最多达50％。
可以理解，在将药物涂层的位于内壁的部分的活性药物移除或减少后，还包括干燥的步骤，以使药物涂层的溶剂尽快挥发。在一实施方式中，可以采用干燥剂、通风、抽真空等方式进行干燥。在其他实施方式中，也可以自然风干。
还可以理解的是，当需要在基体上形成多层药物涂层时，可以采用上述相同的方法，依次制备多层药物涂层。
上述药物洗脱器械的制备方法利用活性药物与药物载体在同一溶剂中的溶解度存在明显差异制备完全包覆基体的外壁、内壁和侧壁的完全的、连续的药物涂层，并实现该药物涂层中的活性药物在外壁和侧壁上的含量均大于在内壁上的含量；或者活性药物仅分布在外壁和侧壁上，内壁不含有活性药物。从而，有利于提高临床使用安全。并且，上述药物洗脱器械的制备方法工艺简单，对设备要求低。
在其他实施方式中，在制备药物涂层之前，还包括制备附着于基体上的含锌保护层。可以采用电镀、喷涂、浸涂、刷涂、静电纺丝等方式制备含锌保护层。
以下通过具体实施例对上述药物洗脱器械及其制备方法进一步阐述。
以下实施例采用的测试方法如下：
1、内皮化速度测试：将药物洗脱器械植入兔子髂动脉，一定时间后，取出药物洗脱器械所在的血管，用戊二醛浸泡(如6h)，干燥，然后沿轴向剪开，喷金，SEM测量观察药物洗脱器械内皮覆盖率，当覆盖率达到95％以上面积，说明该药物洗脱器械完成内皮化。
2、药物涂层完整性评估方法：剥离实验——将药物洗脱器械系统在PBS模拟溶液中，模拟推送后，将药物洗脱器械扩张至爆破压力，用20-50倍显微镜观察药物涂层的形貌，药物涂层与药物洗脱器械的基体无大面积明显剥离，且涂层脱落，药物洗脱器械外壁无明显基体裸露。
3、可吸收的药物洗脱器械在体内的腐蚀速度测试：药物洗脱器械在体内的腐蚀速度，可以用药物洗脱器械的质量损失来表征。例如，通过将可吸收的药物洗脱器械植入兔子体内一定时间后，取出药物洗脱器械和周围的组织，用酒石酸溶液(例如质量分数3％)超声清洗药物洗脱器械，干燥后，测量药物洗脱器械的质量M1,该药物洗脱器械原本裸支架的质量为M 0，则该药物洗脱器械的质量损失为(M 0-M 1)/M 0。药物洗脱器械腐蚀启动是指器械的质量损失为5～10％。
4、药物洗脱器械的活性药物含量的不对称效果表征：可以通过拉曼光谱来表征，具体表征方法为：使用赛默飞世尔公司的拉曼光谱仪，在532nm的波长条件，对药物涂层的位于外壁和内壁的部分进行拉曼光谱分析，当外壁部分出现活性药物的特征峰，而内壁没有，则说明外壁有活性药物，内壁没有活性药物；当外壁部分的活性药物特征峰强度明显高于内壁时，说明内壁部分的活性药物含量少于外壁部分。
5、去除内壁上的活性药物前后的药物洗脱器械的载药量测试方法为：将药物洗脱器械浸泡在一定体积的乙腈中，确保乙腈充分浸没药物洗脱器械，超声一定时间(例如30min)，将该溶液使用安捷伦1260液相色谱测试溶液中的药量，设备参数为紫外波长278nm，流动相为乙腈与水比例为65:35，泵流速为1mL/min。分别测量经过去除内壁药物工艺前后该批次药物洗脱器械代表样品药量，分别为M 0μg、M 1μg,则该药物洗脱器械的药量减少(M 0-M 1)*100％/M 0，支 架上活性药物含量也可以用单位面积的药物含量来表示：M 1/S，其中S为支架杆的表面积mm 2。
6、涂层厚度测试：将制备好的药物洗脱器械进行喷金、树脂包埋、磨样处理，在扫描电镜下观察测量各截面各方向尺寸，取典型截面，每个截面的药物涂层的内壁、外壁和侧壁均分别取各方向中间位置涂层厚度，将各厚度的平均值作为该药物涂层的厚度。
7、药物涂层的位于内壁的部分的孔隙结构的孔隙率：药物涂层的位于内壁部分的孔隙所占体积与药物涂层的位于内壁部分的总体积的百分比。由于药物涂层量少，常规的孔隙率测试方法精密度不够，因此使用SEM的方法进行粗略评估。具体操作方法为：将药物洗脱器械沿轴向脆断，喷金，观察各支架杆内壁涂层，至少选择3个轴向断面，每个断面上至少选择5个2*2μm的区域进行拍照，然后统一用统计软件测算孔隙面积占所选区域的面积的比值，取该比值的15个平均值作为孔隙率。
8、药物洗脱器械的基体表面含锌保护层覆盖率评估方法：显微镜外观来评估。
以下以30008(标称压力下扩张后外径3mm，长度8mm)、40008(标称压力下扩张后外径4mm，长度8mm)和60008(标称压力下扩张后外径6mm，长度8mm)规格的药物洗脱支架为例，对上述药物洗脱器械及其制备方法进一步阐述。
实施例1
配制PDLLA与西罗莫司的混合溶液，PDLLA与西罗莫司浓度均为6mg/mL，溶剂为丙酮，将该混合溶液涂覆在30008规格的支架的基体的外壁、侧壁和内壁上，干燥后形成包覆于基体的外壁、侧壁和内壁上的药物涂层。其中，基体的材料为纯铁。
测得该批次支架的西罗莫司的含量为2.0μg/mm 2。将多孔尼龙材料制成的芯轴贯穿于支架基体的内壁，然后使该芯轴充分吸附乙醇，充分吸附乙醇后，该芯轴膨胀并与药物涂层的位于内壁的部分接触2min，然后取出该芯轴，并将该支架充分干燥。
取该批次支架，测量该批次支架的最终的西罗莫司的含量为1.5μg/mm 2，较溶剂吸附前的支架的药量减少25％。测得药物涂层的厚度为5μm。用拉曼光谱仪测试显示，药物涂层的位于基体的内壁的部分药物含量比位于外壁的部分药物含量小。测得药物涂层的位于基体的内壁的部分的孔隙率为35％。剥离实验结果显示，该支架经过模拟推送并扩张至爆破压，涂层完整。将该批制备的多个支架分别植入多只兔子的髂动脉中，分时间段取样，测试发现，植入2个月后，支架完全内皮化；植入3个月后，支架质量损失25％；植入1年后，支架的质量损失为50％。
实施例2
配制PDLLA与西罗莫司混合溶液，PDLLA与西罗莫司的浓度分别为4mg/mL和6mg/mL，溶剂为丙酮，将该混合溶液涂覆在在30008规格的支架基体的外壁、侧壁和内壁，干燥后形成包覆于基体的外壁、侧壁和内壁上的药物涂层。其中，基体的材料为纯铁。
测得该批次支架的西罗莫司的含量为2.5μg/mm 2，将多孔尼龙材料包覆于圆柱形芯轴的表面上，并将该芯轴贯穿于支架基体的内壁，然后使多孔尼龙材料充分吸附乙醇，充分吸附乙醇后，该多孔尼龙材料膨胀并与药物涂层的位于内壁的部分接触10min，然后取出该芯轴，并将该支架充分干燥。
取该批次支架，测量该批次支架的最终的西罗莫司的含量为1.5μg/mm 2，较溶剂吸附前的支架的药量减少40％。测得药物涂层厚度为5μm。用拉曼光谱仪测试显示，药物涂层的位于基体的内壁的部分不含有药物。测得药物涂层的位于基体的内壁的部分的孔隙率为55％。剥离实验结果显示，该支架经过模拟推送并扩张至爆破压，涂层完整。将该批制备的多个支架分别植入多只兔子的髂动脉，分时间段取样，测试发现，植入1.5个月后，支架完全内皮化；植入3个月后，支架质量损失20％；植入1年后，支架的质量损失为50％。
实施例3
配制PDLLA与西罗莫司的混合溶液，PDLLA与西罗莫司浓度分别为3mg/mL和6mg/mL，溶剂为丙酮，将该混合溶液涂覆在30008规格的支架基体的外壁、侧壁和内壁，干燥后形成包覆于基体的外壁、侧壁和内壁上的药物涂层。其中，基体的材料为纯铁。基体上设有含锌保护层，含锌保护层覆盖基体的一部分外壁、全部的侧壁以及内壁，含锌保护层的覆盖率为90％，含锌保护层的材料为纯锌。药物涂层覆盖含锌保护层的表面。
测得该批次支架的西罗莫司的含量为2.0μg/mm 2。将多孔聚苯乙烯材料包覆在不锈钢芯轴的表面，将该芯轴贯穿于支架基体的内壁，使多孔聚苯乙烯材料充分吸附乙醇，充分吸附乙醇后，该多孔聚苯乙烯材料膨胀并与药物涂层的位于内壁的部分接触2min，然后取出该芯轴，并将该支架充分干燥。
取该批次支架，测量该批次支架的最终的西罗莫司的含量为1.5μg/mm 2，较溶剂吸附前的支架的药量减少25％。测得药物涂层厚度为4μm。用拉曼光谱仪测试显示，药物涂层的位于基体的内壁的部分药物含量比外壁少。测得药物涂层的位于基体的内壁的部分的孔隙率为45％。剥离实验结果显示，该支架经过模拟推送并扩张至爆破压，涂层完整。将该批制备的多个支架分别植入多只兔子的髂动脉，分时间段取样，测试发现，植入2个月后，支架完全内皮化；植入3个月后，支架刚启动腐蚀；植入1年后，支架的质量损失为40％。
实施例4
配制浓度为4mg/mL的PLLA与5mg/mL的西罗莫司混合溶液，溶剂为四氢呋喃，将该混合溶液涂覆在30008规格的支架基体的外壁、侧壁和内壁上，干燥后形成包覆于基体的药物涂层。其中，基体的材料为碳含量不高于2.11wt.％的铁基合金，基体上设有含锌保护层，含锌保护层仅覆盖基体的侧壁和内壁的全部表面，外壁没有覆盖锌，含锌保护层在基体上的覆盖率为70％，含锌保护层的材料为纯锌。药物涂层覆盖含锌保护层的表面。
测得该批次支架的西罗莫司的含量为5μg/mm 2。将多孔聚苯乙烯材料包覆在不锈钢芯轴的表面，将该芯轴贯穿于支架基体的内壁，使多孔聚苯乙烯材料充分吸附甲醇，充分吸附甲醇后，该多孔聚苯乙烯材料膨胀并与药物涂层的位于内壁的部分接触10s，然后取出该芯轴，并将该支架充分干燥。
取该批次支架，测量该批次支架的最终的西罗莫司的含量为4.5μg/mm 2，较溶剂吸附前支架的药量减少10％。测得药物涂层的厚度为8μm。用拉曼光谱仪测试显示，药物涂层的位于基体的内壁的部分的药物含量比位于外壁的部分的药物含量少。测得药物涂层的位于基体的内壁的部分的孔隙率为15％。剥离实验结果显示，该支架经过模拟推送并扩张至爆破压，涂层完整。将该批制备的多个支架分别植入多只兔子的髂动脉，分时间段取样，测试发现，植入2.5个月后，支架完全内皮化；植入3个月后，支架刚启动腐蚀；植入1年后，支架的质量损失为50％。
实施例5
配制浓度为6mg/mL的PLGA与10mg/mL的西罗莫司混合溶液，溶剂为乙酸乙酯，将该混合溶液均匀喷涂在40008规格的支架基体的外壁、侧壁和内壁，干燥后形成包覆于基体药物涂层。其中基体的材料为碳含量不高于2.11wt.％的铁基合金，基体上设有含锌保护层，含锌保护层覆盖基体的外壁、侧壁和内壁，含锌保护层在基体上的覆盖率为100％，药物涂层覆盖含锌保护层的表面，且药物涂层同时覆盖基体的外壁、侧壁和内壁。含锌保护层的材料为纯锌。
测得该批次支架的西罗莫司的含量为10μg/mm 2。将蘸有乙腈的海绵棒，在基体的内壁旋转前进，均匀擦拭基体的内壁，反复进行，蘸有乙腈的海绵棒与支内壁的接触时间为20min，使蘸有乙腈的海绵棒吸附药物涂层的位于内壁的的部分的西罗莫司，将该支架充分干燥。
取该批次支架，测量该批次支架的最终的西罗莫司的含量为6μg/mm 2，较溶剂吸附前支架的药量减少40％。测得药物涂层厚度为15μm。用拉曼光谱仪测试显示，药物涂层的位于基体的内壁的部分不含有药物。测得药物涂层的位于基体的内壁的部分的孔隙率为60％。剥离实验结果显示，该支架经过模拟推送并扩张至爆破压，涂层完整。将该批制备的多个支架分别植入多只兔子的髂动脉，分时间段取样，测试发现，植入2个月后，支架完全内皮化；植入3个月后，支架未启动腐蚀；植入1年后，支架的质量损失为65％。
实施例6
配制浓度为6mg/mL的结晶性PLLA与0.5mg/mL的紫杉醇混合溶液，溶剂为三氯甲烷，将该混合溶液均匀喷涂在直径为30008规格的支架的基体的外壁、侧壁和内壁上，干燥后形成包覆于基体的外壁、侧壁和内壁上的药物涂层。其中，基体的材料为纯铁。基体上设有含锌保护层，含锌保护层覆盖基体的全部内壁和一部分侧壁，含锌保护层在基体上的覆盖率为60％，含锌保护层的材料为纯锌。药物涂层覆盖含锌保护层的表面。
测得该批次支架的紫杉醇的含量为1μg/mm 2。将蘸有乙酸乙酯的无尘布与基体的内壁接触，接触时间为8min，使乙酸乙酯吸附药物涂层中的位于内壁的部分的药物，将该支架充分干燥。
取该批次支架，测量该批次支架的最终的紫杉醇的含量为0.95μg/mm 2，较溶剂吸附前支架的药量减少5％。测得药物涂层的厚度为10μm。用拉曼光谱仪测试显示，药物涂层的位于基体的内壁的部分的药物含量比位于外壁的部分的药物含量少。测得药物涂层的位于基体的内壁的部分的孔隙率为5％。剥离实验结果显示，该支架经过模拟推送并扩张至爆破压，涂层完整。将该批制备的多个支架分别植入多只兔子的髂动脉，分时间段取样，测试发现，植入2个月后，支架完全内皮化；植入3个月后，支架刚启动腐蚀；植入1年后，支架的质量损失为65％。
实施例7
配制浓度为4mg/mL的PLGA与4mg/mL的西罗莫司衍生物混合溶液，溶剂为乙酸乙酯，将该混合溶液均匀喷涂在直径为30008规格的支架的基体的外壁、侧壁和内壁上，干燥后形成包覆于基体的外壁、侧壁和内壁上的药物涂层。其中，基体的材料为纯铁。
测得该批次支架的西罗莫司衍生物的含量为0.8μg/mm 2。将蘸有异丙醇的聚丙烯无纺布与基体的内壁接触，接触时间为5min，使异丙醇吸附药物涂层中的位于内壁的部分的药物，将该支架充分干燥。
取该批次支架，测量该批次支架的最终的西罗莫司衍生物的含量为0.5μg/mm 2，较溶剂吸附前支架的药量减少38％。测得药物涂层的厚度为2μm。用拉曼光谱仪测试显示，药物涂层的位于基体的内壁的部分不含有药物。测得药物涂层的位于基体的内壁的部分的孔隙率为50％。剥离实验结果显示，该支架经过模拟推送并扩张至爆破压，涂层完整。将该批制备的多个支架分别植入多只兔子的髂动脉，分时间段取样，测试发现，植入1个月后，支架完全内皮化；植入3个月后，支架的质量损失为15％；植入1年后，支架的质量损失为40％。
实施例8
配制浓度为5mg/mL的结晶性PLLA溶液，以及5mg/mL PLLA与1mg/mL的西罗莫司混合溶液，溶剂为三氯甲烷，先将PLLA溶液均匀喷涂在直径为60008规格的支架的基体的外壁、侧壁和内壁上，干燥后形成包覆于基体的外壁、侧壁和内壁上的底层涂层。然后再将PLLA和西罗莫司的混合溶液均匀喷涂在支架表面形成载药涂层，该载药涂层覆盖于底层之上，其中，基体的材料为纯铁。基体上设有含锌保护层，且锌层同时覆盖基体的外壁、侧壁和内壁的表面，含锌保护层在基体上的覆盖率为100％，含锌保护层的材料为纯锌。药物涂层覆盖含锌保护层的表面。
测得该批次支架的西罗莫司的含量为4μg/mm 2。将蘸有乙腈的聚丙烯无纺布与基体的内壁接触，接触时间为15min，使乙腈吸附药物涂层中的位于内壁的部分的药物，将该支架充分干燥。
取该批次支架，测量该批次支架的最终的西罗莫司的含量为3.2μg/mm 2，较溶剂吸附前支架的药量减少20％。测得药物涂层的厚度为20μm。用拉曼光谱仪测试显示，药物涂层的位于基体的内壁的部分的药物含量比位于外壁的部分的药物含量小。测得药物涂层的位于基体的内壁的部分的孔隙率为10％。剥离实验结果显示，该支架经过模拟推送并扩张至爆破压，涂层完整。将该批制备的多个支架分别植入多只兔子的髂动脉，分时间段取样，测试发现，植入2.5个月后，支架完全内皮化；植入3个月后，支架刚启动腐蚀；植入1年后，支架的质量损失为70％。
实施例9
配制浓度为3mg/mL的PLGA与5mg/mL的西罗莫司混合溶液，溶剂为乙酸乙酯，将该混合溶液均匀喷涂在30008规格的支架基体的外壁、侧壁和内壁，干燥后形成包覆于基体药物涂层。其中基体的材料为碳含量不高于2.11wt.％的铁基合金，基体上设有含锌保护层，含锌保护层仅覆盖基体的绝大部分内壁表面，含锌保护层在基体上的覆盖率为20％，含锌保护层的材料为纯锌。药物涂层覆盖含锌保护层的表面。
测得该批次支架的西罗莫司的含量为4μg/mm 2。将蘸有丙醇的海绵棒，在基体的内壁旋转前进，均匀擦拭基体的内壁，反复进行，蘸有丙醇的海绵棒与支内壁的接触时间为15min，使蘸有丙醇的海绵棒吸附药物涂层的位于内壁的部分的西罗莫司，将该支架充分干燥。
取该批次支架，测量该批次支架的最终的西罗莫司的含量为2μg/mm 2，较溶剂吸附前支架的药量减少50％。测得药物涂层厚度为7μm。用拉曼光谱仪测试显示，药物涂层的位于基体的内壁的部分的药物含量比位于外壁的部分的药物含量少。测得药物涂层的位于基体的内壁的部分的孔隙率为60％。剥离实验结果显示，该支架经过模拟推送并扩张至爆破压，涂层完整。将该批制备的多个支架分别植入多只兔子的髂动脉，分时间段取样，测试发现，植入1个月后，支架完全内皮化；植入3个月后，支架刚启动腐蚀；植入1年后，支架的质量 损失为50％。
对比例1
配制浓度分别为6mg/mL的PDLLA与西罗莫司的混合溶液，溶剂为丙酮，将该混合溶液涂覆在30008规格的支架的基体的外壁和侧壁上，干燥后形成仅包覆于基体的外壁和侧壁上的药物涂层，基体的内壁没有被药物涂层所覆盖。其中，基体的材料为纯铁。
取该批次支架，测得该批次的支架上的西罗莫司为1.5μg/mm 2，涂层厚度为5μm。用拉曼光谱仪测试显示，基体的外壁和侧壁上含有药物，内壁没有药物；剥离实验表明，该支架经过模拟推送并扩张至爆破压，涂层明显破损，翘起，出现大面积涂层与基体剥离的现象。将该批制备的多个支架分别植入多只兔子的髂动脉，分时间段取样，测试发现，植入1.5个月后，支架完全内皮化；植入3个月后，支架的质量损失为15％；植入1年后，支架的质量损失为40％。
对比例2
配制浓度分别为4mg/mL和6mg/mL的PDLLA与西罗莫司的混合溶液，溶剂为丙酮，将该混合溶液涂覆在30008规格的支架的基体的外壁、侧壁和内壁上，干燥后形成包覆于基体的外壁、侧壁和内壁上的药物涂层。其中，基体的材料为纯铁。
取该批次支架，测得该批次的支架上的西罗莫司为2.5μg/mm 2，涂层厚度为5μm。用拉曼光谱仪测试显示，药物涂层的位于基体的内壁的部分药物含量与位于外壁的部分药物含量无明显区别。剥离实验结果显示，该支架经过模拟推送并扩张至爆破压，涂层完整。将该批制备的多个支架分别植入多只兔子的髂动脉，分时间段取样，测试发现，植入3个月后，支架完全内皮化，支架的质量损失为28％；植入1年后，支架的质量损失为50％。
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发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。

Claims (17)

  1. 一种药物洗脱器械，包括基体和设置于所述基体上的药物涂层，所述基体具有外壁、侧壁和内壁，其特征在于，所述药物涂层中含有活性药物和药物载体，所述活性药物分散于所述药物载体中，所述药物涂层包覆于所述基体的外壁、侧壁和内壁上，且所述活性药物在所述外壁和所述侧壁上的含量均大于在所述内壁上的含量；或者，所述活性药物仅分布在所述外壁和侧壁上，所述内壁不含有所述活性药物。
  2. 根据权利要求1所述的药物洗脱器械，其特征在于，所述药物涂层的位于所述内壁的部分至少有部分区域为孔隙结构。
  3. 根据权利要求2所述的药物洗脱器械，其特征在于，所述孔隙结构的孔隙率为5％～60％。
  4. 根据权利要求1～3任一项所述的药物洗脱器械，其特征在于，所述药物涂层中，所述活性药物的含量为0.5～6微克/平方毫米。
  5. 根据权利要求1～3任一项所述的药物洗脱器械，其特征在于，所述药物载体为可降解聚合物，所述可降解聚合物选自可降解聚酯和可降解酸酐中的至少一种。
  6. 根据权利要求1～3任一项所述的药物洗脱器械，其特征在于，所述药物涂层的厚度为2～20微米。
  7. 根据权利要求1～3任一项所述的药物洗脱器械，其特征在于，所述药物涂层的位于所述外壁的部分的厚度和所述药物涂层的位于所述侧壁的部分的厚度均大于所述药物涂层的位于所述内壁部分的厚度。
  8. 根据权利要求1～3任一项所述的药物洗脱器械，其特征在于，所述基体的材料为纯铁或铁合金。
  9. 根据权利要求8所述的药物洗脱器械，其特征在于，所述药物洗脱器械还包括含锌保护层，所述含锌保护层设置于所述基体上，所述含锌保护层至少覆盖所述基体的内壁，且所述含锌保护层被所述药物涂层所覆盖。
  10. 根据权利要求8所述的药物洗脱器械，其特征在于，所述含锌保护层在所述基体上的覆盖率为20～100％。
  11. 一种药物洗脱器械的制备方法，其特征在于，包括如下步骤：
    提供基体，所述基体具有外壁、侧壁和内壁；
    将含有活性药物和药物载体的溶液施加在所述基体上形成药物涂层，所述活性药物分散于所述药物载体中，所述药物涂层覆盖于所述基体的外壁、侧壁和内壁上；及，
    用溶剂与所述药物涂层的位于所述内壁的部分接触，使所述药物涂层的位于所述内壁的部分的活性药物部分溶解或完全溶解于所述溶剂中，且所述药物载体不溶于所述溶剂中，并从所述基体上移除所述溶剂。
  12. 根据权利要求11所述的药物洗脱器械的制备方法，其特征在于，所述用溶剂与所述药物涂层的位于所述内壁的部分接触，使所述药物涂层的位于所述内壁的部分的活性药物部分溶解或完全溶解于所述溶剂中，且所述药物载体不溶于所述溶剂中，并从所述基体上移除所述溶剂的步骤包括：
    将吸附有所述溶剂的吸附性材料与所述基体的内壁接触，使所述药物涂层的位于所述内壁的部分的活性药物部分溶解或完全溶解于所述溶剂中，且所述药物载体不溶于所述溶剂中，然后移除所述吸附性材料。
  13. 根据权利要求12所述的药物洗脱器械的制备方法，其特征在于，所述 吸附性材料为尼龙材料、聚丙烯、聚四氟乙烯材料、橡胶类材料或纤维类材料。
  14. 根据权利要求12所述的药物洗脱器械的制备方法，其特征在于，所述将吸附有所述溶剂的吸附性材料与所述基体的内壁接触的时间为10s～20min。
  15. 根据权利要求12所述的药物洗脱器械的制备方法，其特征在于，所述将吸附有所述溶剂的吸附性材料与所述基体的内壁接触，使所述药物涂层的位于所述内壁的部分的活性药物部分溶解或完全溶解于所述溶剂中，且所述药物载体不溶于所述溶剂中，然后移除所述吸附性材料的步骤包括：
    提供芯轴，将所述吸附性材料包覆于所述芯轴的外表面上，然后将包覆有所述吸附性材料的所述芯轴伸入所述基体的内部，并使所述吸附性材料吸附所述溶剂，将所述吸附性材料与所述基体的内壁接触，以使所述药物涂层的位于所述内壁的部分的活性药物部分溶解或完全溶解于所述溶剂中，然后将所述吸附性材料和所述芯轴从所述基体上移除；或者，
    提供芯轴，将所述吸附性材料包覆于所述芯轴的外表面上，使所述吸附性材料吸附所述溶剂，然后将包覆有所述吸附性材料的所述芯轴伸入所述基体的内部，并使所述吸附性材料与所述基体的内壁接触，以使所述活性药物的位于所述内壁的部分的活性药物部分溶解或完全溶解于所述溶剂中，然后将所述吸附性材料和所述芯轴从所述基体上移除；或者，
    提供由所述吸附性材料制成的芯轴，使所述芯轴吸附所述溶剂，然后将所述吸附有所述溶剂的芯轴伸入所述基体的内部，并使所述芯轴与所述基体的内壁接触，以使所述药物涂层的位于所述内壁的部分的活性药物部分溶解或完全溶解于所述溶剂中，然后将所述芯轴从所述基体上移除；或者，
    提供由所述吸附性材料制成的芯轴，将所述芯轴伸入所述基体的内部，使所述芯轴吸附所述溶剂，并使所述芯轴与所述基体的内壁接触，以使所述药物涂层的位于所述内壁的部分的活性药物部分溶解或完全溶解于所述溶剂中，然后将所述芯轴从所述基体上移除；或者，
    将吸附有所述溶剂的吸附性材料在所述基体的内壁上擦拭，以使所述药物涂层的位于所述内壁的部分的活性药物部分溶解或完全溶解于所述溶剂中，然后将所述吸附性材料从所述基体上移除。
  16. 根据权利要求15所述的药物洗脱器械的制备方法，其特征在于，所述吸附有所述溶剂的吸附性材料与所述基体的内壁接触的过程中，所述芯轴或所述基体处于旋转状态。
  17. 根据权利要求15所述的药物洗脱器械的制备方法，其特征在于，所述用溶剂与所述药物涂层的位于所述内壁的部分接触，使所述药物涂层的位于所述内壁的部分的活性药物部分溶解或完全溶解于所述溶剂中，且所述药物载体不溶于所述溶剂中，并从所述基体上移除所述溶剂的步骤后，所述基体的活性药物的含量减少最多达50％。
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