WO2019128767A1 - 植入式载药器械 - Google Patents

植入式载药器械 Download PDF

Info

Publication number
WO2019128767A1
WO2019128767A1 PCT/CN2018/121678 CN2018121678W WO2019128767A1 WO 2019128767 A1 WO2019128767 A1 WO 2019128767A1 CN 2018121678 W CN2018121678 W CN 2018121678W WO 2019128767 A1 WO2019128767 A1 WO 2019128767A1
Authority
WO
WIPO (PCT)
Prior art keywords
stent
word
alloy
pure
vascular
Prior art date
Application number
PCT/CN2018/121678
Other languages
English (en)
French (fr)
Inventor
秦莉
林文娇
刘自强
张德元
Original Assignee
先健科技(深圳)有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 先健科技(深圳)有限公司 filed Critical 先健科技(深圳)有限公司
Priority to EP18897786.2A priority Critical patent/EP3733221B1/en
Priority to US16/957,975 priority patent/US20200330642A1/en
Publication of WO2019128767A1 publication Critical patent/WO2019128767A1/zh

Links

Classifications

    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/02—Inorganic materials
    • A61L27/04—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
    • A61L31/02—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
    • A61L31/08—Materials for coatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • 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
    • 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
    • A61L31/08—Materials for coatings
    • A61L31/10—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • 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
    • 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
    • A61L31/148—Materials at least partially resorbable by the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • 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
    • 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
    • A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
    • A61L2300/102—Metals or metal compounds, e.g. salts such as bicarbonates, carbonates, oxides, zeolites, silicates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/216—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with other specific functional groups, e.g. aldehydes, ketones, phenols, quaternary phosphonium groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/23—Carbohydrates
    • A61L2300/236—Glycosaminoglycans, e.g. heparin, hyaluronic acid, chondroitin
    • 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
    • A61L2300/41—Anti-inflammatory agents, e.g. NSAIDs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/42—Anti-thrombotic agents, anticoagulants, anti-platelet agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/606—Coatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2420/00—Materials or methods for coatings medical devices
    • A61L2420/08—Coatings comprising two or more layers
    • 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
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/30—Materials or treatment for tissue regeneration for muscle reconstruction

Definitions

  • Implantable drug delivery device
  • the invention relates to the field of interventional medical devices, and in particular to an implantable drug-loading device. Background technique
  • the commonly used treatment for stenosis is percutaneous transluminal angioplasty and other interventional procedures, that is, the narrowed lumen is expanded to a normal size by an implantable instrument. Therefore, local injury occurs at the implantation site.
  • the proliferation of smooth muscle cells is the most serious.
  • the smooth muscle hyperplasia gradually slows down and finally stabilizes.
  • the active drug can be loaded on the surface of the implantable device to effectively inhibit cell proliferation in the lesion, and the lumen can be kept patency, and the therapeutic effect is achieved, that is, when the implanted drug-loading device is implanted into the human body, the active drug is released to the device and Absorbed and metabolized by tissues.
  • the active drug accumulated in the tissue reaches a certain threshold, the active drug can exert its effects and inhibit cell proliferation.
  • the device When the device carries the same dose, if the release rate of the active drug is slow, the lower the content of the active drug accumulated in the tissue, the inhibition of cell proliferation around the device; if the release rate of the active drug is faster, the activity accumulated in the tissue The higher the content of the drug, the easier to inhibit the endothelialization of the lumen of the instrument implantation, and even lead to necrosis of normal tissue cells.
  • the release rate of the active drug is constant, the less the amount of the active drug carried, the lower the content of the active drug accumulated in the tissue may result in the inability to effectively inhibit cell proliferation around the device; the more the active drug is carried, The higher the amount of active drug accumulated in the tissue, the more likely it is to inhibit the endothelialization of the lumen of the implanted device, or even kill normal cells, while the active drug is released for a longer period of time and may be more toxic to the tissue. Select the appropriate drug release rate. On the basis of establishing the effective tissue active drug concentration, the smaller the drug loading, the better.
  • Corrosion occurs after implantation in human body. Corrosion products include metal ions and solid products. Studies have shown that the sero-corrosion products released during the erosive process have the effect of inhibiting the proliferation of smooth muscle cells when they reach a certain concentration, and it is concluded that it can reduce the stenosis rate of the tissue surrounding the device. However, if excessive words are released during the etching process, it will kill smooth muscle cells and even endothelial cells and other normal tissues. ⁇ 0 2019/128767 ⁇ (:17(: ⁇ 2018/121678
  • the cells eventually cause tissue ulceration or necrosis at the site of implantation.
  • the implanted drug-loading device can release both the words and the drugs that inhibit the proliferation of vascular tissue, the words and drugs will act together on the vascular tissue to synergistically produce an effect of inhibiting neointimal hyperplasia, if not controlled. It is easy to act too strong and produce toxicity leading to adverse tissue reactions and even tissue necrosis. Therefore, it is necessary to design a reasonable drug release concentration for the drug-containing drug-containing device, so as to ensure that the drug-incorporated drug-loading device can be implanted into the body, thereby synergistically effecting the synergistic effect of the drug to effectively inhibit smooth muscle cell proliferation and maintain lumen patency. The purpose; at the same time, there will be no adverse reactions or even necrosis. Summary of the invention
  • An implantable drug-loading device comprising a substrate containing a word and an active drug layer attached to the substrate containing the word, wherein the content of the active drug in the unit-containing matrix of the unit area is The unit is ⁇ ⁇ 111111 ⁇ 2 , and the content of the word-containing substrate per unit area is etched in a unit of pure aqueous acetic acid solution of 8.3 ⁇ ⁇ 1.% per unit time.
  • the ⁇ and the said satisfy the following relationship:
  • the word-containing substrate is a matrix formed by a word or a word alloy; or the word-containing substrate includes a body and a word-containing portion attached to the body, and the word includes The materials of the Ministry are pure words or alloys.
  • the alloy is an alloy formed with at least one of iron, magnesium, palladium, rhodium, gold, platinum, rhodium, and iridium; or the alloy is rhodium-doped carbon, An alloy formed of at least one of nitrogen, oxygen, sulfur, boron, and silicon.
  • the word-containing substrate when the word-containing substrate includes a body and a word-containing portion attached to the body, and the material of the word-containing part is a pure word or an alloy, the word-containing part is at least Partially covering the surface of the body, or the wording is filled inside the body.
  • the speech-containing substrate comprises a body and attached to the body ⁇ 0 2019/128767 ⁇ (:17(: ⁇ 2018/121678
  • the word-containing portion is characterized in that the material of the word-containing portion is a metal alloy, and when the body is a metal body, the word-containing portion is formed by reacting the metal body with a pure word.
  • the active drug layer is completely The word-containing portion is at least partially covered without covering the word-containing portion or the active drug layer.
  • the active drug layer comprises an active drug and a carrier, the active drug being dispersed in the carrier.
  • the active drug is selected from the group consisting of heparin, colchicine, rapamycin and derivatives thereof, paclitaxel and its derivatives, and at least one of hirudin and derivatives thereof.
  • the carrier is selected from the group consisting of a degradable polymer, a non-degradable polymer, and at least two of a monomer forming the degradable polymer and a monomer forming the non-degradable polymer.
  • the degradable polymer is selected from at least one of polylactic acid, polyglycolic acid, polycaprolactone, polysuccinate, and poly-hydroxybutyrate, and the The degradation polymer is selected from at least one of polystyrene, polytetrafluoroethylene, polymethyl methacrylate, polycarbonate, and polyethylene terephthalate.
  • the body is made of a metal that is a degradable metal or a non-degradable metal.
  • the degradable metal is pure iron, a ferroalloy, a pure magnesium or a magnesium alloy.
  • the non-degradable metal is 3161 ⁇ stainless steel, cobalt chromium alloy, platinum grid alloy, pure Qin or Qin alloy.
  • the body is at least partially made of a polymer selected from the group consisting of a degradable polymer, a non-degradable polymer, and a monomer forming the degradable polymer and forming the non-degradable At least one of a copolymer formed by at least two of the monomers of the polymer;
  • the degradable polymer is selected from the group consisting of polylactic acid, polyglycolic acid, polycaprolactone, polysuccinate, and poly-hydroxybutyl At least one of the acid esters, the non-degradable polymer being selected from at least one of polystyrene, polytetrafluoroethylene, polymethyl methacrylate, polycarbonate, and polyethylene terephthalate.
  • the implantable drug delivery device is a vascular stent, a biliary stent, an esophageal stent, a urethral stent, an airway stent, a male implant, a gynecological implant, or a vena cava filter.
  • the above-mentioned implantable drug-loading device comprises a matrix containing a word and an active drug layer, and the content of the active drug and the matrix of the unit area of the substrate containing the unit area are reasonably set at a level of 8.3 ⁇ 1.%.
  • the content of the etched per unit time in the pure aqueous acetic acid solution matches the release rate and the content of the active drug, so that after the implantable device is implanted into the body, the synergistic effect of the drug and the drug can effectively inhibit smooth muscle cell proliferation, and at the same time Does not kill cells to cause tissue necrosis.
  • FIG. 1 is a schematic view showing the structure of a speech-containing substrate of an implantable drug delivery device according to an embodiment
  • Fig. 2 is a schematic view showing the structure of a speech-containing substrate of the implantable drug delivery device shown in Fig. 1 after heat treatment;
  • Figure 3 is a pathological section view of Example 1;
  • Figure 4 is a pathological section of Comparative Example 1;
  • Figure 5 is a pathological section view of Comparative Example 2. Detailed ways
  • An implantable drug delivery device comprises a substrate containing a word and an active drug layer attached to the substrate containing the word.
  • the base of the speech is a luminal member or other shaped member, such as a member of a vena cava filter structure.
  • the matrix containing the words is a matrix formed of pure or rhodium alloys.
  • the base of the rhetoric is the base of the lumen structure formed by pure words.
  • the alloy is an alloy formed with at least one of iron, magnesium, palladium, rhodium, gold, molybdenum, rhodium, and a chain.
  • the alloy is an alloy formed by doping at least one of carbon, nitrogen, oxygen, sulfur, boron, and silicon.
  • the base of the speech includes a body and a vocabulary on the attached body. ⁇ 0 2019/128767 ⁇ (:17(: ⁇ 2018/121678
  • the shape of the body is a lumen member or other shaped member.
  • the body may be made of a degradable metal or made of a non-degradable metal.
  • the degradable metal may be pure iron, iron alloy, pure magnesium or magnesium alloy
  • the non-degradable metal may be 3161 ⁇ stainless steel, cobalt chromium alloy, platinum chromium alloy, pure titanium or alloy.
  • the body is at least partially made of a polymer.
  • the polymer is selected from at least one of a degradable polymer, a non-degradable polymer, and a copolymer of at least two of a monomer forming a degradable polymer and a monomer forming a non-degradable polymer.
  • the degradable polymer is at least one selected from the group consisting of polylactic acid, polyglycolic acid, polycaprolactone, polysuccinate, and poly-hydroxybutyrate.
  • the non-degradable polymer is selected from at least one of polystyrene, polytetrafluoroethylene, polymethyl methacrylate, polycarbonate, and polyethylene terephthalate.
  • the material of the body is not limited to the materials listed above, and any material capable of providing a certain supporting effect and compatible with the living body can be used for preparing the body.
  • the material with the rhetoric is pure rhetoric or rhetoric alloy.
  • the alloy is an alloy formed with at least one of iron, magnesium, palladium, rhodium, gold, molybdenum, rhodium, and a chain.
  • the alloy is an alloy formed by doping at least one of carbon, nitrogen, oxygen, sulfur, boron, and silicon.
  • the word-bearing part is a layered structure, and may be a continuous layered structure or a discontinuous layered structure, whether it is a continuous layered structure or a discontinuous layered structure, including a word.
  • the thickness can be either a hook or a non-height.
  • the rheme may also be a structure formed by a regular or irregular dot, block, line, strip, or the like, which is scattered on the surface of the body, and is regular or irregular.
  • the block containing the shape of a block, a line, a strip, or the like may be a uniform distribution or a non-homogeneous distribution; a regular or irregular point, block, line, or ribbon that is scattered on the surface of the body.
  • the thickness of the vocabulary of the equal shape may be the same or different.
  • the lexicon at least partially covers the surface of the body.
  • the surface of the body refers to the outer surface, inner surface or side of the body. If the developing structure exists in the body and the developing structure is filled with the developing material, the exposed area of the developing material is also a part of the surface area of the body.
  • the surface of the body at least partially covering the body means that the surface containing the word completely covers the body or the surface containing the part only partially covering the body.
  • the lexicon covers only the outer surface, or only the inner surface, or only the side surface.
  • the lexical portion may be simultaneously disposed on the outer surface, the inner surface or the side surface of the body, but not completely covering the outer surface, the inner surface or the side surface of the body, respectively.
  • the wording is filled inside the body.
  • a recess or a micro-hole is formed in the body, and the alloy is filled in the groove or embedded in the micro-hole to form a word-filled portion filled in the inside of the body.
  • the material containing the word when the matrix containing the word includes the body and the word-containing part attached to the body, and the material containing the word is a pure word or an alloy, the material of the body may not be a pure word or a base alloy;
  • the material may contain words, but the content of the words is small.
  • the iron-based alloy or the magnesium-based alloy may contain a trace amount of rhetoric; the bulk material may also contain no words, such as a polymer body.
  • the active drug layer is a layered structure and may be a continuous layered structure or a discontinuous layered structure.
  • the active drug layer is disposed on the surface of the speech-containing substrate.
  • the base of the speech is a matrix formed of a pure or rhodium alloy
  • the active drug layer completely covers the surface of the matrix containing the speech, or the active drug layer partially covers the surface of the substrate containing the speech.
  • the matrix containing the body includes the body and the vocabulary attached to the body, and the active drug layer is disposed on the body, the active drug layer completely covers the vocabulary or the active drug layer at least partially covers the vocabulary.
  • the active drug layer includes the active drug and the carrier.
  • the active drug is dispersed in a carrier.
  • the active drug is selected from the group consisting of heparin, colchicine, rapamycin and its derivatives, paclitaxel and its derivatives, and at least one of hirudin and its derivatives.
  • the carrier is selected from at least one of a degradable polymer, a non-degradable polymer, and a copolymer formed of at least two of a monomer forming a degradable polymer and a monomer forming a non-degradable polymer.
  • the degradable polymer is selected from the group consisting of polylactic acid, polyglycolic acid, polycaprolactone, polysuccinate, and poly-hydroxybutyrate
  • the non-degradable polymer is selected from the group consisting of polystyrene and poly At least one of tetrafluoroethylene, polymethyl methacrylate, polycarbonate, and polyethylene terephthalate.
  • the carrier is not limited to the above-exemplified substances, and any pharmaceutically acceptable carrier having a film-forming property capable of encapsulating the active drug on the conjugated substrate can be used in the above-mentioned active drug layer.
  • the base body including the body includes the body and the word on the attached body, and the body is a metal body
  • a pure layer may be formed on the surface of the metal body, and then the pure layer and the partial portion of the metal body are formed by heat treatment. Alloying forms the alloy, that is, the wording. As shown in Figure 1, the wording of an embodiment ⁇ 0 2019/128767 ⁇ (:17(: ⁇ 2018/121678
  • the base body 100 includes a metal body 10 and a pure layer 20 covering the outer surface of the metal body 10.
  • the substrate 100 containing the words is alloyed. Comparing Fig. 1 and Fig. 2, after the alloying treatment, the pure layer 20 and a portion of the metal body 10 which is adjacent to the pure layer 20 are alloyed to form the alloy 30.
  • the partial region of the metal body 10 refers to a region extending from the surface of the metal body 10 near the pure layer 20 in the radial direction toward the metal body 10.
  • the content of the active drug in the matrix containing the unit area is ⁇
  • the content of the substrate with a unit area of the word in the 8.3 ⁇ 1.% excellent grade pure acetic acid aqueous solution per unit time is (
  • the values and values are made?
  • the numerical value satisfies the above relationship, and it has been experimentally proved that when the implanted drug-loading device is implanted into the body, the release concentration of the sinus corrosion product and the active drug in the body can be controlled, and the synergistic effect of the drug can achieve the effect of inhibiting smooth muscle cells, so that The lumen has a good stenosis rate without apoptosis or tissue necrosis.
  • the temperature of the 8.3 ⁇ 1.% superior pure acetic acid aqueous solution is 25 ° (3, the corrosion time is 20111 ⁇ 1.
  • the matrix containing the words is a matrix formed by a rhetoric or an alloy
  • the content of the active drug in the matrix of the unit area is ⁇ 111111 ⁇ 2
  • the content of the active drug is ⁇ It means that the content of the active drug in the body per unit area is ⁇ ( ⁇ xg ⁇ mpG 2 ).
  • the surface area of the above-mentioned matrix refers to the total surface area of the matrix containing the words, i.e., the sum of the areas of the outer surface, the inner surface, and the side surfaces.
  • the surface area of the base of the speech is the total surface area of the matrix formed by the pure or rhodium alloy, or the surface area of the matrix containing the speech refers to the total surface area of the body and the rheme.
  • the matrix is formed by a pure or rhetoric alloy or the matrix containing the word is set on the body ⁇ 0 2019/128767 ⁇ (:17(: ⁇ 2018/121678
  • the developing structure is filled with a developer, and the exposed area of the developer is also a part of the total surface area.
  • the reason why the 8.5 ⁇ 1.% superior pure acetic acid aqueous solution is used to corrode the substrate 201?11 containing the refilled drug device at 25 ° ( 3) is as follows. The peak period of the drug release rate and the drug concentration of the tissue appears within 1 month after the device is implanted. It is necessary to ensure that the content of the substrate containing the unit area of the drug-loaded device is corroded within the unit time. Does not cause cell apoptosis and tissue necrosis in the implanted tissue ! ( ⁇ 111111 ⁇ The results of the animal experiment with the drug-loading device indicate that the substrate containing the unit area of the device in the animal body is eroded in the unit time.
  • the content of the substrate in the pure aqueous solution of acetic acid at a concentration of 8.3 ⁇ 1% at 25 ° 0 is almost the same as that of the substrate in a unit of time. Therefore, it can represent the implanted drug in a month. ⁇ ) # ! * ) . Therefore, the test-containing substrate containing the implanted drug-loading device is tested at 25 ° ( 3 concentration of 8.3 ⁇ 1.% acetic acid in water, combined with the unit area of the word-filled drug-loaded device).
  • the active drug content ⁇ on the substrate can be judged whether the tissue-injected drug-loading device is implanted in the body, and whether the tissue will cause apoptosis or tissue necrosis under the synergistic effect of the drug.
  • the unit area of the word-containing substrate in the 8.3 ⁇ ⁇ 1.% of the excellent grade of pure acetic acid in the aqueous solution per unit time of the word content ( ⁇ 111111 ⁇
  • the content of active drug in the matrix of the unit area is ⁇ ( ⁇ ⁇ 111111 ⁇ 2 ), which makes the accumulation of certain sloping products and a certain amount of active drug in the tissue, which can inhibit the proliferation of smooth muscle cells.
  • it does not cause an inflammatory reaction due to excessive concentration of corrosive products and active drugs. Therefore, after the implantable drug-loading device is implanted into the body, the drug synergistically acts to inhibit smooth muscle cell proliferation without causing apoptosis and tissue necrosis.
  • the matrix containing the word is formed by the word-forming alloy or the matrix containing the word includes the body and the word-bearing part formed by the alloy, regardless of the word in the alloy What kind of element is the element, and regardless of the content of the word and the content of the non-lexical element in the alloy, and regardless of the ratio of the amount of the active drug to the carrier in the active drug layer, as long as the non-lexical element in the alloy is on the human body
  • the content of non-toxic elements in non-toxic or harmless alloys is not sufficient to cause toxic effects on human body, and as long as the value of ⁇ is equal to 0.1 15 + ⁇ 3.5; wherein 0.005 0.14, synergy between words and medicines can be achieved. Effectively inhibits smooth muscle cell proliferation, while not killing cells to make tissue bad ⁇ 0 2019/128767 ⁇ (:17(: ⁇ 2018/121678
  • the implantable drug delivery device described above is a vascular stent, a biliary stent, an esophageal stent, a urethral stent, an airway stent, a male implant, a gynecological implant or a vena cava filter.
  • the preparation of the above implantable drug delivery device is prepared by methods well known to those skilled in the art. For example, a substrate formed of a pure or an alloy is prepared by a laser cutting method, and then an active drug layer is formed by a spraying method, dipping or the like. Alternatively, a body formed of a degradable metal or a non-degradable metal or the like is prepared by a laser cutting method, and then a body is formed on the body by electroplating, evaporation, vapor deposition, or the like, and then an active drug layer is prepared.
  • the words are detected by ray photoelectron spectroscopy (abbreviation: ⁇ 8) or scanning electron microscopy (SEM), and the resin is embedded according to the actual position of the words in the substrate of the implanted drug-loading device.
  • ray photoelectron spectroscopy abbreviation: ⁇ 8
  • SEM scanning electron microscopy
  • One or more of three methods of post-grinding, direct sanding, and ion sputtering expose a section of the word-containing portion of the implantable device. Then pass In the intercept An energy dispersive spectrometer is used to detect the composition of the square region to confirm that the region is a constituent element containing the word and the alloy.
  • the size of the base of the word is regular, such as a cylindrical shape
  • the size can be directly measured by macroscopic (square ruler, spiral micrometer) or microscopic test (3D stereomicroscope, SEM) to calculate the surface area. If included
  • Mapping calculates the surface area of the instrument.
  • the corrosion rate of the word-bearing part of the implanted drug-loading device was tested at 25 ° (3, 8.3 ⁇ ⁇ 1.% of the excellent pure acetic acid aqueous solution.
  • the active drug layer of the implanted drug-loading device was eluted. , barely revealing the body or revealing the matrix formed by pure rhetoric or rhetoric alloy, weighed, and then placed the instrument at 25 ° (3, 8.3 ⁇ ⁇ 1.% ⁇ 0 2019/128767 ⁇ (:17(: ⁇ 2018/121678
  • the above-mentioned confirmation and the method of measuring the surface area of the substrate are not limited to the use of the above method, and the measurement of the concentration of the excimer is not limited to the detection using atomic absorption spectroscopy (: 88). In practical applications, the detection may be carried out according to actual conditions using more suitable parameters or methods known to those skilled in the art.
  • the implanted drug-loading device to be tested into a brown glass bottle and add the organic solvent that can dissolve the active drug according to the active drug carried by it.
  • the sample bottle after the volume is placed into the ultrasonic device 20111111, to be ultrasonicized.
  • the extract was aspirated with a syringe, filtered through a 0.22 ⁇ 1111 organic filter, and the extract was filtered into a 21111 ⁇ sample vial as a test sample solution, which was tested using a liquid chromatograph.
  • the model number for the LC is the Agilent 1260.
  • the surface of the ferroalloy vascular stent body is formed on the surface of the ferroalloy vascular stent body by electric post-equalization, and then the rapamycin and polylactic acid are uniformly sprayed on the surface of the stencil layer.
  • the mixture was dried to form a rapamycin-polylactic acid coating on the surface of the enamel layer to obtain a blood vessel stent of the present example.
  • the stencil layer is a vocabulary
  • the ferroalloy vascular stent body and the post-speech layer constitute a matrix containing words. ⁇ 0 2019/128767 ⁇ (:17(: ⁇ 2018/121678
  • the content of rapamycin in the matrix containing the unit area is 11.
  • the measured content per unit area of the substrate is 25 ° (3 8.3 ⁇ 1.% of the excellent grade of pure acetic acid in the aqueous solution per unit time of the content of 0.065 I ⁇ ! 111111 ⁇
  • the vascular stent of this example was implanted into the coronary artery of a miniature pig, and the over-expansion ratio was maintained during the implantation range of 5: 1.1:1 to 1.2:1. They were followed up 3 months after implantation. At the time of follow-up, the vascular stent and its surrounding vascular tissue were taken out, and the surrounding tissues of the vascular stent were pathologically analyzed. The pathological picture is shown in Fig. 3.
  • the results of pathological analysis showed that after the vascular stent provided in Example 1 was implanted into the animal for 3 months, no obvious smooth muscle cell proliferation occurred in the tissue surrounding the stent, the endothelial cells of the vascular tissue grew normally, and there was no tissue necrosis around the stent rod. .
  • the stenosis rate of blood vessels measured by the aforementioned detection method is ⁇ 27% ⁇
  • the body of the pure iron vascular stent having a surface area of 34 6111111 2 is immersed in the plating liquid in half of the length direction, and is plated by electroplating to form a rhodium layer on one half of the surface of the pure iron vascular stent body, and then plated.
  • the pure iron vascular stent body was placed in a vacuum furnace for heat treatment.
  • the pressure in the furnace chamber was 20 ⁇ , and the heat treatment temperature was 300 ° ( 3, the heat treatment time was 311. After heat treatment, the sample was taken out, and the temperature naturally dropped to room temperature.
  • the surface of the body is sprayed with a mixture of rapamycin and polylactic acid, and after drying, a rapamycin-polylactic acid coating is formed on the surface of the stent body to obtain a blood vessel stent of the present embodiment.
  • the iron-iron alloy layer on the surface of the body of the iron-vascular stent, the iron-iron alloy layer is the vocabulary, and the pure iron-vascular stent body and the iron-iron alloy layer form a matrix containing the words.
  • the content of rapamycin in the matrix containing the unit area is measured as
  • the vascular stent of the present embodiment was implanted into the coronary artery of a miniature pig, and the over-expansion ratio was maintained during the implantation range of 5 to 1.1 to 1.2:1. They were followed up 3 months after implantation. At the time of follow-up, the vascular stent and its surrounding vascular tissue were taken out, and the surrounding tissues of the vascular stent were pathologically analyzed. The results of pathological analysis showed that the vascular stent provided in Example 2 was implanted in the animal for 3 months, and the tissue surrounding the stent did not appear obvious. Smooth muscle cell proliferation, vascular tissue endothelial cells grow normally, and there is no tissue around the stent rod ⁇ 0 2019/128767 ⁇ (:17(: ⁇ 2018/121678
  • the stenosis rate of the blood vessel was measured by the aforementioned detection method to be 30%.
  • the surface of the ferroalloy vascular stent body with a surface area of 34.6111111 2 is formed on the surface of the ferroalloy vascular stent body by electric post-homogeneous method.
  • the surface of the stencil layer is sprayed with rapamycin and poly A mixture of lactic acid, after drying, forms a rapamycin-polylactic acid coating on the surface of the enamel layer to obtain a blood vessel stent of the present embodiment.
  • the stencil layer is a vocabulary
  • the ferroalloy vascular stent body and the post-speech layer constitute a matrix containing words.
  • the content of rapamycin in the matrix containing the unit area is 0.5.
  • the vascular stent of this example was implanted into the coronary vessels of miniature pigs, and the over-expansion ratio was maintained during the implantation range of 1.1:1 to 1.2:1. They were followed up 3 months after implantation. At the time of follow-up, the vascular stent and its surrounding vascular tissue were taken out, and the surrounding tissue of the vascular stent was analyzed by pathology. The results showed that the vascular stent provided in Example 3 did not show obvious tissue around the vascular stent after being implanted in the animal for 3 months. Smoothing 5 myocyte proliferation, normal growth of endothelial cells in vascular tissue, and no tissue necrosis around the stent rod. The stenosis rate of the blood vessel was measured by the aforementioned detection method to be 32%.
  • the stencil layer is a vocabulary, and the magnesium alloy vascular stent body and the stencil layer constitute a matrix containing a word.
  • the content of rapamycin in the matrix containing the unit area is 55 1.15.
  • the stent of the present embodiment was implanted into the coronary vessels of a miniature pig, and the over-expansion ratio was maintained in the range of 1.1:1 to 1.2:1 during implantation. They were followed up 3 months after implantation. Remove the stent and its surroundings at the time of follow-up ⁇ 0 2019/128767 ⁇ (:17(: ⁇ 2018/121678
  • vascular tissue pathological analysis of the surrounding tissue of the stent showed that the vascular stent provided in Example 4 had no obvious smooth muscle cell proliferation in the tissues surrounding the stent after implantation in the animal for 3 months, and the endothelial cells of the vascular tissue were normal. Growth, and there is no tissue cell necrosis around the stent rod.
  • the stenosis rate of the blood vessel was measured by the above-described detection method to be 35%.
  • the surface of the 3161 ⁇ stainless steel vascular stent body having a surface area of 34.6111111 2 is electroplated with a layer of iron alloy, wherein the atomic ratio of rhodium to iron is 7:3; and the mixture of paclitaxel and polylactic acid is uniformly sprayed on the layer of iron alloy.
  • the iron alloy layer is a rhodium portion, and the 3161 ⁇ stainless steel stent body and the iron-iron alloy layer constitute a matrix containing a word. 0
  • the content of paclitaxel in the matrix containing the unit area is measured as
  • the measured content per unit area of the substrate is etched at a rate of 0.005 per unit time in a 8.3 ⁇ 1.% excellent pure acetic acid aqueous solution.
  • 111111 ⁇ 15 + ⁇ 0.1 ⁇
  • the vascular stent of this example was implanted into the coronary vessels of miniature pigs, and the over-expansion ratio was maintained during the implantation range of 1.1:1 to 1.2:1. They were followed up 3 months after implantation. At the time of follow-up, the vascular stent and the vascular tissue on the 5th side of the vascular stent were taken out, and the surrounding tissue of the vascular stent was subjected to pathological analysis. The pathological analysis showed that the vascular stent provided in Example 5 was implanted in the animal for 3 months, and the tissue surrounding the stent was not Significant smooth muscle cell proliferation occurred, endothelial cells of vascular tissue grew normally, and there was no tissue necrosis around the stent rod. The stenosis rate of the blood vessel was measured by the aforementioned detection method to be 36%.
  • the surface area of ⁇ is 34.
  • the pure powder is filled in a groove on the surface of the polylactic acid vascular stent body, and then a mixture of rapamycin and polylactic acid is sprayed on the surface of the polylactic acid vascular stent body to form a rapamycin-polylactic acid after drying. Coating, the blood vessel stent of the present embodiment is obtained.
  • the pure powder is filled in the groove of the body of the polylactic acid blood vessel stent to form a speech-containing portion disposed on the body of the polylactic acid blood vessel stent.
  • the vascular stent of the present embodiment is implanted into the coronary artery of a miniature pig, and the over-expansion ratio is maintained during the implantation process. ⁇ 0 2019/128767 ⁇ (:17(: ⁇ 2018/121678
  • the range is 1.1 : 1 to 1.2: 1. They were followed up 3 months after implantation. At the time of follow-up, the vascular stent and its surrounding vascular tissue were taken out, and the surrounding tissues of the vascular stent were subjected to pathological analysis. The results of pathological analysis showed that the vascular stent provided in Example 6 was implanted in the animal for 3 months, and the tissue surrounding the stent did not appear obvious. The smooth muscle cell proliferation phenomenon, the endothelial cells of vascular tissue grow normally, and there is no tissue cell necrosis around the stent rod. The stenosis rate of the blood vessel was measured by the aforementioned detection method to be 33%.
  • a mixture of rapamycin and polylactic acid was uniformly sprayed on the outer surface of the pure vascular stent base surface having a surface area of 34.6111111 2 , and after drying, a rapamycin-polylactic acid coating was formed on the outer surface of the pure stent vascular stent base to obtain The blood vessel stent of this embodiment.
  • the pure vascular stent base is a matrix containing words.
  • the content of rapamycin in the matrix containing the unit area is 1.41.4
  • the measured content of the substrate on the unit area is etched at a temperature of 25 ° (3 8.3 ⁇ 1.% of the excellent pure acetic acid aqueous solution per unit time is 0.035 I ⁇ ! 111111 ⁇
  • the vascular stent of this example was implanted into the coronary vessels of miniature pigs, and the over-expansion ratio was maintained during the implantation range of 1.1:1 to 1.2:1. They were followed up 3 months after implantation. At the time of follow-up, the vascular tissue of the stent and its surrounding tissues were taken out, and the pathological analysis of the surrounding tissue of the stent showed that the vascular stent provided in Example 7 had no obvious smooth muscle cell proliferation after being implanted in the animal for 3 months. The endothelial cells of the vascular tissue grow normally, and there is no tissue cell necrosis around the stent rod. The stenosis rate of the blood vessel was measured by the aforementioned detection method to be 36%.
  • the alloy stent substrate is a matrix containing words.
  • the content of rapamycin in the matrix containing the unit area is 2.32.3
  • the stent of the present embodiment was implanted into the coronary vessels of a miniature pig, and the over-expansion ratio was maintained in the range of 1.1:1 to 1.2:1 during implantation. They were followed up 3 months after implantation. Vascular stent and its circumference were taken at follow-up ⁇ 0 2019/128767 ⁇ (:17(: ⁇ 2018/121678
  • the pathological analysis of the surrounding tissue of the vascular stent showed that the vascular stent provided in Example 8 had no obvious smooth muscle cell proliferation after the stent was implanted for 3 months.
  • the endothelial cells of the tissue grow normally, and there is no tissue necrosis around the stent rod.
  • the stenosis rate of the blood vessel was measured by the aforementioned detection method to be 32%.
  • the surface of the 3161 ⁇ stainless steel vascular stent body having a surface area of 34.6111111 2 is electroplated with a layer of iron alloy, wherein the atomic ratio of rhodium to iron is 7:3; and the mixture of paclitaxel and polylactic acid is uniformly sprayed on the layer of iron alloy.
  • the iron alloy layer is a rhodium portion, and the stainless steel blood vessel stent body and the iron-iron alloy layer constitute a matrix containing a word.
  • the content of paclitaxel in the matrix containing the unit area is measured as
  • the measured content per unit area of the substrate is etched at a rate of 0.005 per unit time at 25 ° (3 of 8.3 ⁇ ⁇ 1.% of excellent pure acetic acid in water).
  • the vascular stent of this comparative example was implanted into the coronary vessels of miniature pigs, and the over-expansion ratio was maintained during the implantation range of 1.1:1 to 1.2:1. They were followed up 3 months after implantation. At the time of follow-up, the vascular stent and its peripheral vascular tissue were taken out, and the surrounding tissues of the vascular stent were analyzed for pathology. The pathological picture is shown in Fig. 4. The results of pathological analysis showed that the vascular stent provided in Comparative Example 1 had no obvious smooth muscle cell proliferation in the tissues surrounding the stent after implantation in the animal for 3 months. The endothelial cells of the vascular tissue grew normally, and there was no tissue necrosis around the stent rod. . The stenosis rate of the blood vessel measured by the aforementioned detection method was 45%, which was significantly higher than that of Example 5.
  • the surface area is 34.
  • the electroplating method is used to form a rhodium plate on the surface of the half-base of the pure iron vascular stent, and then the plated pure iron vascular stent body is placed in a vacuum furnace for heat treatment, and the pressure in the cavity is 20 ⁇ .
  • the heat treatment temperature is 300 ° (3, the heat treatment time is 311, the sample is taken out after heat treatment, the temperature is naturally lowered to room temperature, and a mixture of rapamycin and polylactic acid is sprayed on the surface of the stent body, and dried on the surface of the stent body.
  • the rapamycin-polylactic acid coating is formed on the surface to obtain the blood vessel stent of the present embodiment.
  • the iron-iron alloy layer covering the surface of the pure iron blood vessel stent is formed after the heat treatment, and the iron-iron alloy layer is the rhodium-bearing portion, the pure iron blood vessel.
  • the stent body and the iron-iron alloy layer form a matrix containing the words.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Vascular Medicine (AREA)
  • Surgery (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical & Material Sciences (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Transplantation (AREA)
  • Dermatology (AREA)
  • Materials For Medical Uses (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

一种植入式载药器械，包括含锌的基体和附着于所述含锌的基体上的活性药物层，单位面积的所述含锌的基体中，所述活性药物的含量为ρ(μg·mm -2)，单位面积的所述含锌的基体在8.3vol.％的优级纯醋酸水溶液中单位时间内腐蚀出的锌含量为p(μg·mm -2·min -1)，所述ρ的数值与所述p的数值满足如下关系：0.1≤15p+ρ≤3.5；其中，0.005≤p≤0.14。该植入式载药器械的锌释放速率和活性药物的含量相匹配，使得植入体内后，锌和药协同作用可以有效抑制平滑肌细胞增生，同时不会杀死细胞使组织发生坏死。

Description

\¥0 2019/128767 卩（：17（：\2018/121678
1
植入式载药器械
技术领域
本发明涉及介入式医疗器械领域， 具体涉及一种植入式载药器械。 背景技术
目前， 常用的管腔狭窄治疗手段为经皮腔内管腔成形术等介入治疗手术， 即通过植入式器械将已狭窄管腔扩张到正常大小。 因此植入部位会发生局部损 伤， 在组织修复的关键期， 平滑肌细胞的增生最为严重， 当管腔组织度过修复 关键期后， 平滑肌增生逐渐减慢最后达到稳定。 因此， 可在植入式器械表面负 载活性药物来有效抑制病变部位的细胞增生， 保持管腔通畅， 达到治疗效果， 即当植入式载药器械植入人体后， 活性药物释放至器械周围并被组织吸收、 代 谢。 当组织中积累的活性药物达到某一阈值时， 活性药物才能发挥药效， 起到 抑制细胞增生的作用。 当器械携带同等药量时， 若活性药物的释放速率慢， 则 组织中积累的活性药物的含量越低， 导致无法抑制器械周围细胞增生； 若活性 药物的释放速率越快， 组织中积累的活性药物的含量越高， 容易抑制器械植入 段管腔的内皮化，甚至导致正常组织细胞坏死。 当活性药物的释放速度一定时， 携载的活性药物量越少， 则组织中积累的活性药物的含量越低， 可能导致无法 有效抑制器械周围细胞增生； 携载的的活性药物量越多， 组织中积累的活性药 物的含量越高，也可能导致抑制器械植入段管腔的内皮化，甚至杀死正常细胞， 同时活性药物释放时间更长， 对组织的毒性可能更大。 选择合适的药物释放速 率， 在建立有效组织活性药物浓度的基础上， 载药量越小越好。
辞作为一种生物可腐蚀材料可用于制备完全可吸收器械而逐渐受到人们 的关注， 植入人体后发生腐蚀， 辞腐蚀产物包括金属离子和固体产物。 已有研 究表明， 辞腐蚀过程中释放出的辞腐蚀产物达到一定浓度时具有抑制平滑肌细 胞增生的作用， 从而推断其可以降低器械周围组织的管腔狭窄率。 但是若辞腐 蚀过程中释放出过量的辞， 就会杀死平滑肌细胞甚至内皮细胞和其它正常组织 \¥0 2019/128767 卩（：17（：\2018/121678
2
细胞， 最后导致植入部位的组织溃烂或者坏死。
当植入式载药器械既能释放出辞也能释放出抑制血管组织增生的药物时， 辞和药将会共同作用于血管组织， 协同产生抑制血管新生内膜增生的作用， 如 果不加以控制很容易作用过强而产生毒性导致不良组织反应甚至组织坏死。 因 此， 有必要针对含辞载药器械设计合理的药物释放浓度， 以确保含辞植入式载 药器械植入体内后， 既可以使辞药协同作用达到有效抑制平滑肌细胞增生、 维 持管腔通畅的目的； 同时又不会发生组织不良反应甚至坏死的情况。 发明内容
基于此， 有必要提供一种植入式载药器械， 该植入式载药器械能使组织中 的辞腐蚀产物浓度和活性药物浓度相匹配， 实现抑制平滑肌细胞增生且不产生 毒副作用的目的。
一种植入式载药器械， 包括含辞的基体和附着于所述含辞的基体上的活性 药物层， 单位面积的所述含辞的基体中， 所述活性药物的含量为 ， 所述卩的 单位为 ^ · 111111 ~2, 单位面积的所述含辞的基体在 8.3 ¥〇1.%的优级纯醋酸水溶 液中单位时间内腐蚀出的辞含量为 ，
Figure imgf000004_0001
所述 卩与所述 满足如下关系：
0.1 15 +卩 3.5 ; 其中， 0.005 0.14。
在其中一个实施例中，所述含辞的基体为由辞或辞合金形成的基体；或者， 所述含辞的基体包括本体及附着于所述本体上的含辞部， 且所述含辞部的材料 为纯辞或辞合金。
在其中一个实施例中， 所述辞合金为辞与铁、 镁、 钯、 铼、 金、 铂、 钽及 锶中的至少一种形成的合金； 或者， 所述辞合金为辞掺杂碳、 氮、 氧、 硫、 硼 及娃中的至少一种形成的合金。
在其中一个实施例中， 当所述含辞的基体包括本体及附着于所述本体上的 含辞部， 且所述含辞部的材料为纯辞或辞合金时， 所述含辞部至少部分覆盖所 述本体的表面， 或者所述含辞部填充于所述本体的内部。
在其中一个实施例中， 当所述含辞的基体包括本体及附着于所述本体上的 \¥0 2019/128767 卩（：17（：\2018/121678
3
含辞部， 且所述含辞部的材料为辞合金， 所述本体为金属本体时， 所述含辞部 由所述金属本体与纯辞反应形成。
在其中一个实施例中， 当所述含辞的基体包括本体及附着于所述本体上的 含辞部， 且所述含辞部的材料为纯辞或辞合金时， 所述活性药物层完全不覆盖 所述含辞部或所述活性药物层至少部分覆盖所述含辞部。
在其中一个实施例中， 所述活性药物层包括活性药物和载体， 所述活性药 物分散于所述载体中。
在其中一个实施例中， 所述活性药物选自肝素、 秋水仙素、 雷帕霉素及其 衍生物、 紫杉醇及其衍生物及水蛭素及其衍生物中的至少一种。
在其中一个实施例中， 所述载体选自可降解聚合物、 不可降解聚合物及形 成所述可降解聚合物的单体与形成所述不可降解聚合物的单体中的至少两种 形成的共聚物中的至少一种， 所述可降解聚合物选自聚乳酸、 聚乙醇酸、 聚己 内酯、 聚丁二酸酯及聚 -羟基丁酸酯）中的至少一种， 所述不可降解聚合物选 自聚苯乙烯、 聚四氟乙烯、 聚甲基丙烯酸甲酯、 聚碳酸酯及聚对苯二甲酸乙二 酯中的至少一种。
在其中一个实施例中， 所述本体由金属制成， 所述金属为可降解金属或不 可降解金属。
在其中一个实施例中， 所述可降解金属为纯铁、 铁合金、 纯镁或镁合金。 在其中一个实施例中， 所述不可降解金属为 3161^ 不锈钢、 钴铬合金、 铂 格合金、 纯钦或钦合金。
在其中一个实施例中， 所述本体至少部分由聚合物制成， 所述聚合物选自 可降解聚合物、 不可降解聚合物及形成所述可降解聚合物的单体与形成所述不 可降解聚合物的单体中的至少两种形成的共聚物中的至少一种； 所述可降解聚 合物选自聚乳酸、 聚乙醇酸、 聚己内酯、 聚丁二酸酯及聚 -羟基丁酸酯）中的 至少一种， 所述不可降解聚合物选自聚苯乙烯、 聚四氟乙烯、 聚甲基丙烯酸甲 酯、 聚碳酸酯及聚对苯二甲酸乙二酯中的至少一种。
在其中一个实施例中， 所述植入式载药器械为血管支架、 胆道支架、 食道 支架、 尿道支架、 气道支架、 男科植入物、 妇科植入物或者腔静脉滤器。 \¥0 2019/128767 卩（：17（：\2018/121678
4
上述植入式载药器械包括含辞的基体和活性药物层， 合理地设置单位面积 的含辞的基体中活性药物的含量 及单位面积的含辞的基体在 8.3 ¥〇1.%的优级 纯醋酸水溶液中单位时间内腐蚀出的辞含量 ， 使辞释放速率和活性药物的含 量相匹配， 使得将该植入式器械植入体内后， 辞和药协同作用可以有效抑制平 滑肌细胞增生， 同时不会杀死细胞使组织发生坏死。 附图说明
图 1为一实施方式的植入式载药器械的含辞的基体的结构示意图； 图 2为图 1所示的植入式载药器械的含辞的基体经过热处理后的结构示意 图；
图 3为实施例 1的病理切片图；
图 4为对比例 1的病理切片图；
图 5为对比例 2的病理切片图。 具体实施方式
为了对本发明的技术特征、 目的和效果有更加清楚的理解， 现对照附图详 细说明本发明的具体实施方式， 但本发明保护的范围并不局限于此。
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。
一实施方式的植入式载药器械， 包括含辞的基体和附着于含辞的基体上的 活性药物层。
含辞的基体为管腔构件或其他形状的构件， 如腔静脉滤器结构的构件。 含 辞的基体为由纯辞或辞合金形成的基体。 例如， 含辞的基体为由纯辞形成的管 腔结构的基体。 优选地， 辞合金为辞与铁、 镁、 钯、 铼、 金、 钥、 隹及链中的 至少一种形成的合金。 或者， 辞合金为辞掺杂碳、 氮、 氧、 硫、 硼及硅中的至 少一种形成的合金。
在另外的实施方式中， 含辞的基体包括本体及附着本体上的含辞部。 \¥0 2019/128767 卩（：17（：\2018/121678
5
本体的形状为管腔构件或其他形状的构件。 具体地， 本体可以由可降解金 属制成或由不可降解金属制成。 例如， 可降解金属可以为纯铁、 铁合金、 纯镁 或镁合金， 不可降解金属可以为 3161^ 不锈钢、 钴铬合金、 铂铬合金、 纯钛或 钦合金。
或者， 本体至少部分由聚合物制成。 聚合物选自可降解聚合物、 不可降解 聚合物及形成可降解聚合物的单体与形成不可降解聚合物的单体中的至少两 种形成的共聚物中的至少一种。 其中， 可降解聚合物选自聚乳酸、 聚乙醇酸、 聚己内酯、 聚丁二酸酯及聚 -羟基丁酸酯）中的至少一种。 不可降解聚合物选 自聚苯乙烯、 聚四氟乙烯、 聚甲基丙烯酸甲酯、 聚碳酸酯及聚对苯二甲酸乙二 酯中的至少一种。
可以理解， 本体的材料不限于上述所列举的材料， 任何能够提供一定的支 撑作用且与生物体相容性好的材料均可以用于制备本体。
含辞部的材料为纯辞或辞合金。 优选地， 辞合金为辞与铁、 镁、 钯、 铼、 金、 钥、隹及链中的至少一种形成的合金。 或者， 辞合金为辞掺杂碳、 氮、 氧、 硫、 硼及娃中的至少一种形成的合金。
在一实施方式中， 含辞部为层状结构， 可以为连续的层状结构， 也可以为 不连续的层状结构， 无论是连续的层状结构还是非连续的层状结构， 含辞部的 厚度可以是均勾的也可以非均勾。 含辞部还可以是规则或者不规则的点状、 块 状、 线状、 带状等形状零散地分布在本体的表面上的辞或辞合金形成的结构， 并且， 规则或者不规则的点状、 块状、 线状、 带状等形状的含辞部可以是均匀 分布，也可以是非均勾分布；零散分布于本体表面上的规则或者不规则的点状、 块状、 线状、 带状等形状的含辞部的厚度可以相同， 也可以不同。 含辞部至少 部分覆盖本体的表面。 本体的表面是指本体的外表面、 内表面或侧面。 如本体 存在显影结构， 显影结构内填充有显影物， 则显影物裸露面积也算是本体表面 积的一部分。 含辞部至少部分覆盖本体的表面是指含辞部完全覆盖本体的表面 或含辞部仅部分覆盖本体的表面。 例如， 含辞部仅覆盖外表面， 或仅覆盖内表 面， 或仅覆盖侧面。 或者， 也可以是含辞部同时设置于本体的外表面、 内表面 或侧面上， 但分别不完全覆盖本体的外表面、 内表面或侧面。 \¥0 2019/128767 卩（：17（：\2018/121678
6
在其他实施方式中， 含辞部填充于本体的内部。 例如， 在本体上开设有凹 槽或微孔， 纯辞或辞合金填充于凹槽中或镶嵌于微孔中而形成填充于本体内部 的含辞部。
可以理解， 上述辞合金是指辞的含量占主导的辞基合金。
可以理解， 当含辞的基体包括本体及附着于本体上的含辞部， 且含辞部的 材料为纯辞或辞合金时， 本体的材料可以不是纯辞， 也可以不是辞基合金； 本 体的材料可以含有辞， 但辞的含量较少， 例如铁基合金或镁基合金中可以含有 微量的辞； 本体材料也可以不含有辞， 例如聚合物本体。
活性药物层为层状结构， 可以为连续的层状结构， 也可以为不连续的层状 结构。 活性药物层设置于含辞的基体的表面。 当含辞的基体为由纯辞或辞合金 形成的基体时， 活性药物层完全覆盖含辞的基体的表面， 或活性药物层部分覆 盖含辞的基体的表面。 当含辞的基体包括本体及附着于本体上的含辞部， 且活 性药物层设置于本体上时， 活性药物层完全覆盖含辞部或活性药物层至少部分 覆盖含辞部。
活性药物层包括活性药物和载体。 活性药物分散于载体中。
活性药物选自肝素、 秋水仙素、 雷帕霉素及其衍生物、 紫杉醇及其衍生物 及水蛭素及其衍生物中的至少一种。
优选地， 载体选自可降解聚合物、 不可降解聚合物及形成可降解聚合物的 单体与形成不可降解聚合物的单体中的至少两种形成的共聚物中的至少一种。 其中， 可降解聚合物选自聚乳酸、 聚乙醇酸、 聚己内酯、 聚丁二酸酯及聚 - 羟基丁酸酯）中的至少一种， 不可降解聚合物选自聚苯乙烯、 聚四氟乙烯、 聚甲 基丙烯酸甲酯、 聚碳酸酯及聚对苯二甲酸乙二酯中的至少一种。
可以理解， 载体不限于上述所列举的物质， 任何具有成膜性， 能够使活性 药物包载于含辞的基体上的药学上可接受的载体均可以用于上述活性药物层 中。
当含辞的基体包括本体及附着本体上的含辞部， 且本体为金属本体时， 可 以先在金属本体的表面形成纯辞层， 然后通过热处理的方式使纯辞层与金属本 体的部分区域合金化形成辞合金， 即含辞部。 如图 1所示， 一实施方式的含辞 \¥0 2019/128767 卩（：17（：\2018/121678
7
的基体 100， 包括金属本体 10及覆盖金属本体 10的外表面的纯辞层 20。 对该 含辞的基体 100进行合金化处理。 对比图 1和图 2， 经过合金化处理后， 纯辞 层 20和金属本体 10的靠近纯辞层 20的部分区域合金化形成辞合金 30。 金属 本体 10的部分区域是指自金属本体 10的靠近纯辞层 20的表面沿径向向靠近 金属本体 10的方向延伸的区域。
无论含辞的基体为何种具体结构， 也无论含辞的基体和活性药物层的相对 位置关系如何按上述不同的实施方式进行变化， 当单位面积的含辞的基体中， 活性药物的含量为卩
Figure imgf000009_0001
时， 且单位面积的含辞的基体在 8.3 ¥〇1.%的 优级纯醋酸水溶液中单位时间内腐蚀出的辞含量为 （|^ · 111111 ~
Figure imgf000009_0002
0† , 卩的数值与 的数值满足如下关系：
0.1 15 +卩 3.5 ; 其中， 0.005 0.14。
通过合理地设置植入式载药器械的含辞的基体上的辞含量及活性药物的 含量， 使得 的数值和？的数值满足上述关系， 经实验证明， 当将该植入式载 药器械植入体内时， 能够控制体内的辞腐蚀产物和活性药物的释放浓度， 辞药 协同作用实现抑制平滑肌细胞的效果， 使管腔具有较好的狭窄率， 而不发生细 胞凋亡、 组织坏死的情况。 腐蚀过程中， 8.3 ¥〇1.%的优级纯醋酸水溶液的温度 为 25°（3， 腐蚀时间为 20111^1。
需要说明的是， 上述 0.1 15?+ 3.5 中的 和卩分别是指具体的数值， 计算时不带入单位。
可以理解， 当含辞的基体为由辞或辞合金形成的基体时， 单位面积的含辞 的基体中， 活性药物的含量为卩
Figure imgf000009_0003
111111 ~2） 是指单位面积的由辞或辞合金形 成的基体中， 活性药物
Figure imgf000009_0004
当含辞的基体包括本体及附着 于本体上的含辞部时， 活性药物的含量为卩
Figure imgf000009_0005
是指单位面积的本体 中， 活性药物的含量为卩 （^xg · mpG2）。
上述含辞的基体的表面积是指含辞的基体的总表面积， 即外表面、 内表面 和侧面的面积之和。 含辞的基体的表面积是由纯辞或辞合金形成的基体的总表 面积， 或含辞的基体的表面积是指本体和含辞部的总表面积。
需要说明的是， 如果由纯辞或辞合金形成基体或含辞的基体是本体上设置 \¥0 2019/128767 卩（：17（：\2018/121678
8
有显影结构， 且显影结构内填充有显影物， 则显影物裸露面积也算是总表面积 的一部分。
需要说明的是，之所以选取在 25°(3的 8.3 ¥〇1.%的优级纯醋酸水溶液腐蚀含 辞载药器械的含辞的基体 201^11的原因如下， 目前市售的载药器械， 药物释放 率和组织药物浓度的峰值期都出现在器械植入后的 1个月内， 要保证含辞载药 器械的单位面积的含辞的基体在单位时间内腐蚀出的辞含量为不会使植入段 组织出现细胞调亡和组织坏死的 体! ( · 111111 ~
Figure imgf000010_0001
含辞载药器械动物 实验结果表明， 动物体内器械单位面积的含辞的基体在单位时间内腐蚀出的辞 含量 体内
Figure imgf000010_0002
与在 25°0浓度为 8.3 〇1.%的优级纯醋酸水溶液 中含辞的基体在单位时间内腐蚀出的辞含量 相差无几， 因此， 可以代表含 辞载药器械植入体内一个月内的^) # !*)。 所以测试含辞植入式载药器械的含辞的 基体在 25°(3浓度为 8.3 ¥〇1.%醋酸水溶液中的 ， 再结合含辞植入式载药器械的 单位面积的含辞的基体上的活性药物含量 ø就可以判断此植入式载药器械植入 体内后， 组织在辞药协同作用下是否会产生细胞凋亡、 组织坏死的情况。
通过合理地控制单位面积的含辞的基体在 8.3 ¥〇1.%的优级纯醋酸水溶液 中单位时间内腐蚀出的辞含量 ( · 111111 ~
Figure imgf000010_0003
与单位面积的含辞的基体 中的活性药物含量卩 ( ^ · 111111 ~2) , 使得组织中积累一定的辞腐蚀产物和一定量 的活性药物浓度， 即能够对平滑肌细胞起到抑制增生的作用， 但又不至于因辞 腐蚀产物和活性药物的浓度过高而引起炎性反应。 因此， 在将上述植入式载药 器械植入体内后， 辞药协同作用， 起到抑制平滑肌细胞增生的作用， 而不产生 细胞凋亡和组织坏死。
需要说明的是， 上述植入式载药器械中， 当含辞的基体是由辞合金形成基 体或含辞的基体包括本体和由辞合金形成的含辞部时， 无论辞合金中的非辞元 素为何种元素， 也无论辞合金中辞的含量与非辞元素的含量是多少， 也无论活 性药物层中活性药物与载体的量的配比为多少， 只要辞合金中的非辞元素对人 体无毒无害或辞合金中的非辞元素的含量不足以对人体产生毒害作用， 且只要 卩的数值与 的数值满足 0.1 15 +卩 3.5 ; 其中， 0.005 0.14， 就能实现 辞和药协同作用而有效抑制平滑肌细胞增生， 同时不会杀死细胞使组织发生坏 \¥0 2019/128767 卩（：17（：\2018/121678
9
死的效果。
上述植入式载药器械为血管支架、 胆道支架、 食道支架、 尿道支架、 气道 支架、 男科植入物、 妇科植入物或者腔静脉滤器。
上述植入式载药器械的制备采用本领域技术人员熟知的方法制备。 例如， 采用激光切割的方法制备由纯辞或辞合金形成的基体， 然后采用喷雾法、 浸渍 等方法形成活性药物层。 或者， 采用激光切割的方法制备由可降解金属或不可 降解金属等管材形成的本体， 然后采用电镀法、 蒸镀法、 气相沉积等方法在本 体上形成含辞部， 然后再制备活性药物层。
以下通过具体实施例对上述植入式载药器械进一步阐述。
以下实施例采用如下检测方法：
1、 植入式载药器械中的辞的确认
通过 射线光电子能谱 （简称： 卩8） 或扫描电镜 （简称： SEM） 对辞进 行检测， 根据植入式载药器械的含辞的基体中的辞在器械中的实际位置， 通过 树脂包埋后打磨、 直接打磨、 离子溅射这三种方法中的一种或几种， 露出植入 式器械的含辞的部位的一个截面。 然后通
Figure imgf000011_0001
在该截
Figure imgf000011_0002
附件一能量色散谱仪检测 该正方形区域的成分， 以确认此区域为含有辞以及辞合金的组成元素。
Figure imgf000011_0003
为日本电子株式会社的 JSM6510型扫描电镜。
2、 含辞的基体的表面积的检测
若含辞的基体形状规则， 如圆柱形， 则可以直接通过宏观（直尺、 螺旋测微 器）或者微观测试（三维体式显微镜、 SEM）手段检测尺寸， 计算表面积。 若含辞
Figure imgf000011_0004
测绘计算器械的表面积。
3、 植入式载药器械的辞的腐蚀速度检测
将植入式载药器械的含辞部的腐蚀速度在 25°（3、 8.3 ¥〇1.%的优级纯醋酸水 溶液中测试。 首先将植入式载药器械的活性药物层进行洗脱， 裸露出含辞部或 裸露出由纯辞或辞合金形成的基体，称重后，然后将器械放置在 25°（3、8.3 ¥〇1.% \¥0 2019/128767 卩（：17（：\2018/121678
10
的优级纯醋酸水溶液中 20111111, 将器械取出后， 取定量体积醋酸溶液定容后， 进行消解。 用安捷伦 8 6 八八240 8型原子吸收光谱（: ^8）测试腐蚀液中的辞 离子浓度， 通过计算得到此时溶液中的辞含量， 即为含辞部或由纯辞或辞合金 形成的基体的辞失重， 再除以器械的表面积和腐蚀时间得到单位面积的含辞的 5 基体在 8.3 ¥〇1.%的优级纯醋酸水溶液中单位时间内腐蚀出的辞含量 。
以上辞的确认和含辞的基体表面积的测量方法不限于使用上述方法， 辞离 子浓度的测定也不限于使用原子吸收光谱（:八八8）进行检测。 实际应用时， 可根 据实际情况采用本领域技术人员知悉的更合适的参数或方法进行检测。
4、 植入式载药器械中的活性药物的检测
0 将待测植入式载药器械放入棕色玻璃瓶中， 按照其携载的活性药物定量加 入可溶解该活性药物的有机溶剂， 定容后的样品瓶放入超声波仪超声 20111111, 待超声好的样品瓶恢复室温后， 用注射器吸取萃取液， 使用 0.22^1111 的有机过 滤头过滤， 将萃取液过滤至 21111^的进样瓶中， 作为测试样品液， 使用液相色谱 仪进行测试。
5 液相色谱的型号为安捷伦 1260。
5、 植入式载药器械周围组织中的狭窄率检测和病理观察
通过动物植入实验确认植入式载药器械周围组织中的狭窄率。 以血管支架 为例， 具体包括以下步骤： 将血管支架植入试验动物的血管中。 然后在预定观 察时间点， 例如， 1和 3个月， 取出支架段血管进行固定、 包埋、 切片以及染 〇 色后制成病理切片，使用德国 1^1〇八公司的 DM2500型显微镜观察组织病理， 并测量支架段血管所在截面的管腔面积及原始管腔面积。 则， 管腔狭窄率 =（原 始管腔面积 -现有管腔面积） /原始管腔面积 X 100%。
实施例 1
在表面积为 34.61111112的铁合金血管支架本体的表面， 采用电後法均匀地後5 辞从而在铁合金血管支架本体的表面形成辞镀层， 然后在辞镀层的表面均匀喷 涂雷帕霉素和聚乳酸的混合物，干燥后在辞镀层表面形成雷帕霉素-聚乳酸涂层， 得到本实施例的血管支架。 本实施例中辞镀层即为含辞部， 铁合金血管支架本 体和辞後层组成含辞的基体。 \¥0 2019/128767 卩（：17（：\2018/121678
11
通过前述的检测方法， 测得单位面积的含辞的基体中雷帕霉素的含量卩为 1 .4
Figure imgf000013_0001
测得单位面积上的含辞的基体在 25°(3的 8.3 ¥〇1.%的优级纯醋酸 水溶液中单位时间内腐蚀出的辞含量 为 0.065 I·! 111111 ~
Figure imgf000013_0002
将本实施例中的血管支架植入小型猪的冠脉血管， 植入过程中保持过扩比 5 范围为 1.1 : 1至 1.2: 1。 然后在植入后 3个月随访。 随访时取出血管支架及其周 边的血管组织， 对血管支架的周围组织进行病理分析， 病理图片如图 3 所示。 病理分析结果显示， 实施例 1提供的血管支架在植入动物体内 3个月后， 支架 周围组织未发生明显的平滑肌细胞增生现象， 血管组织的内皮细胞正常生长， 且支架杆周围没有组织细胞坏死。 通过前述的检测方法测得血管的狭窄率为 〇 27%〇
实施例 2
将表面积为 34 61111112的纯铁血管支架本体沿长度的方向的一半浸入到镀辞 液中， 采用电镀法均勾地镀辞从而在纯铁血管支架本体的一半表面形成辞镀层， 然后将镀辞后的纯铁血管支架本体放在真空炉中进行热处理，炉腔压力为 20卩 ，5 热处理温度为 300°(3， 热处理时间为 311， 热处理完取出样品， 温度自然降至室 温， 在支架本体表面进行均勾喷涂雷帕霉素和聚乳酸的混合物， 干燥后在支架 本体表面形成雷帕霉素-聚乳酸涂层， 得到本实施例的血管支架。 本实施例中热 处理后形成覆盖纯铁血管支架本体表面的辞铁合金层， 辞铁合金层即为含辞部， 纯铁血管支架本体与辞铁合金层形成含辞的基体。
0 通过前述的检测方法， 测得单位面积的含辞的基体中雷帕霉素的含量卩为
2.3
Figure imgf000013_0003
测得单位面积上的含辞的基体在 25°(3的 8.3 ¥〇1.%的优级纯醋酸 水溶液中单位时间内单位内腐蚀出的辞含量 为 0.005 I·! · 111111 ~2
Figure imgf000013_0004
， 15 + 卩 =2.375。
将本实施例中的血管支架植入小型猪的冠脉血管， 植入过程中保持过扩比5 范围为 1 .1 : 1至 1.2: 1。 然后在植入后 3个月随访。 随访时取出血管支架及其周 边的血管组织， 对血管支架的周围组织进行病理分析， 病理分析结果显示， 实 施例 2提供的血管支架在植入动物体内 3个月后， 支架周围组织未发生明显的 平滑肌细胞增生现象， 血管组织的内皮细胞正常生长， 且支架杆周围没有组织 \¥0 2019/128767 卩（：17（：\2018/121678
12
细胞坏死。 通过前述的检测方法测得血管的狭窄率为 30%。
实施例 3
在表面积为 34.61111112的铁合金血管支架本体的表面， 采用电後法均匀地後 辞从而在铁合金血管支架本体的表面形成辞镀层， 最后在辞镀层的表面进行均 5 勾喷涂雷帕霉素和聚乳酸的混合物，干燥后在辞镀层表面形成雷帕霉素-聚乳酸 涂层， 得到本实施例的血管支架。 本实施例中辞镀层即为含辞部， 铁合金血管 支架本体和辞後层组成含辞的基体。
通过前述的检测方法， 测得单位面积的含辞的基体中雷帕霉素的含量卩为 0.5
Figure imgf000014_0001
测得单位面积上的含辞的基体在 25°(3的 8.3 ¥〇1.%的优级纯醋酸 〇 水溶液中单位时间内腐蚀出的辞含量 为 0.14
Figure imgf000014_0002
15 +卩=2.6。
将本实施例中的血管支架植入小型猪的冠脉血管， 植入过程中保持过扩比 范围为 1.1 : 1至 1.2: 1。 然后在植入后 3个月随访。 随访时取出血管支架及其周 边的血管组织， 对血管支架的周围组织进行病理分析， 结果显示， 实施例 3提 供的血管支架在植入动物体内 3个月后， 血管支架周围组织未发生明显的平滑5 肌细胞增生现象， 血管组织的内皮细胞正常生长， 且支架杆周围没有组织细胞 坏死。 通过前述的检测方法测得血管的狭窄率为 32%。
实施例 4
将表面积为 34.61111112的镁合金血管支架本体长度的方向的一半浸入到後辞 液中， 采用电镀法均勾地镀辞从而在镁合金血管支架本体的一半表面形成辞镀0 层， 然后对辞镀层进行遮挡后， 在镁合金血管支架本体表面均勾喷涂雷帕霉素 和聚乳酸的混合物，干燥后在镁合金血管支架本体表面形成雷帕霉素-聚乳酸涂 层，使得辞镀层和雷帕霉素 -聚乳酸涂层无交叠区域，得到本实施例的血管支架。 本实施例中辞镀层即为含辞部， 镁合金血管支架本体和辞镀层组成含辞的基体。
通过前述的检测方法， 测得单位面积的含辞的基体中雷帕霉素的含量卩为5 1.15
Figure imgf000014_0003
测得单位面积上的含辞的基体在 25°(3的 8.3 ¥〇1.%的优级纯醋 酸水溶液中单位时间内腐蚀出的辞含量为 0.1 I·! · 111111
Figure imgf000014_0004
15 +卩 =2.65。
将本实施例中的血管支架植入小型猪的冠脉血管， 植入过程中保持过扩比 范围为 1.1 : 1至 1.2: 1。 然后在植入后 3个月随访。 随访时取出支架及其周边的 \¥0 2019/128767 卩（：17（：\2018/121678
13
血管组织， 对支架的周围组织进行病理分析， 结果显示， 实施例 4提供的血管 支架在植入动物体内 3个月后， 支架周围组织未发生明显的平滑肌细胞增生现 象， 血管组织的内皮细胞正常生长， 且支架杆周围没有组织细胞坏死。 通过前 述的检测方法测得血管的狭窄率为 35%。
5 实施例 5
在表面积为 34.61111112的 3161^不锈钢血管支架本体的表面电镀辞铁合金层， 其中， 辞铁合金层中辞和铁的原子比为 7:3 ; 再将紫杉醇和聚乳酸混合物均匀 地喷涂在辞铁合金层上， 干燥后得到本实施例的血管支架， 本实施例中辞铁合 金层即为含辞部， 3161^不锈钢血管支架本体和辞铁合金层组成含辞的基体。0 通过前述的检测方法， 测得单位面积的含辞的基体中紫杉醇的含量卩为
0.025 ^ · 111111 ~2, 测得单位面积的含辞的基体在 8.3 ¥〇1.%的优级纯醋酸水溶液 中单位时间内腐蚀出的辞含量 为 0.005
Figure imgf000015_0002
111111 ~
Figure imgf000015_0001
15 +卩 =0.1〇
将本实施例中的血管支架植入小型猪的冠脉血管， 植入过程中保持过扩比 范围为 1.1 : 1至 1.2: 1。 然后在植入后 3个月随访。 随访时取出血管支架及其周5 边的血管组织， 对血管支架的周围组织进行病理分析， 病理分析结果显示， 实 施例 5提供的血管支架在植入动物体内 3个月后， 支架周围组织未发生明显的 平滑肌细胞增生现象， 血管组织的内皮细胞正常生长， 且支架杆周围没有组织 细胞坏死。 通过前述的检测方法测得血管的狭窄率为 36%。
实施例 6
〇 表面积为 34.
Figure imgf000015_0003
将纯辞粉末 填充在聚乳酸血管支架本体表面的凹槽中， 然后在聚乳酸血管支架本体的表面 进行均勾喷涂雷帕霉素和聚乳酸的混合物， 干燥后形成雷帕霉素-聚乳酸涂层， 得到本实施例的血管支架， 本实施例中纯辞粉填充于聚乳酸血管支架本体的凹 槽中形成设置于聚乳酸血管支架本体上的含辞部。
5 通过前述的检测方法， 测得单位面积的含辞基体中雷帕霉素的含量卩为
Figure imgf000015_0004
测得单位面积上的含辞的基体在 8.3 ¥〇1.%的优级纯醋酸水溶 液中单位时间内腐蚀出的辞含量 为 0.12 I·! · 111111 ~
Figure imgf000015_0005
15 +卩 =2.49。
将本实施例中的血管支架植入小型猪的冠脉血管， 植入过程中保持过扩比 \¥0 2019/128767 卩（：17（：\2018/121678
14
范围为 1.1 : 1至 1.2: 1。 然后在植入后 3个月随访。 随访时取出血管支架及其周 边的血管组织， 对血管支架的周围组织进行病理分析， 病理分析结果显示， 实 施例 6提供的血管支架在植入动物体内 3个月后， 支架周围组织未发生明显的 平滑肌细胞增生现象， 血管组织的内皮细胞正常生长， 且支架杆周围没有组织 细胞坏死。 通过前述的检测方法测得血管的狭窄率为 33%。
实施例 7
在表面积为 34.61111112的纯辞血管支架基体的外表面均匀喷涂雷帕霉素和聚 乳酸的混合物，干燥后在纯辞支架血管支架基体的外表面形成雷帕霉素-聚乳酸 涂层， 得到本实施例的血管支架。 本实施例中纯辞血管支架基体即为含辞的基 体。
通过前述的检测方法， 测得单位面积的含辞的基体中雷帕霉素的含量卩为 1.4
Figure imgf000016_0001
测得单位面积上的含辞的基体在 25°(3的 8.3 ¥〇1.%的优级纯醋酸 水溶液中单位时间内腐蚀出的辞含量 为 0.035 I·! 111111 ~
Figure imgf000016_0002
将本实施例中的血管支架植入小型猪的冠脉血管， 植入过程中保持过扩比 范围为 1.1 : 1至 1.2: 1。 然后在植入后 3个月随访。 随访时取出支架及其周边的 血管组织， 对支架的周围组织进行病理分析显示， 实施例 7提供的血管支架在 植入动物体内 3个月后， 支架周围组织未发生明显的平滑肌细胞增生现象， 血 管组织的内皮细胞正常生长， 且支架杆周围没有组织细胞坏死。 通过前述的检 测方法测得血管的狭窄率为 36%。
实施例 8
在表面积为 34.61111112的辞合金血管支架基体的表面均匀喷涂雷帕霉素和聚 乳酸的混合物， 干燥后在辞合金支架基体表面形成雷帕霉素-聚乳酸涂层， 得到 本实施例的血管支架。 本实施例中辞合金支架基体即为含辞的基体。
通过前述的检测方法， 测得单位面积的含辞的基体中雷帕霉素的含量卩为 2.3
Figure imgf000016_0003
测得单位面积上的含辞的基体在 25°(3的 8.3 ¥〇1.%的优级纯醋酸 水溶液中单位时间内腐蚀出的辞含量 为 0.08 I·! · 111111
Figure imgf000016_0004
15 +卩 =3.5。
将本实施例中的血管支架植入小型猪的冠脉血管， 植入过程中保持过扩比 范围为 1.1 : 1至 1.2: 1。 然后在植入后 3个月随访。 随访时取出血管支架及其周 \¥0 2019/128767 卩（：17（：\2018/121678
15
边的血管组织， 对血管支架的周围组织进行病理分析， 病理分析结果显示， 实 施例 8提供的血管支架在植入动物体内 3个月后， 支架周围组织未发生明显的 平滑肌细胞增生现象， 血管组织的内皮细胞正常生长， 且支架杆周围没有组织 细胞坏死。 通过前述的检测方法测得血管的狭窄率为 32%。
对比例 1
在表面积为 34.61111112的 3161^不锈钢血管支架本体的表面电镀辞铁合金层， 其中， 辞铁合金层中辞和铁的原子比为 7:3 ; 再将紫杉醇和聚乳酸混合物均匀 地喷涂在辞铁合金层上， 干燥后得到本实施例的血管支架， 本实施例中辞铁合 金层即为含辞部， 不锈钢血管支架本体和辞铁合金层组成含辞的基体。
通过前述的检测方法， 测得单位面积的含辞的基体中紫杉醇的含量卩为
0.01
Figure imgf000017_0001
测得单位面积的含辞的基体在 25°(3的 8.3 ¥〇1.%的优级纯醋酸 水溶液中单位时间内腐蚀出的辞含量 为 0.005
Figure imgf000017_0002
将本对比例中的血管支架植入小型猪的冠脉血管， 植入过程中保持过扩比 范围为 1.1 : 1至 1.2: 1。 然后在植入后 3个月随访。 随访时取出血管支架及其周 边的血管组织， 对血管支架的周围组织进行病理分析， 病理图片如图 4 所示。 病理分析结果显示， 对比例 1提供的血管支架在植入动物体内 3个月后， 支架 周围组织未发生明显的平滑肌细胞增生现象， 血管组织的内皮细胞正常生长， 且支架杆周围没有组织细胞坏死。 通过前述的检测方法测得血管的狭窄率为 45%, 明显高于实施例 5的狭窄率。
对比例 2
在表面积为 34.
Figure imgf000017_0003
液中， 采用电镀法均勾地镀辞从而在纯铁血管支架一半基体的表面形成辞镀层， 然后将镀辞后的纯铁血管支架本体放在真空炉中进行热处理，炉腔压力为 20卩 ， 热处理温度为 300°(3， 热处理时间为 311， 热处理完取出样品， 温度自然降至室 温， 在支架本体表面进行均勾喷涂雷帕霉素和聚乳酸的混合物， 干燥后在支架 本体表面的表面形成雷帕霉素-聚乳酸涂层， 得到本实施例的血管支架。 本实施 例中热处理后形成覆盖纯铁血管支架表面的辞铁合金层， 辞铁合金层即为含辞 部， 纯铁血管支架本体与辞铁合金层形成含辞的基体。

Claims

\¥0 2019/128767 卩（：17（：\2018/121678 16 通过前述的检测方法， 测得单位面积的含辞的基体中雷帕霉素的含量卩为 3.6 测得单位面积上的含辞的基体在 25°(3的 8.3 ¥〇1.%的优级纯醋酸 水溶液中单位时间内腐蚀出的辞含量 为 0.005 I·! 111111 ~ 将本对比例中的血管支架植入小型猪的冠脉血管， 植入过程中保持过扩比 5 范围为 1.1 : 1至 1.2: 1。 然后在植入后 1个月随访。 随访时取出血管支架及其周 边的血管组织， 对血管支架的周围组织进行病理分析， 病理图片如图 5 所示。 病理分析结果显示， 对比例 2的血管支架植入 1个月后， 支架杆周围出现明显 的内膜细胞增生， 支架所在血管出现明显的管腔狭窄， 且支架杆周围产生明显 的炎性细胞。 〇 结果表明， 与实施例 2提供的血管支架相比， 对比例 2的血管支架由于药 物携载过多， 导致支架周围组织中的细胞坏死。 对比例 3 在表面积为 34.61111112的铁合金血管支架本体的表面， 采用电後法均匀地後 辞从而在铁合金血管支架基体的表面形成辞镀层， 最后在辞镀层的表面进行均5 勾喷涂雷帕霉素和聚乳酸的混合物，干燥后在辞镀层表面形成雷帕霉素-聚乳酸 涂层， 得到本实施例的血管支架。 本实施例中辞镀层即为含辞部， 铁合金血管 支架本体和辞後层形成含辞的基体。 通过前述的检测方法， 测得单位面积上的含辞的基体中雷帕霉素的含量卩 为 0.5 测得单位面积上的含辞的基体在 25°(3的 8.3 〇1.%的优级纯0 醋酸水溶液中单位时间内腐蚀出的辞含量 为 0.22 I·! · 111111 ~ 15 +卩=3.8〇 将本对比例中的血管支架植入小型猪的冠脉血管， 植入过程中保持过扩比 范围为 1.1 : 1至 1.2: 1。 然后在植入后 1个月随访。 随访时取出血管支架及其周 边的血管组织， 对血管支架的周围组织进行病理分析， 结果显示， 对比例 3的5 血管支架植入 1个月后， 支架杆周围出现明显的内膜细胞增生， 支架所在血管 出现明显的管腔狭窄， 且支架杆周围产生明显的炎性细胞。 结果表明， 与实施例 3提供的血管支架相比， 对比例 3的血管支架由于含 辞部腐蚀速度过快， 导致支架周围组织中的细胞坏死。 \¥0 2019/128767 卩（：17（：\2018/121678 17 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。 \¥0 2019/128767 卩（：17（：\2018/121678 18 权利要求书
1、 一种植入式载药器械， 包括含辞的基体和附着于所述含辞的基体上的 活性药物层， 其特征在于， 单位面积的所述含辞的基体中， 所述活性药物的含 量为 ，
Figure imgf000020_0001
单位面积的所述含辞的基体在 8.3 ¥〇1.%的 优级纯醋酸水溶液中单位时间内腐蚀出的辞含量为 ， 所述 的单位为
Figure imgf000020_0002
0.1 15 +卩 3.5 ; 其中， 0.005 0.14。
2、 根据权利要求 1 所述的植入式载药器械， 其特征在于， 所述含辞的基 体为由辞或辞合金形成的基体； 或者， 所述含辞的基体包括本体及附着于所述 本体上的含辞部， 且所述含辞部的材料为纯辞或辞合金。
3、 根据权利要求 2 所述的植入式载药器械， 其特征在于， 所述辞合金为 辞与铁、 镁、 钯、 铼、 金、 钥、 隹及链中的至少一种形成的合金； 或者， 所述 辞合金为辞掺杂碳、 氮、 氧、 硫、 硼及硅中的至少一种形成的合金。
4、 根据权利要求 2 所述的植入式载药器械， 其特征在于， 当所述含辞的 基体包括本体及附着于所述本体上的含辞部， 且所述含辞部的材料为纯辞或辞 合金时， 所述含辞部至少部分覆盖所述本体的表面， 或者所述含辞部填充于所 述本体的内部。
5、 根据权利要求 2 所述的植入式载药器械， 其特征在于， 当所述含辞的 基体包括本体及附着于所述本体上的含辞部， 且所述含辞部的材料为辞合金， 所述本体为金属本体时， 所述含辞部由所述金属本体与纯辞反应形成。
6、 根据权利要求 2 所述的植入式载药器械， 其特征在于， 当所述含辞的 基体包括本体及附着于所述本体上的含辞部， 且所述含辞部的材料为纯辞或辞 合金时， 所述活性药物层完全不覆盖所述含辞部或所述活性药物层至少部分覆 盖所述含辞部。
7、 根据权利要求 1 所述的植入式载药器械， 其特征在于， 所述活性药物 层包括活性药物和载体， 所述活性药物分散于所述载体中。
8、 根据权利要求 7 所述的植入式载药器械， 其特征在于， 所述活性药物 选自肝素、 秋水仙素、 雷帕霉素及其衍生物、 紫杉醇及其衍生物及水蛭素及其 \¥0 2019/128767 卩（：17（：\2018/121678
19
衍生物中的至少一种。
9、 根据权利要求 7 所述的植入式载药器械， 其特征在于， 所述载体选自 可降解聚合物、 不可降解聚合物及形成所述可降解聚合物的单体与形成所述不 可降解聚合物的单体中的至少两种形成的共聚物中的至少一种， 所述可降解聚
5 合物选自聚乳酸、 聚乙醇酸、 聚己内酯、 聚丁二酸酯及聚 -羟基丁酸酯）中的 至少一种， 所述不可降解聚合物选自聚苯乙烯、 聚四氟乙烯、 聚甲基丙烯酸甲 酯、 聚碳酸酯及聚对苯二甲酸乙二酯中的至少一种。
10、 根据权利要求 2所述的植入式载药器械， 其特征在于， 所述本体由金 属制成， 所述金属为可降解金属或不可降解金属。
〇 11、 根据权利要求 10 所述的植入式载药器械， 其特征在于， 所述可降解 金属为纯铁、 铁合金、 纯镁或镁合金。
12、 根据权利要求 10 所述的植入式载药器械， 其特征在于， 所述不可降 解金属为 3161^不锈钢、 钴铬合金、 铂铬合金、 纯钛或钛合金。
13、 根据权利要求 2所述的植入式载药器械， 其特征在于， 所述本体至少5 部分由聚合物制成， 所述聚合物选自可降解聚合物、 不可降解聚合物及形成所 述可降解聚合物的单体与形成所述不可降解聚合物的单体中的至少两种形成 的共聚物中的至少一种；所述可降解聚合物选自聚乳酸、聚乙醇酸、聚己内酯、 聚丁二酸酯及聚 -羟基丁酸酯）中的至少一种， 所述不可降解聚合物选自聚苯 乙烯、 聚四氟乙烯、 聚甲基丙烯酸甲酯、 聚碳酸酯及聚对苯二甲酸乙二酯中的0 至少一种。
14、 根据权利要求 1所述的植入式载药器械， 其特征在于， 所述植入式载 药器械为血管支架、胆道支架、食道支架、尿道支架、 气道支架、 男科植入物、 妇科植入物或者腔静脉滤器。
PCT/CN2018/121678 2017-12-28 2018-12-18 植入式载药器械 WO2019128767A1 (zh)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP18897786.2A EP3733221B1 (en) 2017-12-28 2018-12-18 Implantable drug delivery device
US16/957,975 US20200330642A1 (en) 2017-12-28 2018-12-18 Implantable drug-loaded device

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201711461899.7A CN109966563B (zh) 2017-12-28 2017-12-28 植入式载药器械
CN201711461899.7 2017-12-28

Publications (1)

Publication Number Publication Date
WO2019128767A1 true WO2019128767A1 (zh) 2019-07-04

Family

ID=67063106

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2018/121678 WO2019128767A1 (zh) 2017-12-28 2018-12-18 植入式载药器械

Country Status (4)

Country Link
US (1) US20200330642A1 (zh)
EP (1) EP3733221B1 (zh)
CN (1) CN109966563B (zh)
WO (1) WO2019128767A1 (zh)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20220354999A1 (en) 2021-05-10 2022-11-10 Cilag Gmbh International Bioabsorbable staple comprising mechanisms for slowing the absorption of the staple

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050267560A1 (en) * 2000-02-03 2005-12-01 Cook Incorporated Implantable bioabsorbable valve support frame
CN101161299A (zh) * 2006-10-09 2008-04-16 北京乐普医疗器械有限公司 孔洞及聚合物共载的药物释放结构及其制备方法
CN101185779A (zh) * 2007-12-19 2008-05-28 上海赢生医疗科技有限公司 一种药物缓释支架的制备方法
CN102772831A (zh) * 2012-08-20 2012-11-14 道淼科技(北京)有限公司 一种可降解载药支架
CN104857570A (zh) * 2015-05-05 2015-08-26 乐普（北京）医疗器械股份有限公司 一种可降解锌基合金支架及其制备方法
CN104888282A (zh) * 2015-05-05 2015-09-09 乐普（北京）医疗器械股份有限公司 一种可降解锌基微孔载药支架及其制备方法
CN106955374A (zh) * 2016-01-08 2017-07-18 先健科技(深圳)有限公司 植入式器械

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104593650A (zh) * 2013-11-01 2015-05-06 上海交通大学医学院附属第九人民医院 一种具有抗菌功能可降解吸收的镁锌铜合金及其应用
CN104195369B (zh) * 2014-08-21 2016-09-21 北京大学 一种Zn-Ca系锌合金及其制备方法与应用
CN106474545B (zh) * 2015-08-28 2020-04-10 元心科技(深圳)有限公司 可吸收铁基合金植入医疗器械
CN106606801B (zh) * 2015-10-21 2019-04-16 北京大学 一种Zn-ZnO系锌合金及其制备方法与应用
CN106806938B (zh) * 2015-11-27 2020-04-14 先健科技(深圳)有限公司 可吸收铁基合金植入医疗器械
CN106267378A (zh) * 2016-10-10 2017-01-04 同济大学 一种可控降解的金属支架的制备方法

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050267560A1 (en) * 2000-02-03 2005-12-01 Cook Incorporated Implantable bioabsorbable valve support frame
CN101161299A (zh) * 2006-10-09 2008-04-16 北京乐普医疗器械有限公司 孔洞及聚合物共载的药物释放结构及其制备方法
CN101185779A (zh) * 2007-12-19 2008-05-28 上海赢生医疗科技有限公司 一种药物缓释支架的制备方法
CN102772831A (zh) * 2012-08-20 2012-11-14 道淼科技(北京)有限公司 一种可降解载药支架
CN104857570A (zh) * 2015-05-05 2015-08-26 乐普（北京）医疗器械股份有限公司 一种可降解锌基合金支架及其制备方法
CN104888282A (zh) * 2015-05-05 2015-09-09 乐普（北京）医疗器械股份有限公司 一种可降解锌基微孔载药支架及其制备方法
CN106955374A (zh) * 2016-01-08 2017-07-18 先健科技(深圳)有限公司 植入式器械

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
YUFENG ZHENG; HONGTAO YANG: "Research Progress in Biodegradable Metals for Stent Application", ACTA METALLURGICA SINICA, vol. 53, no. 10, 31 October 2017 (2017-10-31), pages 1227 - 1237, XP055718484, DOI: 10.11900/0412.1961.2017.00270 *

Also Published As

Publication number Publication date
EP3733221C0 (en) 2023-09-13
EP3733221A1 (en) 2020-11-04
EP3733221B1 (en) 2023-09-13
CN109966563B (zh) 2021-08-03
US20200330642A1 (en) 2020-10-22
EP3733221A4 (en) 2021-10-06
CN109966563A (zh) 2019-07-05

Similar Documents

Publication Publication Date Title
EP2555811B1 (en) Endoprosthesis
RU2642254C2 (ru) Рассасывающие стенты, которые содержат магниевые сплавы
US8337878B2 (en) Medical devices having coatings for therapeutic agent delivery
US20090118818A1 (en) Endoprosthesis with coating
JP5329435B2 (ja) 非対称性の薬剤放出が制御されたコーティングを有する冠状動脈ステント
US20130018455A1 (en) Method of inhibiting vascular intimal hyperplasia using stent
EP2380528A1 (en) Medicament eluting apparatus with micro-hole structure capable of storing and releasing multiple medicines and preparation method
JP2004173770A (ja) 体内埋込医療器具
JP2013215332A (ja) 生体吸収性医療器具及びその分解速度調整方法
US20050234545A1 (en) Amorphous oxide surface film for metallic implantable devices and method for production thereof
US20100092534A1 (en) Combination Local Delivery Using a Stent
WO2019128767A1 (zh) 植入式载药器械
JP2015154925A (ja) 耐食性に優れたステント
US8591571B2 (en) Drug-eluting stent
US20120239140A1 (en) Medical product comprising an active coating
US20200215235A1 (en) Implantable device
US8920490B2 (en) Endoprostheses
CN113491796B (zh) 含锌医疗器械
EP3689385B1 (en) Implantable device
JP2016005533A (ja) ステント
EP2550033A1 (en) Bioerodible medical implants

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18897786

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2018897786

Country of ref document: EP

Effective date: 20200728