EP3986341A1 - Stent pourvu d'un revêtement à séparation immédiate - Google Patents

Stent pourvu d'un revêtement à séparation immédiate

Info

Publication number
EP3986341A1
EP3986341A1 EP20734859.0A EP20734859A EP3986341A1 EP 3986341 A1 EP3986341 A1 EP 3986341A1 EP 20734859 A EP20734859 A EP 20734859A EP 3986341 A1 EP3986341 A1 EP 3986341A1
Authority
EP
European Patent Office
Prior art keywords
active ingredient
medical product
stents
coating
stent
Prior art date
Legal status (The legal status 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 status listed.)
Pending
Application number
EP20734859.0A
Other languages
German (de)
English (en)
Inventor
Sebastian SCHURMANN-KAUFELD
Nadia BRUNACCI
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Innora GmbH
Original Assignee
Innora GmbH
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 Innora GmbH filed Critical Innora GmbH
Publication of EP3986341A1 publication Critical patent/EP3986341A1/fr
Pending legal-status Critical Current

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
    • 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
    • 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
    • A61F2/86—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure
    • A61F2/90—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure
    • A61F2/91—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure made from perforated sheet material or tubes, e.g. perforated by laser cuts or etched holes
    • A61F2/915—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure made from perforated sheet material or tubes, e.g. perforated by laser cuts or etched holes with bands having a meander structure, adjacent bands being connected to each other
    • 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
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—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
    • A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/86—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure
    • A61F2/90—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure
    • 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
    • A61F2/95—Instruments specially adapted for placement or removal of stents or stent-grafts
    • A61F2/958—Inflatable balloons for placing stents or stent-grafts
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A61L27/28—Materials for coating prostheses
    • A—HUMAN NECESSITIES
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    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/08—Materials for coatings
    • A—HUMAN NECESSITIES
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    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A61L29/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
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    • 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
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    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • 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
    • A61F2/95—Instruments specially adapted for placement or removal of stents or stent-grafts
    • A61F2002/9528—Instruments specially adapted for placement or removal of stents or stent-grafts for retrieval of 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
    • A61F2210/00—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2210/0057—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof stretchable
    • 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
    • A61F2220/00—Fixations or connections for prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2220/0008—Fixation appliances for connecting prostheses to the body
    • A61F2220/0016—Fixation appliances for connecting prostheses to the body with sharp anchoring protrusions, e.g. barbs, pins, spikes
    • 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
    • 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
    • A61F2310/00—Prostheses classified in A61F2/28 or A61F2/30 - A61F2/44 being constructed from or coated with a particular material
    • A61F2310/00389—The prosthesis being coated or covered with a particular material
    • A61F2310/0097—Coating or prosthesis-covering structure made of pharmaceutical products, e.g. antibiotics
    • A—HUMAN NECESSITIES
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    • 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
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    • 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
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    • A61M25/00—Catheters; Hollow probes
    • A61M25/10—Balloon catheters
    • A61M2025/1043—Balloon catheters with special features or adapted for special applications
    • A61M2025/105—Balloon catheters with special features or adapted for special applications having a balloon suitable for drug delivery, e.g. by using holes for delivery, drug coating or membranes

Definitions

  • the invention relates to an implantable medical product, preferably a stent for arteriosclerotic vascular stenosis, and a method for its production.
  • vascular lumen referred to as stents or stent-grafts
  • the vascular wall is treated mechanically by means of a balloon of a balloon catheter and at the same time with a drug to prevent unwanted effects
  • Stents are tubular structures that usually have a small diameter which are inserted into the body, e.g. be introduced into blood vessels, bile ducts or other duct-shaped structures, occasionally also into tissue or more or less solid structures.
  • a second step and only at the point of application they achieve a larger diameter, which ensures a sufficient inner lumen (e.g. for unhindered blood flow).
  • This step can be done by releasing the radially compressed stent consisting of elastic material (e.g. nitinol) from a tube or catheter or by active expansion by means of a balloon of a balloon catheter for stents made of plastically deformable materials such as steel or cobalt-chromium or also other alloys. Frequent locations for stents are narrowed or blocked blood vessels, narrowed passages or directly in the tissue to create passages.
  • elastic material e.g. nitinol
  • the drug-coated or uncoated stents available to date are permanent implants. Even the recently propagated and occasionally used biodegradable stents remain at the site of implantation for weeks, months or years.
  • stents are ideal for delayed long-term release.
  • stents are extremely filigree structures in order to be implantable as little invasively as possible and to grow in quickly after implantation and to cause little local irritation.
  • the small mass and surface area of the stents severely limit the dose of drug that can be deposited on them.
  • Highly effective, delayed-release drugs on stents for coronary arteries have gained almost complete acceptance.
  • the first effective products have also been approved for peripheral arteries and are already being used there.
  • drug-coated balloon catheters have been developed, approved and introduced into the clinic in selected indications over the past 15 years.
  • the preferred drug is paclitaxel.
  • Balloon catheter balloons block blood flow when inflated. In most cases, they can only be inflated for a maximum of 1 minute in coronary arteries; inflation times of a few minutes are possible in leg arteries. In this short time, the medicinal substance must be released from the balloon membrane as completely as possible and a sufficient proportion must be transferred into the vessel wall.
  • Coated balloons of balloon catheters contain much more medicinal substance than coated ones for a vessel to be treated of the same diameter and the same length Stents.
  • the higher drug dose on the balloons could be understood as compensation for the incomplete transfer from the balloon into the vessel wall in a short period of time, or as compensation for the lack of sustained drug flow from a permanent implant.
  • Table 1 Coating of medical devices for opening or keeping open passages or cavities in the body with drugs / active substances (coronary)
  • the delayed release of the active ingredients from stents is achieved by diffusion.
  • the diffusion takes place from water-insoluble polymers or from very special, very well adhering, very slowly soluble or biodegradable coatings.
  • the delay in the delivery of stents is also promoted by the creation of particularly poorly soluble modifications of the drugs, e.g. by subsequent treatment of the coated stents (annealing).
  • Drugs are the formation of thrombotic occlusions in the stent (stent thrombosis) as well as degeneration of the arterial wall, which becomes detached from the stent, thereby preventing or delaying its growth into the vessel wall and can lead to a change in the position of the stent in the enlarging vessel lumen.
  • Self-expanding stents are one approach to solving these problems. Based on these, drug carriers have been developed in recent years, as they are known, for example, from US 2017/0 196 717. These are designed to stretch the vascular wall and at the same time introduce drugs deep into the vascular wall. In contrast to the stents that have been used up to now, such stents only remain at the treatment site for a few minutes and are then completely removed from the vessel and the patient's body. They consist of metals with a pronounced shape memory which, like conventional self-expanding stents, have approximately the desired diameter of the vascular lumen to be treated, but are compressed to a much smaller diameter for introduction into the body. Problems with coating such stents are:
  • One object of the invention is thus to solve the problems mentioned and in particular to provide a coating for implantable medical products, such as stents, which immediately after contact with the tissue, e.g. the vascular wall an effective
  • a first aspect of the invention relates to a
  • implantable medical device e.g. a stent for arteriosclerotic
  • Vascular stenosis having a base body, with a on a surface of the
  • the dose of the active ingredient or the active ingredient mixture is at least 5 pg / mm 2 based on the coated surface. This advantageously leads to the active substance being released quickly. This ensures that even with short dwell times of the implantable medical product (hereinafter only medical product, balloons of balloon catheters are not implanted and are not meant), that a sufficient amount of active substance is transferred to the target location in order to counteract renewed vasoconstriction. For the replacement of the implantable medical product (hereinafter only medical product, balloons of balloon catheters are not implanted and are not meant), that a sufficient amount of active substance is transferred to the target location in order to counteract renewed vasoconstriction. For the replacement of the implantable medical product (hereinafter only medical product, balloons of balloon catheters are not implanted and are not meant), that a sufficient amount of active substance is transferred to the target location in order to counteract renewed vasoconstriction. For the replacement of the implantable medical product (hereinafter only medical product, balloons of balloon catheters are not implant
  • a period of up to 20 minutes is preferred for active ingredients, and also pharmaceuticals in the following, even faster transmission speeds, such as 15 minutes or 10 minutes and less, are more preferred.
  • a release time of up to 5 minutes is particularly preferred.
  • the active ingredient is rapidly released when at least 40%, preferably more than 45%, more preferably at least 60%, particularly preferably at least 65% of the active ingredient originally arranged on the surface of the medical product, i.e. prior to contact with the human body was released to the surrounding tissue in the time specified above.
  • a rapid and complete release is understood to mean that 10 to 20 minutes after the implantable medical product has been completely introduced into the human body, on average not more than 20%, preferably not more than 30%, in particular not more than 40% remain on the surface of the medical device.
  • the active substance or the active substance mixture is present on the medical product unbound, ie not in connection with substances which
  • the coating on the surface of the medical product does not have any polymers or other compounds that significantly reduce the rate of release of the active ingredient in addition to the restenosis-inhibiting active ingredient. This accelerates the release of the active ingredient compared to
  • additives and auxiliaries are, for example, suitable for the adhesion, release and stability of the active ingredient or active ingredient mixture or the layer containing the active ingredient or active ingredient mixture on the surface of the
  • the active ingredients can be pharmacologically inactive or ineffective
  • Auxiliaries are added. Auxiliaries are suitable for improving the adhesion before the intended release of the active ingredients, accelerating the release of the active ingredients,
  • auxiliaries that help improve their chemical stability, adjust the pH value of the coating solutions, or also influence the structure of the layer, e.g. change their flexibility, lubricity and solubility in water.
  • auxiliaries are known and customary in pharmacy and have also been used in admixture with medicinal substances for coating balloon catheters; the hydrophilic auxiliaries that have proven themselves on coated balloon catheters, such as iodized, are particularly suitable
  • X-ray contrast media such as urea or even the lipophilic antioxidants, such as
  • Butylated hydroxytoluene (BHT), resveratrol, nordihydroguajaretic acid (NDGA) and propyl gallate are butylated hydroxytoluene (BHT), resveratrol, nordihydroguajaretic acid (NDGA) and propyl gallate.
  • the base body preferably comprises a metal, a plastic, a natural product or a combination of these materials or is made from them.
  • the base body is particularly preferably made at least in some areas of steel, cobalt-chromium or nitinol, a nickel-titanium alloy.
  • the base bodies can be plastically deformable or elastic. Alternatively or in addition, the base body can be deformed by a specific arrangement of recesses and cavities.
  • the medical product according to the invention is advantageously implanted only temporarily, that is to say remains in the operative position only for a predetermined time.
  • the period of time is preferably up to 30 minutes, in particular up to 15 minutes. Permanent implants and therefore permanent
  • the medical product has a lumen and a balloon for post-dilatation is also located in the lumen of self-expanding stents.
  • a balloon for post-dilatation is also located in the lumen of self-expanding stents.
  • the main body has an elongated shape that delimits the lumen.
  • elements extending laterally outward can be arranged like spikes.
  • the active ingredient in the sense of the invention is arranged in intermediate areas between and / or on these spike-like elements.
  • the introduction of the active ingredient into the tissue by means of the spike-like elements supports the rapid release of the active ingredient according to the invention and its penetration into the tissue and is therefore particularly advantageous in combination.
  • the active ingredient is a taxane, a statin or an mTOR inhibitor or contains such a mixture with other active ingredients. It turned out that these substances are suitable for the application of the
  • an active ingredient is paclitaxel.
  • Paclitaxel shows strong restenosis-inhibiting properties and is well tolerated.
  • active ingredients of the Limus group such as, in particular, sirolimus, everolimus, zotarolimus, biolimus and temsirolimus, so that it is likewise preferred that the active ingredient is selected from this group or represents an active ingredient mixture thereof.
  • Statins preferably cerivastatin, atorvastatin and / or fluvastatin, and / or active substances with an antimicrobial effect and / or blood coagulation inhibiting and / or thrombolysis promoting active substances are particularly preferred.
  • the dose of the active ingredient or mixture of active ingredients is particularly advantageously> 10 pg / mm 2 surface, in particular a dose in the range from 10 pg / mm 2 to 50 pg / mm 2 is preferred.
  • Another aspect of the invention relates to a method for coating stents and shape-related medical products, a coating solution being applied to a surface to be coated at a low temperature, preferably in the range from approximately 0 to minus 20 ° C.
  • the coating solution is applied to the surface with the aid of a volume measuring device, preferably a syringe, microsyringe or semi or fully automatically operated piston syringe.
  • a volume measuring device preferably a syringe, microsyringe or semi or fully automatically operated piston syringe.
  • All medical products are suitable if they are coated with drugs with rapid release and which are introduced into the body for a short time or permanently.
  • the materials are metals, plastics or natural products and
  • the materials can be plastically or elastically deformable and have a shape memory.
  • the surfaces can be smooth, e.g. be polished, or porous, or textured, or covered with additional materials.
  • Medical products that are only used for a short time, i.e. come into contact with the tissue or lumen to be treated for seconds to a few hours. This includes medical devices that are removed soon after use or whose position in the body shifts during implantation.
  • An example of this are self-expanding or balloon-expandable stents, the struts of which move relative to the vessel wall, for example due to expansion / post-dilation, during or shortly after implantation.
  • vessel wall sections are supplied with active ingredient which later have no direct contact with the coated stent struts.
  • the coating of such stents is described in Example 15.
  • the stent struts which are known to be well tolerated, do not contain any polymers or other components of the coating that delay the release of the drugs and that could impair the compatibility of the stent material.
  • the coatings disclosed here with a particularly high drug dose / mm 2 surface of the medical products are particularly advantageous for the very thin-walled and short stents ('tacks', stents used for 'spot stenting') that are only used punctually on vessel sections that are not sufficiently expandable with balloons alone. These vascular segments, which are mechanically difficult to expand, particularly require additional treatment with a drug that inhibits re-narrowing.
  • Particularly preferred medical products are stents, which are also mentioned below as examples for other medical products.
  • Anti-inflammatory agents substances that inhibit the progression of processes leading to arteriosclerosis and the arteriosclerosis itself or promote the regression of arteriosclerotic plaques, such as e.g. Statins (cerivastatin, atorvastatin, fluvastatin) and antimicrobially active substances, furthermore substances for influencing blood coagulation such as heparin and heparin fragments and thrombolytics such as urokinase, streptokinase or recombinant tissue plasmin activators.
  • Statins cerivastatin, atorvastatin, fluvastatin
  • antimicrobially active substances furthermore substances for influencing blood coagulation such as heparin and heparin fragments and thrombolytics such as urokinase, streptokinase or recombinant tissue plasmin activators.
  • the medical products and methods according to the invention are used for the targeted therapy of spatially limited diseased body regions. Due to the type of administration, high active ingredient concentrations are achieved locally despite the low amount of medicinal substance, while the exposure to the entire body remains very low.
  • the drugs are applied to medical devices or are contained in medical devices. They are released when medical devices come into contact with tissues in the body.
  • the dose relates to the surface of the medical device that comes into close contact with surfaces within the body, such as arterial walls. This related to the surface of the medical device in the state of contact with the target tissue dose is after the sterilization of the medical device> 5 pg active ingredient or active ingredient mixture / mm 2, preferably> 10 pg / mm 2, and most preferably> 15 pg / mm 2. In the case of stents, these limits also apply to the abluminal surfaces of the stent struts.
  • Stents and other medical products are coated with paclitaxel (representative of the taxanes) and / or rapamycin (mTOR inhibitor, macrolide) and / or with other, preferably the above-mentioned active ingredients, in that the medicinal substances are immiscible or miscible with water, possibly also water containing organic solvents partly or wholly dissolves or also suspended.
  • Preferred solvent mixtures contain> 10% by volume of water, more preferably> 15% by volume of water, most preferably> 20% by volume of water.
  • Preferred concentrations are 10-100 mg of active ingredient or mixture of active ingredients in one ml of solution.
  • Preferred water-miscible organic solvents are methanol, ethanol, isopropanol, acetone, tetrahydrofuran, dioxane, and dimethyl sulfoxide. These can contain additions of water-immiscible or little water-absorbing solvents such as ethers,
  • halogen-containing solvents such as chloroform, dichloromethane or trifluoroethanol.
  • the stents or other medical products can be coated by being immersed in the active ingredient solutions.
  • the problem with this is that very little solution and drug adheres to smooth surfaces.
  • the applied drug dose became lower at
  • Temperature for example at about 0 to minus 20 ° C (Example 1) and / or through
  • Dip solution is soluble. Overall, more active ingredient was applied than would be calculated for a clinically effective balloon of the same size (4.0 x 60 mm) at the usual dose of 3 pg / mm 2 (2261 pg) and with a significantly higher drug density (pg / mm 2 ) on the surface of the Medical device (Tab. 3, right column).
  • the coating solution can be sprayed onto the surface. In the case of stents, a coating of the stent surfaces on the lumen side (side facing the blood flow) after implantation can be avoided by directed spraying or by suitable protective measures.
  • the medical devices After being coated with a liquid preparation, the medical devices are dried.
  • Stents and comparable medical devices must be reduced to the smallest possible diameter for introduction into the body.
  • self-expanding stents are compressed in diameter and pushed or pulled into narrow tubes.
  • the transfer of the product from the expanded state into an application catheter is achieved by using a funnel-shaped
  • Insertion aid facilitated.
  • Balloons that have been coated in the expanded, inflated state are folded after coating or, if they were folded before coating, for example, by applying a vacuum and stored in a removable protective cover. Deformation of the coated structures and friction of the structures against one another as well as at the tube inlet and in the tube lumen cause the loss of coating or drug.
  • the products for use on patients are sterile. They are preferred by means of
  • Ethylene oxide sterilized other processes such as production and packaging under sterile conditions or heat or radiation sterilization are possible.
  • the coated medical products are brought to the place of use in the body in a minimally invasive manner, where they are released or inflated. After a therapeutically or prophylactically effective dose of a substance has been given, they are removed again shortly thereafter, their position changed completely or in part or left as implanted. The desired effect is also achieved if the implant is only in contact with the tissue to be treated or a nearby tissue for a short period of time.
  • Stents measuring 4.0 x 60 mm were coated with protruding elements for drug application (see ReFlow US 2017/0196717 or Fig. 1-3); total surface of a stent 188.5 mm 2 , by briefly dipping 8 times in the coating solution. Each coating means that the stents were immersed in the solution for 1 second and then dried in a stream of air at 50 ° C. for 20 seconds.
  • Stents measuring 4.0 x 60 mm were coated with protruding elements for drug application (see ReFlow US 2017/0196717), the entire surface of a stent 188.5 mm 2 by briefly dipping 10 times in cooled coating solutions (- 20 ° C). Each coating means that the stents were immersed in the solution for 1 second and then dried in a stream of air at 50 ° C. for 20 seconds.
  • the balloon (clinically tested, effective product) is coated with 3.5 pg paclitaxel / mm 2 , a total of approx. 2850 pg paclitaxel.
  • Tab. 3 it was possible to deposit approximately the same dose on a significantly smaller surface.
  • FIG. 1 shows an uncoated stent in FIG. 1a and, in partial FIG. 1b, a stent coated by means of dipping, a so-called spiked stent.
  • Stents were coated, as described in Example 1, by briefly repeated immersion in cooled (-20 ° C.) coating solutions. Each coating means that the stents were immersed in the solution for 1 second and then dried in a stream of air at 50 ° C. for 20 seconds.
  • Stents 4.0 x 60 mm were coated with protruding elements for
  • Coating cycle means that the stents were immersed in the solution for 1 second and then dried in a stream of air at 50 ° C. for 20 seconds.
  • the total surface of the stent is 188.5 mm 2 and is therefore much smaller than the surface of a correspondingly large balloon (810 mm 2 ).
  • Stents 4.0 x 60 mm were coated with protruding elements for
  • Coating cycle means that the stents were immersed in the solution cooled to -20 ° C. for 1 second and then dried in a stream of air at 50 ° C. for 20 seconds. Eight coating cycles were carried out.
  • Coating solution ethanol / acetone / water, the proportion of ethanol and acetone being 40% by volume and the proportion of water being 20% by volume.
  • the paclitaxel concentration in the coating solution was 24 mg / ml.
  • Table 5 Paclitaxel on the stents after eight dip coatings
  • coated stents were compressed to a narrow diameter by passage through a stainless steel block with a conical bore and then inserted into the lumen of the
  • Coating solution (a) ethanol / acetone / water or (b) ethanol / THF / water, the proportion of ethanol being 40% by volume, the proportion of acetone or THF being 40 or 50% by volume and the proportion of water being 20 or 10% by volume.
  • Coating solution was 12.5 mg / ml.
  • the coating was carried out with the rotating Medical device (21 rpm) via a Hamilton microsyringe with a volume of 75 pl / stent (4.0 x 60 mm).
  • Stents 4.0 x 60 mm were coated with protruding elements for
  • the stent shown in FIG. 2 has a coating. This was applied by means of a coating solution of RF-3d, (paclitaxel 12.5 mg / ml ethanol / acetone / water 40/50/10 V / V / V, which was applied via a Hamilton syringe.
  • RF-3d paclitaxel 12.5 mg / ml ethanol / acetone / water 40/50/10 V / V / V, which was applied via a Hamilton syringe.
  • Table 7 Paclitaxel on the stents after insertion into the application system
  • Coating solution ethanol / acetone / THF / water, the ethanol, acetone and THF content each being 30% by volume and the water content corresponding to 10% by volume.
  • the paclitaxel concentration in the coating solution was 20 mg / ml.
  • the coating was carried out with a rotating medical device (21 rpm) using a Hamilton microsyringe with a volume of 75 ml / per stent (4.0 x 60 mm).
  • Stents 4.0 x 60 mm were coated with protruding elements for
  • FIG. 3 shows a photographic representation of part of a coated stent.
  • a coating solution of RF-G-20 paclitaxel 20 mg / ml ethanol / acetone / TFIF / water 30/30/30/10 (V / V) was also applied with a Hamilton syringe.
  • Table 8 Paclitaxel on the stents directly after coating and loss during introduction into the application system
  • Coating solution ethanol / acetone / water, the proportion of ethanol and acetone being 40% by volume and the proportion of water corresponding to 20% by volume.
  • the paclitaxel concentration in the coating solution was 20 mg / ml. Additionally, lopromid was given a
  • Stents 4.0 x 60 mm were coated with protruding elements for
  • FIG. 1 A stent coated in this way is shown in FIG. A solution of RF-C-20-UV-2, (paclitaxel 20 mg / ml and lopromide (2 mg / ml)
  • Coating solution ethanol / acetone / water, the proportion of ethanol and acetone being 40% by volume and the proportion of water corresponding to 20% by volume.
  • the paclitaxel concentration in the coating solution was 20 mg / ml.
  • dexpanthenol was added at a concentration of 2 mg / ml. The coating was carried out with the rotating
  • Stents 4.0 x 60 mm were coated with protruding elements for
  • FIG. 5 shows one with the coating solution RF-C-20-DP-2, according to Table 10
  • Coating solution ethanol / acetone / water, the proportion of ethanol and acetone being 40% by volume and the proportion of water corresponding to 20% by volume.
  • the paclitaxel concentration in the coating solution was 20 mg / ml.
  • urea was combined with a
  • Stents 4.0 x 60 mm were coated with protruding elements for
  • the stent coating for the stent shown in FIG. 6 was carried out by means of a coating solution according to RF-C-20-UR-2, (paclitaxel 20 mg / ml and urea (2 mg / ml) ethanol / acetone / water 40) applied via a Hamilton syringe / 40/20 (V / V).
  • Table 11 Paclitaxel on the stents immediately after the coating Loss on introduction into the application system, no increase in loss due to urea
  • the coating solution contained 20 mg / ml paclitaxel or 20 mg / ml paclitaxel and 2 mg / ml dexpanthenol.
  • the solvent mixture used was ethanol / acetone / water, the proportion of ethanol and acetone being 40% by volume and the proportion of water corresponding to 20% by volume.
  • the coating was carried out with rotation (21 rpm) using a Hamilton microsyringe with a volume of 75 ml / stent.
  • the stents were pushed over a folded balloon of the balloon catheter and then glued to the shaft of the balloon catheter so that the balloon was located in the lumen of the coated stent.
  • the balloon and stent were inserted into the balloon shaft with an application catheter
  • Metal block with conical bore compressed to the diameter of the application catheter and inserted into it.
  • Folded balloons (4.0 x 80 mm) of balloon catheters were inflated and coated with rotation (21 rpm).
  • the coating solution contained 20 mg / ml paclitaxel or 20 mg / ml paclitaxel and 2 mg / ml dexpanthenol.
  • the solvent mixture was
  • Ethanol / acetone / water was used, the ethanol and acetone proportions each being 40% by volume and the water proportion corresponding to 20% by volume.
  • the coating was carried out with a volume of 75 ml using a Hamilton microsyringe.
  • the coated balloons were deflated and refolded under vacuum by sliding a PTFE tube.
  • Balloon catheters with coated folded balloons were inserted from proximally into the
  • the stent's delivery catheter was inserted so that the distal balloon protruded completely out of the delivery catheter.
  • the coating solution contained 20 mg / ml paclitaxel or 20 mg / ml paclitaxel and 2 mg / ml dexpanthenol.
  • the solvent mixture used was ethanol / acetone / water, the proportion of ethanol and acetone being 40% by volume and the proportion of water corresponding to 20% by volume.
  • the coating was carried out with rotation (21 rpm) using a Hamilton microsyringe with a volume of 75 ⁇ l / stent.
  • the stents were pushed over the above-described balloon catheter, which was folded back after coating, and glued to the shaft of the balloon catheter in such a way that the balloon was located in the lumen of the coated stent.
  • the balloon and stent were pulled through a metal block with a conical bore to the diameter of the balloon shaft in the application catheter
  • the initially uncoated stents with the uncoated balloons of the balloon catheter were located in an application catheter.
  • Balloon catheter with balloon and stent protruded from the application catheter Balloon catheter with balloon and stent protruded from the application catheter.
  • the stents with protruding elements for drug application which are attached to the shaft of a balloon catheter and the balloon of which was located in the lumen of the stent, were provided with a coating that ensures immediate, largely complete drug delivery upon implantation.
  • the coating solution contained 20 mg / ml paclitaxel or 20 mg / ml paclitaxel and 2 mg / ml dexpanthenol.
  • the solvent mixture used was ethanol / acetone / water, the ethanol and acetone proportions each being 40% by volume and the water proportion correspondingly 20% by volume.
  • the coating was carried out with rotation (21 rpm) with a volume of 75 ⁇ l / per stent (4.0 ⁇ 60 mm) using a Hamilton microsyringe.
  • Balloon catheter with folded balloons of the appropriate size (balloon diameter
  • Stent diameter, balloon length stent length + 20 mm
  • the stent's application catheter was introduced so that the distal balloon protruded completely out of the application catheter.
  • the balloons (4.0 x 80 mm) were inflated and coated with rotation (21 rpm).
  • the coating solution contained 20 mg / ml paclitaxel or 20 mg / ml paclitaxel and 2 mg / ml dexpanthenol.
  • the solvent mixture used was ethanol / acetone / water, the ethanol and acetone proportions each being 40% by volume and the water proportion correspondingly 20% by volume.
  • the coating was carried out with a volume of 75 ml using a Hamilton microsyringe.
  • the coated balloons were deflated after drying and passed under vacuum
  • the balloon and stent were pulled through a metal block with a conical bore to the diameter of the balloon shaft in the application catheter
  • stents of Examples 4, 5a, 7 and 8 were introduced into the internal iliac, femoral arteries and deep femoral arteries of pigs (approx. 30 kg body weight) and released from the application catheter, then fully expanded for 2 min with an uncoated balloon catheter and then completely removed by a special return mechanism without injuring the animal. Approx. 15 minutes after removal of the stent, 4.2 ⁇ 4.0% of the paclitaxel dose was obtained in the case of using stents according to Example 4, from Example 5a 5.1 ⁇ 2.4% of the dose, from Example 7 4.0 ⁇ 0.6% of the dose and, from Example 8, 9.9 ⁇ 7.0% of the dose found in the arterial wall.
  • Table 12 Paclitaxel on the stents immediately after coating; Loss on insertion into the application system, reproducible coating of stents with a nitiniol base body with a coating solution containing resveratrol.

Abstract

L'invention concerne un dispositif médical implantable pourvu d'un revêtement à base de principe actif. Selon l'invention, le principe actif est à libération rapide.
EP20734859.0A 2019-06-21 2020-06-18 Stent pourvu d'un revêtement à séparation immédiate Pending EP3986341A1 (fr)

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DE102019116791.4A DE102019116791B4 (de) 2019-06-21 2019-06-21 Stent mit sofort ablösbarer Beschichtung
PCT/EP2020/066852 WO2020254454A1 (fr) 2019-06-21 2020-06-18 Stent pourvu d'un revêtement à séparation immédiate

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NZ574597A (en) 2006-07-03 2011-11-25 Hemoteq Ag Stent coated with a biodegradable polymer and rapamycin
JP5541593B2 (ja) * 2006-08-15 2014-07-09 アボット ラボラトリーズ ラパマイシン類似体及びパクリタキセルを含む組成物及び薬物送達システム
NZ588816A (en) * 2007-01-21 2011-11-25 Hemoteq Ag Medical device for the treatment of stenoses of corporal lumina and for the prevention of impending restenoses
DE102007036685A1 (de) 2007-08-03 2009-02-05 Innora Gmbh Verbesserte arzneimittelbeschichtete Medizinprodukte deren Herstellung und Verwendung
WO2010024898A2 (fr) 2008-08-29 2010-03-04 Lutonix, Inc. Procédés et appareils pour poser un revêtement sur des cathéters à ballonnet
US20130302381A1 (en) * 2012-05-09 2013-11-14 Cook Medical Technologies Llc Implantable Medical Devices Including a Water-Insoluble Therapeutic Agent
DE102014106422A1 (de) * 2014-05-08 2015-11-12 Dot Gmbh Verfahren, Vorrichtung und Zusammensetzung zur Herstellung von beschichteten Ballonkathetern
CN108366866A (zh) 2015-10-12 2018-08-03 瑞弗罗医疗公司 具有突出的药物递送特征部的支架以及相关的系统和方法

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DE102019116791A1 (de) 2020-12-24
CN114126678A (zh) 2022-03-01

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