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WO2006027992A1 - Endoprothese vasculaire se plaçant dans le corps - Google Patents

Endoprothese vasculaire se plaçant dans le corps Download PDF

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Publication number
WO2006027992A1
WO2006027992A1 PCT/JP2005/016000 JP2005016000W WO2006027992A1 WO 2006027992 A1 WO2006027992 A1 WO 2006027992A1 JP 2005016000 W JP2005016000 W JP 2005016000W WO 2006027992 A1 WO2006027992 A1 WO 2006027992A1
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WO
WIPO (PCT)
Prior art keywords
stent
polymer
coating layer
lactic acid
weight
Prior art date
Application number
PCT/JP2005/016000
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English (en)
Japanese (ja)
Inventor
Takuji Nishide
Original Assignee
Kaneka Corporation
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 Kaneka Corporation filed Critical Kaneka Corporation
Priority to US11/574,877 priority Critical patent/US20080077232A1/en
Priority to EP05781548A priority patent/EP1787676A4/fr
Priority to JP2006535705A priority patent/JP5056013B2/ja
Publication of WO2006027992A1 publication Critical patent/WO2006027992A1/fr

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Classifications

    • 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 sheets 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 sheets 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
    • 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 sheets or tubes, e.g. perforated by laser cuts or etched holes
    • 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 sheets 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 sheets or tubes, e.g. perforated by laser cuts or etched holes with bands having a meander structure, adjacent bands being connected to each other
    • A61F2002/91525—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 sheets or tubes, e.g. perforated by laser cuts or etched holes with bands having a meander structure, adjacent bands being connected to each other within the whole structure different bands showing different meander characteristics, e.g. frequency or amplitude
    • 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 sheets 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 sheets or tubes, e.g. perforated by laser cuts or etched holes with bands having a meander structure, adjacent bands being connected to each other
    • A61F2002/91533—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 sheets or tubes, e.g. perforated by laser cuts or etched holes with bands having a meander structure, adjacent bands being connected to each other characterised by the phase between adjacent bands
    • 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
    • A61F2230/00—Geometry of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2230/0002—Two-dimensional shapes, e.g. cross-sections
    • A61F2230/0028—Shapes in the form of latin or greek characters
    • A61F2230/0054—V-shaped

Definitions

  • the present invention relates to a medical indwelling stent used for dilatation treatment of a vascular stenosis portion.
  • vascular stenosis due to arteriosclerosis.
  • PTA angioplasty
  • PTCA angioplasty
  • restenosis repeated stenosis
  • Attempts, laser treatment, radiotherapy, etc. have been attempted as methods for reducing the frequency of restenosis (restenosis rate), and in recent years, stent placement techniques have become widespread.
  • a stent When a blood vessel or other in-vivo lumen is stenotic or occluded, a stent is a medical device that is placed in order to maintain the size of the stenosis or occlusion after the stenosis or occlusion. is there. Stents are typically composed of metals, polymers, or composites of them. Most commonly, stents are composed of metals such as stainless steel.
  • the stent For treatment with a stent, the stent is inserted into the blood vessel by a catheter and expanded to contact an unhealthy portion of the vessel wall to provide mechanical support for the vessel lumen.
  • Such stent placement significantly reduces the rate of restenosis compared to balloon-only angioplasty, but at present, the rate of restenosis is still high.
  • a restenosis rate with a frequency of about 20 to 30% has been reported even after stenting.
  • This restenosis is an excessive repair response to physical vessel damage caused by stent placement, that is, smooth muscle cell proliferation in the media after vessel injury It is caused by excessive thickening of the intima due to migration of proliferated smooth muscle cells to the intima, migration of T cells and macrophages to the intima, etc.
  • drugs that limit occlusion include drugs such as anticoagulant drugs, antiplatelet drugs, antibacterial drugs, antitumor drugs, antimicrobial drugs, anti-inflammatory drugs, antimetabolite drugs, and immunosuppressive drugs. It is being considered.
  • immunosuppressive agents include cyclosporine, tacrolimus (FK506), sirolimus (rapamycin), mycofenol tomofuethyl, and their analogs (evalolimus, ABT-578, CCI 779, AP 23573, etc.) coated on the restenosis. Attempts have been made to reduce this.
  • Patent Document 2 discloses a stent coated with sirolimus (lavamycin), which is known as an immunosuppressive agent
  • Patent Document 3 discloses a stent coated with taxol (paclitaxel), which is an antitumor agent.
  • Patent Documents 4 and 5 disclose a stent coated with tacrolimus (FK506).
  • Tacrolimus is a compound having CAS number 104987-11-3, and is disclosed, for example, in Patent Document 6.
  • Tacrolimus (FK506) forms a complex with intracellular FK506-binding protein (FKBP) and inhibits the production of cytokines such as IL-2 and INF- ⁇ , which are mainly differentiated growth factors, from sputum cells. It is well known that it can be used as a prophylactic or therapeutic agent for organ rejection and autoimmune diseases.
  • Non-patent document 1 confirms that tacrolimus (FK506) has anti-proliferative activity of human vascular cells.
  • Patent Document 1 discloses holding a drug using a polymer, and discloses using a biodegradable polymer.
  • Patent Document 7 discloses the use of a biodegradable polymer, and examples include polylactic acid.
  • Patent Document 1 and Patent Document 7 include such peeling and cracking. There is a specific description of how to prevent this.
  • Patent Document 1 Japanese Patent Publication No. 5-502179
  • Patent Document 2 JP-A-6-009390
  • Patent Document 3 Japanese Patent Publication No. 9-503488
  • Patent Document 4 Publication of WO02Z065947
  • Patent Document 5 EP1254674
  • Patent Document 6 Japanese Patent Laid-Open No. 61-148181
  • Patent Document 7 Japanese Translation of National Publication No. 5-509008
  • Non-Patent Document 1 Paul J. Mohacsi MD, et al. The Journal of Heart and Lung Transplantation May 1997 Vol. 16, No. 5, 484-491 Disclosure of the Invention
  • the present invention intends to solve the problem that a stent having a coating layer made of a polymer is placed in a living body that can efficiently prevent peeling and cracking of the coating layer accompanying expansion of the stent. It is easy to provide a stent for use.
  • the present invention provides:
  • An indwelling stent substantially formed in a tubular body, wherein the stent is extensible radially outward of the tubular body, and the stent is made of a non-degradable material in vivo as a stent substrate.
  • a stent body including the first polymer and a drug-containing coating layer, and a second polymer having a weight average molecular weight higher than that of the first polymer between the coating layer and the stent body surface.
  • a living indwelling stent wherein the coating layer and the intermediate layer are on at least a part of the surface of the stent body;
  • first polymer and the second polymer are a first biodegradable polymer and a second biodegradable polymer, respectively.
  • the first biodegradable polymer and the second biodegradable polymer are at least one selected from polylactic acid, polyglycolic acid, and lactic acid-glycolic acid copolymer force (5)
  • the biodegradation period of the first biodegradable polymer is shorter than the biodegradation period of the second biodegradable polymer; and the indwelling stent according to (5),
  • the weight average molecular weight of the first polymer is 10,000 or more and 50,000 or less, and the weight average molecular weight of the second polymer is 80,000 or more and 200,000 or less (1)
  • the stent for indwelling according to the present invention is a stent containing a non-degradable material in vivo as a stent base material, and has a coating layer mainly composed of a polymer on the surface of the stent body, Since the intermediate layer having a polymer force having a weight average molecular weight higher than that of the polymer is provided between the stent body surfaces, it is possible to efficiently prevent peeling and cracking of the coating layer accompanying expansion of the stent.
  • Stents can be readily provided compared to conventional indwelling stents. Brief Description of Drawings
  • the present invention is a stent formed in a substantially tubular body, the stent being extensible radially outward of the tubular body, and a non-degradable material in vivo as a stent base material.
  • a stent body including a coating layer containing a polymer and a drug on at least a part of the surface of the stent body, the gap between the coating layer and the stent surface being higher than the polymer. It has a form characterized by having an intermediate layer made of a polymer having a high weight average molecular weight.
  • the stent base material in the present invention means a stent material in a form having no coating layer. For example, a cylindrical material tube of such a stent base material can be cut into a stent design by laser cutting or the like to produce a stent body.
  • the coating layer and the intermediate layer are provided on substantially the entire outer surface, inner surface, and side surface of the stent body.
  • the coating layer and the intermediate layer are provided on almost the entire surface of the stent body, it becomes difficult for the platelets to adhere to the body lumen, particularly the surface of the stent placed in the blood vessel, resulting in excessive thrombus formation. The risk of vascular blockage can be significantly reduced.
  • non-degradable material in the living body used in the present invention means that the material is not biodegradable, but does not require that it is not decomposed at all in the living body. It is sufficient if it can be maintained, and these are referred to as “non-degradable materials in vivo”.
  • Non-degradable materials in vivo according to the present invention include stainless steel, Ni-Ti alloy, Cu-A1-Mn alloy, tantalum, Co-Cr alloy, iridium, Inorganic materials such as iridium oxide, niobium, ceramics, iron, idroxyapatite Is mentioned.
  • the stent body can be produced by a method that is usually produced by those skilled in the art. As described above, the stent body can be produced by cutting a cylindrical material tube containing the stent base material into a stent design by laser cutting or the like. Electropolishing may be performed after laser cutting.
  • the biologically non-degradable material in the present invention is not limited to inorganic materials, but is not limited to polyolefins, polyolefin elastomers, polyamides, polyamide elastomers, polyurethanes, polyurethane elastomers, polyesters, polyester elastomers, polyimides, polyamideimides.
  • Polymeric materials such as polyetheretherketone can also be used. As a method for producing a stent main body using these polymer materials, it is possible to arbitrarily select a method suitable for each material that does not limit the effects of the present invention.
  • the stent of the present invention contains a non-degradable material in vivo as a base material for the stent, it is sufficient when compared with a stent in which the stent body itself is composed of a biodegradable material cover. Stent strength is maintained over a long period of time, and the effect of dilatation treatment for vascular stenosis and occlusion is extremely high.
  • the surface of the stent body has a coating layer containing a drug as a main component and a drug, and the weight average molecular weight is higher than that of the polymer between the coating layer and the stent surface.
  • the intermediate layer it is possible to reduce peeling and cracking of the coating layer accompanying the expansion of the stent.
  • the weight average molecular weight of the polymer constituting the intermediate layer can be reduced to that of the polymer forming the coating layer. By controlling it higher than the weight average molecular weight, peeling and cracking can be suppressed more effectively.
  • the polymer forming the coating layer has a weight average molecular weight of 10,000 or more and 50,000 or less
  • the polymer forming the intermediate layer has a weight average molecular weight of 80,000 or more. , 000 or less is preferable. If a coating layer having a weight average molecular weight of 10,000 or more and 50,000 or less and having a high molecular force is directly provided on the surface of the stent body, there is a high possibility that the coating layer is cracked or peeled off due to the expansion of the stent.
  • the coating layer having a high molecular weight having a weight average molecular weight of 10,000 or more and 50,000 or less contains a low-molecular compound such as a drug (generally having a molecular weight of 5,000 or less)
  • a drug generally having a molecular weight of 5,000 or less
  • the intermediate layer is provided between the stent body surface and the coating layer, and the weight average molecular weight of the polymer forming the intermediate layer is controlled to 80,000 or more and 200,000 or less. Effectively suppresses peeling and cracking
  • the polymer forming the coating layer and the intermediate layer is preferably a biodegradable polymer.
  • the biodegradable polymer is selected from polylactic acid, polyglycolic acid, and lactic acid-glycolic acid copolymer.
  • Polylactic acid has three types of structures, poly-L lactic acid, poly-D lactic acid, poly-D, and L-lactic acid, depending on the optical activity of the lactic acid monomer. Any of these structures limits the effects of the present invention. That's right.
  • biodegradable polymers exemplified here are affected by the composition and the like, most of them have a glass transition temperature equal to or higher than the body temperature, and thus exhibit a rigid glass state at about the body temperature.
  • Poly L-lactic acid, poly-D lactic acid, polyglycolic acid and the like are known to exhibit high crystallinity.
  • the biodegradable polymer exemplified as described above has a tensile strength at break and a high tensile strength as compared with other high molecules such as a thermoplastic elastomer.
  • the biodegradation period of the biodegradable polymer forming the coating layer is preferably shorter than the biodegradation period of the biodegradable polymer forming the intermediate layer.
  • the coating layer and the intermediate layer are composed of a biodegradable polymer, the coating layer and the intermediate layer disappear due to biodegradation in the chronic period after the stent is implanted in the living body lumen. Since the intermediate layer has an action of improving adhesion between the coating layer and the stent surface, it is not preferable that the intermediate layer disappears by biodegradation before the coating layer.
  • the biodegradation period of the biodegradable polymer is calculated using as an index the weight change, strength change, molecular weight change, etc. of the biodegradable polymer.
  • the biodegradation period calculated from the molecular weight change is the shortest, the biodegradation period calculated from the intensity change next, and the biodegradation period calculated from the weight change force is generally the longest.
  • the biodegradation period does not limit the effect of the present invention even if any index power is calculated.
  • the biodegradation period calculated from different indices shows different values for a single biodegradable polymer as described above
  • the biodegradation period of the biodegradable polymer constituting the intermediate layer and the The biodegradation period of the biodegradable polymer constituting the coating layer needs to be a value calculated from the same index column.
  • the method for forming the intermediate layer and the coating layer on the surface of the stent body is not particularly limited.
  • the polymer constituting the intermediate layer is dissolved in an arbitrary solvent, adhered to the surface of the stent body in a solution state to remove the solvent, and then the polymer constituting the coating layer is removed from the arbitrary solvent.
  • a method of removing the solvent by dissolving it in the solution and adhering to the outer surface of the intermediate layer in a solution state.
  • a polymer film that forms the intermediate layer is separately prepared and attached to the stent body, and then a polymer film that forms the coating layer is separately prepared and attached to the outer surface of the intermediate layer. You can attach it.
  • a high molecular force film constituting the coating layer is separately prepared.
  • a high-molecular-weight film constituting the intermediate layer may be separately formed and attached to the stent body.
  • the polymer constituting the coating layer may be dissolved in an arbitrary solvent and attached to the outer surface of the intermediate layer in a solution state to remove the solvent.
  • the coating layer contains a drug.
  • the drug is an immunosuppressive agent.
  • the immunosuppressive agent is takuguchi rimus (FK506), cyclosporine, sirolimus (rapamycin), azathioprine, mycophenolate morphethyl, or an analog thereof. Tacrolimus (FK506) is more preferable.
  • the method for applying the drug to the coating layer is as follows. After the intermediate layer is produced by the above-described method or the like, the polymer and the drug constituting the coating layer are dissolved in an arbitrary solvent, and the solution is in a solution state. A film made of a polymer film constituting the coating layer, which may be attached to the outer surface of the intermediate layer and remove the solvent, was separately prepared, and the film was immersed in a solution in which the drug was dissolved in an arbitrary solvent. It may be post-dried and attached to the outer surface of the intermediate layer. After separately preparing a film made of a polymer film constituting the coating layer and attaching the film to the outer surface of the intermediate layer, the drug is added to any solvent. It may be dried after being soaked in a solution dissolved in.
  • the polymer or Z constituting the coating layer and the polymer constituting the intermediate layer and the polymer constituting the intermediate layer are dissolved in an arbitrary solvent and adhered in a solution state, or the polymer and drug constituting the coating layer are arbitrarily selected.
  • the method of dissolving in the solvent and adhering in the solution state does not limit the effect of the present invention. That is, various methods such as a method of dating the stent body on each solution and a method of spraying each solution onto the stent body by spraying can be used.
  • the kind of solvent to be used is not particularly limited. A solvent having a desired solubility can be suitably used, and a mixed solvent using two or more solvents may be used in order to adjust volatility and the like.
  • the concentration of the solute is not particularly limited, and can be set to any concentration in consideration of the surface properties of the intermediate layer and the coating layer.
  • the polymer constituting the coating layer or Z and the polymer constituting the intermediate layer are dissolved in an arbitrary solvent and are attached in the solution state, or after Z is attached. ⁇ is a surplus during or after Z and the polymer and drug constituting the coating layer are dissolved in an arbitrary solvent and deposited in a solution state Such solution may be removed. Examples of the removing means include vibration, rotation, decompression, etc., and a plurality of these may be combined.
  • the stent body is cut into a stent design by laser cutting a cylindrical tube of stainless steel (SUS316L) with an inner diameter of 1.50 mm and an outer diameter of 1.80 mm in the same manner as those usually made by those skilled in the art, and then electropolished. It was made with.
  • the developed view of the stent used is shown in Fig. 1, and the schematic diagram is shown in Fig. 2.
  • the stent length was 13 mm, the thickness was 120 m, and the nominal diameter after expansion was 3.5 mm.
  • the stent is said to be a balloon etaspan double type, and is a type in which the stent is expanded and indwelled using a neuron catheter provided with a neuron near the tip of the force taper. Balloon etaspun double-type stents are set in the balloon part of the balloon catheter in a deflated state, and after being delivered to the target location, the balloon is expanded and placed.
  • the solution prepared using a spray gun with a nozzle diameter of 0.3 mm was sprayed onto the stent, and the solution was adhered to the stent.
  • the distance from the spray gun nozzle force to the stent was 75 mm, and the air pressure during spraying was 0.15 MPa. After spraying, it was vacuum dried at room temperature for 1 hour. The spray time was adjusted to form an intermediate layer in which the weight of the lactic acid-glycolic acid copolymer per unit axial length of the stent body was 4 gZmm (52 g per stent).
  • the solution prepared using a spray gun with a nozzle diameter of 0.3 mm was sprayed onto the stent on which the intermediate layer was formed, and the solution was adhered to the stent.
  • the distance from the spray gun nozzle cover to the stent was 75 mm, and the air pressure during spraying was 0.15 MPa. After spraying, it was vacuum dried at room temperature for 1 hour.
  • a stent was prepared by adjusting the spray time and forming a coating layer with a weight force of 0 gZmm (520 g per stent) of the lactic acid-glycolic acid copolymer per axial unit length of the stent body. .
  • the intermediate layer weighs 2 gZmm (26 g per stent), and the coating layer is formed from a different lactic acid-glycolic acid copolymer (Product Number: RG504H, Boehringer
  • lactic acid Z glycolic acid 50/50, weight average molecular weight 50,000), and the weight per axial unit length of the stent body was 35 ⁇ gZmm (455 ⁇ g per stent) It was produced in the same manner as in Example 1.
  • the weight of the intermediate layer is 2 gZmm (26 g per stent), and the polymer forming the coating layer is poly-D, L-lactic acid (Product No .: R202H, Boehringer Ingelheim, weight average molecular weight 12,000)
  • the stent body was produced in the same manner as in Example 1 except that the weight per unit length in the axial direction of the stent body was 50 g Zmm (650 / zg per stent).
  • the intermediate layer weighs 4 ⁇ g / mm (52 ⁇ g per stent), and the polymer that forms the coating layer is poly-D, L-lactic acid (Product Number: R203H, Boehringer Ingelheim, weight average molecular weight 22) , 000) and the weight per unit axial length of the stent body was 42 g Zmm (546 ⁇ g per stent).
  • the polymer that forms the intermediate layer is poly-D, L-lactic acid (Product No .: 100D065, Absorbable Polymers International, weight average molecular weight 83, 000).
  • the weight average molecular weight was 50,000
  • the weight per axial unit length of the stent body was 48 ⁇ g / mm (624 ⁇ g per stent).
  • the weight of the intermediate layer is 2 gZmm (26 g per stent), and the polymer forming the coating layer is poly-D, L-lactic acid (Product No .: R202H, Boehringer Ingelheim, weight average molecular weight 12,000)
  • the stent body was prepared in the same manner as in Example 5 except that the weight per unit length in the axial direction of the stent body was 41 ⁇ g Zmm (533 ⁇ g per stent).
  • the weight of the intermediate layer is 7 g / mm (91 ⁇ g per stent), and the polymer forming the coating layer is poly-D, L-lactic acid (Product No .: R203H, Boehringer Ingelheim, weight average molecular weight 22, 000), and the weight per unit axial length of the stent body was 47 g Zmm (611 g per stent).
  • the weight of the intermediate layer is 4 ⁇ g / mm (52 ⁇ g per stent), and the polymer forming the coating layer is poly-D, L-lactic acid (Product No .: R202H, Boehringer Ingelheim, weight average molecular weight 12) , 000), and the weight per unit axial length of the stent body was 50 g Zmm (650 / zg per stent).
  • the intermediate layer weighs 5 ⁇ g / mm (65 ⁇ g per stent) and the polymer that forms the coating layer is poly-D, L-lactic acid (Product Number: R203H, Boehringer Ingelheim, weight average molecular weight 22) , 000) and the weight per unit axial length of the stent body was 39 ⁇ g Zmm (g per stent).
  • the stent body is cut into a stent design by laser cutting a cylindrical tube of stainless steel (SUS316L) with an inner diameter of 1.50 mm and an outer diameter of 1.80 mm in the same manner as those usually made by those skilled in the art, and then electropolished. It was made with.
  • the developed view of the stent used is shown in Fig. 1, and the schematic diagram is shown in Fig. 2.
  • the stent length was 13 mm, the thickness was 120 m, and the nominal diameter after expansion was 3.5 mm.
  • the stent is said to be a balloon etaspan double type, and is a type in which the stent is expanded and indwelled using a neuron catheter provided with a neuron near the tip of the force taper. Balloon etaspun double-type stents are set in a deflated state on the balloon part of the balloon catheter. After being delivered to the target location, the stent is expanded and placed.
  • a stainless steel wire with a diameter of 100 m was fixed to one end of the stent, and the other end was fixed to a stainless steel rod with a diameter of 2 mm. With the stent connected, the end of the stainless steel rod on the side was connected to a motor to hold the stent vertically in the length direction.
  • the solution prepared using a spray gun with a nozzle diameter of 0.3 mm was sprayed onto the stent, and the solution was adhered to the stent.
  • the distance from the spray gun nozzle force to the stent was 75 mm, and the air pressure during spraying was 0.15 MPa. After spraying, it was vacuum dried at room temperature for 1 hour. The spray time was adjusted to form an intermediate layer in which the weight of lactic acid-glycolic acid copolymer per unit axial length of the stent body was 3 ⁇ 8 ! 11111 (39 ⁇ g per stent).
  • the stent was held vertically in the length direction by connecting the end of the stainless steel rod to the motor! While rotating the stent at lOOrpm using a motor, the solution prepared using a spray gun with a nozzle diameter of 0.3 mm was sprayed onto the stent on which the intermediate layer was formed, and the solution was adhered to the stent.
  • the distance from the spray gun nozzle to the stent was 75 mm, and the air pressure during spraying was 0.15 MPa. After spraying, it was vacuum dried at room temperature for 1 hour. Adjust the spray time, the weight force of lactic acid-glycolic acid copolymer per unit axial length of the stent body 2 ⁇ 8 ! 11111 (520 ⁇ g per stent), tacrolimus weight 16 ⁇ g / mm
  • a stent with a coating layer (208 ⁇ g per stent) was used as a sample.
  • the polymer that forms the intermediate layer is poly-D, L-lactic acid (Product No .: 100D065, Absorbable Polymers International, weight average molecular weight 83, 000), and poly D, L lactic acid per axial unit length of the stent body
  • the weight of the polymer is 3 ⁇ g / mm (39 g per stent)
  • the polymer that forms the coating layer is poly-D, L lactic acid (product number: R202H, Boehringer Ingelheim, weight average molecular weight 12,000).
  • the intermediate layer weighs 4 ⁇ g / mm (52 ⁇ g per stent), and the polymer that forms the coating layer is poly-D, L-lactic acid (Product Number: R203H, Boehringer Ingelheim, weight average molecular weight 22) , 000), the weight of poly D, L-lactic acid per axial unit length of the stent body is 42 ⁇ g / mm (546 ⁇ g per stent), and the weight of tacrolimus is 16 ⁇ g / mm (stent It was produced in the same manner as in Example 15 except that the amount was 208 ⁇ g per piece.
  • the polymer forming the intermediate layer is poly-L-lactic acid (Product No. 100L105, Absorbable Polymers International, weight average molecular weight 145, 000), and the weight of poly-L-lactic acid per axial unit length of the stent body is 5 ⁇ 8 !! 1111 (65 ⁇ g per stent), the weight of lactic acid-glycolic acid copolymer per unit axial length of the stent body in the coating layer is 40 ⁇ g / mm (520 ⁇ g per stent) g), and prepared in the same manner as in Example 13 except that the weight of tacrolimus was changed to 15 g / mm (195 g per stent). [0048] (Example 18)
  • SIGMA sirolimus
  • the weight of lactic acid-glycolic acid copolymer per unit is 6 ⁇ gZmm (78 ⁇ g per stent)
  • the weight of lactic acid dalico-colic acid copolymer per axial unit length of the stent body is 37 ⁇ g Zmm (per stent) 481 ⁇ g)
  • the drug was cyclosporine (Ciba Geigy Japan)
  • the polymer that forms the coating layer is poly-D, L-lactic acid (product number: R202H, Boe hringer Ingelheim, weight average molecular weight 12,000), and the weight per axial unit length of the stent body is 50 gZmm ( It was produced in the same manner as in Comparative Example 1 except that 650 g per stent was used.
  • the polymer that forms the coating layer is poly-D, L-lactic acid (product number: R203H, Boe hringer Ingelheim, weight average molecular weight 22,000), and the weight per unit length in the axial direction of the stent body is 39 gZmm ( It was produced in the same manner as in Comparative Example 1 except that 507 g) was used per stent.
  • the weight of the lactic acid-glycolic acid copolymer per unit axial length of the stent body in the coating layer is 40 gZmm (520 g per stent), and the weight of tacrolimus is 15 gZmm ( It was produced in the same manner as in Example 13 except that 195 ⁇ g per stent was used.
  • the weight of the lactic acid-glycolic acid copolymer per unit axial length of the stent body in the coating layer is 42 gZmm (546 g per stent), and the drug is cyclosporine (Nippon Ciba-Geigy Corporation). And the weight of cyclosporine was 16 ⁇ g Zmm (208 ⁇ g per stent).
  • the weight of poly-D, L-lactic acid per unit axial length of the stent body in the coating layer was 39 g / mm (507 g per stent), and the drug was sirolimus (SIGMA And the weight of sirolimus was 15 ⁇ g / mm (195 ⁇ g per stent).
  • SIGMA sirolimus
  • the weight of poly D and L lactic acid per unit axial length of the stent body in the coating layer was 38 gZmm (494 g per stent), and the weight of tacrolimus was 14 gZmm (Stent 1
  • the same procedure as in Example 16 was performed except that the amount was 182 g per unit.
  • a prototype PTC A balloon catheter equipped with a 5 x 15 mm balloon was fabricated, and the above-mentioned stent was mounted on the balloon.
  • the balloon was expanded at 8 atm (810 kPa) under conditions of room temperature and air, and the stent was expanded. After 1 minute, the balloon was depressurized and the balloon was removed from the stent.
  • the expanded stent was fixed on a sample stage for electron microscope observation, a Pt—Pd alloy was deposited, and the surface was observed with a scanning electron microscope (S 3000N, Hitachi High-Technologies Corporation).
  • Tables 1 to 3 show the results of qualitative evaluation of the frequency of coating cracking and peeling. As typical examples of cracking and peeling of the coating, Fig. 3 shows an SEM observation image of Example 3, and Fig. 4 shows an SEM observation image of Comparative Example 6.
  • Type Composition amount Type Composition amount Crack Peeling
  • Example 1 PLGA 85DG065 4 PLGA RG502H 40 1 o ⁇
  • Example 2 PLGA 85DG065 2 PLGA RG504H 35 ⁇ oo
  • Example 3 PLGA 85DG065 2 PDLLA R202H 50 ⁇ ⁇ ⁇
  • Example 4 PLGA 85DG065 4 PDLLA R203H 42 ⁇ oo
  • Example 5 PDLLA 100D065 5 PLGA RG502H 43 ⁇ oo
  • Example 6 PDLLA 100D065 3 PLGA RG504H 48 ⁇ oo
  • Example 7 PDLLA 1 00D065 2 PDLLA R202H 41 ⁇ o ⁇
  • Example 8 PDLLA 1000065 7 PDLLA R203H 47 ⁇ ⁇ ⁇
  • Example 9 PLLA 100L105 3 PLGA RG502H 30 ⁇ ⁇ ⁇
  • Example 10 PLLA 100L105 5 PLGA RG504H 48 ⁇ ⁇ ⁇
  • PDLLA Poly-D, L lactic acid
  • Example 1 1 PLLA 100L105 4 PDLLA R202H 50 ⁇ ⁇ ⁇ Example 12 PLLA 100L105 5 PDLLA R203H 39 ⁇ ⁇ o Example 13 PLGA 85DG065 3 PLGA RG502H 42 16 ⁇ ⁇ Example 14 PLGA 85DG065 7 PLGA RG504H 47 18 ⁇ ⁇ Example 15 PDLLA 100D065 3 PDLLA R202H 46 17 o Yes Example 16 PDLLA 100D065 4 PDLLA R203H 42 16 o Yes Example 17 PLLA 100L105 5 PLGA RG502H 40 15 Yes Yes Example 18 PLLA 100L105 4 PLGA RG504H 39 15 o Yes Example 19 PLGA 85DG065 6 PLGA R6502H 37 14 oo
  • PDLLA Poly-D, L lactic acid
  • the stent for indwelling includes a non-degradable material in vivo as a stent base material, and at least a part of the stent body has a coating layer containing a polymer as a component.
  • a coating layer containing a polymer as a component.
  • an intermediate layer with a higher molecular weight than that of the polymer is present between the coating layer and the stent body surface, so that the coating layer can be effectively prevented from peeling and cracking due to stent expansion. It is.

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Abstract

L'endoprothèse vasculaire se plaçant dans le corps ci-décrite est facile à fabriquer et possède une couche de revêtement composée d'un polymère qui permet d'empêcher efficacement le décollement ou le fissurage de la couche de revêtement dû à l'expansion de l'endoprothèse vasculaire. L'invention concerne en particulier une endoprothèse vasculaire se plaçant dans le corps qui comprend une couche de revêtement composée d'un polymère et une couche intermédiaire placée entre la couche de revêtement et la surface de l'endoprothèse vasculaire et composée d'un polymère ayant une masse moléculaire de poids moyen plus élevé que le polymère de la couche de revêtement. Les polymères sont de préférence biodégradables, et peuvent contenir un agent thérapeutique.
PCT/JP2005/016000 2004-09-08 2005-09-01 Endoprothese vasculaire se plaçant dans le corps WO2006027992A1 (fr)

Priority Applications (3)

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US11/574,877 US20080077232A1 (en) 2004-09-08 2005-09-01 Stent for Placement in Body
EP05781548A EP1787676A4 (fr) 2004-09-08 2005-09-01 Endoprothese vasculaire se plaçant dans le corps
JP2006535705A JP5056013B2 (ja) 2004-09-08 2005-09-01 生体留置用ステント

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Cited By (1)

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WO2008142977A1 (fr) * 2007-05-11 2008-11-27 Kaneka Corporation Endoprothèse

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JP2008119199A (ja) * 2006-11-10 2008-05-29 Kagoshima Univ カルシニューリン産生亢進を抑制する薬剤コーティングステント
EP2134380A2 (fr) * 2007-03-28 2009-12-23 Boston Scientific Scimed, Inc. Dispositifs médicaux ayant des couches bioérodables pour la libération d'agents thérapeutiques
JP2009247506A (ja) * 2008-04-03 2009-10-29 Kaneka Corp ステント

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JP2004097810A (ja) * 2002-08-20 2004-04-02 Terumo Corp 体内埋込医療器具
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EP0604022A1 (fr) * 1992-12-22 1994-06-29 Advanced Cardiovascular Systems, Inc. Endoprothèse résorbable, à plusieurs couches, pour le maintien des vaisseaux, et sa méthode de fabrication
US6120536A (en) * 1995-04-19 2000-09-19 Schneider (Usa) Inc. Medical devices with long term non-thrombogenic coatings
DE60130032D1 (de) * 2000-12-22 2007-09-27 Avantec Vascular Corp Vorrichtung zur Abgabe von therapeutischen Wirkstoffen
US7041308B2 (en) * 2002-04-18 2006-05-09 Poly-Med, Inc. Drug-polymer coated stents with segmented homochain copolyesters

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JP2004097810A (ja) * 2002-08-20 2004-04-02 Terumo Corp 体内埋込医療器具
WO2004026361A1 (fr) * 2002-09-18 2004-04-01 Medtronic Vascular, Inc. Revetement a gradient de liberation de medicament controlee pour dispositifs medicaux
JP2004222953A (ja) * 2003-01-22 2004-08-12 Kanegafuchi Chem Ind Co Ltd 生体留置用ステント

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WO2008142977A1 (fr) * 2007-05-11 2008-11-27 Kaneka Corporation Endoprothèse

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