WO2016067994A1 - 薬剤溶出型ステント - Google Patents
薬剤溶出型ステント Download PDFInfo
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- WO2016067994A1 WO2016067994A1 PCT/JP2015/079693 JP2015079693W WO2016067994A1 WO 2016067994 A1 WO2016067994 A1 WO 2016067994A1 JP 2015079693 W JP2015079693 W JP 2015079693W WO 2016067994 A1 WO2016067994 A1 WO 2016067994A1
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- stent
- drug
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- cilostazol
- lactide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- 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
- A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6957—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a device or a kit, e.g. stents or microdevices
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
-
- 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
- A61L31/10—Macromolecular materials
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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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
- A61L2300/432—Inhibitors, antagonists
- A61L2300/434—Inhibitors, antagonists of enzymes
Definitions
- the present invention relates to a stent coated with cilostazol and a method for producing the same.
- PTCA is a narrow tube (balloon catheter) or stent with a balloon attached to the tip, inserted through the artery of the arm or thigh and passed through the stenosis of the coronary artery of the heart. It is a technique to restore blood flow by expanding and expanding the blood vessels. This dilates the vascular lumen of the lesion, thereby increasing blood flow through the vascular lumen.
- This PTCA is used not only for arteriosclerotic diseases but also for the treatment of stenosis of shunt blood vessels formed on the arms of hemodialysis patients.
- the blood vessel site subjected to PTCA has suffered injury such as endothelial cell detachment or elastic plate damage, and the intima proliferation, which is a healing reaction of the blood vessel wall, occurs, and PTCA causes the stenotic lesion to open. Restenosis occurs in about 30-40% of successful cases.
- the cause of restenosis in humans is mainly due to the inflammatory process observed in monocyte adhesion and invasion that occurs 1 to 3 days after PTCA, and smooth muscle cells that peak most proliferatively after about 45 days An intimal thickening process is considered.
- PTCA vascular endothelial growth factor
- the surface of a stent or balloon catheter made of a metal or a polymer material has a drug-eluting lumen in which an anticancer agent, an immunosuppressive agent, or an anti-inflammatory agent or a smooth muscle cell proliferation inhibitor is supported.
- an anticancer agent or an immunosuppressive agent is generally a rims-based drug.
- Patent Document 1 discloses a drug-eluting stent (Drug-Eluting Stent: hereinafter abbreviated as “DES”) in which a stent body is coated with biocompatible nanoparticles encapsulating a physiologically active substance for treatment, and a method for producing the same Has been proposed, and a spherical crystallization method is described as a method for producing biocompatible nanoparticles.
- DES drug-eluting stent
- Patent Document 2 discloses a method of attaching a drug by dipping a stent or catheter as a carrier in a drug solution insoluble in water and drying it.
- a stent or catheter as a carrier in a drug solution insoluble in water and drying it.
- there is a limit to the amount of adhesion so it was difficult to attach a necessary and sufficient amount of drug.
- the adhered drug is released in a short time, it is difficult to control the release time.
- Patent Document 3 discloses a drug-release-controlled multilayer coating stent in which a drug component and a biocompatible polymer are coated on the stent surface as a secondary coating layer, and probucol is described as an example of the drug component.
- Patent Document 4 discloses a medical device coated with a biocompatible substrate containing a pharmaceutical substance
- Patent Document 5 discloses a balloon and an implant at least partially coated with a film containing a drug and a carrier.
- a drug delivery system using an embedded prosthesis (stent) is disclosed.
- probucol is described as a drug.
- cilostazol which has another effect of inhibiting platelet aggregation, which is another poorly water-soluble drug, has been tried to be applied to the same medical device as described above (Patent Documents 3, 6 to 20). Attempts have been made to nano-size biocompatible particles used for coating and to attach them to the stent together with the cilostazol particles with electric charge, but the manufacturing is complicated, and other methods have the same problems as described above. It was.
- the present invention is expected to be difficult to prepare because it is hardly soluble in water, but by using cilostazol, which is not cytotoxic, as a drug, (1) suppression of intimal thickening and (2) blood vessels
- cilostazol which is not cytotoxic, as a drug
- suppression of intimal thickening and (2) blood vessels
- the inventors of the present invention have intensively studied to solve the above-mentioned problems, and as a result of coating cilostazol on a stent together with a bioabsorbable polymer having a certain range of molecular weight, coating strength capable of stably holding cilostazol, moderate elution It has been found that a speed can be obtained, and in particular, since the elution rate is optimal, it has been found that a cilostazol-eluting stent has an excellent effect of suppressing intimal thickening, and the present invention has been completed.
- the present invention provides a stent and a method for producing the stent described in [Item 1] to [Item 14] below.
- [Item 1] On the surface of the stent body made of a metal or polymer material, Coated with a mixture comprising cilostazol and a bioabsorbable polymer, A drug-eluting stent, wherein the bioabsorbable polymer has a molecular weight of 40,000 to 600,000.
- the bioabsorbable polymer comprises: (A) a polymer comprising DL lactide and glycolide in a weight ratio of 7: 3 to 9: 1 and having a molecular weight of 40,000 to 400,000; (B) a polymer comprising DL lactide having a molecular weight of 50,000 to 100,000, (C) a polymer comprising L lactide and DL lactide in a weight ratio of 6: 4 to 8: 2, and having a molecular weight of 300,000 to 600,000, (D) a polymer containing L-lactide having a molecular weight of 50,000 to 150,000, or (e) containing L-lactide and caprolactone in a weight ratio of 6: 4 to 8: 2, and having a molecular weight of 150,000 to 400,000 Item 2.
- the drug eluting stent according to Item 1 comprising any one of the following polymers.
- a drug-eluting stent wherein a surface of a stent body made of a metal or a polymer material is ultrasonically spray-coated with a mixture containing cilostazol and a bioabsorbable polymer having a molecular weight of 40,000 to 600,000. Production method.
- the bioabsorbable polymer comprises: (A) a polymer comprising DL lactide and glycolide in a weight ratio of 7: 3 to 9: 1 and having a molecular weight of 40,000 to 400,000; (B) a polymer comprising DL lactide having a molecular weight of 50,000 to 100,000, (C) a polymer comprising L lactide and DL lactide in a weight ratio of 6: 4 to 8: 2, and having a molecular weight of 300,000 to 600,000, (D) a polymer containing L-lactide having a molecular weight of 50,000 to 150,000, or (e) containing L-lactide and caprolactone in a weight ratio of 6: 4 to 8: 2, and having a molecular weight of 150,000 to 400,000 Item 10.
- the method according to Item 9 comprising any one of the following polymers.
- the coating agent containing cilostazol is stably coated on the stent, has a high coating strength, and particularly its dissolution rate is optimal, so that the inflammatory process and intimal thickening after placement of the stent
- the drug is eluted at the time when restenosis occurs during the formation process, acts on vascular cells, and has an effective effect of suppressing intimal thickening, greatly increasing the restenosis after stent placement, which has occurred with a high probability until now. It can be improved.
- intimal thickening can be suppressed without causing the inhibition of regeneration of vascular endothelial cells that occurs when a limus system is used as a drug.
- Example 2 The entire shape of the stent (a) and the cross-sectional view between AA (b) are shown.
- Example 2 the example of a malfunction at the time of coating (water web shape).
- Example 2 the example of the malfunction at the time of coating (coating unevenness).
- the result of Example 2 is shown.
- the result of Example 3 is shown.
- the result of Example 4 is shown.
- Explanatory drawing of Example 5 is shown.
- the intima / media ratio as a result of Example 5 is shown.
- the neointimal area which is a result of Example 5 is shown.
- the endothelial covering degree which is a result of Example 5 is shown.
- Cilostazol used in the present invention has a chemical name of 6- [4- (1-cyclohexyl-1H-tetrazol-5-yl) butoxy] -3,4-dihydrocarbostyril, a platelet aggregation inhibitory action, phosphodiesterase (PDE). ) Inhibitory action, anti-ulcer action, antihypertensive action and anti-inflammatory action, and is useful as an antithrombotic agent, cerebral circulation improving agent, anti-inflammatory agent, anti-ulcer agent, antihypertensive agent, anti-asthma agent, phosphodiesterase inhibitor, etc. It is known. Cilostazol also includes pharmaceutically acceptable salts thereof.
- bioabsorbable polymer used in the present invention examples include polylactic acid containing lactide and / or glycolide, and the molecular weight thereof is 40,000 to 600,000. That is, a polymer containing DL lactide, L lactide, glycolide, caprolactone, etc. More specifically, (a) DL lactide and glycolide are contained in a weight ratio of 7: 3 to 9: 1, and the molecular weight is 40,000.
- a polymer of ⁇ 400,000 (b) a polymer containing DL lactide having a molecular weight of 50,000 to 100,000, (c) a weight ratio of L lactide and DL lactide of 6: 4 to 8: 2, and a molecular weight of A polymer of 300,000 to 600,000, (d) a polymer comprising L lactide having a molecular weight of 50,000 to 150,000, (e) comprising L lactide and caprolactone in a weight ratio of 6: 4 to 8: 2. Examples thereof include polymers having a molecular weight of 150,000 to 400,000.
- Preferred bioabsorbable polymers include the bioabsorbable polymers listed in Table 1 of the examples below or mixtures thereof, more preferably RG858S, RG755S, LR704S, 755/703, or mixtures thereof. Can be mentioned.
- the coating agent 3 contains a mixture of cilostazol, which is a drug, and the bioabsorbable polymer.
- the bioabsorbable polymer needs to maintain high strength while preventing peeling of the coating because cilostazol is poorly soluble.
- the mixing weight ratio of cilostazol and polylactic acid is preferably 4: 6 to 7: 3. If it is within the range of this ratio, a good intimal thickening effect can be obtained. When the mixing weight ratio is 4: 6 to 6: 4, the coating strength can be further increased.
- the stent used in the present invention is a commonly used stent of a metal or a polymer material, and examples of the metal stent include a suitable alloy of nickel, cobalt, chromium, titanium or stainless steel, preferably a cobalt chromium alloy. It is a metal stent as a component.
- the conventional simple spraying method dipping method, electrodeposition method, ultrasonic spraying method, and the like can be mentioned.
- the ultrasonic spray method is preferable.
- FIG. 1 (a) is a schematic view showing a drug-eluting stent of the present invention.
- FIG. 1B is a cross-sectional view taken along the line AA in FIG.
- the stent 1 has a configuration in which a mesh pattern is provided around a cylindrical lumen having a longitudinal axis, and is formed to be expandable in the circumferential direction. Then, it is inserted into the body in an unexpanded form, expanded at the treatment site in the blood vessel, and placed in the blood vessel. Dilation may be achieved intravascularly with a balloon catheter.
- the mesh is schematically shown in FIG. 1, it goes without saying that the present invention can be applied to any mesh pattern.
- the stent 1 of the present invention has a base member 2 coated with a coating agent 3.
- the base member 2 can be manufactured using any method. For example, it can be fabricated from hollow or formed stainless steel tubes by laser, electrical discharge milling, chemical etching or other means.
- the base member 2 can be formed of a suitable alloy such as nickel, cobalt, chromium, titanium, or stainless steel.
- FIG. 2 is a schematic view showing an ultrasonic spray coating apparatus 4 for applying a coating agent 3 on the base member 2.
- the coating process first, the surface of the base member 2 is subjected to plasma processing before the coating process by a plasma processing apparatus (not shown). After the plasma treatment, the base member 2 is attached to the mandrel and attached to the ultrasonic spray coating apparatus 4.
- the coating liquid is fed through the pipe 6 by a syringe pump, atomized by the ultrasonic spray nozzle 5, and sprayed.
- the base member 2 is rotated and linearly moved under the ultrasonic nozzle 5 to deposit the coating agent 3 on the base member 2.
- the stent 1 can be produced by drying in a nitrogen stream while rotating the base member 2 while moving linearly, and further drying in a desiccator under reduced pressure.
- a solution obtained by dissolving cilostazol and a polymer in a solvent is used.
- a volatile solvent having a low boiling point can be used so that it can be easily removed after coating.
- volatile solvent examples include methanol, ethanol, trifluoroethanol, hexafluoroisopropanol, isoamyl alcohol, methyl acetate, ethyl acetate, acetone, methyl ethyl ketone, methylene chloride, chloroform, dichloroethane, and at least two mixed solvents thereof. Is mentioned.
- Example 1 Cobalt chromium alloy is used as the base member 2, and the coating weight is applied by ultrasonic spray coating by changing the mixing weight ratio of cilostazol and polymer using the polymers of (e), (j) and (p) above. A coating strength test was performed. Table 2 shows the results. In the table, ⁇ indicates that the strength is very high, ⁇ indicates that the strength is high, and ⁇ indicates that the strength is low. When the mixing weight ratio (D / P ratio) between cilostazol and polymer is 6: 4 or less, that is, when the amount of cilostazol is less than this ratio, the strength is high, and particularly when the ratio is 5: 5 or less, sufficient strength is obtained.
- D / P ratio the mixing weight ratio
- the D / P ratio is preferably 4: 6 or more.
- Example 2 A cobalt-chromium alloy was used as the base member 2, and a coating agent in which cilostazol and 17 types of polymers (a) to (q) shown in Table 1 were mixed was applied onto the base member 2 by ultrasonic spray coating.
- the mixing weight ratio of cilostazol and each polymer was 5: 5.
- the appearance of coating application was observed. In the appearance observation, it was judged that “no good” was obtained after application without the presence of water scoops as shown in FIG. 3 or coating unevenness as shown in FIG. The results are shown in FIG.
- the vertical axis represents the molecular weight of the polymer layer mixed with cilostazol
- the horizontal axis represents the dissolution rate of the coating agent.
- (A) to (q) in the graph represent data when the above 17 types of polymers are used.
- FIG. 5 there was a tendency that the coating was good in the area surrounded by the ellipse. From this figure, it can be seen that the degree of goodness does not greatly affect the elution rate and tends to depend on the molecular weight of the polymer. That is, the polymer used for the coating agent containing cilostazol preferably has a molecular weight of 40,000 to 600,000.
- (e) (h) (j) (m) (p) (q) good application of the coating agent was observed.
- Example 3 Using the above polymers (e), (h), (j), (m), (p), and (q), a stent produced in the same manner as in Example 2 was prepared as follows. The stent was placed in the iliac blood vessel, and the intimal thickening inhibitory effect of the stent was confirmed. First, an incision is made in the rabbit neck, the right carotid artery is exposed, and an introducer is placed. A balloon catheter guide wire is inserted through the introducer and moved under fluoroscopy to the distal portion of the iliac artery treatment site. Thereafter, an imaging catheter is inserted along the guide wire, and angiography of the treatment site of the iliac artery is performed.
- the balloon catheter of the specimen is inserted along the balloon catheter guide wire to the treatment site under fluoroscopy.
- the balloon is 14 atm (overexpanded) using an indeflator.
- the balloon was deflated, the indeflator was removed, and the balloon catheter was replaced with a guidewire for the balloon catheter. Pull along.
- the left and right iliac arteries are treated in the same way.
- the contrast catheter is moved to the front of the treatment site along the balloon catheter guide wire, and angiography is performed using the diluted contrast agent.
- the contrast catheter is withdrawn.
- the blood vessel at the sheath insertion site is ligated and the skin and muscle layer are sutured.
- the stent is placed in the iliac blood vessel of the rabbit. Intimal thickening was performed by recording angiography before treatment, immediately after stent placement (reference diameter) and before autopsy (after 28 days) on DVD, and observing the stent placement site.
- intimal thickening was evaluated by taking the difference between the reference diameter immediately after placement of the stent and the narrowest blood vessel diameter before the site examination.
- the result is shown in FIG. What is indicated as “no drug” in the figure is the result when only the stent is placed without applying cilostazol.
- Others show stents coated with a coating agent in which the above polymer and cilostazol are mixed at 5: 5.
- the vertical axis represents intimal thickening, and the smaller the value, the higher the thickening suppressing effect. It can be seen that (j) with cilostazol significantly suppresses intimal thickening.
- intimal thickening could be suppressed by the coating containing cilostazol.
- endothelial cells were able to regenerate well, and could not be realized when using the rims system as a drug, (1) suppression of intimal thickening, (2) Both inhibition of endothelial cell regeneration inhibition could be realized.
- Example 4 Using the polymer of (e) above, the mixing weight ratio (D / P ratio) of cilostazol (D) and polymer (P) was changed to produce a stent, and the produced stent was placed in the iliac blood vessel of a rabbit. The indwelling suppression effect by the stent was confirmed.
- FIG. 7 shows the result. It can be seen that the intimal thickening can be suppressed to a greater extent than the case of only the base member (BMS) or the case of only the base member (BMS) or the mixture weight ratio (D / P ratio) of 4: 6, 7: 3.
- Example 5 Similarly, using the polymer (e), the mixing weight ratio (D / P ratio) of cilostazol and polymer (e) was fixed at 5: 5, and a stent was prepared with a weight of cilostazol of 300 ⁇ g to 600 ⁇ g. The stent was placed in the porcine iliac blood vessel, and (I) intima / media ratio, (II) neointimal area, (III) vascular endothelial cell coating of the iliac blood vessel at the indwelling site after 28 days The degree was observed.
- the neointimal area refers to the cross-sectional area of the intima 81 newly formed in the inner part of the blood vessel in the cross section of the blood vessel 80 at the placement site of the stent with reference to FIG. .
- the intima / media ratio is the ratio of the neointimal area to the area of the media 82 in the blood vessel cross section.
- FIG. 9 Shows the (I) intima / media ratio when varying the cilostazol weight.
- a blood vessel cross-sectional photograph after 28 days indwelling when each cilostazol weight is used is placed.
- the data marked BMS is data when using a metal stent to which no drug and polymer are applied.
- FIG. 9 shows that when the cilostazol weight is more than 400 ⁇ g, the intima / media ratio is greatly reduced below 100%, and the intima formation at the stent placement site can be suppressed.
- intimal thickening can be suppressed with a significant difference from the case of only a metal stent (BMS) having an intima / media ratio exceeding 260%. Yes.
- BMS metal stent
- the weight of cilostazol becomes too large, the amount of polymer increases accordingly, and the total amount applied to the stunt increases, making it difficult to form a uniform and strong film. From the results of FIG. 9, the decrease in the intima / media ratio is saturated when the weight of cilostazol is 500 ⁇ g to 600 ⁇ g.
- the weight of cilostazol is preferably more than 400 ⁇ g and less than 700 ⁇ g, and more preferably 500 ⁇ g or more and 600 ⁇ g or less.
- FIG. 10 is a diagram showing (II) neointimal area when cilostazol weight is changed.
- FIG. 10 shows that the neointimal area is reduced compared to the case of only the metal stent (BMS) at any weight, especially when the cilostazol weight is more than 400 ⁇ g. I understand.
- the neointimal area decreased with a significant difference from the case of only the metal stent (BMS).
- FIG. 11 shows (III) vascular endothelial cell coverage when cilostazol weight was changed. It can be seen that the application of cilostazol and polymer makes it easier to stretch the vascular endothelium compared to the case of only the metal stent (BMS) at any weight. As shown in the results of FIGS. 9 to 11, according to the present invention, it is possible to suppress intimal thickening at the stent placement site and to prevent the regeneration of vascular endothelial cells.
- the cilostazol weight is preferably more than 400 ⁇ g and less than 700 ⁇ g, and more preferably 500 ⁇ g or more and 600 ⁇ g or less.
- Stent 2 Base member 3: Coating agent 4: Ultrasonic spray coating device 5: Ultrasonic spray nozzle 6: Piping 80: Cross section of blood vessel 81: Intima 82: Media
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Abstract
Description
薬剤溶出型ステントに塗布する薬剤としては、抗癌剤や免疫抑制剤であるリムス系の薬剤が一般的である。これらの薬剤はその強い細胞毒性によって、再狭窄の主な要因である血管平滑筋細胞の増殖、いわゆる内膜肥厚を強力に抑制する効果がある。しかしながら一方で、血管内皮細胞の再生をも強力に抑制するため、遅発性ステント内血栓症を誘発するという臨床上の大きな課題を残している。遅発性ステント内血栓症は、発現率が1%以下と少ないものであるが、一旦発症すると心臓死を招くほど予後が悪くシリアスな問題を生じさせる。
この問題を解決するため、現在、ステントに塗布する上記リムス系薬剤の薬剤量を少なくするなどして、血管内皮細胞再生の阻害を抑制するための開発が盛んに行われている。しかしながら、リムス系の薬剤を使用している以上、上記の問題を根本的に解決はできていない。
リムス系以外の薬剤、例えば、プロブコールやシロスタゾールを使用する試みもなされているが、リムス系以外での薬剤溶出性ステントの実用例はまだ無い。
このシロスタゾール溶出型ステントでは、細胞毒性のないシロスタゾールを薬剤として使用するため、リムス系を薬剤として使用した場合に生じる血管内皮細胞の再生阻害を起こすことなく、内膜肥厚を抑制できることが期待できる。
[項1]金属または高分子材料からなるステント本体の表面に、
シロスタゾールと生体吸収性ポリマーとを含む混合物がコーティングされて含まれ、
前記生体吸収性ポリマーの分子量が40,000から600,000である薬剤溶出型ステント。
(a)DLラクチドとグリコリドを7:3~9:1の重量比率で含み、分子量が40,000~400,000のポリマー、
(b)分子量が50,000~100,000のDLラクチドを含むポリマー、
(c)LラクチドとDLラクチドを6:4~8:2の重量比率で含み、分子量が300,000~600,000のポリマー、
(d)分子量が50,000~150,000のLラクチドを含むポリマー、または
(e)Lラクチドとカプロラクトンを6:4~8:2の重量比率で含み、分子量が150,000~400,000のポリマー
のいずれかを含む項1の薬剤溶出型ステント。
(a)DLラクチドとグリコリドを7:3~9:1の重量比率で含み、分子量が40,000~400,000のポリマー、
(b)分子量が50,000~100,000のDLラクチドを含むポリマー、
(c)LラクチドとDLラクチドを6:4~8:2の重量比率で含み、分子量が300,000~600,000のポリマー、
(d)分子量が50,000~150,000のLラクチドを含むポリマー、または
(e)Lラクチドとカプロラクトンを6:4~8:2の重量比率で含み、分子量が150,000~400,000のポリマー
のいずれかを含む項9の製造方法。
また、細胞毒性のないシロスタゾールを薬剤として使用するため、リムス系を薬剤として使用した場合に生じる血管内皮細胞の再生阻害を起こすことなく、内膜肥厚を抑制できる。
シロスタゾールとポリ乳酸の混合重量比率は4:6~7:3が好ましい。この比率の範囲内であれば、良好な内膜肥厚効果を得ることができる。また、混合重量比率が4:6~6:4の場合にはコーティング強度を更にあげることができる。
本発明者は、従来における薬剤溶出型ステントの問題点を解決すべく、鋭意努力した結果、シロスタゾールと以下に示すポリマーとを金属ステントまたは高分子材料ステント上にコーティングすることにより、シロスタゾールを安定に保持することができ、且つ、内膜肥厚抑制効果の高い薬剤溶出型ステントを実現できることを見いだした。
コーティング液は、シロスタゾールとポリマーとを溶媒に溶かしたものを使用する。溶媒としては、コーティング後に容易に除去できるように沸点の低い揮発性溶媒が使用できる。揮発性溶媒としては、例えば、メタノール、エタノール、トリフルオロエタノール、ヘキサフルオロイソプロパノール、イソアミルアルコール、酢酸メチル、酢酸エチル、アセトン、メチルエチルケトン、塩化メチレン、クロロホルム、ジクロロエタンや、それらの中の少なくとも2つの混合溶媒が挙げられる。
ベース部材2としてコバルトクロム合金を用い、上記の(e)、(j)、(p)のポリマーを用いて、シロスタゾールとポリマーの混合重量比を変えて、超音波スプレイコーティングによりコーティングを行い、そのコーティングの強度試験を行った。表2にその結果を示す。表中で○は強度が非常に高いこと、△は強度が高いこと、×は強度が低いことを示している。
シロスタゾールとポリマーとの混合重量比(D/P比)が6:4以下、すなわちこの比率よりシロスタゾールが少ない場合において強度が高くなっており、特に5:5以下の場合に十分な強度が得られていることが分かる。ただし、D/P比が4:6よりも小さくなると、薬剤溶出性ステントとして、シロスタゾールの薬剤としての効果が出にくくなるため、D/P比は4:6以上であることが望ましい。
ベース部材2としてコバルトクロム合金を用い、シロスタゾールと表1に示した(a)から(q)の17種類のポリマーを混合したコーティング剤を、そのベース部材2上に超音波スプレイコーティングにより塗布した。ここでシロスタゾールと各ポリマーの混合重量比は5:5とした。
作製したステントについて、コーティングの塗布具合を外観観察した。外観観察では、塗布後に図3に示すような水かきや図4に示すような塗りむらが存在することなく、且つ、表面がオレンジピール状にならず平滑なものを“良好”と判断した。結果を図5に示す。この図において縦軸は、シロスタゾールと混合したポリマー層の分子量であり、横軸はコーティング剤の溶出速度を示す。グラフ中の(a)から(q)は上記17種類のポリマーを用いた場合のデータを表わしている。
図5において楕円にて囲んだ領域内においてコーティングが良好となる傾向が見られた。この図より、良好度は溶出速度には大きくは影響されず、ポリマーの分子量により左右される傾向にあることがわかる。つまり、シロスタゾールを含有するコーティング剤に使用するポリマーとしては分子量40,000~600,000のものが好ましい。特に、(e)(h)(j)(m)(p)(q)において、コーティング剤の良好な塗布が観察された。
上記の(e)、(h)、(j)、(m)、(p)、(q)のポリマーを用いて、実施例2と同様の方法で作製したステントを、以下のようにしてウサギの腸骨血管内に留置して、ステントによる内膜肥厚抑制効果を確認した。
まず、ウサギの頚部を切開し、右頚動脈を露出させて、イントデュサーを留置する。バルーンカテーテル用ガイドワイヤーをイントデュサーから挿入して、X線透視下で腸骨動脈の処置部位の遠位部まで移動させる。その後、造影用カテーテルをガイドワイヤーに沿って挿入し、腸骨動脈の処置部位の血管造影を行う。処置部位の血管造影終了後、X線透視下にて、検体のバルーンカテーテルを処置部位までバルーンカテーテル用ガイドワイヤーに沿って挿入する。検体のステント(標準径拡張圧9atm時ステント径2.75mm)が腸骨動脈の処置部(予定血管径2.5mm)にあることを確認した後、インデフレーターを用いてバルーンを14atm(過拡張、予定ステント径3.0mm、20%過拡張)で1回20秒間拡張を保持しステントが拡張したことを確認した後、バルーンを収縮させてインデフレーターを取り外し、バルーンカテーテルをバルーンカテーテル用ガイドワイヤーに沿って引き抜く。左右の腸骨動脈に同様の方法で処置を行う。
次いで、バルーンカテーテル用ガイドワイヤーに沿って造影用カテーテルを処置部位の手前まで移動させて、希釈造影剤を用いて血管造影を行う。左右の腸骨動脈に同様の方法で処置を行った後、造影用カテーテルを引き抜く。最後にシース挿入部位の血管を結紮し、皮膚及び筋層を縫合する。以上により、ウサギの腸骨血管内にステントが留置される。
内膜肥厚は、処置前、ステント留置直後(リファレンス径)および剖検前(28日後)の血管造影をDVDに録画し、ステント留置部位を観察することにより行った。そして、ステント留置直後のリファレンス径と、部検前における最も狭い血管径との差を取ることで内膜肥厚を評価した。
図6にその結果を示す。図中の「薬剤なし」と表記しているものはシロスタゾールを塗布せずにステントのみを留置した場合の結果である。その他は上記のポリマーとシロスタゾールを5:5にて混合させたコーティング剤を塗布したステントを示している。
図6において、縦軸は内膜肥厚であり、この値が小さいほど肥厚抑制効果が高いことになる。シロスタゾールを加えた(j)では内膜肥厚を大きく抑制できていることが分かる。同様に、(e)、(p)においてもシロスタゾールを含むコーティングにより内膜肥厚を抑制できた。また、ステント留置部において内皮細胞を観察したところ、内皮細胞が良好に再生できていることが観測でき、リムス系を薬剤として用いたときには実現できなかった、(1)内膜肥厚の抑制と、(2)内皮細胞の再生阻害の抑制の両方を実現できていた。
上記の(e)のポリマーを用いて、シロスタゾール(D)とポリマー(P)の混合重量比(D/P比)を変えて、ステントを作製し、作製したステントをウサギの腸骨血管内に留置して、ステントによる内膜肥厚抑制効果を確認した。図7にその結果を示す。
混合重量比(D/P比)が4:6、7:3のものともに、ベース部材のみの場合(BMS)やポリマーのみの場合よりも大きく内膜肥厚が抑制できていることが分かる。
また、ステント留置部において内皮細胞を観察したところ、内皮細胞が良好に再生できていることが観測でき、リムス系を薬剤として用いたときには実現できなかった、(1)内膜肥厚の抑制と、(2)内皮細胞の再生阻害の抑制の両方を実現できていた。
同じく上記の(e)のポリマーを用い、シロスタゾールとポリマー(e)の混合重量比(D/P比)を5:5に固定してシロスタゾールの重量を300μg~600μgとしてステントを作製した。そのステントをブタの腸骨血管内に留置して、28日後の留置部位における該腸骨血管の(I)内膜/中膜比率、(II)新生内膜面積、(III)血管内皮細胞被覆度を観察した。
ここで、(II)新生内膜面積は、図8を参照して、ステントの留置部位における血管80の断面において、血管の内側部分に新たに形成された内膜81の断面積を指している。(I)内膜/中膜比率は、血管断面における中膜82の面積に対する、上記の新生内膜面積の比率である。
なお、観察は次の工程により行った。
(a)腸骨血管の取り出し
(b)洗浄後、脱脂
(c)樹脂を浸透させた後、樹脂を重合させることで固定化
(d)目標部位において切断
(e)染色し、顕微鏡観察
図9は、シロスタゾール重量を変えたときの(I)内膜/中膜比率を示している。上部には各シロスタゾール重量を用いたときの28日留置後の血管断面写真を載せている。ここでBMSと標記されているデータは、薬剤およびポリマーが塗布されていない金属ステントを用いた場合のデータである。
図9より、シロスタゾール重量が400μgより多い場合に、内膜/中膜比率が100%を下回って大きく低下しており、ステント留置部位での内膜の生成を抑制できていることが分かる。特にシロスタゾール重量が500μg、600μgの場合には、内膜/中膜比率が260%を超えている金属ステントのみ(BMS)の場合とは、有意差を持って内膜肥厚を抑えることができている。
ところで、シロスタゾールの重量が大きくなり過ぎると、それに伴ってポリマー量も大きくなるため、スタントへの塗布量全体が増大し、均一で強固な膜を形成しにくくなる。また、図9の結果から、シロスタゾールの重量が500μg~600μgの場合で内膜/中膜比率の低下が飽和してきている。これらより、シロスタゾールの重量は400μgより多く700μg未満が望ましく、特に、500μg以上600μg以下がより望ましい。
図10は、シロスタゾール重量を変えたときの(II)新生内膜面積を示す図である。図10より、どの重量の場合にも金属ステントのみ(BMS)の場合に比べて新生内膜面積が減少し、特に、シロスタゾール重量が400μgより多い場合に新生内膜面積が大きく減少していることが分かる。特に600μgの場合には、金属ステントのみ(BMS)の場合とは、有意差を持って新生内膜面積が少なくなった。
図11は、シロスタゾール重量を変えたときの(III)血管内皮細胞被覆度を示している。シロスタゾールおよびポリマーを塗布したことにより、どの重量の場合にも金属ステントのみ(BMS)の場合に比べて血管内皮が張りやすくなっていることが分かる。
図9~図11の結果にて示したように、本発明により、ステント留置部位における内膜肥厚を抑えることができ、且つ、血管内皮細胞の再生抑制を防止することができる。シロスタゾール重量としては400μgより多く700μg未満が望ましく、特に、500μg以上600μg以下がより望ましい。
2:ベース部材
3:コーティング剤
4:超音波スプレイコーティング装置
5:超音波噴霧ノズル
6:配管
80:血管断面
81:内膜
82:中膜
Claims (12)
- 金属または高分子材料からなるステント本体の表面に、
シロスタゾールと生体吸収性ポリマーとを含む混合物がコーティングされて含まれ、
前記生体吸収性ポリマーの分子量が40,000から600,000である薬剤溶出型ステント。 - 前記生体吸収性ポリマーが、
(a)DLラクチドとグリコリドを7:3~9:1の重量比率で含み、分子量が40,000~400,000のポリマー、
(b)分子量が50,000~100,000のDLラクチドを含むポリマー、
(c)LラクチドとDLラクチドを6:4~8:2の重量比率で含み、分子量が300,000~600,000のポリマー、
(d)分子量が50,000~150,000のLラクチドを含むポリマー、または
(e)Lラクチドとカプロラクトンを6:4~8:2の重量比率で含み、分子量が150,000~400,000のポリマー
のいずれかを含む請求項1の薬剤溶出型ステント。 - シロスタゾールと前記生体吸収性ポリマーの重量比が4:6から7:3である、請求項1又は2の薬剤溶出型ステント。
- シロスタゾールと前記生体吸収性ポリマーの重量比が4:6から6:4である、請求項3の薬剤溶出型ステント。
- 前記ステント本体がコバルトクロム合金を主成分として有する、請求項1乃至4のいずれかに記載の薬剤溶出型ステント。
- 前記コーティングが超音波スプレー法で行われる、請求項1乃至5のいずれかに記載の薬剤溶出型ステント。
- 1つのステントあたりにコーティングされるシロスタゾールの重量が400μgより大きく700μg未満である、請求項1乃至6のいずれかに記載の薬剤溶出型ステント。
- 1つのステントあたりにコーティングされるシロスタゾールの重量が500μg以上600μg以下である、請求項7に記載の薬剤溶出型ステント。
- 金属または高分子材料からなるステント本体の表面に、シロスタゾールと分子量が40,000から600,000である生体吸収性ポリマーとを含む混合物を超音波スプレーコーティングする、薬剤溶出型ステントの製造方法。
- 前記生体吸収性ポリマーが、
(a)DLラクチドとグリコリドを7:3~9:1の重量比率で含み、分子量が40,000~400,000のポリマー、
(b)分子量が50,000~100,000のDLラクチドを含むポリマー、
(c)LラクチドとDLラクチドを6:4~8:2の重量比率で含み、分子量が300,000~600,000のポリマー、
(d)分子量が50,000~150,000のLラクチドを含むポリマー、または
(e)Lラクチドとカプロラクトンを6:4~8:2の重量比率で含み、分子量が150,000~400,000のポリマー
のいずれかを含む請求項9の製造方法。 - シロスタゾールと生体吸収性ポリマーの重量比が4:6から7:3である請求項9又は10の製造方法。
- 1つのステントあたりにコーティングされるシロスタゾールの重量が400μgより大きく700μg未満である、請求項9乃至11のいずれかに記載の製造方法。
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