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    • 专利摘要:
    STENT The present invention relates to a stent that minimizes the occurrence of stress and strain concentration in a drug coating layer with expansive deformation of the stent in the radial direction and is free from the possibility that the drug can be withdrawn. The stent is characterized in that the thickness (B) of a drug coating layer (4) coated on the outer surface of a stent body (2) is gradually reduced towards a bent portion (K) so that stress or tension in the drug coating layer (4) by expansive deformation of the stent (1) is reduced and drug peeling is avoided.
    公开号:BR112012007578B1
    申请号:R112012007578-0
    申请日:2010-09-13
    公开日:2021-04-20
    发明作者:Kazuhiro Maruyama；Noboru Saito；Hiroki Goto
    申请人:Terumo Kabushiki Kaisha；
    IPC主号:
    专利说明:

    Technical Field Order Cross Reference
    [0001] The present application is based on Japanese patent application No. 2009-227417 filed on September 30, 2009, and the contents described therein are hereby incorporated by reference in their entirety. Technical Field
    [0002] The present invention relates to a stent that is arranged in a region with stenosis or an occluded region that appears in a lumen of an organism so that the patency state of the light is maintained, and particularly to a stent of the type of drug elution called DES (Drug Elution Stent) in which drug is coated on the outer surface of a stent body. Background
    [0003] A stent is a medical device used for the enhancement of a stenotic region or an occluded region that appears in a light in an organism such as a blood vessel, bile duct, trachea, esophagus, urethra, or similar, and is a net-shaped cylindrical body formed by successively forming, using a thin support, a straight or linear curved portion or a bent portion of a U-shape or the like in the same plane, apparently in a wavy shape and arranging a plurality of annular corrugated bodies, in each of which said corrugated supports are annularly disposed and connected to each other, in an aligned relationship with each other in an axial direction.
    [0004] Although a stent is used, for example, in a coronary artery of the heart, to prevent restenosis after percutaneous transluminal coronary angioplasty (PTCA), it is recognized that if a stent in which the drug is not coated, that is, an empty metal stent, is used so that it is reduced in diameter early and reaches a target region, in which it is expanded so as to be disposed in a light, then, although the coefficient of restenosis is low compared to that in the case where only PTCA is used without using a stent at all, restenosis occurs at a coefficient of approximately 20 to 30% in the region of stent placement. The main causes of restenosis are intimal hypertrophy due to the migration and growth of vascular smooth muscle cells.
    [0005] Thus, the development of a DES is carried out recently in which a drug capable of suppressing the migration and growth of vascular smooth muscle cells is coated on the external surface of a stent (sometimes referred to as "stent body") so that the drug is eluted in the region of stent placement to avoid restenosis. As the drug, for example, sirolimus or carcinostatics which are used antibiotics. Drug coating is carried out such that liquid coating including a drug and a biocompatible polymer that are dissolved in solvent is coated by an immersion method, a spray method, or a direct application method (applying drug together with a support that sets up a stent body) or the like so that a predetermined amount of drug exists on the surface of the stent body and then the liquid coating is dried and solidified.
    [0006] However, since, in order to cause the DES to be disposed in a light, after the stent reaches the target region in a light in a state in which the stent is reduced in diameter once, the stent is expanded and laid out, a problem occurs that the drug coating layer coated on a folded or similar portion is exfoliated from the surface of the stent body in response to expansion and deformation of the stent (particularly in the portion folded) and the drug itself is destroyed and exits from the stent body. Particularly where the drug coating layer exhibits brittleness, the problem just above is considerable.
    [0007] Therefore, in WO03/009779A2 (with reference to paragraph numbers [0065], [0066] and so on), it is described to form a drug coating layer in the form of a line or in the form of a dot on a region other than a bent portion ("stress region" or "mechanical profile") of the stent or forms a drug coating layer in the form of a dot on the bent portion.
    [0008] However, there is the possibility that, in a stent in which a drug coating layer is formed in the shape of a dot, the amount of drug may be insufficient, and this is not preferable. Furthermore, even in a stent in which a drug coating layer is formed in the form of a line on a different portion of the curved portion, there is the possibility that a deformation starting point by expansion may coincide with an end portion of the drug coating layer or, depending on the case, a deformation starting point may exist in a portion on which the drug coating layer is formed. Therefore, there is the possibility that stress or stress concentration may occur in the drug coating layer and the drug may be exfoliated from the surface of the stent body and then the exfoliation may propagate around it to destroy the drug coating layer and cause great flaking. In particular, where the stent is expanded in a radial direction, the magnitude or the like of expansion is not constant and is different for each procedure, and drug coating is performed for a bent portion to be expanded regardless of which position is makes a starting point of deformation. Therefore, even if the coating is carried out uniformly except for the bent portion, if a deformation starting point and an end portion of the drug coating layer coincide with each other, then the stress or stress concentration occurs in the coating layer of drug and exfoliation, destruction and peeling of the drug occurs.
    [0009] WO 03/009779 A2 deals with the provision of agents with therapeutic capabilities with stents, for example by applying therapeutic agents to discrete portions or smaller surface areas, for example rings or ligatures.
    [00010] US 2003/0088307 A1 reveals potent coatings for stents, capable of releasing bioactive agents over time in tissues.
    [00011] US 5,282,823 reveals radially expandable stents for implantation. Invention Summary
    [00012] The present invention was created to solve the problem described above, and it is an objective of the present invention to provide a stent that minimizes the occurrence of stress and stress concentration in a drug coating layer with deformation by stent expansion in a radial direction, and it is free from drug flaking and good in convenience in use.
    [00013] A stent of the present invention that achieves the objective described above is characterized in that the thickness of a drug coating layer coated on the outer surface of a stent body gradually reduces towards a bent portion so that the occurrence of a stress or stress concentration in the drug coating layer with deformation by expansion of the stent is greatly reduced and the drug coating layer itself can be easily deformed according to the deformation of the stent, and drug peeling is prevented by both of these.
    [00014] In the present invention of claim 1, since the gradually reduced portion in which the thickness of the drug coating layer is gradually reduced towards the folded portion is formed, even if a starting point of deformation by expansion of the stent moves relatively from the folded portion of the support, the drug coating layer at the starting point of the deformation and the proximity of the starting point is thinner. In this way, the occurrence of stress or stress concentration in the drug coating layer is greatly reduced, and drug peeling can be avoided. The drug coating layer is formed by a plurality of film coating layers and has the gradually reducing portion formed by gradually reducing the thickness of said drug coating layer towards the folded portion, wherein the number of layers of the film coating layers is gradually reduced.
    [00015] In addition, since the drug application amount is small in the gradually reduced portion, also the drug itself readily follows the deformation of the stent, and also in relation to this, the drug peeling can be avoided.
    [00016] Particularly, since the stent is configured so that drug flaking can be avoided without using an additive such as a plasticizer, no bad influence occurs on an organism and safety is high.
    [00017] According to the present invention of claim 2, a predetermined band around the starting point (a bending point) of deformation by expansion of the folded portion is configured as an uncoated layer (a non-coated drug coating layer is formed in a predetermined band around a bending point in the bent portion). Therefore, the drug is not coated in a region in which the occurrence of stress or strain concentration is more likely to appear. Therefore, the stent can suppress drug desquamation and can readily handle various states of expansion in a disposed region of the stent, and is easy to manipulate, easy and determined to proceed, and very good in convenience in use.
    [00018] According to the present invention of claim 3, since a drug thin film coating layer is formed within a predetermined range around a bending point of the bent portion (wherein thickness b of said film coating layer is preferably from 1 µm to 5 µm), the drug can be readily quantitatively fixed although drug flaking is suppressed.
    [00019] According to the present invention of claim 4, since the drug coating layer is formed from a mixture of the drug and the polymer, a coating process for the outer surface of the support can be readily carried out, and also the handling is improved.
    [00020] According to the present invention of claims 5 and 6, the polymer is a biodegradable polymer such as, for example, polylactic acid, polyglycolic acid or a copolymer of lactic acid - glycolic acid. Therefore, after the stent is placed in an organism, the polymer that covers and protects the drug is biodegraded and the drug is released, and consequently, restenosis in the region where the stent is placed can be avoided with certainty. "
    [00021] According to the present invention of claim 7, since a primer coating layer is provided between the stent body and the drug coating layer, the stent is good in bonding between the stent body and the drug, and low on exfoliation.
    [00022] According to the present invention of claim 8, since a slope angle of the gradually reduced portion is 1 to 45 degrees, when the stent is deformed by the expansion, the stress or strain concentration is less likely to occur in the drug coating layer, and said stent can be formed or produced readily.
    [00023] According to the present invention of claim 9, the stent body is formed into a cylindrical shape by arranging and joining together a plurality of annular corrugated bodies, each of which is formed from a corrugated support having a portion bent, in an aligned relationship with each other in an axial direction. Therefore, a stent of a predetermined length can be obtained by connecting the undulating annular bodies, and not only the production of the stent body, but also the production of a DES are facilitated.
    [00024] According to the present invention of claim 10, when the drug coating layer in which a plurality of thin film coating layers that are laminated is to be formed by discharging the liquid coating from a nozzle and moving the nozzle next to the holder, the coating length of the thin film coating layer of an upper layer is set shorter than the coating length of the thin film coating layer of a lower layer so that the gradually reduced portion is formed in a stairway format. Therefore, the gradually reduced portion can be readily formed.
    [00025] According to the present invention of claim 11, with said formation of the portion gradually reduced as described above, the mouthpiece is moved from one of said supports towards the other support in the bent portion. Therefore, the gradually reduced portion can be formed or produced quickly.
    [00026] According to the present invention of claim 12, once the drug coating layer is formed using a spray or an ink jet, the formation of the drug coating layer can be carried out promptly and quickly. Particularly where an ink jet is used for forming, drug loss is small, and the drug coating layer can be formed with a high degree of precision.
    [00027] Other objectives, features and advantages of the present invention will become apparent by reference to the embodiment illustrated in the following description and in the accompanying drawings. Brief Description of Drawings
    [00028] Figure 1 is a schematic front view showing an embodiment of the present invention.
    [00029] Figure 2 is a schematic front view showing the modality in a used state.
    [00030] Figure 3 is an enlarged plan view of a stent in a state in which it is reduced in diameter.
    [00031] Figure 4 is an enlarged plan view of the stent in an expanded state.
    [00032] Figure 5 is an enlarged plan view of the folded portion.
    [00033] Figure 6 is a schematic sectional view taken along line 6-6 of figure 5.
    [00034] Figure 7 is a schematic front view of a coating apparatus.
    [00035] Figure 8 is a schematic sectional view taken along line 8-8 of figure 7.
    [00036] Figure 9 is a sectional view of a mandrel part.
    [00037] Figure 10 is a flow chart of a coating process.
    [00038] Figure 11 is a flow chart of the coating process followed by the flow chart of figure 10. How to carry out the present invention
    [00039] In the following, an embodiment of the present invention is described in detail with reference to the drawings.
    [00040] First, when generally describing a stent, as shown in figure 1, the stent is configured from a cylindrical stent body 2 formed from thin supports 3 and having apparently a reticulated state, and a drug coating layer 4 (referring to figure 6) coated on the surface of the stent body 2.
    [00041] Stent 1 is disposed on the inside of a blood vessel or the like using, for example, a stent delivery system as shown in figure 2. The stent delivery system 10 is configured from a body of axle 13 of a dual tube structure formed from an inner tube 11 and an outer tube 12 disposed coaxially with one another, a collapsible and expandable balloon 14 provided at the distal end portion of the axle body 13, and a hub branch 16 having an injection port 15 for injecting fluid for balloon expansion.
    [00042] In order to position the stent 1 within a blood vessel using said stent delivery system 10, the stent 1 is first reduced in diameter and mounted on the stent delivery system 10 in such a way as to enclose the balloon 14 in a folded state, and a guidewire is fitted inside the inner tube 11 which is open at the distal end thereof, after the stent delivery system 10 in which the stent 1 is mounted is guided to a predetermined position in the blood vessel when using the guidewire as a guide. Then, fluid is injected from injection port 15 so that it flows into balloon 14 through a light between inner tube 11 and outer tube 12 to expand balloon 14. When stent 1 is attached to balloon 14 is expanded outwardly in the radial direction from the inside, then the stent 1 is extended and plastically deformed in the radial direction and/or an axial direction and is allowed to position in the expanded state in the blood vessel.
    [00043] Stent 1 of this modality is described in more detail. In the stent body 2 of the present embodiment, as shown in Figures 1 and 3, alternative arrangements of a bent portion K1 of a U-shape having a small opening angle α, another bent portion K2 of a V-shape having a large angle of opening α, and a linear portion S formed from a straight portion or a curved portion are formed annularly to form an annular wavy body C (also referred to as "cellular portion C"). The length of each cell part C in the axial direction is "L1." Then, the distal end of the U-shaped bent portion K1 in a cell part C and a proximal end of the U-shaped bent portion K1 in an adjacent cell part C are joined together successively in a joining portion F to generally form a cylindrical body, apparently in a reticulated state, in which a plurality of cell parts C are connected to each other and the length of which in the axis direction is "L2". It should be noted that the stent body 2 shown in Figure 1 is configured from 14 cell parts C.
    [00044] When the stent body 2 is expanded in the radial direction from a contracted state shown in figure 3, it is changed into an expanded state in which the opening angle α increases as shown in figure 4 and the portions of brackets 3 which configure the folded portion K1 or the folded portion K2 are spaced apart from each other so that a portion of space O is greatly enlarged.
    [00045] In the bent portions K1 and K2 of stent body 2, preferably the bent portion is bent not at an acute angle, but bent or bent into a U-shape or a gently arcuate shape. By the configuration, also the stress occurrences applied to the drug coating layer 4 described hereinafter with expansion can be reduced, and the effect of suppressing exfoliation, damage, destruction or peeling of the drug coating layer 4 is high. However, the curved structure of the flexed end portion is preferably curved to such a degree that it does not swell by a large amount towards an outward direction, i.e. to such a degree that the flexed end portion does not swell outwards. in an arc. Since the flexed end portion is formed in this way, the outer diameter with shrinkage in diameter can be reduced, and also insertion into an in vivo organism (eg a blood vessel) of a small diameter is facilitated.
    [00046] As the material to form the stent body 2, preferably a material having biocompatibility is used, and for example stainless steel, tantalum or tantalum alloy, platinum or platinum alloy, gold or gold alloy , cobalt based alloy, cobalt chromium alloy, titanium alloy, niobium alloy and so on are preferably used. As stainless steel, SUS316L having the highest corrosion resistance is most preferable.
    [00047] In the stent body 2, the area occupied by the bracket 3 in a state in which it is mounted on the balloon 14 preferably is 60% to 80% of the area of the entire outer peripheral face including the O space portions.
    [00048] The width of support 3 preferably is 40 µm to 150 µm, and particularly preferably is 80 µm to 120 µm. The length L1 of each cell part C in the axial direction preferably is 0.5 mm to 2.0 mm, and particularly preferably is 0.9 mm to 1.5 mm. The diameter D1 of the non-expanding stent body 2 preferably is 0.8 mm to 2.5 mm, and more particularly is 0.9 mm to 2.0 mm. Length L2 with non-expansion preferably is approximately 8 mm to 40 mm.
    [00049] Formation of the stent body 2 is accomplished by removing any other portion besides the brackets from a tubular body (particularly a metal tube) to form a predetermined pattern. For example, formation is performed by removing the O-space portions from a metal tube by an engraving method that uses masking called photo fabrication and a chemical machining method, an electrical discharge based on a mold, a cutting method (eg mechanical grinding, laser cutting) or the like.
    [00050] After said formation, an edge of the supports 3 is removed by chemical polishing or electrolytic polishing to finish the supports 3 so that they can have a smooth face.
    [00051] Furthermore, after forming into a predetermined pattern, annealing can be performed. Annealing improves overall stent plasticity and flexibility, the property of positioning in a flexed blood vessel and reduces the physical stimulus to be applied to the inner wall of the blood vessel, and may reduce the main causes of restenosis. The annealing is preferably carried out so that the stent is cooled slowly after it is heated to 900°C to 1200°C under an inert gas environment (eg, mixed nitrogen and hydrogen gas) so that an oxide film may not form on the stent surface.
    [00052] Although various methods such as, for example, an immersion method, a spray method, an ink jet method and a nozzle jet method can be used for the formation of the drug coating layer 4, in In the present invention, a spray method, an ink jet method and a nozzle jet method are preferable.
    [00053] Here, the spray method is to blast drug to an outer surface of the stent body 2 together with an air flow to form the drug coating layer 4, and the inkjet method is to apply drug to the form of fine particles to an outer surface of the stent body 2. In addition, the nozzle jet method is to apply drug to the outer surface of the stent body 2 from a nozzle.
    [00054] When spray method or inkjet method is used, drug coating layer formation can be carried out promptly and quickly. When the ink jet method or the nozzle jet method is used, drug loss is small and a drug coating layer can be formed with a high degree of precision.
    [00055] Since the spray method, inkjet method and nozzle jet method are basically different only in the process of applying the drug to an outer surface of the stent body 2, although the configuration of the coating layer of drug 4 to be formed is similar, a case in which the nozzle injection method is used to form the drug coating layer 4 is described below.
    [00056] Figure 5 is an enlarged plan view of the folded portion, and Figure 6 is a schematic sectional view taken along line 6-6 of Figure 5. In the present embodiment, said drug coating layer 4 as shown in Figures 5 and 6 is formed on the outer surface of the stent body 2 described herein above. In the present embodiment, a lamination method of spraying and applying liquid coating for a large number of times near the support 3 is used to form the drug coating layer 4, so that the thickness B thereof gradually reduces towards a bent portion K. Then, preferably a primer coating layer 5 is provided between the stent body 2 and the drug coating layer 4. Since the primer coating layer 5 is configured from a material having an adhesive property for polymer that configures a drug coating layer described hereinafter, the bond between the stent body 2 and the drug is good. Consequently, the stent has low exfoliation.
    [00057] In the drug coating layer 4 of the present embodiment, the thickness B of the linear portion S of the stent body 2 that is formed from a linear portion or the curved portion is substantially uniform as shown in Figure 5, although the thickness B from the linear portion S to the bent portion K gradually reduces, and a gradually reducing portion 6 is formed so that, at and near the bending point P, it has no coating layer without a coating of drug or has a very thin drug coating layer.
    [00058] In particular, when a nozzle described hereinafter is moved along a predetermined pattern of the stent body 2 and forms a drug coating layer 4 of the predetermined thickness B using a lamination method of discharging drug to a surface of the stent body 2 to form a plurality of thin film coating layers 4a of a small thickness b, if the coating region of each thin film coating layer 4a is adjusted as the nozzle approaches a point of bending P and the proximity of the bending point P and the number of layers of the thin film coating layers 4a are reduced in steps, so the thickness B of the drug coating layer can be gradually reduced readily. Thus, a gradually reduced valley-shaped portion 6 centered on the bending point P and close to the bending point P can be formed. It should be noted that the formation of the thin film coating layer 4a is hereinafter described in detail.
    [00059] In case the thickness B of the drug coating layer 4 is gradually reduced towards the bent portion K and the proximity of the bent portion K thereby, then when the stent 1 is to be expanded in a radial direction, even if the starting point at which the stent body 2 begins its deformation is shifted somewhat from the bending point P of the bent portion K, since the thickness of the drug coating layer 4 that exists at the starting point of the deformation and close to the starting point is small, occurrence of stress or stress concentration in the drug coating layer 4 significantly reduces.
    [00060] In particular, although the position of the flexion point P on the stent body 2 geometrically is the so-called inflection point on the bent portion K, when in fact a balloon or the like is used so that the expansion force is brought about to act from the inside of the stent to expand stent 1 in the radial direction, the starting point at which deformation of the bent portion K of stent body 2 occurs is not always an inflection point, but varies depending on the direction. action of the expansion force applied to brackets 3 and cannot be unambiguously specified. However, in case the gradually reduced portion 6 of the drug coating layer 4 is formed and the thickness B of the drug coating layer 4 is gradually reduced towards the folded portion K and the proximity of the folded portion K, then even if the position of the bending point P of the stent body 2 is shifted a little, the drug coating layer 4 deforms following the stent body 2, and the stress or stress concentration that occurs in the drug coating layer 4 is too small. In addition, since the drug application amount is small in said portion, also the drug itself is prone to following the deformation of the stent body 2. As a result, both can enhance the drug peeling-preventing effect. significantly.
    [00061] It should be noted that since the bending point P is not clearly specified in such a way as described above in figure 5, it is indicated by a dotted line as a region in which the bending point P may possibly exist .
    [00062] When a particular example of the gradually reduced portion 6 is shown in figure 6 which indicates the folded portion K directly, preferably the thickness b of a thin film coating layer 4a is 1 µm to 5 µm; the number of layers of thin film coating layers 4a is 1 to 50; the length X of the bent portion K is 50 µm to 1000 µm; and the length Y between end portions of the thin film top and bottom coating layers 4a (however, the lengths between the end portions are sometimes not equal) is 1 µm to 1000 µm. Then, the inclination angle θ of the gradually reduced portion 6 is less than 90 degrees, and preferably it is 1 to 60 degrees and more preferably it is 1 to 45 degrees. In the case where the tilt angle θ is less than 1 degree, the effect of preventing drug peeling is displayed over a wide range, although there is a possibility that the amount of drug to be coated may decrease, which is not preferable. Conversely, where the tilt angle θ exceeds 60 degrees, since there is a possibility that the drug flaking-preventing effect may diminish, this is not preferable. Then, the gradually reduced portion 6 whose inclination angle θ is 1 to 45 degrees can be readily produced by a lamination method described hereafter.
    [00063] Although the example described above refers to a case in which the 50 μm to 1000 μm range centered on the bending point P is determined as an uncoated layer in which the drug coating layer 4 is not formed, since whereas, in said uncoated layer as described, the drug is not coated in the position in which stress concentration is most likely to occur, the stent has a high drug withdrawal suppression ability. Thus, even if a situation in which the stent must be expanded by a large amount in the stent's disposed position occurs, the referred situation can be dealt with promptly. Thus, the stent is easy to handle, easy and reliable to operate, and good in convenience to use.
    [00064] However, the present invention is not necessarily limited to only the uncoated layer, and the folded portion K may have only one or several layers of thin film coating 4a.
    [00065] The drug coating layer 4 is configured from a mixture of a drug and a polymer. Said mixture is preferably configured as a mixture of a drug and a biodegradable polymer. When a polymer that covers and protects the drug is biodegraded after the stent is placed in an organism, the drug is released and restenosis in the region where the stent is placed is certainly avoided. As the biodegradable polymer, it is preferable to use one of polylactic acid, polyglycolic acid, and lactic acid-glycolic acid copolymer.
    [00066] The drug and polymer mixing coefficients of the thin film coating layers 4a of the drug coating layer 4 may be the same as each other or may be different from each other. For example, the ratio of drug to polymer can gradually increase from the lower layer towards an upper layer of thin film coating layers 4a which are in contact with primer coating layer 5.
    [00067] Figure 7 is a schematic front view of a coating apparatus; Figure 8 is a schematic sectional view taken along line 8-8 of Figure 7; and Figure 9 is a sectional view of the mandrel part.
    [00068] Insofar as a coating apparatus which forms the thin film coating layer 4a on the supports by a lamination method, for example, said coating apparatus as shown in figures 7 and 8 is used. In the coating apparatus 20, a frame 22 provided vertically on the base 21 is covered with a transparent synthetic resin plate (not shown) from the outer face thereof to form a chamber 23 having air tightness on the inside thereof. A duct 24 is provided contiguously in the top portion of chamber 23 so that air, whose temperature and humidity are controlled, is supplied from an air conditioner 25 to position the interior of the chamber in a state of constant temperature and constant humidity to thereby always keep the solidification and drying condition constant when coating material W described hereinafter is applied to the stent body 2.
    [00069] In the lower portion in chamber 23, a bracket 30 for supporting the stent body 2 and moving means 40 for moving the bracket 30 is provided, and in the middle portion in chamber 23, an application head 50 for applying the coating material W to the support 3 of the stent body 2, first position information acquisition means 60 for acquiring position information in the XY directions in a Cartesian coordinate system on the surface of the stent body 2, i.e. on the surface of the support 3, and second position information acquisition means 70 for acquiring position information in the Z direction in the Cartesian coordinate system are provided on the support structure 26 fixed to the structure 22.
    [00070] In the meantime, a control section 80 is provided externally of the chamber 23 and controls the support 30, moving means 40, application head 50, and position information acquisition means 60 and 70.
    [00071] As shown in figure 8, a mandrel 34 of the bracket 30 is secured at the proximal end thereof by a clamping section 33 connected to a motor M2 that can rotate bidirectionally, and the stent body 2 is detachably mounted on the outer periphery of the mandrel 34.
    [00072] The M2 motor is arranged in a slide section 32, and the slide section 32 is provided for movement (in the Y direction) on a base plate 31. The base plate 31 is disposed on a movable table 42 which it is moved (in the X direction) along a moving rail 41 which is a drive source of the so-called linear type motor. Consequently, the bracket 30 can move the stent body 2 in the X direction and the Y direction by rotation back and forth.
    [00073] Although the outer diameter of the mandrel 34 preferably is substantially equal to or slightly larger than the inner diameter of the stent body 2, insofar as the mandrel 34, mandrels that can be exchanged according to the inner diameter of the stent body 2 and have various outside diameters are prepared. Each of the mandrels is coated with black paint so that they can absorb light in this way to increase the contrast ratio between the bracket 3 of the mounted stent body 2 and the space portion O. Furthermore, the mandrel 34 has slotted portions 35 formed on an outer circumferential face thereof as shown in Figure 9 so that when the stent body 2 is mounted on the mandrel 34, a space G is produced between the outer circumferential face of the mandrel 34 and a lower face 3a of the holder 3 of the stent body 2. Consequently, when the coating material W is applied to the holder 3, the coating material W is prevented from returning to a place between the surface of the mandrel 34 and the inside surface of the stent body 2 in this way to achieve the formation of a uniform coating layer and work convenience.
    [00074] As shown in figures 7 and 8, the application head 50 has a dispenser 53 which is mounted on a support 51 which is fixed to the support structure 26 through a vertical table (not shown), which is moved in the direction Z by a screw feed mechanism or the like which is driven by the motor M3 and which gradually discharges the coating material W reserved therein, and a nozzle section 54 for discharging the coating material W.
    [00075] As shown in Figure 8, the dispenser 53 has a cylindrical portion 55 that serves as a syringe operating mechanism and in which the coating material W is reserved, a piston portion 56 provided for sliding movement in the cylindrical portion 55, and a drive section (not shown) such as a motor or a hydraulic mechanism for depressing the piston portion 56 by a predetermined force F.
    [00076] The nozzle section 54 is configured from a clamping member 57 provided at a lower end of the cylindrical portion 55, and a nozzle 58 depending on the clamping member 57, and a flow path (not shown) along from which the coating material W flows from the cylindrical portion 55 to the nozzle 58 is formed.
    [00077] The outer diameter of the distal end of the nozzle 58 is 10 μm to 1000 μm, and the inner diameter of the distal end of the nozzle 58 is 1 μm to 500 μm, preferably 5 μm to 250 μm, so that the coating material W having a viscosity described hereinafter can be extruded at a predetermined discharge rate. Where the diameter is less than 5 µm, the coating material W does not flow out smoothly, and a high pressure is sometimes required for discharge. On the other hand, where the diameter exceeds 250 µm, there is the possibility that the coating material W may not substantially be able to be smoothly applied to the 2 stent body that is currently used.
    [00078] In the meantime, the nozzle 58 is preferably polished so as to minimize the indentations and projections of the surface thereof as much as possible so as to avoid the adhesion of a discharged coating material W thereto, and preferably, for example, stainless steel, carbon steel, nickel, titanium, chromium, glass, aluminum oxide, zirconium oxide, diamond or a complex thereof are used.
    [00079] The dispenser 53 is provided so that it is spaced from the supports 3 so that the distance N between the nozzle 58 and the support 3 can be a predetermined length and the coating material W is continuously extruded without being interrupted towards the surface of the supports 3 from the nozzle 58 and disposed on the surface of the supports 3. Where said continuous extrusion method as described is used, uniform application of the coating material W to the desired portion of the stent body 2 can be achieved. Furthermore, the coating material W can be quantitatively discharged having a high level of control, and the quantitative adjustment of the therapeutic substance can be performed with a high degree of precision and certainty. Furthermore, since, in the chamber that is adjusted to a state of constant temperature and constant humidity, the conditions for drying and solidifying the coating material W are fixed, the production of stent 1 to which the coating material W adheres can be carried out promptly and quickly.
    [00080] The viscosity of the coating material W discharged from the nozzle 58 is 0.1 cp to 10 cp, preferably 1.0 cp to 4.0 cp. Where the viscosity is higher than the range, high pressure is required or the coating material W cannot sometimes be discharged from the nozzle 58. Where the viscosity is lower than the range, the coating material W sometimes overflows from support 3, resulting in failure to form a uniform application layer.
    [00081] The distance N between the nozzle 58 and the support 3 is 0.1 μm to 200 μm, preferably 1 μm to 100 μm. Where the distance N is greater than the range, there is a problem that the coating material W is broken. Where the distance N is less than the range, there is another problem that the coating material W overflows from the surface of the support.
    [00082] The first position information acquisition means 60 is the image capture means firmly fixed in position on the support structure 26 through a bracket (not shown) as shown in figure 7, and has a camera section 62 , and a line sensor section (not shown) arranged to extend in the axial direction of the stent body 2. The first position information acquisition means 60 reads the surface of the stent body 2 in synchronization with rotation. of the stent body 2 of the holder 30 to capture an image on the surface of the stent body 2 and transmit the image to a control section 80. As described above, since the mandrel 34 is painted with a black paint so as to elevate the contrast ratio between the bracket 3 of the mounted stent body 2 and the O space portion and absorbs light, an image obtained from the stent surface is high in luminescence of the bracket 3, but low in luminescence of the O space portion. , the control section 80 can bin image the surface image obtained from the stent body 2 with an adequate luminescence to fractionate the surface image within the support 3 and the space portion O to obtain the coordinates of the support 3, i.e., position information of the support 3 in the XY directions. Furthermore, the control section 80 calculates the coordinates of a trajectory passing the center of support 3 based on the position information obtained in the XY directions (XY coordinates of support 3), and the data obtained from the central trajectory is stored in the memory of the control section 80. With the application of coating material W, it is essential that the application is carried out without being removed from the supports 3, and also for this purpose it is quite significant to specify the center of the supports 3.
    [00083] The second position information acquisition means 70 is displacement measurement means in the Z direction firmly fixed in position to the lower end of the support 71 fixed to the support structure 26, and is configured from a displacement sensor laser 73 called vertical sensor to measure the displacement of brackets 3 in the Z direction.
    [00084] The surface of the support 3 is not strictly smooth, but has indentations and projections, and in order to quantitatively accurately apply the coating material W to the support having said indentations and projections, the predetermined amount of coating material W must be applied such that the distal end of the nozzle 58 moves strictly parallel to the surface of the holder 3. In this way, the laser displacement sensor 73 initiates acquisition from position information of the holder 3 at the predetermined position of the body of stent 2, for example, at an application starting point, reads stent body 2 along the trajectory that passes through the center of bracket 3 while rotating stent body 2 back and forth, collects displacement data from the general stent body 2 in the Z direction. In addition, the acquired displacement data is stored in the memory of the control section 80.
    [00085] Although not shown, the control section 80 has a processor, a monitor, a keyboard, and so on, and from the position information thereof, makes adjustments to an application method to apply the coating material. W and determining an application path along which the application head 50 should apply the coating material W to the support 3 of the stent body 2. In addition, the control section 80 controls the rotation of the mandrel 34 of the support 30, moving the moving means 40, discharging the amount of coating material W to be discharged from the application head 50, reading the image capturing means or the vertical sensor, and so on.
    [00086] An application method means an application route in the case where the application is to be carried out close to the support 3. Although the application route is preferably a route along which the coating material W can be applied to the general support 3 continuously without an interval in which the overlap application is performed, in the case of the stent 1 in which the supports 3 cross each other in a complicated way, it is sometimes difficult to adjust a way that does not include an interval of said application of overlay. In such a case, an interval in which the overlay application is to be performed, or an interval through which the application point goes from a certain point to another point on the support 3 is provided. By partially providing a gap in which overlapping application is to be performed or a gap in which an application point thus jumps out, the application path can be shortened. Furthermore, when the movement speed within an overlapping interval (interval that is passed a plural number of times) is set higher than the movement speed within an interval that is passed only once, the drug can be applied uniformly on the desired portion of the stent body 2, and the effect of reducing the coefficient of restenosis can be sufficiently exhibited in the case of PTCA or the like. Particularly, in the case where the coating material W is applied so that it forms the gradually reduced portion 6 whose thickness gradually decreases towards the bent portion K as in the present embodiment, it is preferable to move the nozzle 58 from a side of the support 3 of the folded portion K towards the other side opposite the one side. By said movement, the gradually reduced portion 6 can be formed quickly.
    [00087] With determination of an application route, it is preferable to adopt several preventive measures described below. (1) Where the coating material W is applied to the support 3 of the stent body 2, on the linear portion S of the support 3, it is preferable to set the trajectory passing the center of the support 3 as the application route. However, in the bent portion K of the support 3, it is preferable to adjust the trajectory passing the offset position by a predetermined distance in a direction across the width of the support 3 as the application route. The coating material W is liquid and comes out in a state in which it swells upwards on the surface of the support 3 by virtue of the surface tension of the liquid, and even if it is dry and solidified, it is likely to form a layer of casing having an arcuate cross section. Thus, where the coating material W is applied several times, since it is able to swell in an arcuate fashion, it is preferable to adjust the trajectory that passes the position displaced by the predetermined amount from the support coating layer 3 for the first time as an application path to form the coating layer for the second time and adjust, for the coating layer for the third time, the trajectory passing the different position from the application paths for the first time and for the second time as the route of application. (2) with the determination of an application path, it is preferable to use different application paths for the linear portion S and the bent portion K. In the linear portion S, the trajectory that passes the center of the support 3 can be set as the route of application as described above. However, in the bent portion K, if the path passing the center of the support 3 in the widthwise direction is set as the application path, then the coating material W discharged from the application head 50 does not follow the path of movement of the application head 50 by an influence of the viscosity of the coating material W, the falling velocity of the coating material W from the nozzle and so on. Thus, it is preferable to fit the outside with respect to a line passing through the center of the bent portion K of support 3 as the application route. (3) at the crossing point of the supports 3, it is preferable to set a crossing point of the central axial lines of the various supports 3 or the proximity of the crossing point as the application route. In a place where the supports 3 cross each other, since also the application paths P of the same cross each other, if a crossing point of the central axial lines of the various supports 3 or the proximity of the point The crossover is set as the application route, so also the downward flow of the coating material W can be favorably avoided.
    [00088] Now a coating method is described. Figure 10 is a flow chart of the coating process, and Figure 11 is a flow chart of the coating process following Figure 10. Preparation step
    [00089] First, before coating is started, the air conditioner 25 is made operational to position the interior of the chamber 23 in a state of constant temperature and constant humidity. Then, the syringe operating mechanism 53 formed by the combination of the nozzle section 54 having the nozzle 58 of an inner diameter corresponding to the width of the holder 3 or the coating material W, the cylindrical portion 55 in which the coating material W is injected and so on is fitted to the support structure 26.
    [00090] In the meantime, the stent body 2 is fixed, after mounted on the mandrel 34, in the fixation section 33 of the support 30 positioned in a waiting position and adjusted so that a starting point of application of the support 3 is positioned in the slotted portion 35 of the mandrel 34. It should be noted that the holding position is the position in proximity to an inlet portion 23A of the chamber 23 in the case where the moving means 40 are provided in the lower portion of the chamber 23, as shown in figure 7. Image Capture Step
    [00091] The control section 80 accepts an image capture parameter information and stores the informed image capture parameters within the storage device (S1). Image capture parameters are entered, for example, from a keyboard by an operator. The image capture parameters include the rotation speed of the mandrel 34, an image capture line number, an image capture line width, and an image capture operating speed.
    [00092] Control section 80 issues an instruction to start imaging after the entered imaging parameters are stored. Simultaneously, the control section 80 makes the means of moving the X direction 40x operational (S2). Consequently, the support 30 moves from the waiting position to the position below the first position information acquisition means 60 along the movable rail 41. The control section 80 confirms that the support 30 reaches the predetermined position (S3. ), and when the bracket 30 reaches the predetermined position, the control section 80 makes the motor M2 of the bracket 30 operational to initiate rotation of the stent 1 (S4).
    [00093] In the meantime, the line sensor of the first position information acquisition means 60 starts capturing the image according to an instruction to start image capturing and reads the surface of the stent body 2 to capture a pattern of surface image (S5). The captured image is stored as a flat developed image on a storage device (eg a memory, a hard disk or the like) in the control section 80. The image can be output to a monitor so that it can be confirmed by visual observation.
    [00094] Since, in a surface image of stent body 2, the luminescence of bracket 3 is high and the luminescence of the O space portion is low, the control section 80 converts the surface image into a binarized image of white and black with reference to a certain luminescence (S6), and calculates the coordinates of the trajectory passing the center of support 3 by a process of reducing the width of support 3 (S7). Adjustment step of an application method
    [00095] Decide from the acquired image of the surface of the stent body 2 and obtain either an interval within which the overlay application must be performed and an interval through which an application point must jump and the position of said intervals in In this regard, an application route is set so that, although application is carried out to a desired surface portion of the support 3, said gaps for overlapping application and said gaps for skipping are reduced in number or length as much as possible ( S8). Displacement measurement step in the Z direction
    [00096] Furthermore, the control section 80 accepts and stores a displacement measurement parameter information from the second position information acquisition means 70 which serves as the displacement measurement means in the Z direction (S9). Also said displacement measurement parameters are informed by the operator. Displacement measurement parameters include a measurement start position, a measurement direction, a direction at a branch point, a measurement speed, and a measurement range.
    [00097] The control section 80 makes an M1 motor means to move from the Y direction 40y after storing the displacement measurement parameter (S10). If necessary, although the stent body 2 is observed by means of a video camera and a monitor, the measurement positions of both the stent body 2 and the displacement measurement means are adjusted so that the measurement position of the displacement measuring means and the designation position on the path coincide with each other (S11).
    [00098] After the measurement position and the designation position are brought into coincidence with each other by adjustment (it should be noted that said coincidence is reported to control section 80 by the operator) (S12, Yes)), the section control panel 80 issues an instruction to start measuring the displacement in the Z direction from the holder 3 to the second position information acquisition means 70 (S13). Control section 80 causes forward and backward rotation by motor M2 and movement in axial direction by motor M1 to be repeated. Consequently, the stent body 2 repeats the rotation and movement in the axial direction (S14).
    [00099] Consequently, as the second position information acquisition means 70 moves along the path passing the center of the support 3, the control section 80 collects displacement data in the Z direction (S15). The displacement data is stored within the control section storage device 80 along with the central trajectory coordinates. Application Step
    [000100] Control section 80 accepts and stores application parameter information (S16). The application parameters are also information provided by the operator. Application parameters include an application start position, application direction, direction at a crossing point, trajectory adjustment interval setting, a trajectory adjustment amount, an application speed, the material discharge speed of coating W, the height of the application head, the number of application times (coating number) and the selection of an application head.
    [000101] Control section 80 issues an instruction to start the application after storing the application parameters. Simultaneously, the control section 80 issues an instruction to move the support 30 by means of moving the X direction 40x (S17). Consequently, stent body 2 is moved to the initial delivery position below delivery head 50 (S18). After the stent body 2 reaches the initial application position below the application head 50 (S19: Yes), the control section 80 issues an instruction to perform the forward and backward rotation by the M2 motor and the movement in the axial direction. by motor M1 so that the stent body 2 is moved in the X-axis direction and in the y-axis direction according to the parameters assigned by forward and backward rotation by motor M2 and movement in an axial direction by motor M1 ( S20). Simultaneously, the control section 80 causes the application head 50 to move in the Z-axis direction by means of the motor M3 according to the designated parameters (S21). At this time, the coating material W is continuously discharged from the application head 50. Consequently, although the application head 50 moves along a determined application path in advance, the application of the coating material W is carried out.
    [000102] During application, since the space between the distal end of the mouthpiece 58 and the stent body 2 is in a state in which it is filled with the coating material W, the coating material W is discharged into a fixed amount, and also the amount of drug in the stent body 2 is adjusted to the predetermined value with certainty. Furthermore, a strip or a bridge does not appear between the supports 3, and the drug coating layer 4 can be formed with a very high degree of precision.
    [000103] After coating is completed, the support 30 is moved to the waiting position by the means of moving the 40x X direction, and withdraws the mandrel 34 from the support 30 to the outside of the chamber 23 and then removes the stent body 2 in which the drug coating layer 4 is formed from the mandrel 34.
    [000104] The present invention is not limited only to the embodiment described above, but can be modified in various ways by those skilled in the art within the technical scope of the present invention. For example, although the embodiment described above discloses the gradually reduced portion 6 along which the thickness B of the drug coating layer linearly varies towards the folded portion K or the proximity of the folded portion K, the shape of the gradually reduced portion 6 of the present invention is not limited thereto, but it is only necessary for the thickness B of the drug coating layer to be reduced in the bent portion K and in the vicinity of the bent portion K and the gradually reduced portion 6 can have various shapes such as a shape arched.
    [000105] Furthermore, for coating material W, not only one type, but also a plurality of material types can be used. Where a plurality of coating materials W are to be applied, a plurality of syringes, nozzles and syringe operating mechanism are prepared and successively changed to carry out the coating. Said successive change of syringe operating mechanism and so on is controlled by the control section 80. Here, the different coating material W refers to the case where different polymers are used or a single polymer is used, but in different amounts, or different drugs are used, or a single drug is used but in different amounts, or even different solvents are used. When a plurality of types of coating materials are used in this way, the effectiveness is also complex, which is quite advantageous in the sense that the patient's physical and spiritual strain is reduced and so on.
    [000106] Furthermore, also the method of forming the drug coating layer 4 is not only limited to that of the modality described above, but, for example, a spray or an ink jet can be used.
    [000107] Furthermore, although the modality described above is a corrugated stent having a predetermined pattern, the stent is not limited to said stent as described, but can present any other pattern if it has a K-bent portion. Industrial Applicability
    [000108] The present invention can be used as a stent that greatly reduces the coefficient of restenosis after percutaneous transluminal coronary angioplasty (PTCA).
    权利要求:
    Claims (12)
    [0001]
    1. Stent (1) including a cylindrical stent body (2) formed from a plurality of corrugated supports (3) having a bent portion (K), and a drug coating layer (4) formed by coating. a drug on the outer surface of said stent body (2), at least the bent portion (K) being deformed for expansion and contraction along with expansion and contraction of said stent body (2) in a radial direction, characterized in that said drug coating layer (4) is formed by a plurality of film coating layers (4a) and has the taper portion (6) formed by gradually reducing the thickness of said coating layer of drug (4) in the direction of the folded portion (K), wherein the number of layers of the film coating layers (4a) is gradually reduced.
    [0002]
    2. Stent according to claim 1, characterized in that a drug coating layer (4) is not formed in a predetermined range around a bending point (P) in the folded portion (K).
    [0003]
    3. Stent according to claim 1, characterized in that a film coating layer (4a) of the drug is formed within a predetermined range around a bending point (P) in the folded portion (K), wherein the thickness b of said film coating layer (4a) is preferably from 1 µm to 5 µm.
    [0004]
    4. Stent according to any one of claims 1 to 3, characterized in that said drug coating layer (4) is formed from a mixture of the drug and a polymer.
    [0005]
    5. Stent according to claim 4, characterized in that the polymer is a biodegradable polymer.
    [0006]
    6. Stent according to claim 5, characterized in that the biodegradable polymer is any one of polylactic acid, polyglycolic acid and lactic acid - glycolic acid copolymer.
    [0007]
    7. Stent according to any one of claims 1 to 6, characterized in that a primer coating layer (5) is provided between said stent body (2) and said drug coating layer (4 ).
    [0008]
    8. Stent according to claim 1, characterized in that an inclination angle of the gradually reduced portion (6) is from 1 to 45 degrees.
    [0009]
    9. Stent according to any one of claims 1 to 8, characterized in that said stent body (2) is formed in a cylindrical shape by forming an annular corrugated body (C) from the corrugated support (3 ) having the bent portion (K), and by arranging and joining together a plurality of said annular corrugated bodies (C) in an aligned relationship with one another in an axial direction.
    [0010]
    10. Stent according to any one of claims 1 to 9, characterized in that said drug coating layer (4) is formed by laminating a plurality of thin film coating layers (4) individually formed to the discharge the liquid coating including drug and polymer dissolved in solvent from a nozzle section (54) and move the nozzle section (54) along the support (2), and the coating length of the film coating layer (4a ) of an upper layer from among the several layers is set shorter than the coating length of the film coating layer (4a) of a lower layer so that the gradually reduced portion (6) is formed into a shape of Staircase.
    [0011]
    11. Stent according to claim 10, characterized in that the gradually reduced portion of said drug coating layer is formed by moving the nozzle section (54) from one of said supports (2) which forms the bent portion (K) towards the other opposite of said supports (2) when the nozzle section (54) reaches the bent portion (K) or the proximity of the bent portion (K).
    [0012]
    12. Stent according to any one of claims 1 to 9, characterized in that said drug coating layer (4) is formed using a spray or an ink jet.
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    同族专利:
    公开号 | 公开日
    EP2444034A4|2012-11-28|
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    CA2767994C|2017-07-04|
    JPWO2011040218A1|2013-02-28|
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    US20120165923A1|2012-06-28|
    CN102448406B|2014-08-27|
    CA2767994A1|2011-04-07|
    EP2444034A1|2012-04-25|
    WO2011040218A1|2011-04-07|
    KR20120090944A|2012-08-17|
    US9095459B2|2015-08-04|
    AU2010301898A1|2012-01-19|
    KR101687436B1|2016-12-19|
    BR112012007578A2|2020-08-11|
    CN102448406A|2012-05-09|
    US9737423B2|2017-08-22|
    ES2638548T3|2017-10-23|
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    法律状态:
    2020-08-25| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2020-09-08| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2021-02-09| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2021-04-20| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 13/09/2010, OBSERVADAS AS CONDICOES LEGAIS. PATENTE CONCEDIDA CONFORME MEDIDA CAUTELAR DE 07/04/2021 - ADI 5.529/DF |
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    JP2009227417|2009-09-30|
    JP2009-227417|2009-09-30|
    PCT/JP2010/065740|WO2011040218A1|2009-09-30|2010-09-13|Stent|
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