Patent Publication Number: US-2018028190-A1

Title: Vascular embolization device and production method therefor

Description:
TECHNICAL FIELD 
     The present invention relates to a vascular embolization device to be placed at a predetermined site in a blood vessel and to embolize the blood vessel. 
     BACKGROUND ART 
     Less invasive therapies widely used to treat, for example, aneurysm include vascular embolization in which an embolization device is placed in the dome (Patent Literatures 1 and 2). In the vascular embolization, the embolization device placed in the aneurysm serves as a physical barrier against blood flow and causes the formation of a thrombus around the embolization device, so that the risk of aneurysm rupture will decrease. A known embolization device to be placed at a predetermined site in a blood vessel, such as aneurysm, includes a metal coil (hereinafter such a device will also be called an “embolization coil”) (Patent Literatures 3 to 5). Such an embolization coil is introduced into the aneurysm through an appropriate catheter by pushing means (an introducer), which is detachably connected to an end of the embolization coil. 
     In some target sites (cases) where the embolization coil is to be placed, however, a biochemical active material needs to be administered to the target sites. 
     For example, if no biochemical active material is administered, biological tissues may insufficiently form around the embolization coil placed in the aneurysm, so that the blood may enter the aneurysm to cause recanalization, which may enlarge the dome again. Therefore, it is preferable that an organization promoter be administered into the aneurysm to promote the formation of biological tissues around the embolization coil placed in the aneurysm. 
     Patent Literature 6 describes an embolization device capable of administering a biochemical active material or a drug, which includes a metal coil and a resin wire that is provided over the inside of the metal coil and contains the biochemical active material or the drug. 
     CITATIONS LIST 
     Patent Literatures 
     Patent Literature 1: U.S. Pat. No. 4,884,579 
     Patent Literature 2: U.S. Pat. No. 4,739,768 
     Patent Literature 3: Japanese Translation of PCT International Application Publication No. 05-500322 
     Patent Literature 4: Japanese Translation of PCT International Application Publication No. 08-501015 
     Patent Literature 5: Japanese Translation of PCT International Application Publication No. 07-502674 
     Patent Literature 6: Japanese Unexamined Patent Application Publication No. 11-76249 
     SUMMARY OF INVENTION 
     Technical Problems 
     However, the addition of a biochemical active material to a wire made of a single resin material can cause the resin wire to have insufficient flexibility depending on the composition of the resin, which means that there is room for improvement in ease of handling vascular embolization devices to be inserted into blood vessels. 
     It is an object of the present invention to provide a vascular embolization device having the function of administering a biochemical active material and having good flexibility. 
     Solutions to Problems 
     As a measure to solve the above problems, the inventors have considered a method of inserting a polyvinyl alcohol-based resin wire containing a biochemical active material into the inside of a coil, as described in Patent Literature 6, to allow a vascular embolization device to carry the biochemical active material. However, there has been a problem in that the addition of a biochemical active material to a polyvinyl alcohol-based resin reduces the strength of the resin itself depending on the composition of the resin, and makes it difficult to draw the resin into a linearly elongated shape. This results in difficulty in forming the resin into a wire and difficulty in inserting the resin into a coil. There has also been a problem in that if the wire is made thick in order to compensate for that, the coil will be too hard to be practically used. 
     As solutions to the above problems, the inventors have come up with first forming only a resin wire and then coating the resin wire with a biochemical active material-containing resin, in which resins with solubilities different from each other in the same organic solvent are used for forming the resin wire and for the coating, respectively, so that a resin wire containing a biochemical active material, which has a constant strength and is insertable into a coil can be formed. 
     As a result of intensive studies to solve the above problems, the inventors have accomplished the present invention. 
     Specifically, the present invention provides a vascular embolization device defined by any one of items [1] to [14] below and a vascular embolization device producing method defined by item [15] below. 
     [1] A vascular embolization device including: a coil; and a resin wire that contains a biochemical active material and is inserted in an inside of the coil, wherein
         the resin wire is a multilayer strand including a core and at least one outer layer, and   the core and the at least one outer layer individually contain resin compositions with solubilities different from each other in the same organic solvent.       

     [2] The vascular embolization device according to item [1], wherein the resin composition in the at least one outer layer has a solubility higher than the solubility of the resin composition in the core. 
     [3] The vascular embolization device according to item [1] or [2], wherein the resin composition in either the core or the at least one outer layer is composed of an ethylene-vinyl acetate copolymer. 
     [4] The vascular embolization device according to any one of items [1] to [3], wherein the resin compositions in the outer layer and the core individually contain ethylene-vinyl acetate copolymers with compositions different from each other. 
     [5] The vascular embolization device according to item [4], wherein the ethylene-vinyl acetate copolymer in the core has a vinyl acetate unit content of 10 to 30% by weight, and the ethylene-vinyl acetate copolymer in the outer layer has a vinyl acetate unit content of 30 to 50% by weight. 
     [6] The vascular embolization device according to any one of items [1] to [5], wherein the resin wire is disposed in the inside of the coil in a primary form. 
     [7] The vascular embolization device according to any one of items [1] to [6], further including an stretch resistant wire disposed in the inside of the coil in the primary form. 
     [8] The vascular embolization device according to any one of items [1] to [7], wherein the stretch resistant wire has a break strength of 0.05 N or more per wire. 
     [9] The vascular embolization device according to any one of items [1] to [8], wherein the stretch resistant wire is corrugated or spirally shaped. 
     [10] The vascular embolization device according to any one of items [1] to [9], wherein the stretch resistant wire has a natural length at least 5% longer than the natural length of the coil. 
     [11] The vascular embolization device according to any one of items [1] to [10], wherein the stretch resistant wire is made of a metal. 
     [12] The vascular embolization device according to any one of items [1] to [10], wherein the stretch resistant wire is made of a resin. 
     [13] The vascular embolization device according to item [11], wherein the stretch resistant wire is made of gold, platinum, iridium, tungsten, tantalum, titanium, nickel, copper, iron, or an alloy of any combination thereof. 
     [14] The vascular embolization device according to item [12], wherein the stretch resistant wire is made of polyethylene, polypropylene, nylon, polyester, polydioxanone, polytetrafluoroethylene, polyglycolic acid, polylactic acid, silk, or a composite material of any combination thereof. 
     [15] The vascular embolization device according to any one of items [1] to [14], wherein the biochemical active material is contained in any one of the at least one outer layer of the resin wire. 
     [16] The vascular embolization device according to any one of items [1] to [15], wherein the biochemical active material is contained in the outermost layer of the resin wire. 
     [17] The vascular embolization device according to any one of items [1] to [16], wherein the biochemical active material is contained in the core of the resin wire. 
     [18] The vascular embolization device according to any one of items [1] to [17], wherein the biochemical active material is a statin or includes a statin. 
     [19] The vascular embolization device according to item [18], wherein the statin is simvastatin, pravastatin, atorvastatin, pitavastatin, or any combination thereof. 
     [20] The vascular embolization device according to any one of items [1] to [19], wherein the resin wire has a thickness of 0.01 to 0.20 mm. 
     [21] The vascular embolization device according to any one of items [1] to [20], wherein the coil in a primary form is coiled into a secondary form. 
     [22] A method for producing the vascular embolization device according to any one of items [1] to [21], the method including the three steps of:
         (a) coating the surface of the resin wire with a solution containing the biochemical active material and the resin composition;   (b) drying the solution to form a layer containing the biochemical active material; and   (c) inserting the resin wire having thereon the layer containing the biochemical active material, in the inside of the coil to form the vascular embolization device.       

     Advantageous Effects of Invention 
     The present invention makes it possible to provide a vascular embolization device having the function of administering a desired biochemical active material to target sites and also having good flexibility so that it can provide a good embolization effect at various target sites in blood vessels. 
    
    
     
       BRIEF DESCRIPTION OF DRAWINGS 
         FIG. 1  is a cross-sectional view showing an example of a specific structure of a vascular embolization device according to the present invention. 
         FIG. 2  is a cross-sectional view showing another example of a specific structure of the vascular embolization device according to the present invention. 
         FIG. 3  is a cross-sectional view showing another example of a specific structure of the vascular embolization device according to the present invention. 
         FIG. 4  is an explanatory view showing the cross-section of a resin wire  20  constituting a vascular embolization device  1  according to the present invention. 
         FIG. 5  is an explanatory view showing an example of a secondary shape formed by winding, into a coil, the vascular embolization device  1  according to the present invention. 
         FIG. 6  is an explanatory view showing the connection of pushing means  30  to the vascular embolization device  1  according to the present invention. 
         FIG. 7  is an explanatory view showing how to use the vascular embolization device  1  according to the present invention in the human body. 
         FIG. 8  is an explanatory view showing a method for measuring the coil flexibility of the vascular embolization devices prepared in Example 1 and Comparative Example 1. 
         FIG. 9  is a graph showing the results of measurement of the coil flexibility of the vascular embolization devices prepared in Example 1 and Comparative Example 1. 
         FIG. 10  is a cross-sectional view showing another example of a specific structure of the vascular embolization device according to the present invention. 
         FIG. 11  is a cross-sectional view showing another example of a specific structure of the vascular embolization device according to the present invention. 
     
    
    
     DESCRIPTION OF EMBODIMENTS 
     Hereinafter, a vascular embolization device according to an embodiment of the present invention will be described, with reference to the drawings. It will be understood that such an embodiment is not intended to limit the present invention. 
     (Vascular Embolization Device) 
       FIG. 1  is a cross-sectional view showing an example of a specific structure of a vascular embolization device  1  according to the present invention. 
     The vascular embolization device  1  includes a coil  10  and a resin wire  20  inserted in the inside of the coil  10 . 
     (Coil) 
     The coil  10  constituting the vascular embolization device  1  is preferably made of an X-ray-impermeable metal wire, such as a wire of any of platinum, gold, tungsten, iridium, palladium, rhodium, indium, iron, nickel, cobalt, chromium, manganese, molybdenum, aluminum, titanium, niobium, silicon, metal phosphide, sulfide mineral, zirconium, copper, stainless steel, and alloys thereof. 
     The wire used to form the coil  10  preferably has a diameter (wire diameter) of 0.02 mm to 0.12 mm, more preferably 0.03 mm to 0.10 mm, in view of its insertion or placement in blood vessels. The coil  10  preferably has a diameter of 0.1 mm to 1.0 mm, more preferably 0.2 mm to 0.5 mm, in view of its insertion or placement in blood vessels. 
     In the vascular embolization device  1 , the coil  10  preferably has a length of 1 mm to 1,000 mm, more preferably 1 mm to 500 mm, even more preferably 10 mm to 500 mm. 
     (Resin Wire) 
     As shown in the cross-sectional view of  FIG. 4 , the resin wire  20  is a multilayer strand including a core  21  and at least one outer layer  22  with which at least part of the surface of the core  21  is covered. 
     In  FIG. 4 , a single outer layer  22  is provided. Alternatively, two or more outer layers  22  may be provided to form a multilayer structure. 
     Although not shown, the resin wire  20  may include the core  21  which has two resin wires or three or more resin wires. 
     The thickness of the resin wire  20  (including the thicknesses of the core  21  and the outer layer  22 ) may be any thickness that makes the resin wire  20  insertable into the inside of the coil  10 . For example, the thickness of the resin wire  20  is preferably from 0.01 mm to 0.20 mm, more preferably from 0.06 mm to 0.15 mm, even more preferably from 0.08 mm to 0.12 mm. 
     In this regard, two or more resin wires  20  may be inserted in the inside of the coil  10 . For example, as shown in  FIG. 3 , one resin wire  20  may be inserted into the inside of the coil  10  and then folded back at the ring part  13  of a tip  11  at the front end, so that the resin wire  20  may be double-folded and inserted in the inside of the coil  10 . 
     The resin wire  20  may be linearly-shaped as shown in  FIG. 1  or may be partially or entirely corrugated or spirally shaped. The corrugated or spirally-shaped resin wire  20  can have a greater entire length and thus contain a larger amount of a biochemical active material than the corresponding linearly-shaped resin wire has. 
     The corrugated shape may be, for example, a substantially sine wave shape or a substantially square wave shape. 
     The spiral shape may be any helical shape with a size enough to fit in the inside of the coil  10 . 
     The present invention has the feature that a core  21  and at least one outer layer  22  in the resin wire  20  include resin compositions with solubilities different from each other in the same organic solvent. 
     The core  21  and the outer layer  22  are formed by resin compositions with solubilities different from each other in the same organic solvent, to thereby stably form the outer layer  22  without dissolution and breakage of the resin wire for forming the core  21 , even when the surface of the core  21  is coated with a resin composition for forming the outer layer  22 . 
     In the present invention, any type of organic solvent capable of dissolving the resin for forming the resin wire  20  may be used in the evaluation of the solubility, and the type of the organic solvent is not particularly limited. The term “solubility” refers to the solubility attained when the resin wire  20  or the resin for forming the resin wire  20  is immersed in the organic solvent. Specifically, the solubility can be determined by the method described below in the section entitled “EXAMPLES.” 
     In order to form the outer layer  22  by coating without dissolution and breakage of the core  21 —forming resin wire, it is particularly preferable that the resin composition contained in the outer layer  22  should have a solubility higher than that of the resin composition contained in the core  21 . 
     In addition, the resin used to form either the core  21  or the outer layer  22  of the resin wire  20  is preferably selected from resins with good flexibility (such a degree of flexibility as to be easily deformable by the shape retaining force of the coil  10 ) and no adverse effect on the living body. 
     Specific examples of the resin for forming the resin wire  20  include flexible synthetic polymer materials such as an ethylene-vinyl acetate copolymer, a styrene-isobutylene-styrene block copolymer, a styrene-ethylene-propylene-styrene block copolymer, a styrene-ethylene-butadiene-styrene block copolymer, and a styrene-ethylene-ethylene-propylene-styrene block copolymer. 
     Among them, an ethylene-vinyl acetate copolymer can surely hold a necessary and sufficient amount of a biochemical active material, have sufficient flexibility, and properly release the biochemical active material upon contact with blood. From these points of view, the resin composition for forming either the core  21  or the outer layer  22  preferably includes an ethylene-vinyl acetate copolymer. 
     Particularly in order to prevent delamination of the coating layer, a resin composition including an ethylene-vinyl acetate copolymer is preferably used to form each of the core  21  and the outer layer  22 . 
     Resin compositions each including an ethylene-vinyl acetate copolymer may be used to form the core  21  and the outer layer  22 , respectively. In this case, the ethylene-vinyl acetate copolymers used to form the core  21  and the outer layer  22 , respectively, should preferably have different compositions so that the surface of the resin wire for forming the core  21  can be successfully coated with the outer layer  22  without dissolution and breakage of the resin wire for forming the core  21 . 
     When such ethylene-vinyl acetate copolymers with different compositions are used, for example, the copolymer selected for the core  21  should preferably have a vinyl acetate unit content of 10% to 30%, and the copolymer selected for the outer layer  22  should preferably have a vinyl acetate unit content of 30% to 50%. 
     In the present invention, the vinyl acetate unit content of ethylene-vinyl acetate copolymers can be measured by saponification method (provided in Japanese Industrial Standards (JIS K 7192)), infrared spectroscopy (IR spectroscopy), nuclear magnetic resonance spectroscopy (NMR spectroscopy), or thermogravimetry. 
     The resin wire  20  constituting the vascular embolization device  1  contains at least one biochemical active material. 
     In the present invention, the “resin wire containing a biochemical active material” is intended to include (1) a resin wire containing a biochemical active material uniformly dissolved or dispersed in the resin, (2) a resin wire containing a biochemical active material localized at and near the surface of the wire-shaped resin material (e.g., a resin wire containing a biochemical active material applied to the surface of the resin), and (3) a resin wire containing a biochemical active material localized at the center of the wire-shaped resin material (e.g., a resin wire containing a biochemical active material (inner part) covered with a resin film (outer part)). 
     Specifically, the biochemical active material may be contained in the core  21  or at least one outer layer  22  depending on the purpose. 
     For example, the biochemical active material should preferably be contained in at least one outer layer  22 , particularly, in the outermost layer, so that the release of the biochemical active material can be completed in a short period of time including the initial burst release period. 
     In addition, the biochemical active material should preferably be contained in the core  21  or in at least one core  21  and at least one outer layer  22 , so that the biochemical active material can be continuously released over a long period of time. 
     When two or more outer layers  22  are provided to form a multilayer structure, the position of a layer containing the biochemical active material may be controlled so that the duration of release of the biochemical active material can be controlled. For example, a resin composition layer including only a resin or having a lower content of the biochemical active material may be formed on the outer side of the biochemical active material-containing layer, so that the biochemical active material can be continuously released at a lower rate over a longer period of time as compared to the case where the outermost layer contains the biochemical active material. 
     The biochemical active material contained in the core  21  or the outer layer  22  may be uniformly distributed over the core  21  or the outer layer  22  or may be localized at a predetermined site such as the center or periphery of the core  21  or the outer layer  22 . 
     The biochemical active material may be an organization promoter, a blood coagulation accelerator, an anticancer drug, or any other drug according to the desired purpose. 
     For example, an organization promoter may be added to the resin for forming the resin wire  20 , so that the resulting vascular embolization device  1  can promote the formation of biological tissues when placed in the aneurysm to be embolized. 
     In the present invention, such an organization promoter is preferably any of statins such as simvastatin, pravastatin, atorvastatin, pitavastatin, fluvastatin, lovastatin, and rosuvastatin. Particularly for promotion of endothelium formation at the entrance (neck) of aneurysm, the organization promoter is preferably simvastatin, pravastatin, atorvastatin, pitavastatin, or any combination thereof. 
     A blood coagulation accelerator may also be added to the resin for forming the resin wire  20 , so that vascular closure can be accelerated in the blood vessel where the resulting vascular embolization device  1  is used for embolization. Examples of such a blood coagulation accelerator include coagulation accelerators such as phytonadione, protamine sulfate, hemocoagulase, and menatetrenone, external hemostatics such as sodium alginate, gelatin, and oxidized cellulose, blood coagulation factor preparations such as eptacog alfa, octocog alfa, turoctocog alfa, desmopressin acetate hydrate, thrombin, and rurioctocog alfa, sclerosants for esophageal varices, such as oleic acid monoethanolamine and polidocanol, antiplasmin agents such as tranexamic acid, and capillary stabilizers such as ascorbic acid, carbazochrome, phytonadione, carbazochrome sodium sulfonate hydrate, and adrenochrome monoaminoguanidine mesilate. 
     An anticancer drug may also be added to the resin for forming the resin wire  20 , which makes it possible to accelerate degeneration and elimination of cancer tissues around the blood vessel where the resulting vascular embolization device  1  is used for embolization. Examples of such an anticancer drug include alkaloids such as paclitaxel, cytochalasin, docetaxel, vincristine, vinblastine, vinorelbine, etoposide, teniposide, misplatin, vindesine, and irinotecan; antibiotics such as mitomycin, adriamycin, doxorubicin, actinomycin, daunorubicin, idarubicin, mitoxantrone, bleomycin, plicamycin, aclarubicin, pirarubicin, epirubicin, peplomycin, neocarzinostatin, and zinostatin stimalamer; alkylating agents such as nitrogen mustard, mechlorethamine, cyclophosphamide, melphalan, chlorambucil, ethyleneimine, thiotepa, methyl melanin, busulfan, carmustine, streptozocin, dacarbazine, procarbazine, carboquone, nimustine, ranimustine, mitobronitol, and temozolomide; antimetabolites such as methotrexate, fluorouracil, floxuridine, cytarabine, mercaptopurine, thioguanine, mentostatin, chlorodeoxyadenosine, hydroxycarbamide, Starasid ocfosphate, enocitabine, fludarabine, gemcitabine, doxifluridine, Tegafur, Tegafur uracil, Levofolinate, carmofur, methotrexate, TS One (registered trademark), and capecitabine; platinum-based agents such as cisplatin, carboplatin, and nedaplatin; hormone drugs such as leuprorelin, goserelin, medroxyprogesterone, tamoxifen, toremifene citrate, fadrozole, estramustine sodium phosphate ester, flutamide, and bicalutamide; retinoids such as tretinoin; and other drugs such as imatinib, dasatinib, nilotinib, gefitinib, folinate, mozavaptane, sunitinib, sorafenib, axitinib, lapatinib, azathioprine, cyclosporine, tacrolimus, sirolimus, zotarolimus, everolimus, Biolimus A9, mycophenolate mofetil, mizoribine, calcipotriol, gusperimus, muromonab-CD3, thalidomide, lenalidomide, bicalutamide, aceglatone, octreotide, pentostatin, sobuzoxane, porfimer sodium, tranilast, sodium aurothiomalate, penicillamine, lobenzarit, bucillamine, losartan potassium, candesartan cilexetil, valsartan, lisinopril, captopril, cilazapril, enalapril, temocapril hydrochloride, quinapril hydrochloride, trandolapril, delapril hydrochloride, perindopril erbumine, nifedipine, nilvadipine, efonidipine hydrochloride, felodipine, and colchicine. 
     The content of the biochemical active material in the resin wire  20  is preferably from 1 part by weight to 99 parts by weight, more preferably from 1 part by weight to 60 parts by weight, even more preferably from 1 part by weight to 50 parts by weight, based on 100 parts by weight of the resin. 
     (Stretch Resistant Wire) 
     The vascular embolization device  1  of the present invention, which has the resin wire  20  inserted in the inside of the coil  10  as shown in  FIG. 10 , may further include, as shown in  FIG. 1 , a stretch resistant wire  12  provided in the inside of the coil  10 . 
     In this case, the stretch resistant wire  12  is preferably fixed at the front and rear ends of the coil  10  so that it can prevent the coil  10  from stretching when the coil  10  is placed at the target site in the blood vessel. 
     The stretch resistant wire  12  may have any thickness that allows it to be inserted into the inside of the coil  10 , and thus the thickness is not particularly limited. In view of the balance between properties such as stretch resistant properties and flexibility, the stretch resistant wire  12  preferably has a thickness of 0.01 mm to 0.10 mm, more preferably 0.01 mm to 0.06 mm. 
     In order to prevent the stretching of the coil  10 , the stretch resistant wire  12  preferably has a break strength of 0.05 N or more per wire, more preferably 0.10 N or more per wire. 
     The break strength can be measured using a tensile tester. 
     The stretch resistant wire  12 , which should be linear as shown in  FIG. 1 , may be partially or entirely corrugated or spirally-shaped. 
     The stretch resistant wire  12  corrugated or spirally-shaped partially or entirely can resist straightening (a phenomenon in which when the coil  10  is folded into a compact form and placed in the living body, the stretch resistant wire  12  becomes not long enough so that an end of the coil  10  becomes stiff), so that the coil  10  can be placed in a wider variety of forms depending on the situation in the body. In addition, the corrugated or spirally-shaped stretch resistant wire  12  can have an entire length greater than that of the straight type, so that a larger amount of the biochemical active material can be held inside the coil  10  when the biochemical active material is carried by the stretch resistant wire  12  as described later. 
     The corrugated shape may be, for example, a substantially sine wave shape or a substantially square wave shape. For example, as shown in  FIG. 11 , the stretch resistant wire  12  may be substantially sine wave-shaped over the entire length. 
     The spiral shape may be any helical shape with a size enough to fit in the inside of the coil  10 . 
     The stretch resistant wire  12  prevents excessive stretching of the coil  10  while allowing the coil  10  to deform flexibly. From this point of view, the natural length of the stretch resistant wire  12  is preferably adjusted to be at least 5% longer, more preferably at least 10% longer, even more preferably at least 20% longer than the natural length of the coil  10 . 
     In this regard, the natural length of the stretch resistant wire  12  is a longitudinal length of the stretch resistant wire  12 . For example, as shown in  FIG. 1 , it refers to the length of the stretch resistant wire  12  between the ring part  13  and the connection part  50  when the stretch resistant wire  12  is a stranded wire composed of two strands. 
     The stretch resistant wire  12  may be made of a metal or a resin composition. Examples of the material for the stretch resistant wire  12  include: metals such as platinum, gold, tungsten, tantalum, iridium, palladium, rhodium, indium, iron, nickel, cobalt, chromium, manganese, molybdenum, aluminum, titanium, niobium, silicon, metal phosphide, sulfide mineral, zirconium, copper, stainless steel, and alloys thereof; polymers such as polyethylene, polypropylene, polyethylene terephthalate, polyamide, polyester, polylactic acid, polyglycolic acid, poly(lactic acid-glycolic acid) copolymers, polyhydroxybutyric acid, polyhydroxybutyrate valeric acid, 3-hydroxybutyric acid-3-hydroxyhexanoic acid copolymer polyester; and polymers derived from biodegradable polymers, such as cellulose, polydioxanone, proteins, and vinyl polymers. 
     Particularly, in view of biocompatibility, gold, platinum, iridium, tungsten, tantalum, titanium, nickel, copper, iron, or an alloy of any combination thereof is preferred when the stretch resistant wire  12  is made of a metal material. For the same reason as in the case of the metal, polyethylene, polypropylene, nylon, polyester, polydioxanone, polytetrafluoroethylene, polyglycolic acid, polylactic acid, silk, or a composite material of any combination thereof is preferred when the stretch resistant wire  12  is made of a resin material. 
     The stretch resistant wire  12  may also carry at least one biochemical active material. The use of this feature makes it possible to further increase the amount of the biochemical active material in the vascular embolization device  1 . 
     The biochemical active material may be the same as that used in the resin wire  20 . The biochemical active material carried by the stretch resistant wire  12  may be the same as or different from that in the resin wire  20 . 
     Examples of methods for allowing the stretch resistant wire  12  to carry the biochemical active material include, but are not limited to, immersion of the stretch resistant wire  12  in a biochemical active material solution and methods including applying or spraying the solution onto the stretch resistant wire  12  and removing the solvent by drying. 
     (Tip) 
     The stretch resistant wire  12  should be fixed at the front end of the vascular embolization device  1  of the present invention. For this purpose, a tip  11  is preferably provided at the front end of the coil  10 . 
     When the coil  10  is placed at the target site in the blood vessel, the coil  10  should be prevented from stretching. For this purpose, the stretch resistant wire  12  inserted in the inside of the coil  10  is preferably fixed at at least two sites including the rear end of the coil  10  and the tip  11  fixed at the front end of the coil  10 . 
     As shown in  FIG. 1 , the tip  11  has a ring part  13  that is provided on the inside side of the coil  10  to fix the stretch resistant wire  12 . 
     In addition, the outer surface of the tip  11  is preferably smooth sphere- or hemisphere-shaped in order to prevent any damage to the target site in the blood vessel. 
     The tip  11  may be formed by melting and shaping a front end portion of the wire of the coil  10  into a desired shape. Alternatively, a tip-forming member separate from the coil  10  may be fixed to the coil  10  with an adhesive or by heat welding to form the tip  11 . 
     The ring part  13  may also be used to fix the resin wire  20  at the front end of the vascular embolization device  1 . For example, in the vascular embolization device  1  shown in  FIG. 3 , one resin wire  20  is inserted into and folded back at the ring part  13  so that the front end of the resin wire  20  is fixed to the tip  11 . 
     Alternatively, the resin wire  20  does not have to be fixed in the vascular embolization device  1  of the present invention. For example, in the vascular embolization device  1  shown in  FIG. 1 or 2 , the front end of the resin wire  20  is in contact with but not fixed to the tip  11 . 
       FIGS. 1 to 3  show the vascular embolization device  1  in a linearly extended form. For example, when moved in a catheter, the vascular embolization device  1  takes this form. When not restrained by a catheter tube wall or other structure, the vascular embolization device  1  preferably takes the form of a secondary coil, in which the coil  10  is further wound as shown in  FIG. 5 . 
     In this regard, the diameter of the secondary coil, which is appropriately selected according to the inner diameter of the target site (e.g., aneurysm), is preferably from 1 mm to 40 mm, more preferably from 1.5 mm to 20 mm. 
     (Pushing Means) 
     In the vascular embolization device  1  of the present invention, the rear end of the coil  10  is attached, as shown in  FIG. 6 , to pushing means  30  with a connection part  50  interposed therebetween. 
     For example, as shown in  FIGS. 1 to 3 , the coil  10  is fixed to the connection part  50 . In the vascular embolization device  1  shown in each of  FIGS. 1 to 3 , the coil  10  is fixed to the surface of a wire constituting the connection part  50 . 
     The resin wire  20  may be fixed or not fixed to the connection part  50 . For example, in the vascular embolization device  1  shown in each of  FIGS. 2 and 3 , the resin wire  20  is fixed to the surface of a wire constituting the connection part  50 . On the other hand, in the vascular embolization device  1  shown in  FIG. 1 , the resin wire  20  is not fixed to the connection part  50 . 
     To perform the stretch resistant function, the stretch resistant wire  12  is fixed to the connection part  50 . 
     In this regard, the resin wire  20  and the stretch resistant wire  12  may be fixed to any position of the connection part  50 , such as the surface or interior, and thus the position is not particularly limited. 
     Any known method such as adhesion or welding may be used to fix the connection part  50  to the coil  10 , the resin wire  20 , or the stretch resistant wire  12 , and thus no limitation is imparted on the method. 
     In addition, the connection part  50  is so designed as to detachably connect the vascular embolization device  1 . 
     Various methods may be used to detach the vascular embolization device  1 . Typical detaching methods include, for example, detachment by thermally dissolving a resin wire of the connection part  50 , detachment by electrolysis of a metal wire of the connection part  50 , detachment by water pressure pushing, and detachment by mechanical unlocking. Among them, the method of detaching the coil by dissolving the wire of the connection part  50  is preferably used. Examples of the resin for forming the resin wire for coil separation include hydrophilic resins of synthetic polymers, including polyvinyl alcohol-based polymers such as polyvinyl alcohol (PVA), cross-linked PVA polymers, elastomers produced by freezing and thawing water absorption PVA gel, and ethylene-vinyl alcohol copolymers. 
     Among them, polyvinyl alcohol-based polymers are preferred because they can swell upon being in contact with water while maintaining a constant strength and can dissolve upon being heated at such a level as not to damage the living body. 
       FIG. 6  shows that pushing means  30  as an introducer is connected to the vascular embolization device  1  of the present invention (the vascular embolization device  1  with the features shown in  FIG. 1 ). The pushing means  30  shown in  FIG. 6  includes a wire portion  31  and a radiopaque distal portion  32  extending therefrom, in which the wire portion  31  includes a core wire and a resin coating layer formed on the outer surface of the core wire. The radiopaque distal portion  32  is connected and fixed to the rear end  50 B of the resin wire constituting the connection part  50  fixed to the rear end  10 B of the coil  10 , so that the pushing means  30  is connected to the vascular embolization device  1 . In this case, the rear end  10 B of the coil  10  and the front end  50 A of the resin wire constituting the connection part  50  for coil separation may be fixed to each other by any means, such as bonding with an adhesive, welding, connection by physical force, or other fixing means, and the radiopaque distal portion  32  of the pushing means  30  and the rear end  50 B of the resin wire constituting the connection part  50  may also be fixed to each other by any means, such as bonding with an adhesive, welding, connection by physical force, or other fixing means. 
     The pushing means  30  preferably has an outer diameter of 0.1 mm to 2.0 mm. The pushing means  30  preferably has a length of 0.1 m to 2.0 m. 
     The core wire constituting the pushing means  30  is preferably a wire made of an electrically-conductive material such as stainless steel. 
     The resin coating layer in the wire portion  31  of the pushing means  30  can be formed by, for example, applying a fluororesin or a hydrophilic resin to the outer surface of the core wire. The resin coating layer made of a fluororesin or a hydrophilic resin is advantageous in that it can reduce the surface friction coefficient. 
     At the outer end of the wire portion  31 , the core wire is exposed to form a terminal portion  33 , through which electric power can be supplied to the core wire via an appropriate conductive member such as an electric connector, plugs, or clips. The terminal portion  33  with a length of about  1  cm to about  3  cm is long enough. 
     The radiopaque distal portion  32  of the pushing means  30  has a secondary form in which a winding wire is further wound into a coil on the outer surface of the core wire. A wire made of a metal such as platinum, silver, gold, tungsten, or stainless steel may be used for the winding wire that forms the radiopaque distal portion  32 . 
     The vascular embolization device  1  of the present invention to which the pushing means  30  is connected as shown in  FIG. 6  is introduced through any appropriate catheter to the target site in the living body. 
     Specifically, as shown in  FIG. 7 , a catheter  42  is first inserted in such a manner that its front end opening reaches a target site P in the living body  41 , and the vascular embolization device  1  as a front part is then inserted from a hand operation unit  43  into the catheter  42 . Thus, the vascular embolization device  1  is moved in a linearly extended form through the catheter  42  while being pushed by the pushing means  30  and pushed out to the target site P from the front end opening of the catheter  42 . When the connection part  50  reaches the front end opening of the catheter  42 , an earth electrode  44  is attached to an appropriate skin surface of the living body  41 , and, for example, a monopolar high-frequency current is supplied to the pushing means  30  from a high-frequency power supply  45  connected to the terminal portion  33  of the pushing means  30 . 
     As a result, the high-frequency current generates heat to melt and cut off the rear end  50 B of the resin wire constituting the connection part  50  between the vascular embolization device  1  and the pushing means  30 , so that the vascular embolization device  1  is separated from the pushing means  30  and successfully placed at the target site P. 
     Therefore, when a resin with a melting point of 100° C. or less is selected as a component of the resin wire constituting the connection part  50 , the rear end  50 B of the resin wire can be cut off in a short time by heating during high-frequency current supply. 
     Specifically, the resin wire constituting the connection part  50  may be made of a hydrophilic resin including a polyvinyl alcohol based polymer. In this case, the rear end  50 B of the resin wire can be melted and cut off in a very short time of at most 3 seconds by supplying a high-frequency current. 
     This makes it possible to significantly reduce the burden on not only the operator but also the living body undergoing the operation and also makes it possible to significantly reduce the possibility of occurrence of unexpected events on the living body during the placement operation. 
     The vascular embolization device having the features described above can provide a good therapeutic effect by having good coil delivery performance, a good embolization function, and a drug delivery function. 
     Hereinafter, a method for producing the vascular embolization device of the present invention will be described, which, however, is not intended to limit the present invention. 
     A method for producing the vascular embolization device of the present invention includes the following three steps (a), (b), and (c). 
     (a) The step of coating the surface of a resin wire with a solution containing a biochemical active material and a resin composition
 
(b) The step of drying the solution to form a biochemical active material-containing layer on the surface of the resin wire as a core
 
(c) The step of inserting the resin wire with the biochemical active material-containing layer formed thereon into the inside of a coil to form a vascular embolization device
 
     The details of the steps (a), (b), and (c) may be appropriately controlled according to the features of the vascular embolization device. 
     For example, the vascular embolization device  1  shown in  FIGS. 1 and 6  (the vascular embolization device  1  with the resin wire  20  neither fixed to the tip  11  nor to the connection part  50 ) can be produced by the following steps. 
     (a1) A spinning step including performing melt spinning to form a resin wire for forming a core  21 
 
(a2) A coating step including coating the surface of the resin wire (core  21 ) with a solution containing a biochemical active material and a resin composition
 
(b) A drying step including drying the solution to form a biochemical active material-containing layer (outer layer  22 )
 
(c) An assembling step including inserting, into the inside of a coil  10 , a stretch resistant wire  12  and the resin wire  20  with the biochemical active material-containing layer  22  formed thereon
 
(d) A tip forming step including forming a tip  11  at the front end of the coil  10 
 
(e) A bonding step including bonding a resin wire (connection part  50 ) for coil separation to the base end of the coil  10  and to the front end of the wire of pushing means  30 
 
(f) A trimming step including removing, by cutting, an excess part of the stretch resistant wire  12  protruding from the base end of the coil  10 
 
     Hereinafter, each step will be described in detail. 
     (a1) Spinning Step 
     A resin for forming a core  21  is melted by heating with a heater and spun into a fiber with a thickness of about 30 to about 150 μm. The resulting resin wire is taken up on a bobbin. 
     (a2) Coating Step 
     Using an X stage and a dispenser, a die, a spray, or other means, the resin wire placed linearly is subjected to coating. 
     (b) Drying Step 
     In a vacuum heating oven, the coating is dried under reduced pressure at 40 to 80° C. for 1 to 24 hours. 
     (c) Assembling Step 
     Under microscopic observation, the stretch resistant wire  12  and the resin wire  20  with the biochemical active material-containing layer formed thereon are inserted into the inside of the coil  10 . 
     (d) Tip Forming Step 
     The part of the resin wire  20  protruding from the front end of the coil  10  is removed by cutting. Subsequently, using a YAG laser irradiation device, a tip  11  is formed by irradiating the coil  10  with laser light focused on the front end of the coil  10 . 
     In addition, a ring part  13  is formed on the side close to the inside of the coil  10 , and the stretch resistant wire  12  is inserted into the ring part  13  and then folded back at the ring part  13 . 
     (e) Bonding Step 
     Under microscopic observation, the part of the resin wire  20  protruding from the base end of the coil  10  is removed by cutting so that the resin wire  20  is completely inserted in the coil  10 . Using a dispenser, a resin wire  50  for coil separation is bonded to the base end of the coil  10  with an instantaneous adhesive. At the same time, the stretch resistant wire  12  is also bonded to the surface of the resin wire  50  for coil separation. After the adhesive is cured, the resin wire  50  for coil separation, which extends from the coil  10 , is similarly bonded to the front end of the wire of the pushing means  30  with an instantaneous adhesive. 
     (f) Trimming Step 
     Under microscopic observation, an excess part of the stretch resistant wire  12  protruding from the base end of the coil  10  is removed by cutting. 
     When the vascular embolization device  1  shown in  FIG. 2  is produced, the base end-side part of the resin wire  20  may be bonded to the resin wire  50  for coil separation in the step (e) of the production method described above. 
     When the vascular embolization device  1  shown in  FIG. 3  is produced, the resin wire  20  and the stretch resistant wire  12  may be inserted into and folded back at the ring part  13  of the tip  11  and both ends of the resin wire  20  may be placed at the base end of the coil  10  in the step (d) of the production method described above. 
     Both ends of the resin wire  20  may be bonded to, attached to, brought into contact with, or not in contact with the resin wire  50  for coil separation, which is disposed at the base end-side part of the coil  10 . 
     Both ends of the stretch resistant wire  12  may also be fixed to the base end of the coil  10  by bonding, adhesion, or other methods. 
     The stranding machine, X stage, dispenser, vacuum heating oven, microscope, YAG laser irradiation device, instantaneous adhesive, and other means for use in the steps described above may be of any type useful for medical device production. 
     EXAMPLES 
     Hereinafter, the present invention will be more specifically described with reference to examples. It will be understood that the examples below are not intended to limit the present invention. 
     Example 1 
     Pellets of an ethylene-vinyl acetate copolymer with a vinyl acetate content of 25% (EVA25) were subjected to melt spinning to form a core wire with a thickness of about 0.10 mm. 
     A solution was prepared by dissolving 0.40 g of atorvastatin (AV) and 1.20 g of an ethylene-vinyl acetate copolymer with a vinyl acetate content of 40% (EVA40) in 24 mL of tetrahydrofuran. The surface of the wire was coated with the resulting solution at room temperature. The tetrahydrofuran was then evaporated to dryness by heating under reduced pressure, so that a drug-carrying resin wire was obtained. 
     In this process, the core wire was successfully coated with the solution without being broken because the EVA25 of the core wire with a vinyl acetate content of 25% was insoluble in tetrahydrofuran at room temperature, whereas the EVA40 with a vinyl acetate content of 40% used for the coating of the resin wire was soluble in tetrahydrofuran. 
     The cross-section of the prepared drug-carrying resin wire was observed with an electron microscope. As a result, it was observed that a drug-containing layer (outer layer) with a thickness of about 0.01 mm was formed on the surface of the base wire (core). 
     The drug-carrying resin wire with a thickness of 0.12 mm prepared in the same manner as in Example 1 and a stretch resistant wire (a stranded wire composed of two platinum-tungsten (Pt-W) alloy wires each with a diameter of 0.01 mm and a break strength of 0.4 N) were inserted in the inside of a metal coil with an element wire diameter of 0.045 mm, a primary coil diameter of 0.30 mm, and a secondary coil diameter of 4 mm. 
     Subsequently, the product was subjected to the steps (d), (e), and (f) described above, so that a vascular embolization device with the structure shown in  FIGS. 1 and 6  was obtained. 
     The resulting vascular embolization device  1  was evaluated for coil flexibility. In the evaluation, the vascular embolization device  1  was fixed in the form of a loop with a diameter of 4 mm, which was equal to the secondary diameter of the coil  10  to be tested, and the load required to compress the coil loop by a predetermined distance from the top was measured ( FIG. 8 ).  FIG. 9  shows the results. 
     Comparative Example 1 
     A conventional vascular embolization device (bare coil) with no resin wire being inserted therein was prepared and then evaluated for coil flexibility as in Example 1.  FIG. 9  shows the results. 
     The coil flexibility is compared at the same compression distance. A higher compression load means a higher coil stiffness and therefore a lower flexibility. 
     The measurement results of Example 1 and Comparative Example 1 show that the vascular embolization device  1  of Example 1 according to the present invention has a similar degree of flexibility to that of the vascular embolization device (bare coil) of Comparative Example 1 without any resin wire  20  being inserted therein, and thus can be safely placed at a desired target site in the blood vessel. The vascular embolization device of Example 1 also has a high embolization effect because it contains atorvastatin in the resin wire  20  disposed inside the coil  10  so that atorvastatin can be slowly released from the resin wire when it is placed in blood vessels. 
     REFERENCE SIGNS LIST 
       10  Coil 
       11  Tip 
       12  Stretch resistant wire 
       13  Ring part 
       20  Resin wire 
       21  Core 
       22  Outer layer 
       30  Pushing means 
       31  Wire portion 
       32  Radiopaque distal portion 
       33  Terminal portion 
       41  Living body 
       42  Catheter 
       43  Hand operation unit 
       44  Earth electrode 
       45  High-frequency power supply 
       50  Connection part