JP2016077651A - Microcatheter - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel microcatheter in which a plurality of medicines can be injected into the catheter separately, mixed immediately before being discharged from the catheter, and administered into a blood vessel in a uniform mixed state.SOLUTION: A microcatheter 1 comprises a tube-shaped catheter body 10 opening at a distal end. An inner cavity 101 and an outer cavity 102 having the same axis are partitioned by a partition wall 100 inside the catheter body 10. The inner cavity 101 and the outer cavity 102 are open at a distal end 1a side of the catheter body 10, respectively. Because the partition wall 100 is positioned deeper at a proximal end 1b side of the catheter body 10 than the distal end 1a, a mixing chamber 103 for mixing liquids L, Lsupplied to the inner cavity 101 and the outer cavity 102 can be formed between the opening of the inner cavity 101 and the distal end 1a of the catheter body 10.SELECTED DRAWING: Figure 2

Description

  The present invention relates to a microcatheter.

  2. Description of the Related Art Conventionally, a microcatheter having a plurality of tubes (lumens) for delivering a liquid to a mammalian circulatory system or for removing a liquid from the circulatory system is known. Such a microcatheter is used to supply a different drug to the patient's circulatory system for the purpose of disease treatment or the like, or to perform blood feeding and blood removal with a plurality of lumens in dialysis therapy or the like.

  As a microcatheter having a plurality of lumens, for example, Patent Document 1 discloses a multi-lumen catheter for insertion into the body of a mammal, which has a proximal end and a distal end, and includes at least three The at least three separate lumens comprising an elongated catheter body having an outer wall surrounding the separate lumens and first, second, and third lumens, the first lumens relative to the second and third lumens Centrally disposed, and each of the first, second, and third lumens includes a lumen having a distal opening located at a distal portion of the catheter, the distal of the second and third lumens An opening is disposed at approximately the same location adjacently along the length of the catheter, and the distal opening of the first lumen is the distal opening of the second and third lumens. They are arranged along the longitudinal direction of the catheter distally or proximally, multilumen catheters have been disclosed to.

  In Patent Document 2, a double lumen catheter having a catheter body having a blood return lumen and a blood removal lumen partitioned by a partition wall, the blood return hole, which is an opening of the blood return lumen, is provided on the catheter body. A blood removal hole, which is an opening of the blood removal lumen, is provided at a position 3 to 11 cm away from the distal end of the catheter body toward the base side, and the opening surface of the blood removal hole extends in the longitudinal direction of the catheter body. It has an angle of 5 to 90 °, and the shape of the catheter main body on the distal end side from the position where the blood removal hole is located has a narrow-diameter portion with a small cross-sectional area, and a wide-diameter portion with a large cross-sectional area that follows. The structure which consists of is disclosed. Further, (Patent Document 3) is constituted by a catheter tube and a balloon composed of an inner tube and an outer tube, the inner tube has a first lumen having an open end, and the outer tube has an inner tube inside. The distal end is provided at a position slightly retracted from the distal end of the inner tube, and a second lumen is formed by the inner surface of the outer tube and the outer surface of the inner tube. The second lumen has a distal end in the balloon. A balloon catheter that is in communication with the rear end and into which a liquid for inflating the balloon is introduced is disclosed.

Special table 2008-504897 gazette JP 2001-340466 A JP 7-328124 A

  Conventional microcatheters having multiple lumens avoid mixing of the drugs by feeding each drug to a separate lumen. Alternatively, one of the plurality of lumens is used to inflate the balloon and dilate the blood vessel and function independently of the remaining lumens.

  On the other hand, when administering a plurality of drugs, the drugs are managed separately before administration and cannot be mixed with each other. It may be necessary to react. However, the conventional microcatheter cannot cope with a method of administering a plurality of drugs as described above in a mixed state.

  Therefore, an object of the present invention is to provide a novel microcatheter that can be injected into a blood vessel or the like in a uniform mixed state by injecting a plurality of drugs separately and mixing them immediately before being released from the catheter. .

  As a result of intensive studies by the present inventors, the problem described above is obtained by forming a mixing chamber for mixing drugs supplied through separate lumens (lumen and outer lumen) at the distal end of the catheter. We found that it was solved and completed the invention. That is, the gist of the present invention is as follows.

（式中、Ｐは生体適合性ポリマーであり、Ａは単結合であるか、又は−ＯＣＯ−Ｃ_２〜Ｃ_４−アルケニレン基、−ＣＯＮＨ−Ｃ_１〜Ｃ_４−アルキレン基もしくは−ＨＮＣＯ−Ｃ_１〜Ｃ_４−アルキレン基であり、Ｘは水素又はＣ_１〜Ｃ_３−アルコキシ基である）
で表されるフェノール性水酸基修飾ポリマー、並びに、ペルオキシダーゼ、ラッカーゼ、チロシナーゼ、カタラーゼ及び鉄ポルフィリン錯体から選択される一種以上を含む第１溶液、又は
過酸化水素を含む第２溶液のいずれか一方を供給するためのものであり、
前記外腔が、他方を供給するためのものである、上記（１）に記載のマイクロカテーテル。
（３）生体適合性ポリマーが、ゼラチン、ペクチン、アルブミン、ヒアルロン酸、アミロペクチン、キトサン、アルギン酸、カルボキシル基を有する変性ポリビニルアルコール、カルボキシメチルセルロース又はコラーゲンである上記（２）に記載のマイクロカテーテル。
（４）式（１）で表されるフェノール性水酸基修飾ポリマーが、フェルラ酸基を有する甜菜由来ペクチンである上記（２）に記載のマイクロカテーテル。 (1) A microcatheter having a tubular catheter body that opens at a distal end,
A coaxial lumen and an outer space partitioned by a partition wall are formed inside the catheter body,
Each of the lumen and the outer lumen opens on the distal end side of the catheter body, but the partition wall is located deeper toward the proximal end side than the distal end of the catheter body, whereby the lumen The microcatheter in which a mixing chamber is formed in which the liquid supplied to each of the inner cavity and the outer cavity is mixed between the opening of the catheter and the distal end of the catheter body.
(2) The lumen is represented by the following formula (1):

(Wherein, P is a biocompatible polymer, or A is a single bond, or _-OCO-C 2 ~C ₄ - alkenylene group, _-CONH-C 1 _{~C 4} - alkylene or -HNCO-C _{1 to} C ₄ -alkylene group, X is hydrogen or C _{1 to} C ₃ -alkoxy group)
And a first solution containing at least one selected from a peroxidase, a laccase, a tyrosinase, a catalase and an iron porphyrin complex, or a second solution containing hydrogen peroxide. Is intended to
The microcatheter according to (1) above, wherein the outer space is for supplying the other.
(3) The microcatheter according to (2) above, wherein the biocompatible polymer is gelatin, pectin, albumin, hyaluronic acid, amylopectin, chitosan, alginic acid, modified polyvinyl alcohol having a carboxyl group, carboxymethylcellulose, or collagen.
(4) The microcatheter according to (2) above, wherein the phenolic hydroxyl group-modified polymer represented by formula (1) is a sugar beet-derived pectin having a ferulic acid group.

  According to the microcartel of the present invention, a plurality of drugs can be separately injected into the lumen and the lumen, mixed immediately before being released from the catheter, and administered into the blood vessel or the like in a uniform mixed state. .

  In particular, the microcatheter of the present invention is prepared by mixing a first solution containing a phenolic hydroxyl group-modified polymer such as sugar beet-derived pectin and a peroxidase with a second solution containing hydrogen peroxide and reacting with injection into the blood vessel. It is suitably used as a catheter suitable for administration of an embolization preparation (injectable gel) for quickly gelling and occluding a blood vessel.

It is a figure which shows one Embodiment of the microcatheter of this invention. It is an expanded sectional view of the tip part of a microcatheter. It is a figure which shows the pathological tissue image (Alcian blue dyeing | staining) in Day0 after administering the formulation for embolization formation intraportal using the microcatheter of this invention. It is a figure which shows the pathological tissue image (Alcian blue dyeing | staining) in Day1 after administering the formulation for embolization formation intraportal using the microcatheter of this invention. It is a figure which shows the pathological tissue image (Alcian blue dyeing | staining) in Day3 after administering the formulation for embolization formation intraportal using the microcatheter of this invention. It is a figure which shows the pathological tissue image (Alcian blue dyeing | staining) in Day7 after administering the formulation for embolization intraportal using the microcatheter of this invention. It is a graph which shows AST and ALT change after administering the formulation for embolization formation into the portal vein using the microcatheter of this invention. It is a graph which shows (gamma) GTP and a total bilirubin change after administering the formulation for embolization in the portal vein using the microcatheter of this invention.

Hereinafter, the present invention will be described in detail.
One embodiment of the microcatheter of the present invention will be described based on FIG. 1 and FIG. As shown in FIG. 1, the microcatheter 1 of the present invention has a tubular catheter body 10 that opens at a distal end 1a.

  The catheter body 10 is made of various materials such as stainless steel and plastic, and usually has flexibility. Moreover, it is preferable that it is compatible with a target site such as a blood vessel, and a coating for imparting hydrophilicity or antibacterial properties may be applied to the surface as necessary. For the purpose of improving the visibility of the microcatheter under fluoroscopy, an X-ray impermeable tip may be attached outside or inside the tip of the catheter body 10 (tip portion including the distal end 1a). .

As shown in FIG. 2, coaxial inner lumen 101 and outer lumen 102 partitioned by partition wall 100 are formed inside catheter body 10. Each of the lumen 101 and the outer lumen 102 opens on the distal end 1a side of the catheter body 10, but the partition wall 100 is located deeper toward the proximal end 1b side than the distal end 1a of the catheter body 10. Thus, the mixing chamber 103 in which the liquids L ₁ and L ₂ supplied to the lumen 101 and the outer lumen 102 are mixed is provided between the opening 101 a of the lumen 101 and the distal end 1 a of the catheter body 10. Is formed.

The size of the mixing chamber 103 is not particularly limited as long as the supplied L ₁ and L ₂ are sufficiently mixed before being discharged from the distal end 1a. As an example, a first solution containing a phenolic hydroxyl group-modified polymer and peroxidase as described later and a second solution containing hydrogen peroxide are added in an amount of 0.1 ml / min to 1.0 ml in each of the lumen 101 and the outer lumen 102. In order to supply at a pressure of about / min and achieve a uniform mixing state in the mixing chamber 103, the diameter of the mixing chamber 103 can be about 1.5 to 5.0 mm and the length can be about 5 to 10 mm. The pressure can be about 1.5 ml / second during angiography.

The liquids L ₁ and L ₂ are supplied to each of the inner cavity 101 and the outer cavity 102 by connecting a syringe or the like to the connecting portions 104 and 105 located on the proximal end 1b side. Alternatively, a micropump or the like may be connected to control the amount of liquid injected into the catheter and / or the injection pressure. Further, if necessary, a balloon can be provided outside the catheter body 10 and a target tube such as a blood vessel can be expanded by the balloon.

  The tube into which the microcatheter 1 is introduced is an arbitrary tube located inside or outside a mammal such as a human. For example, a vein, an artery, an esophagus, a urethra, an intestine, etc. can be mentioned. The organs and tissues that can be treated by the microcatheter 1 include any organs and tissues of mammals. Specific examples include liver, heart, lung, brain, kidney, bladder, intestine, stomach, pancreas, and ovary. And prostate.

The liquids L ₁ and L ₂ administered by the microcatheter 1 are not particularly limited, but the microcatheter of the present invention needs to be supplied separately via the lumen 101 and the outer lumen 102. Yes, it is preferably used for liquids that are required to be mixed with the liquids L ₁ and L ₂ immediately before being discharged from the microcatheter 1 and to react in some cases. Examples of liquids include pharmaceutically active compounds such as anticancer agents and anti-inflammatory agents, carriers, solvents, polymers, cells, contrast agents, DNA, gene / vector systems, anti-angiogenic agents, antioxidants, An oxidizing agent, an antibacterial agent, an anesthetic, etc. can be mentioned.

  In particular, the microcatheter of the present invention is preferably used to administer a preparation (injectable gel) that is liquid before being injected into a living body but quickly gels after injection into the living body. This preparation is used as an embolization preparation for forming a gel having the same shape as a blood vessel in a blood vessel without any gap, thereby closing the blood vessel. The formed gel is degraded after a certain time.

（式中、Ｐは生体適合性ポリマーであり、Ａは単結合であるか、又は−ＯＣＯ−Ｃ_２〜Ｃ_４−アルケニレン基、−ＣＯＮＨ−Ｃ_１〜Ｃ_４−アルキレン基もしくは−ＨＮＣＯ−Ｃ_１〜Ｃ_４−アルキレン基であり（Ｐに結合する側から記載している）、Ｘは水素又はＣ_１〜Ｃ_３−アルコキシ基である）
で表されるフェノール性水酸基修飾ポリマー、並びに、ペルオキシダーゼ、ラッカーゼ、チロシナーゼ、カタラーゼ及び鉄ポルフィリン錯体から選択される一種以上（以下、「ペルオキシダーゼ等」という場合がある）を含む第１溶液と、過酸化水素を含む第２溶液とを含む。これらの第１溶液及び第２溶液のいずれか一方を、カテーテル本体１０の内腔１０１に供給し、第１溶液及び第２溶液の他方を外腔１０２に供給し、混合室１０３において均一に混合した上で放出する。混合により、フェノール性水酸基修飾ポリマーのフェノール部分において、過酸化水素が酸化剤として機能し、ペルオキシダーゼ等による酸化的重合反応が起こってフェノール性水酸基修飾ポリマー同士が架橋し速やかにゲル化する。このような反応は生体内で起こっている反応であり、毒性がほとんどないという利点がある。 One embodiment of the embolization formulation is represented by the following formula (1):

(Wherein, P is a biocompatible polymer, or A is a single bond, or _-OCO-C 2 ~C ₄ - alkenylene group, _-CONH-C 1 _{~C 4} - alkylene or -HNCO-C _{1 to} C ₄ -alkylene group (described from the side bonded to P), X is hydrogen or C _{1 to} C ₃ -alkoxy group)
A first solution containing a phenolic hydroxyl group-modified polymer represented by formula (1) and at least one selected from peroxidase, laccase, tyrosinase, catalase and iron porphyrin complex (hereinafter sometimes referred to as “peroxidase etc.”); And a second solution containing hydrogen. Either one of the first solution and the second solution is supplied to the inner cavity 101 of the catheter body 10, and the other of the first solution and the second solution is supplied to the outer cavity 102, and mixed uniformly in the mixing chamber 103. And then release. By mixing, hydrogen peroxide functions as an oxidant in the phenol portion of the phenolic hydroxyl group-modified polymer, and an oxidative polymerization reaction with peroxidase or the like occurs to crosslink the phenolic hydroxyl group-modified polymers and quickly gel. Such a reaction is a reaction occurring in the living body and has an advantage that it has almost no toxicity.

In the above formula (1), examples of the —OCO—C ₂ -C ₄ -alkenylene group include linear or branched groups such as —OCO—CH═CH— group. Examples of the —CONH—C ₁ -C ₄ -alkylene group include linear or branched groups such as —CONH—CH ₂ — group and —CONH—CH ₂ CH ₂ — group, Examples of the HNCO-C ₁ -C ₄ -alkylene group include linear or branched groups such as —HNCO—CH ₂ — group and —HNCO—CH ₂ CH ₂ — group. Furthermore, the OH group and X may be bonded to any part of the benzene ring. Examples of the C ₁ -C ₃ -alkoxy group corresponding to X include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, and the like. Can be mentioned.

  Since the gelation immediately starts when oxygen peroxide comes into contact with the phenolic hydroxyl group-modified polymer and peroxidase, the above-mentioned embolization preparation is divided into the phenolic hydroxyl group-modified polymer and peroxidase and hydrogen peroxide. It is necessary to mix immediately before injection into the blood vessel. On the other hand, since the phenolic hydroxyl group-modified polymer and peroxidase and the like may be mixed in advance, from the viewpoint of handleability as a preparation, the above embolization-forming preparation contains a phenolic hydroxyl group-modified polymer and peroxidase and the like. The kit is composed of a first solution and a second solution containing hydrogen peroxide.

  The biocompatible polymer is applicable when it is used in a living body as long as it does not show toxicity in the amount used, is chemically inert, and is non-immune. Preferable examples include gelatin, pectin, albumin, hyaluronic acid, amylopectin, chitosan, alginic acid, modified polyvinyl alcohol having a carboxyl group, carboxymethylcellulose, collagen and the like. As a method for introducing a side chain containing a phenol moiety represented by the formula (1) into these biocompatible polymers, a generally known method can be used. That is, 3- (p-hydroxyphenyl) propionic acid or tyramine containing a phenol moiety may be reacted and introduced into the amino group or carboxyl group of the biocompatible polymer by a reaction called general carbodiimide chemistry. it can. The biocompatible polymer having an amino group includes chitosan, and the biocompatible polymer having a carboxyl group includes gelatin, pectin, albumin, hyaluronic acid, amylopectin, alginic acid, modified polyvinyl alcohol having a carboxyl group, and carboxymethylcellulose. And collagen.

  In particular, sugar beet-derived pectin is preferably used as the phenolic hydroxyl group-modified polymer represented by the formula (1). Sugar beet-derived pectin is a polysaccharide extracted and purified from sugar beet. Specifically, beet sugar cane (sugar beet pulp) or beet remaining after producing sucrose from sugar beet is used as a starting material, and these are suspended in water, at a temperature of 50 ° C. to 120 ° C. under acidic conditions of pH 1-7. However, it is not limited to this production method.

Sugar beet-derived pectin has a neutral sugar, and ferulic acid is ester-bonded to the neutral sugar as shown in the following formula. This sugar beet-derived pectin is capable of forming a gel quickly by cross-linking of the phenol part by causing an oxidative polymerization reaction with peroxidase or the like using oxygen peroxide as an oxidizing agent.

  The peroxidase, laccase, tyrosinase, catalase and iron porphyrin complex are not particularly limited, and natural and synthetic ones can be applied. For example, as peroxidase, those derived from animals such as humans and cows, those derived from plants such as horseradish, and those derived from microorganisms such as bacteria and molds can be appropriately selected and used. Moreover, what was prepared by the gene recombination technique which incorporates the gene of peroxidase, such as microorganisms, in microorganisms, such as colon_bacillus | E._coli, is applicable.

  The concentration of the phenolic hydroxyl group-modified polymer, peroxidase, etc. and hydrogen peroxide varies depending on the specific type and molecular weight of each component and the target gelation time, and is not particularly limited. As an example, when an embolization preparation is composed of a first solution containing sugar beet-derived pectin and peroxidase and a second solution containing hydrogen peroxide, the concentration of sugar beet-derived pectin in the first solution is 0.5-10. It is preferable to adjust the concentration of wt% and peroxidase to 0.5 to 200 units / ml. In the second solution, the concentration of hydrogen peroxide is preferably 0.1 to 200 mmol / l. Further, the first solution and the second solution are preferably mixed at a ratio of 1: 1 to 9: 1 (volume ratio) and gelled. From the viewpoint of injection into the blood vessel, the viscosity of the first solution is preferably about 1 to 200 mPa · s at 37 ° C. The relationship between the activity of peroxidase and its weight is 210 units / mg. The amount of enzyme that oxidizes 1 μmol of guaiacol per minute at pH 7.0 and 25 ° C. is defined as 1 unit.

  Furthermore, the embolization preparation may contain, if necessary, another type of phenolic hydroxyl group-modified polymer represented by formula (1) in addition to the phenolic hydroxyl group-modified polymer represented by formula (1). good. Such another kind of phenolic hydroxyl group-modified polymer can be used as a solution together with the other phenolic hydroxyl group-modified polymer, peroxidase, etc., as long as it is a solution different from hydrogen peroxide. These other types of phenolic hydroxyl group-modified polymers are mainly used to adjust the degradation time of the gel. For example, sugar beet-derived pectin has a relatively slow degradation rate because there is no sugar beet-derived pectin degrading enzyme in the living body. Therefore, for example, by mixing gelatin that is more easily decomposed in the range of sugar beet-derived pectin: gelatin = 1: 9 to 9: 1 (weight ratio), not only sugar beet-derived pectin but also beet-derived pectin and gelatin are mixed. Are also crosslinked to form a gel. This gel breaks down the gelatin more quickly, so that the cross-linked structure is broken, and the degradation time of the gel can be shortened by about 50 to 200% compared to the sugar beet-derived pectin alone.

  Furthermore, the embolization preparation may contain aniline or a derivative thereof in addition to the phenolic hydroxyl group-modified polymer represented by the formula (1) as necessary. As derivatives of aniline, compounds having an alkyl group, amino group, cyano group, sulfonic acid group, hydroxy group, carboxyl group, etc. in the aniline skeleton are applicable, and specific examples include aminophenol, diaminobenzene and the like. However, it is not limited to these. Aniline or a derivative thereof can react with a phenolic hydroxyl group-modified polymer by an oxidative polymerization reaction in the presence of the above-mentioned peroxidase and the like and hydrogen peroxide to form a gel. When the phenolic hydroxyl group-modified polymer and aniline or a derivative thereof are used in combination, the mixing ratio can be appropriately set so as to obtain a desired gelation time. For example, phenolic hydroxyl group-modified polymer: aniline or a derivative thereof = It can be set to 1: 9 to 9: 1 (weight ratio).

  The embolization preparation further includes pharmaceutically active compounds such as anticancer agents and anti-inflammatory agents, carriers, solvents, polymers, proteins, cells, contrast agents, DNA, gene / vector systems, anti-angiogenic agents, Various agents such as an antioxidant, an oxidizing agent, an antibacterial agent and an anesthetic can be contained. These drugs are held in a gel that occludes blood vessels and can be released slowly as the gel degrades. Therefore, it can be used as a drug delivery system (DDS). Examples of the anticancer agent include conventionally known substances such as epirubicin and cisplatin. Here, the term “anticancer agent” may be any agent that is intended to suppress the growth of malignant tumors (cancer), and includes not only a narrowly defined anticancer agent but also a so-called anticancer agent. It is also intended to include. Further, the concentration of the drug in the gel can be appropriately set according to the type of drug and the target disease.

  Furthermore, various additives can be contained in the embolization preparation as necessary. Specific examples of the additive include pH adjusters such as 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid.

  EXAMPLES Next, although an Example demonstrates this invention further in detail, this invention is not limited to these.

Example 1
Assuming intravascular administration, gelation was confirmed using a blood vessel model capable of adjusting blood pressure, pulse and humidity. The blood vessel model is a closed circuit, and in the middle of it, a capillary vessel is assumed with an acrylic plate up to a tube with a diameter smaller than 1.5 mm. This model is useful for confirming gelation in a flowing liquid. is there. Distilled water was circulated through this blood vessel model at a pressure of 125 mmHg.

  Next, a microcatheter as shown in FIGS. 1 and 2 was produced. In this microcatheter, the diameter of the opening of the distal end 1a is 3 mm, the diameter of the opening of the lumen 101 is 0.43 mm, and the length of the mixing chamber 103 (from the distal end 1a to the septum 100) The distance) is 5 mm.

  An aqueous solution (first solution) containing sugar beet-derived pectin (concentration: 3.3% by weight) and peroxidase (concentration: 11.1 unit / ml) was poured into the lumen of the microcatheter at a rate of 0.9 ml / min. In the other outer space, an aqueous solution (second solution) containing hydrogen peroxide (concentration 10 mmol / l) is allowed to flow at a rate of 0.1 ml / min, and the mixed solution 1 of the first solution and the second solution 1 from the tip of the catheter. 0.0 ml was injected into the blood vessel model. After the injection, the mixed solution flowed into the tubule in the blood vessel model, and after a few seconds, the tubule was closed and gelled.

(Example 2)
First, sugar beet-derived pectin (concentration: 3.3% by weight), peroxidase (concentration: 11.1 unit / ml), and an aqueous solution (first solution) containing epirubicin (concentration: 5 mg / ml) as an anticancer agent, An aqueous solution (second solution) containing hydrogen peroxide (concentration 10 mmol / l) was prepared. Next, the first solution is caused to flow at a rate of 0.9 ml / min in the lumen of the same microcatheter as in Example 1, and the second solution is allowed to flow at a rate of 0.1 ml / min in the other outer space. 1.0 ml of the mixed solution of the first solution and the second solution was discharged to the outside from the tip of the microcatheter. After release, the mixture gelled in a few seconds. Compared to the case where epirubicin was not added, the gelation time did not tend to be prolonged, and it was confirmed that gelation occurred almost instantaneously and the drug was retained on the gel. In addition, when a similar experiment was performed using cisplatin, which is an anticancer agent, instead of epirubicin, there was no tendency to extend the gelation time as in the case of epirubicin.

(Example 3)
Next, side effects when an embolization preparation was administered into an artery using the microcatheter of the present invention were confirmed in an animal model.
First, after performing general anesthesia on the rabbit, the abdomen was opened to expose the cecum, the portal vein was punctured, and the same microcatheter as in Example 1 was placed in the portal vein under fluoroscopy. Sugar beet-derived pectin (concentration: 3.3 wt%) and an aqueous solution (first solution) in which peroxidase (concentration 11.1 units / ml) is dissolved, and an aqueous solution (second solution) containing hydrogen peroxide (concentration 10 mmol / l) ) To the microcatheter, and using a syringe pump (press-in device), the hydrogen peroxide aqueous solution is 0.1 ml / min, and the sugar beet-derived pectin and peroxidase dissolved solution is 0.9 ml / min. The mixed solution was intravascularly administered from the catheter tip. The dose was set so that sugar beet-derived pectin was 5 ml. Rabbits after intraportal administration were bled immediately after administration (30 minutes), 1 day, 3 days, and 7 days later, the liver was removed, and blood biochemical examination and histopathological examination were performed.

  After intraportal administration of an embolization preparation, Day 3 liver macroscopic findings showed a reddish brown color change in the right hepatic lobe and a punctate white tone change thought to be due to the gel formed or associated inflammation. It was. The time-lapse pathological image (Alcian blue staining) is shown in FIGS. In Day 0 (FIG. 3), Day 1 (FIG. 4), Day 3 (FIG. 5), and Day 7 (FIG. 6) after injection of the embolization preparation, each gel was injected into the portal vein and remained in the portal vein as an embolic substance. Was stained blue (FIGS. 3-6, gray arrows). The embolization preparation flowed into the peripheral portal vein immediately after the injection, and Day 1 was able to identify the gel into the distal portal vein. In addition, an image that was swept away from the central side to the peripheral side was observed in Day 3, and liver injury associated with embolism was particularly remarkable in Day 3 (FIG. 5, white arrow). However, in Day 7, although the gel remained in the portal vein, inflammation was improved. In the pathological tissues of Day 0 to Day 7, no gel spillage into the hepatic artery was observed, and no rabbit death related to intraportal administration was observed.

  The effects of portal vein embolism on the liver were also confirmed by blood biochemistry. As shown in FIG. 7, hepatic disorder of AST was Day 1 and ALT was Day 3 with a maximum of less than 300 IU / L, but Day 7 was improved to the same extent as the control group. These changes were similar in γGTP (FIG. 8), and total bilirubin was slightly higher in Day 7, but it was not a significant increase indicating signs of liver failure. As described above, gelation and embolization effect in blood vessels were confirmed by administration of an embolization preparation using the microcatheter of the present invention. As side effects caused by intravascular administration of embolization preparations, hepatic damage due to embolism was observed, but all were transient, and it was found that all showed a trend of improvement on the 7th day.

  In addition, this invention is not limited to above-described embodiment, Various modifications are included. For example, with respect to a part of the configuration of the embodiment, it is possible to add, delete, or replace another configuration.

1 microcatheter 1a distal end 1b proximal 10 catheter body 100 partition wall 101 lumen 102 outside lumen 103 mixing chamber 104 connection portion 105 connection portion _L 1, _{L 2} Liquid

Claims (4)

A microcatheter having a tubular catheter body opening at a distal end,
A coaxial lumen and an outer space partitioned by a partition wall are formed inside the catheter body,
Each of the lumen and the outer lumen opens on the distal end side of the catheter body, but the partition wall is located deeper toward the proximal end side than the distal end of the catheter body, whereby the lumen The microcatheter in which a mixing chamber is formed in which the liquid supplied to each of the inner cavity and the outer cavity is mixed between the opening of the catheter and the distal end of the catheter body. The lumen is represented by the following formula (1):

(Wherein, P is a biocompatible polymer, or A is a single bond, or _-OCO-C 2 ~C ₄ - alkenylene group, _-CONH-C 1 _{~C 4} - alkylene or -HNCO-C _{1 to} C ₄ -alkylene group, X is hydrogen or C _{1 to} C ₃ -alkoxy group)
And a first solution containing at least one selected from a peroxidase, a laccase, a tyrosinase, a catalase and an iron porphyrin complex, or a second solution containing hydrogen peroxide. Is intended to
The microcatheter according to claim 1, wherein the outer lumen is for supplying the other.   The microcatheter according to claim 2, wherein the biocompatible polymer is gelatin, pectin, albumin, hyaluronic acid, amylopectin, chitosan, alginic acid, modified polyvinyl alcohol having a carboxyl group, carboxymethylcellulose, or collagen.   The microcatheter according to claim 2, wherein the phenolic hydroxyl group-modified polymer represented by the formula (1) is a sugar beet-derived pectin having a ferulic acid group.

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