JP5787566B2 - Antibacterial catheter and method for producing the same - Google Patents

Description

  The present invention relates to an antibacterial catheter and a method for producing the same, and more particularly to a central venous catheter placed in a blood vessel.

One example of an antibacterial catheter is a central venous catheter. This central venous catheter is an instrument that is used by inserting the skin piercing portion of the central venous catheter into the subclavian vein or the jugular vein and placing the distal end portion of the central venous catheter in the superior vena cava for a long period of time.
The central venous catheter is given antibacterial properties in order to avoid the possibility of bacteria entering the body via the skin puncture site or lumen of the central venous catheter and causing bacterial infection. .
In addition, since the central venous catheter may be used after being placed in the body for a long period of time, it is desired that antibacterial properties be maintained for a long period of time.

  Here, as disclosed in Patent Document 1, as a method for producing an antibacterial catheter to which antibacterial properties are imparted, there is a production method in which an antibacterial agent is kneaded into a polymer compound which is a raw material of the catheter. Further, as disclosed in Patent Document 2, there is a manufacturing method in which a catheter is immersed in a solution in which an antibacterial agent is dissolved, and the attached solution is dried to coat the surface of the catheter with an antibacterial agent layer.

  Further, according to the above-described method for producing an antibacterial catheter, when the same amount of the antibacterial agent is used, the antibacterial agent layer is formed on the surface of the catheter as compared with the case where the antibacterial agent is kneaded into a polymer compound. More antibacterial agents are distributed on the surface of the catheter when coated with. Therefore, the antibacterial property is more advantageous when the catheter surface is coated with an antibacterial agent layer.

Japanese Patent Laid-Open No. 5-220216 Japanese Patent Laid-Open No. 11-290449

  However, in the coating method described in Patent Document 2, for example, when an antibacterial agent particle that does not dissolve in a solvent such as zeolite silver particles is used to coat the surface of the catheter, the zeolite silver particles do not dissolve in the solvent. In a state where the particle size is large, it is fixed to the surface of the catheter, and the surface roughness becomes large. Therefore, during use, when the catheter is inserted into the blood vessel, the silver silver particles may fall off the catheter surface and the antibacterial property may not be maintained. On the other hand, when the catheter is left in the blood vessel for a long time, a thrombus is formed on the surface of the catheter, which may reduce blood compatibility.

  Also, if the particle size of the zeolite silver particles is too small, the particles aggregate in the solvent, and the dispersion of the particles in the solvent becomes unstable, so the zeolite silver particles are not uniformly coated on the catheter surface, As with the large particle size, a thrombus is formed on the surface of the catheter during use. In addition, nonuniform coating of zeolite silver particles on the catheter surface also leads to a decrease in antibacterial properties.

  Therefore, the present invention was devised in view of the above problems, and even if the antibacterial agent particles are insoluble in the solvent, the antibacterial agent particles are prevented from falling off from the surface of the catheter, and the antibacterial property is maintained for a long time. An object is to provide an antibacterial catheter having excellent blood compatibility and a method for producing the same.

  In order to solve the above-mentioned problems, an antibacterial catheter according to the present invention has a coating layer composed of antibacterial agent particles formed on the surface of at least the intravascular insertion site of the catheter, and the antibacterial agent constituting the coating layer Of the particles, the total volume% of the antibacterial agent particles having a particle size of 0.04 to 1.0 μm is 97% or more, and the surface roughness of the coating layer is 0. 0 in terms of arithmetic average roughness (Ra). It is characterized by being less than 1 μm.

  According to the above configuration, when the ratio of the antibacterial agent particles having a predetermined diameter constituting the coating layer on the catheter surface is in the predetermined range and the surface roughness of the coating layer is in the predetermined range, the catheter is inserted and placed in the blood vessel. Antibacterial and antithrombogenic properties are maintained over time.

In the antibacterial catheter, the antibacterial agent particles preferably include at least one of silver-supported silica particles, zeolite silver particles, and silver particles.
According to the said structure, antimicrobial property is further maintained by using the antimicrobial agent particle containing silver excellent in the antimicrobial effect.

  The antibacterial catheter manufacturing method according to the present invention includes a dispersion crushing step in which antibacterial agent particles are dispersed in an organic solvent, and a particle size distribution of the antibacterial agent particles is prepared using a pulverizer to obtain an antibacterial agent-containing solution. An attachment step of attaching the antibacterial agent-containing solution to at least the surface of the intravascular insertion site of the catheter, and a drying step of drying the antibacterial agent-containing solution attached to the surface of the catheter. The prepared particle size distribution is 97% or more in total of the volume% of the antibacterial particles having a particle diameter of 0.04 to 1.0 μm, and the volume% of the antibacterial particles having a particle diameter of 0.04 to 0.2 μm. The total of the above is 70% or less.

  According to the above procedure, in the dispersion pulverization step, by preparing using a pulverizer so that the particle size distribution of the antibacterial agent particles in the antibacterial agent-containing solution is within a predetermined range, the adhesion surface and the drying step are performed on the catheter surface. A coating layer composed of antibacterial agent particles having a particle size in a predetermined range is formed, and the surface roughness of the coating layer is in a predetermined range. As a result, an antibacterial catheter that maintains antibacterial and antithrombogenic properties over a long period of time can be manufactured.

  In the method for producing an antibacterial catheter, the particle size distribution prepared in the dispersion and pulverization step may be such that the particle size (mode) in which the volume% of the antibacterial agent particles is maximum is 0.08 μm or more. preferable.

  According to the above procedure, when the mode diameter of the antibacterial agent particles is within a predetermined range, it becomes easy to prepare a total of the volume% of the antibacterial agent particles having a particle size of 0.04 to 0.2 μm. The particle size of the antibacterial agent particles and the surface roughness of the coating layer are within a predetermined range. As a result, an antibacterial catheter that can further maintain antibacterial and antithrombogenic properties can be produced.

In the method for producing an antibacterial catheter, the antibacterial agent particles preferably include at least one of silver-carrying silica particles, zeolite particles, and silver particles.
According to the said procedure, the antimicrobial catheter in which antimicrobial property is further maintained can be manufactured by using the antimicrobial agent particle containing silver excellent in the antimicrobial activity.

  As described above, according to the present invention, even when the antibacterial agent particles are not soluble in the solvent, the antibacterial agent particles are prevented from dropping from the surface of the catheter, and the antibacterial property can be maintained for a long time, and excellent blood compatibility can be obtained. An antibacterial catheter having the same and a method for producing the same can be provided.

It is a figure which shows the whole structure of the central venous catheter which is embodiment of this invention. Example No. FIG. 2 is a diagram showing a particle size distribution of an antibacterial agent-containing solution used in 1. Example No. It is a figure which shows the particle size distribution of the antibacterial agent containing solution used by 2. FIG. Comparative Example No. 3 is a graph showing the particle size distribution of an antibacterial agent-containing solution used in No. 3. FIG. Comparative Example No. It is a view showing a particle size distribution of the antimicrobial-containing solution used in 4. Comparative Example No. 5 is a view showing a particle size distribution of the antimicrobial-containing solution used in. Comparative Example No. 6 is a graph showing the particle size distribution of the antibacterial agent-containing solution used in FIG. It is a figure which shows typically the structure of the TAT output measurement apparatus used for evaluation of blood compatibility.

An embodiment of an antibacterial catheter according to the present invention will be described.
An antibacterial catheter has a coating layer made of antibacterial agent particles formed on the surface of at least the intravascular insertion site of the catheter, and the particle size of the antibacterial agent particles constituting the coating layer and the roughness of the surface of the coating layer. Is defined within a predetermined range. Each configuration will be described below.

  In the antibacterial catheter, the structure of the catheter in which the coating layer is formed is not particularly limited as long as it is used by being inserted into a blood vessel. For example, the antibacterial catheter of the present invention is used as a central venous catheter. If so, the following configuration is provided.

  As shown in FIG. 1, the central venous catheter 1 includes a tubular main body 2 having a lumen (not shown) through which a drug solution and the like flow, and a tubular distal end 3 joined to the distal end side of the main body 2. A hub 4 joined to the base end side of the main body 2, a connection tube 5 for injecting a chemical solution joined to the hub 4, and a connector 6 joined to the base end side of the connection tube 5. Yes.

  This central venous catheter 1 has a distal end portion 3 (main body portion 2) inserted from a subclavian vein or a jugular vein, and the main body portion 2 is left in the superior vena cava, etc. It is a medical device for performing administration, blood collection, and the like, and is formed of a polymer material conventionally used for antibacterial catheters. As the polymer material, polyurethane, polyvinyl chloride, polyamide, polyolefin, polyester, silicon resin, or the like can be used.

  In the central venous catheter 1, the intravascular insertion site where a coating layer (not shown) made of antibacterial particles is formed is the main body 2 and the distal end 3, and the surface of the intravascular insertion site is The inner surface and the outer surface of the tube-shaped main body 2 and the tip 3 are indicated.

  In the antibacterial catheter, the antibacterial agent particles constituting the coating layer may be either inorganic antibacterial agent particles or organic antibacterial agent particles. For example, silver-supported silica particles, zeolite silver particles, silver particles, copper particles Platinum fine particles, titanium oxide particles, zinc oxide particles, tungsten oxide particles, silver sulfadiazine, carbon nanotubes, silver-carrying carbon nanotubes, silver-coated carbon nanotubes, and the like. And it is preferable that an antibacterial agent particle contains at least any one of silver carrying | support silica particle, zeolite silver particle, and silver particle at the point containing the silver which is excellent in antibacterial action.

Further, among the antibacterial agent particles constituting the coating layer, the total volume% of the antibacterial agent particles having a particle size of 0.04 to 1.0 μm needs to be 97% or more. In the particle size of the antibacterial agent particles constituting the coating layer, if the proportion of particles having a particle size in the range of 0.04 to 1.0 μm is less than 97%, coarse particles having a particle size exceeding 1.0 μm in the coating layer As the surface roughness of the coating layer increases, the antibacterial agent particles fall off from the catheter surface during use of the catheter, and a thrombus is formed on the catheter surface. Here, the particle size of 0.04 μm is a measurement limit value of a commercially available particle size measuring device (particle size distribution meter). The control of the particle size of the antimicrobial agent particles constituting the coating layer, in the production of antimicrobial catheters is accomplished by particle size distribution made a tone of the antimicrobial agent particles of the antimicrobial agent-containing solution to form a coating layer ( (Refer to the dispersion and pulverization step described later).

In the antibacterial catheter, the surface roughness of the coating layer needs to be less than 0.1 μm in terms of arithmetic average roughness (Ra). When the surface roughness (Ra) of the coating layer is 0.1 μm or more, the surface roughness of the coating layer increases, and when the catheter is used, the antibacterial agent particles fall off from the catheter surface and a thrombus is formed on the catheter surface. Is done. The control of the surface roughness of the coating layer (Ra) is, in the production of antimicrobial catheter and (later is achieved by made the particle size distribution of the antimicrobial agent particles of the antimicrobial agent-containing solution to form a coating layer tone (Refer to the dispersion grinding process).

Next, an embodiment of a method for producing an antibacterial catheter according to the present invention will be described.
The production method of the present invention includes a dispersion pulverization step, an adhesion step, and a drying step, and defines the particle size distribution of the antibacterial agent particles of the antibacterial agent-containing solution in the dispersion pulverization step within a predetermined range. Hereinafter, each step will be described.

(Dispersion grinding process)
The dispersion pulverization step is a step in which the antibacterial agent particles are dispersed in an organic solvent, and the particle size distribution of the antibacterial agent particles is prepared using a pulverizer to obtain an antibacterial agent-containing solution. In the dispersion and pulverization step, the particle size distribution of the antibacterial agent particles in the antibacterial agent-containing solution is within a predetermined range in the total volume percent of the antibacterial agent particles having a particle size of 0.04 to 1.0 μm, and the particle size is 0.00. It prepares using a grinder so that it may become a predetermined range in the sum total of the volume% of 04-0.2 micrometer antibacterial agent particle | grains. In the particle size distribution, it is preferable that the particle size (mode) at which the volume% of the antibacterial agent particles has a maximum value is within a predetermined range.

  In the dispersion and pulverization step, the organic solvent used for the preparation of the antibacterial agent-containing solution is selected from those that are suitable for attachment to the catheter surface in the next step and can disperse the antibacterial particles in the solvent. -Methyl-pyrrolidone (NMP), tetrahydrofuran (THF), N, N-dimethylformamide (DMF), di-methylacetamide (DMA), cyclohexanone and the like are preferable. Moreover, when using an antibacterial agent containing solution at an adhesion | attachment process, it is preferable to use it, diluting with a solvent suitably. As a dilution solvent, the solvent used in the dispersion treatment, methanol, ethanol, or the like is used. Moreover, since it is as having already described about the antimicrobial agent particle | grains, description is abbreviate | omitted. Furthermore, the content of the antibacterial agent particles in the antibacterial agent-containing solution is appropriately set according to the degree of antibacterial and blood compatibility required for the antibacterial catheter, but when the antibacterial catheter is used as a central venous catheter, 0.1 to 3 wt / v% is preferable.

In the dispersion milling step, pulverizing machine used to, prepare the particle size distribution of the antimicrobial agent particles is not particularly limited as long, prepare particle size distribution in a predetermined range, a jet mill is preferred. Then, the particle size distribution of the antibacterial agent particles is prepared by controlling the pulverization conditions of the pulverizer. When a jet mill apparatus is used as the pulverizer, the pulverization conditions are preferably 50 to 200 MPa and 50 to 1000 pass.

  The particle size distribution of the antibacterial particles is 97% or more in the total of the volume% of the antibacterial particles having a particle size of 0.04 to 1.0 μm, and the volume of the antibacterial particles having a particle size of 0.04 to 0.2 μm. It is necessary to be 70% or less in the total of%. In the particle size distribution, the mode diameter of the antibacterial agent particles is preferably 0.08 μm or more.

  In the particle size distribution, when the total volume% of the antibacterial agent particles having a particle size of 0.04 to 1.0 μm is less than 97%, coarse particles having a particle size exceeding 1.0 μm are formed in the coating layer formed in the subsequent step. As a result, the surface roughness of the coating layer increases, and when the catheter is used, the antibacterial agent particles fall off from the catheter surface, and a thrombus is formed on the catheter surface. Here, the particle size of 0.04 μm is a measurement limit value of a commercially available particle size distribution meter.

  Moreover, in the particle size distribution, when the total volume percentage of the antibacterial agent particles having a particle size of 0.04 to 0.2 μm exceeds 70%, the antibacterial agent particles having a small particle size dispersed in the antibacterial agent-containing solution increase. Then, the particles are re-aggregated after being pulverized by a pulverizer to form coarse particles having a large particle size. As a result, coarse particles are present in the coating layer formed in the subsequent process, the surface roughness of the coating layer is increased, and when the catheter is used, the antibacterial agent particles fall off from the catheter surface, and the thrombus on the catheter surface. Is formed. Further, the formation of the coating layer on the catheter surface becomes non-uniform, which also causes a thrombus to form on the catheter surface.

  Furthermore, in the particle size distribution, when the mode diameter of the antibacterial agent particles is less than 0.08 μm, the total of the volume percentages of the antibacterial agent particles having a particle size of 0.04 to 0.2 μm is likely to exceed 70%. The antibacterial particles having a small particle size dispersed in the antibacterial agent-containing solution are increased, and the particles are aggregated again after being pulverized by a pulverizer to easily form coarse particles having a large particle size. As a result, coarse particles are likely to be present in the coating layer formed in the subsequent process, the surface roughness of the coating layer is increased, and antibacterial particles are dropped from the catheter surface during use of the catheter, and thrombus is formed on the catheter surface. Is easily formed. In addition, the coating layer is not uniformly formed on the catheter surface, and thrombi are easily formed.

(Adhesion process)
The attachment step is a step of attaching the antibacterial agent-containing solution whose particle size distribution is prepared in the above step to at least the surface of the intravascular insertion site of the catheter. The method for attaching the antibacterial agent-containing solution to the surface of the catheter is preferably performed by immersing the catheter in the antibacterial agent-containing solution. Moreover, as an adhesion method, spray coating etc. may be used besides immersion. Further, the amount of the antibacterial agent-containing solution attached is appropriately set according to the degree of antibacterial properties and blood compatibility required for the antibacterial catheter, and is controlled by appropriately adjusting the immersion time, the coating amount, and the like.

(Drying process)
A drying process is a process of drying the antibacterial agent containing solution adhering to the surface of the catheter at the said process. And in a drying process, a solvent evaporates from an antibacterial agent containing solution by drying, and the coating layer which consists of antibacterial agent particles on the surface of a catheter is formed. Drying may be performed either by heat treatment or standing at room temperature, and is appropriately selected depending on the solvent type of the antibacterial agent-containing solution.

Next, examples of the present invention will be described.
(Example No. 1, Reference Example No. 7)
When a particle powder of silver-supported silica particles (silver content 20% by mass) was dispersed in N-methylpyrrolidone (NMP) at a rate of 5 wt / v%, a large agglomerate instantly precipitated after dispersion (stirring). (Untreated liquid). 20 ml of this untreated liquid was pulverized (180 MPa, 800 Pass) with an jet mill device (manufactured by Joko) to obtain an antibacterial agent-containing solution, and the particle size distribution was measured with a particle size distribution meter (manufactured by COULTER). The results are shown in FIG.

  This antibacterial agent-containing solution was diluted with methanol (Me) and prepared to a 1 wt / v% antibacterial agent-containing solution with a mixed solvent of N-methylpyrrolidone and methanol (mixing ratio 1: 1). Next, a tube having a length of 30 cm was formed from polyurethane (manufactured by Nippon Milactone Co., Ltd., trade name “E990”) (corresponding to the catheter of Reference Example No. 7). This tube was immersed in an antibacterial agent-containing solution and then dried to obtain a catheter (corresponding to the catheter of Example No. 1). The surface roughness (arithmetic mean roughness Ra) of this catheter was measured with a laser microscope. The results are shown in Table 1. Reference Example No. Similarly, the surface roughness (arithmetic average roughness Ra) of the catheter No. 7 was measured, and the results are shown in Table 1.

(Example No. 2)
When a particle powder of silver-supported silica particles (silver content 20% by mass) was dispersed in tetrahydrofuran (THF) at a rate of 5 wt / v%, a large agglomerate instantly precipitated after dispersion (stirring) ( Untreated liquid). 20 ml of this untreated liquid was pulverized (100 MPa, 400 Pass) with an jet mill device (manufactured by Joko) to obtain an antibacterial agent-containing solution, and the particle size distribution was measured with a particle size distribution meter (manufactured by COULTER). The results are shown in FIG.

  This antibacterial agent-containing solution was diluted with THF to prepare a 1 wt / v% antibacterial agent-containing solution. Next, a tube having a length of 30 cm was formed with polyurethane (manufactured by Nippon Milactone Co., Ltd., trade name “E990”), this tube was immersed in an antibacterial agent-containing solution, and then dried to obtain a catheter. The surface roughness (arithmetic mean roughness Ra) of this catheter was measured with a laser microscope. The results are shown in Table 1.

(Comparative Example No. 3)
Example No. No. 1 untreated liquid was used as the antibacterial agent-containing solution. In the same manner as in 1, a catheter was prepared. In addition, the particle size distribution of the untreated liquid and the surface roughness of the catheter (arithmetic mean roughness Ra) were also determined in Example No. 1 and the results are shown in FIG.

(Comparative Example No. 4)
Using a bead mill apparatus (manufactured by Imex), Example No. Example No. 1 except that the untreated liquid of No. 1 was ground (2000 rpm, 3 hours). In the same manner as in 1, an antibacterial agent-containing solution was prepared. Using this antibacterial agent-containing solution, Example No. In the same manner as in 1, a catheter was prepared. In addition, the particle size distribution of the antibacterial agent-containing solution and the surface roughness of the catheter (arithmetic average roughness Ra) are also shown in Example No. 1 and the results are shown in FIG. This antibacterial agent-containing solution was re-agglomerated after standing for 1 hour.

(Comparative Example No. 5)
Example No. No. 2 untreated liquid was used as the antibacterial agent-containing solution. In the same manner as in 2, a catheter was prepared. In addition, the particle size distribution of the untreated liquid and the surface roughness of the catheter (arithmetic mean roughness Ra) were also determined in Example No. The measurement was performed in the same manner as 2 and the results are shown in FIG.

(Comparative Example No. 6)
Using a jet mill apparatus (manufactured by Joko), Example No. Example No. 1 except that the untreated liquid of No. 1 was pulverized (180 MPa, 40 pass). In the same manner as in 1, an antibacterial agent-containing solution was prepared. Using this antibacterial agent-containing solution, Example No. In the same manner as in 1, a catheter was prepared. In addition, the particle size distribution of the antibacterial agent-containing solution and the surface roughness of the catheter (arithmetic average roughness Ra) are also shown in Example No. 1 and the results are shown in FIG.

  Next, Example No. 1, Example No. 2, Comparative Example No. 3-6, Reference Example No. For 7 catheters, blood compatibility was evaluated by the following method, and the results are shown in Table 1.

[Blood compatibility]
The catheter was subjected to a blood circulation experiment for 60 minutes in the system shown in FIG. After circulation, the amount of TAT (thrombin-antithrombin III complex) produced, which is an index of the degree of thrombus formation, was measured. It can be said that the smaller the measured value of the TAT output, the less the thrombus is formed and the better the blood compatibility.

  As shown in Table 1, No. of the example satisfying the requirements of the present invention. 1, no. No. 2 is a reference example No. in which a coating layer is not formed. 7 and Comparative Example No. which does not satisfy the requirements of the present invention. Compared to 3-6, it was confirmed that the blood compatibility was excellent.

DESCRIPTION OF SYMBOLS 1 Central venous catheter 2 Body part 3 Tip part 4 Hub 5 Connection tube 6 Connector

Claims (5)

An antibacterial catheter in which a coating layer made of antibacterial agent particles is formed on the surface of at least the intravascular insertion site of the catheter,
Among the antibacterial agent particles constituting the coating layer, the total volume% of the antibacterial agent particles having a particle size of 0.04 to 1.0 μm is 97% or more,
The antibacterial catheter characterized in that the surface roughness of the coating layer is an arithmetic average roughness (Ra) of less than 0.1 μm.   The antibacterial catheter according to claim 1, wherein the antibacterial agent particles include at least one of silver-supported silica particles, zeolite silver particles, and silver particles. Dispersing and crushing step of dispersing the antibacterial agent particles in an organic solvent, preparing a particle size distribution of the antibacterial agent particles using a pulverizer to obtain an antibacterial agent-containing solution,
An attachment step of attaching the antibacterial agent-containing solution to at least the surface of the intravascular insertion site of the catheter;
A drying step of drying the antibacterial agent-containing solution attached to the surface of the catheter;
Including
The particle size distribution prepared in the dispersion and pulverization step is a total of 97% or more of antibacterial particles having a particle size of 0.04 to 1.0 μm, and an antibacterial having a particle size of 0.04 to 0.2 μm. A method for producing an antibacterial catheter, wherein the total volume% of the agent particles is 70% or less.   4. The antibacterial according to claim 3, wherein the particle size distribution prepared in the dispersion and pulverization step has a particle size (mode) in which the volume% of the antibacterial agent particles has a maximum value of 0.08 μm or more. Method for manufacturing a catheter.   The method for producing an antibacterial catheter according to claim 3 or 4, wherein the antibacterial agent particles include at least one of silver-carrying silica particles, zeolite particles, and silver particles.

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