JP6830814B2 - Drug release catheter device and drug release method - Google Patents

Description

The present invention relates to a drug release catheter device in which a drug is coated on the outer surface of a balloon, and a drug release method including a step of releasing the drug coated on the outer surface of the balloon.

Conventionally, treatment for dilating a narrowed blood vessel with a catheter has been performed. For example, in balloon dilatation, to dilate an arterial stenosis with a balloon catheter, a guide wire is inserted into the guiding catheter and its tip reaches the vicinity of the stenosis. Guided by this guide wire, the balloon catheter is inserted into the guiding catheter so that the balloon portion reaches the narrowed portion of the artery. Then, the balloon portion is inflated to dilate the narrowed portion of the artery (see Patent Documents 1 to 3).

In addition, in order to prevent the narrowed portion of the blood vessel dilated by the balloon catheter from being narrowed again, a treatment is performed in which a drug is locally administered to the narrowed portion of the blood vessel. For example, by using a balloon catheter coated on the outer surface of the balloon with a drug having an effect of preventing restenosis such as paclitaxel in the narrowed portion of the dilated blood vessel as described above, the balloon is inflated in the blood vessel. , The outer surface of the balloon is pressed against the inner wall of the narrowed portion of the blood vessel. As a result, the drug coated on the outer surface of the balloon is applied to the inner wall of the blood vessel (see Patent Documents 4 and 5).

Japanese Unexamined Patent Publication No. 2006-326226 JP-A-2007-20737A JP-A-2009-536546 Special Table 2005-510315 Special Table 2010-509991

In order for the drug to be effective, it is desirable to infiltrate the inner wall of the blood vessel. However, inflating the balloon in the blood vessel for a long time is not preferable because the blood flow is blocked for a long time and the possibility of inducing myocardial necrosis or tissue damage increases.

The present invention has been made in view of the above-mentioned circumstances, and an object of the present invention is to provide a drug release catheter device capable of infiltrating a drug into the inner wall of a blood vessel in a relatively short time.

(1) The drug release catheter device in the present invention is provided on a shaft having a flow path through which a fluid flows and on the tip end side of the shaft, and can be expanded by the inflow of the fluid, and the drug can be applied to the outer surface. A coated balloon, a heating unit that heats the fluid, a pump that causes the fluid to flow into the balloon, a detection unit that detects the temperature of the fluid, and a control unit that controls the operation of the pump and the heating temperature of the heating unit. And. The control unit causes the balloon to flow into the balloon by the pump to inflate the balloon, and heats the fluid in the range of 60 ° C. to 90 ° C. by the heating unit in response to the detection signal of the detection unit.

When the fluid flows into the balloon and is inflated, the drug coated on the outer surface of the balloon comes into contact with the inner wall of the blood vessel. Further, when the fluid is heated in the range of 60 ° C. to 90 ° C., the inner wall of the blood vessel is also heated to the same temperature. As a result, the drug infiltrates the inner wall of the blood vessel in a relatively short time.

(2) Preferably, the heating unit heats the fluid in the internal space of the balloon, and the detection unit detects the temperature of the fluid in the internal space of the balloon.

Since the fluid is heated in the internal space of the balloon and the temperature of the fluid in the internal space of the balloon is detected, the temperature at which the blood vessel is heated is accurately controlled.

(3) Preferably, the heating portion is inserted into the metal heating member that generates heat when irradiated with light and the shaft, and extends to the internal space of the balloon, and is input to the base end. A light guide member for irradiating the heat generating member with the generated light from the tip is provided.

This allows the fluid to be heated in the balloon with a simple structure.

(4) Preferably, the control unit drives the pump to return the fluid to the balloon.

The reflux of the fluid can suppress an excessive temperature rise of the fluid in the internal space of the balloon.

(5) Preferably, the above-mentioned agent is a hydrophobic agent.

(6) Preferably, the agent comprises at least paclitaxel or an analog thereof.

Thereby, the restenosis of the blood vessel can be effectively suppressed.

(7) In the present invention, a step of inflowing a fluid into a balloon of a balloon catheter to inflate the balloon and a drug coated on the outer surface of the balloon by heating the fluid in the range of 60 ° C. to 90 ° C. It may be regarded as a drug release method including a release step.

(8) In the present invention, a step of inflowing a fluid into a balloon of a balloon catheter to inflate the balloon, a step of heating the fluid in the range of 60 ° C. to 90 ° C., and a drug coated on the outer surface of the balloon catheter. It may be regarded as a method of releasing a drug, which comprises a step of releasing a drug.

The balloon in which the internal fluid is heated and the balloon in which the outer surface is coated with the drug do not necessarily have to be the same, and need not be provided in the same balloon catheter.

According to the present invention, when the fluid flows into the balloon and is inflated, the drug coated on the outer surface of the balloon comes into contact with the inner wall of the blood vessel, and the fluid is heated within the range of 60 ° C to 90 ° C. As a result, the inner wall of the blood vessel is also heated to the same temperature, so that the drug can be infiltrated into the inner wall of the blood vessel in a relatively short time.

FIG. 1 is a diagram showing an external configuration of a drug release catheter device 100 in a state in which the balloon 11 is in a contracted posture. FIG. 2 is a cross-sectional view of the balloon 11. FIG. 3 is a cross-sectional view taken along the line III-III of FIG. FIG. 4 is a diagram showing a locus of laser light emitted from the optical fiber 20. FIG. 5 is a diagram showing the relationship between the concentration of the drug adhering to the intima of the blood vessel and the heating temperature. FIG. 6 is a diagram showing the relationship between the drug invasion length in the blood vessel radial direction and the heating temperature. FIG. 7 is a diagram showing fluorescence brightness at each distance from the lumen. FIG. 8 is a diagram showing the results of observing the surface of the intima elastic plate of a blood vessel with an environment-controlled electron microscope. FIG. 9 is a diagram showing the results of observing the surface of the intima elastic plate of a blood vessel with a field emission scanning electron microscope. FIG. 10 is a diagram showing the relationship between the heating temperature of the sliced blood vessel and the ANS fluorescence brightness.

Hereinafter, preferred embodiments of the present invention will be described with reference to the drawings. Needless to say, the present embodiment is only one embodiment of the present invention, and the embodiments can be changed without changing the gist of the present invention.

As shown in FIG. 1, the drug release catheter device 100 includes a balloon catheter 10, a laser generator 25, a control device 30 (corresponding to a control unit), and a pump 31.

As shown in FIGS. 1 and 2, the balloon catheter 10 has a shaft 12 provided with a balloon 11 on the distal end side. The shaft 12 is a member elongated in the axial direction 101. The shaft 12 is a tubular body that can be elastically bent so as to be curved with respect to the axial direction 101. The direction in which the shaft 12 in the non-curved state extends is defined as the axial direction 101 in the present specification. Further, in the balloon catheter 10 shown in FIG. 1, the posterior side (right side in FIG. 1) with respect to the direction of insertion into the blood vessel is defined as the "base end side", and the anterior side (right side with respect to the direction of insertion into the blood vessel). The left side in FIG. 1) is defined as the "tip side".

A guide wire tube 14, an in-side tube 17, an out-side tube 18, a cable 19, and an optical fiber 20 are inserted into the shaft 12. The outer diameter and inner diameter of the shaft 12 do not necessarily have to be constant with respect to the axial direction 101, but from the viewpoint of operability, it is preferable that the rigidity of the proximal end side is higher than that of the distal end side. For the shaft 12, a known material used for a balloon catheter, such as synthetic resin or stainless steel, can be used. Further, the shaft 12 does not necessarily have to be composed of only one kind of material, and may be configured by assembling a plurality of parts made of other materials.

The balloon 11 provided on the tip end side of the shaft 12 elastically expands when a fluid (for example, a liquid such as physiological saline or a contrast medium, a gas such as air) flows into the internal space through the inner tube 17. , The fluid contracts due to the outflow of fluid from the internal space through the out-side tube 18. That is, the internal space of the balloon 11 communicates with each internal space (corresponding to a flow path) of the in-side tube 17 and the out-side tube 18 inserted through the shaft 12. The size of the balloon 11 is, for example, about 20 mm to 40 mm in length in the axial direction 101, and about 6 mm to 8 mm in diameter when inflated. 1 and 2 show the balloon 11 in a contracted state. As the material of the balloon 11 and the method of fixing the balloon 11 to the shaft 12, known materials and methods used in the balloon catheter can be used.

The outer surface 24 of the balloon 11 is coated with a drug. The physical state of the drug is not particularly limited. As the drug, those used for tissue treatment of blood vessels are preferable. Further, the drug is not limited to one type, and a plurality of types of drugs may be combined. In addition, the action of improving the infiltration of the drug into the inner wall of the blood vessel is particularly effective in the hydrophobic drug. Specific examples include paclitaxel, rapamycin, daunorubicin, doxorubicin, rapacon, vitamins D2 and D3, and analogs and derivatives thereof. Further, from the viewpoint of effectively suppressing restenosis of blood vessels, it is preferable that the drug contains at least paclitaxel or an analog thereof.

The drug is coated on the outer surface 24 of the balloon 11 in a state of being dispersed, solubilized and mixed in a solvent. As the solvent, water, physiological saline, an organic solvent, a mixture thereof, or the like can be used. Further, an appropriate additive may be added to the solvent. The concentration of the drug with respect to the solvent is preferably, for example, 0.01 to 20% by weight.

As a method of coating the outer surface 24 of the balloon 11 with a solvent containing a drug, casting, spinning, spraying, immersion (immersion), inkjet printing, electrostatic technology, or the like can be used. Further, another layer may be laminated on the outer surface 24 of the balloon 11 above and below the layer containing the drug. For example, a hydrophilic layer may be laminated on the lower side of the layer containing the drug so that the drug can be easily eluted from the outer surface 24 of the balloon 11. Further, another layer may be laminated on the upper side of the layer containing the drug in order to protect the layer containing the drug and to provide smoothness when it is inserted into a blood vessel.

A hub 13 is provided at the base end of the shaft 12. The guide wire tube 14, the in-side tube 17, the out-side tube 18, the cable 19, and the optical fiber 20 are inserted into the shaft 12 through the hub 13 and extend in the axial direction 101. That is, the extending directions of the guide wire tube 14, the in-side tube 17, the out-side tube 18, the cable 19, and the optical fiber 20 in the shaft 12 substantially coincide with the axial direction 101. As shown in FIG. 3, the guide wire tube 14 and the in-side tube 17 are adjacent to each other inside the out-side tube 18. The optical fiber 20 is arranged inside the inner tube 17. The materials constituting the guide wire tube 14, the in-side tube 17, and the out-side tube 18 are not particularly limited, but may be formed of, for example, a flexible thermoplastic elastomer such as Pebax (registered trademark). it can.

As shown in FIGS. 1 and 2, the tip of the guide wire tube 14 inserted into the shaft 12 through the hub 13 is exposed and opened from the tip side of the balloon 11 to the outside. A tip tip 29 is provided around the tip end side of the guide wire tube 14. The tip tip 29 seals the tip side of the balloon 11. The tip tip 29 is provided with a marker made of a contrast medium. Examples of the contrast medium include barium sulfate, bismuth oxide, and bismuth subcarbonate.

As shown in FIG. 2, the tip position of the in-side tube 17 inserted into the inside of the shaft 12 through the hub 13 is the position P1, and the tip position of the out-side tube 18 inserted into the inside of the shaft 12 through the hub 13. Is the position P2. That is, the tip of the in-side tube 17 is located closer to the tip of the balloon 11 than the tip of the out-side tube 18. In other words, a part of the tip end side of the in-side tube 17 is exposed from the out-side tube 18. However, the positional relationship between the tips of the in-side tube 17 and the out-side tube 18 is not limited to this.

As shown in FIG. 1, the ends of the in-side tube 17 and the out-side tube 18 on the proximal end side are connected to the pump 31. When the pump 31 is driven, the fluid flows into the internal space of the balloon 11 through the in-side tube 17, and the fluid flowing out of the balloon 11 through the out-side tube 18 is circulated to the pump 31. Then, the fluid continues to flow into the balloon 11 at the pressure required for the balloon 11 to maintain its expansion, so that the balloon 11 has a radial direction orthogonal to the axial direction 101 so that the center of the axial direction 101 has the maximum diameter. Inflate to.

As shown in FIGS. 2 to 4, a heat generating member 22 (corresponding to a member constituting the heating portion) is provided inside the tip end side of the inner tube 17. In the present embodiment, the tip position of the heat generating member 22 is the position P3, and the base end position of the heat generating member 22 is the position P4. That is, the heat generating member 22 is provided along the inner wall surface of the portion of the in-side tube 17 exposed from the out-side tube 18. The length of the heat generating member 22 in the axial direction 101 is, for example, about 17 mm to 35 mm, and is appropriately selected according to the length of the balloon 11 in the axial direction 101.

The heat generating member 22 is a cylindrical member that covers the inner wall surface of the inner tube 17, and is, for example, a metal wire wound in a coil shape as shown in FIG. However, the specific configuration of the heat generating member 22 is not limited to this, and for example, a metal wire may be woven in a grid pattern, or a film or a point sputtered on the inner wall surface of the inner tube 17. It may be a shape deposit or the like. As a result, the heat generating member 22 can be curved along the shape of the blood vessel into which the balloon catheter 10 is inserted. Further, the heat generating member 22 is made of, for example, stainless steel.

As shown in FIG. 2, a temperature sensor 23 (corresponding to a detection unit) is provided in the internal space of the balloon 11. The installation position of the temperature sensor 23 is not particularly limited as long as it is in contact with the fluid flowing out from the in-side tube 17, but in the present embodiment, it is the outer wall surface of the in-side tube 17. Specific examples of the temperature sensor 23 are not particularly limited, but for example, a known one such as a thermocouple can be used. The cable 19 extends in the axial direction 101 along the outer wall surface of the inner tube 17, and electrically connects the temperature sensor 23 and the control device 30. That is, the output signal from the temperature sensor 23 is transmitted to the control device 30 through the cable 19.

The laser generator 25 is a known device that outputs laser light generated under the control of the control device 30. The wavelength and output of the laser light to be generated are not particularly limited, but the laser generator 25 in the present embodiment can output, for example, a near-infrared laser light having a maximum of 25 W. The laser generator 25 is connected to an optical fiber 20 (corresponding to a light guide member). The laser light generated by the laser generator 25 is output to the optical fiber 20.

The optical fiber 20 inserted into the shaft 12 through the hub 13 is inserted into the internal space of the inner tube 17 in the middle of the shaft 12. Then, the optical fiber 20 extends along the shaft 12 to the inside of the heat generating member 22. As shown in FIG. 2, the tip 21 of the optical fiber 20 in the axial direction 101 is located inside the heat generating member 22. More specifically, the tip 21 is located on the proximal end side from the center of the heat generating member 22 in the axial direction 101.

The optical fiber 20 irradiates the laser beam input to the proximal end side from the tip 21 toward the heat generating member 22. Specifically, the laser light generated by the laser generator 25 is input to the base end of the optical fiber 20 and transmitted to the tip side while repeating total internal reflection in the optical fiber 20, and is generated as diffused light from the tip 21. The member 22 is irradiated.

As shown by the alternate long and short dash line in FIG. 4, the laser light output from the tip 21 of the optical fiber 20 travels toward the tip side while being repeatedly reflected by the inner wall surface of the heat generating member 22. The heat generating member 22 generates heat when irradiated with laser light. Note that FIG. 4 omits the illustration of the locus after the laser beam reaches the heat generating member 22. The diffusion angle of the laser light varies depending on the diameter of the optical fiber 20 and the frequency of the laser light.

The control device 30 includes an arithmetic unit that controls the entire drug release catheter device 100. The arithmetic unit is a known one, and is composed of a CPU, a ROM, a RAM, a program stored in the CPU, and the like. The control device 30 measures the temperature inside the balloon 11 based on the output signal acquired from the temperature sensor 23 through the cable 19. Further, the control device 30 causes the laser generator 25 to output a laser beam having a predetermined output. The output of the laser beam and the irradiation time are controlled based on, for example, the temperature inside the balloon 11 specified by the output signal from the temperature sensor 23. Further, the control device 30 causes the pump 31 connected to the in-side tube 17 and the out-side tube 18 to output a fluid having a predetermined pressure and flow rate. The fluid output from the pump 31 flows into the internal space of the balloon 11 through the in-side tube 17 and circulates to the pump 31 through the out-side tube 18. Although not shown in each figure, a pressure sensor is provided in the internal space of the in-side tube 17 or the out-side tube 18, and the control device 30 receives the signal of the pressure sensor to return the fluid to the balloon 11. The pressure of the resulting fluid may be monitored.

[How to use the drug release catheter device 100]
The usage of the drug release catheter device 100 will be described below. This method of use includes a step of inflowing a fluid into the balloon 11 of the balloon catheter 10 to inflate the balloon 11 and a drug coated on the outer surface 24 of the balloon 11 by heating the fluid in the range of 60 ° C to 90 ° C. Including the step of releasing.

The balloon catheter 10 is inserted into the blood vessel to apply the drug to the narrowed portion of the dilated blood vessel. The guide wire (not shown) previously inserted into the blood vessel reaches the stenotic portion. Such insertion of the guide wire is performed by, for example, a known method disclosed in JP-A-2006-326226 and JP-A-2006-230442.

When the balloon catheter 10 is inserted into the blood vessel, no fluid is press-fitted into the balloon 11, and the balloon 11 is in a contracted state. The balloon catheter 10 in this state is inserted into the blood vessel along the guide wire inserted through the opening at the tip of the guide wire tube 14. The insertion position of the balloon catheter 10 in the blood vessel is grasped, for example, by confirming the marker installed on the guide wire tube 14 by radiation.

After the balloon 11 reaches the narrowed portion of the blood vessel, the pump 31 is driven under the control of the control device 30, so that the fluid flows into the inner tube 17. Further, the laser generator 25 generates the laser beam under the control of the control device 30. A part of the laser beam emitted from the optical fiber 20 and reaching the heat generating member 22 is absorbed to raise the temperature of the heat generating member 22, and the other part is reflected and travels to the tip side of the heat generating member 22. That is, the laser beam is gradually attenuated in the process of traveling toward the tip end side of the heat generating member 22. The fluid flowing through the in-side tube 17 is heated by the heat generating member 22 and flows into the internal space of the balloon 11, and flows out of the balloon 11 through the out-side tube 18. The fluid flowing into the internal space of the balloon 11 inflates the balloon 11 and heats the balloon 11. In this way, the pressurization due to the expansion of the balloon 11 and the heating due to the heat generation of the heat generating member 22 can act on the narrowed portion of the blood vessel.

The outer surface 24 of the inflated balloon 11 is in close contact with the inner wall of the blood vessel. That is, the layer containing the drug coated on the outer surface 24 is in close contact with the inner wall of the blood vessel. Further, by heating the fluid in the balloon 11, the layer containing the drug coated on the outer surface 24 and the inner wall of the blood vessel are heated.

The heating of the fluid in the balloon 11 is performed to raise the inner wall of the narrowed portion of the blood vessel to a target temperature. Specifically, the control device 30 lasers the temperature of the fluid in the balloon 11 so as to be a target temperature X ± 5 ° C. within a range of 60 ° C. to 90 ° C. based on the output signal of the temperature sensor 23. Control the output of light. When the inner wall of the blood vessel is heated to 60 ° C. or higher, the collagen fibers constituting the inner wall of the blood vessel are locally heat-denatured, and the hydrogen bonds of the diversion are partially dissociated and transferred to an amorphos-like state. The drug coated on the outer surface 24 infiltrates the inside of the collagen fibers that have been transferred into an amorphous shape. That is, the drug coated on the outer surface 24 is released into the blood vessel.

When the heat-denatured collagen fibers are subsequently returned to the body temperature of 37 ° C., some of them irreversibly become random coils, but most of them reversibly reconnect to the original fiber state. It is considered that such reversible heat denaturation of collagen fibers causes the drug to infiltrate the inside of the collagen fibers and then be retained in the collagen fibers.

On the other hand, heating the fluid above 90 ° C. increases the risk of thrombi formation in blood vessels and thermal denaturation of proteins. From such a viewpoint, the temperature of the fluid in the balloon 11 is more preferably in the range of 60 ° C. to 80 ° C., and particularly preferably in the range of 60 ° C. to 70 ° C.

The heating time (elapsed time after the balloon 11 reaches a predetermined temperature) varies depending on the target temperature X of the fluid in the balloon 11, but is in the range of about 15 to 60 seconds. The output of the laser beam and the irradiation time are controlled by the control device 30 based on a model function indicating a temperature change of the balloon 11 with respect to the irradiation time of the laser beam, an output signal from the temperature sensor 23, and the like.

[Action and effect of this embodiment]
According to the present embodiment, when the fluid flows into the balloon 11 and is inflated, the drug coated on the outer surface 24 of the balloon 11 comes into contact with the inner wall of the blood vessel. Further, when the fluid is heated in the range of 60 ° C. to 90 ° C., the inner wall of the blood vessel is also heated to the same temperature. As a result, the drug infiltrates the inner wall of the blood vessel in a relatively short time.

Further, since the heat generating member 22 heats the fluid in the internal space of the balloon 11 and the temperature sensor 23 detects the temperature of the fluid in the internal space of the balloon 11, the temperature at which the blood vessel is heated is accurately controlled. ..

Further, a metal heat generating member 22 that generates heat when irradiated with light and a metal heat generating member 22 that is inserted through the shaft 12 and extends to the internal space of the balloon 11, and the light input to the base end is emitted from the tip to the heat generating member. Since the optical fiber 20 for irradiating the 22 is provided, the fluid can be heated in the balloon 11 with a simple structure.

Further, since the control device 30 drives the pump 31 to return the fluid to the balloon 11, an excessive temperature rise of the fluid in the internal space of the balloon 11 is suppressed.

[Modification example]
In the above-described embodiment, the light transmitted through the optical fiber 20 is a laser beam having high directivity, but the light for generating heat of the heat generating member 22 is not limited to the laser beam, but is diffused light. You may. Further, the heating of the fluid may be performed outside the balloon 11. For example, a known heating portion such as a heating wire for heating the fluid may be provided on the proximal end side of the balloon catheter 10, and the heated fluid may flow into the balloon 11 through the inner tube 17 of the balloon catheter 10.

Further, in the above-described embodiment, an example in which the fluid flows into the balloon 11 through the in-side tube 17 and the fluid flows out from the balloon 11 through the out-side tube 18 (that is, the fluid is recirculated) has been described. The invention is not limited to this, and the fluid may flow into the balloon 11 through the in-side tube 17 and may flow out of the balloon 11 through the in-side tube 17 after the balloon dilatation is completed.

Further, in the above-described embodiment, when the fluid flows into the balloon 11 and is expanded, the drug coated on the outer surface 24 of the balloon 11 comes into contact with the inner wall of the blood vessel and exists in the inner space of the balloon 11. At least a part of the state in which the fluid is heated in the range of 60 ° C. to 90 ° C. overlaps, but these two states do not necessarily have to overlap. For example, after the fluid existing in the internal space of the balloon 11 is heated in the range of 60 ° C. to 90 ° C., the drug coated on the outer surface 24 of the balloon 11 comes into contact with the inner wall of the blood vessel. It may be done. For example, in the embodiment of the balloon catheter 10, in which two balloons coated with a drug on the outer surface and a balloon capable of heating the fluid inside are independently provided, the two states described above are independent. Can be done. That is, one of the two balloons is inflated to heat the internal fluid, then one of the balloons is contracted, and then the other of the two balloons is moved to the inner wall of the heated blood vessel. By moving and inflating, the drug coated on the outer wall of the other balloon is applied to the inner wall of the blood vessel. According to such an embodiment, the heat-sensitive drug can be heated by the balloon at the inner wall portion of the desired blood vessel without being heated by the fluid flowing into the balloon.

Examples of the present invention are shown below.

[Confirmation test of drug adhesion concentration on blood vessel intima and drug invasion length on blood vessel wall]
(experimental method)
The porcine carotid artery (blood vessel) was immersed in Rhodamine B warmed to 37 ° C., 50 ° C., 55 ° C., 60 ° C., 65 ° C., and 70 ° C. in a constant temperature bath for 15 seconds while holding it with tweezers. The blood vessel was taken out and immediately immersed in a saline solution at 37 ° C. for 1 minute to cool. At this time, a thermocouple was sandwiched between tweezers located on the lumen side of the blood vessel, and the temperature history was recorded with a digital pen recorder (DL8500, Yokogawa). After cooling the blood vessel, about 1 mm at both ends of the blood vessel was cut off, sliced with a frozen microtome, and observed and photographed with a fluorescence microscope. The slice thickness was 20 μm. From the fluorescent image, the concentration of the adhering drug to the intima (0.1 mm from the lumen) and the length of drug invasion in the blood vessel radial direction were determined by image analysis. Specifically, two sliced specimens were prepared from one blood vessel and image analysis was performed. For the drug adhesion concentration to the intima and the drug invasion length in the blood vessel radial direction, the average value of the substances obtained from the specimens of the two sliced sections was set to N = 1.

(Measurement of drug adhesion concentration on the intima of blood vessels)
The brightness of the intima of the blood vessel was measured at four points using the image analysis software Image J (NIH, USA). Squares with a side of 0.07 mm were made in the image, and the fluorescence brightness in each square was measured. The measured luminance was converted to a density using a calibration curve. The average value of the concentrations at the four locations was calculated.

(Measurement of drug invasion length in the radial direction of blood vessels)
The fluorescence brightness on a straight line drawn from the blood vessel lumen toward the adventitia was measured using image analysis software Image J (NIH, USA), and converted to a concentration using a calibration curve. The distance until the brightness decreased to the brightness corresponding to ^10-8 M, which is the threshold value of the drug efficacy of paclitaxel, was defined as the drug invasion length. This procedure was repeated 4 times and the average value of 4 was calculated.

(Measurement result)
The relationship between the concentration of the drug adhering to the intima of the blood vessel and the heating temperature is shown in FIG. The drug concentration increased as the heating temperature was raised. Comparing the control at 37 ° C. with each of the other temperatures, the drug concentration increased significantly above 60 ° C.

The relationship between the drug invasion length in the blood vessel radial direction and the heating temperature is shown in FIG. Comparing the control at 37 ° C. with each of the other temperatures, the drug invasion length increased significantly above 65 ° C.

[Confirmation test of drug delivery efficiency using paclitaxel]
(experimental method)
Oregongreen488-labeled paclitaxel (Invitrogen) was used as the drug. In the same manner as described above, the pig carotid artery (blood vessel) was immersed in paclitaxel warmed to 37 ° C. and 70 ° C. in a constant temperature bath for 15 seconds for 1 minute while holding the pig carotid artery (blood vessel) with tweezers. The blood vessels were taken out and immediately immersed in physiological saline at 37 ° C. for 1 minute to cool. After cooling the blood vessel, about 1 mm at both ends of the blood vessel was cut off, sliced with a frozen microtome, and observed and photographed with a fluorescence microscope. The slice thickness was 20 μm.

Image analysis software Image J (NIH, USA) is used to measure the fluorescence brightness on a straight line drawn from the blood vessel lumen toward the adventitia, and the state of attenuation of the fluorescence brightness in the blood vessel radial direction is compared at 37 ° C and 70 ° C. did. The result is shown in FIG.

(Test results)
It was observed that paclitaxel was taken up more into the blood vessels at 70 ° C. than at 37 ° C. for both the immersion time of 15 seconds and 1 minute.

[Confirmation test of drug delivery efficiency using FITC-dextran]
(experimental method)
FITC-dextran (molecular weight 4 kDa) was used as a drug. In the same manner as described above, the porcine carotid artery (blood vessel) was immersed in 0.2 mg / mL FITC-dextran warmed to 37 ° C., 60 ° C., and 70 ° C. in a constant temperature bath for 15 seconds while holding the pig carotid artery (blood vessel) with tweezers. Immediately after removing the blood vessels, they were immersed in physiological saline at 37 ° C. for 1 minute to cool them. After cooling the blood vessel, about 1 mm at both ends of the blood vessel was cut off, sliced with a frozen microtome, and observed and photographed with a fluorescence microscope. The slice thickness was 20 μm.

In the same manner as described above, the concentration of the drug attached to the intima of the blood vessel was measured using the image analysis software Image J (NIH, USA). As a result, the adhesion concentrations of FITC-dextran at the immersion temperatures of 37 ° C., 60 ° C., and 70 ° C. were 0.29 μg / mL, 0.03 μg / mL, and 0.03 μg / mL, respectively.

[Structural change of intima due to heating]
The porcine carotid artery was immersed in physiological saline warmed to 37 ° C. and 70 ° C. in a constant temperature bath for 15 seconds and 30 seconds, respectively. The blood vessels were taken out and immediately immersed in physiological saline at 37 ° C. for 1 minute to cool. After dehydrating the blood vessels with ethanol, ethanol was replaced with t-butyl alcohol, and the blood vessels were dried using a freeze-drying device (VFD-21S, vacuum device). FIG. 8 shows the results of conductive staining of the dried blood vessels with an osmium coater (HPC-1S, vacuum device) and observation of the surface of the intima elastic plate with an environment-controlled electron microscope. Further, FIG. 9 shows the results of observing the surface of the intima elastic plate with a field emission scanning electron microscope.

Comparing the heating temperatures of 37 ° C. and 70 ° C., many holes having a diameter of 3 to 7 μm were observed on the surface of the intima elastic plate of the blood vessel having a heating temperature of 70 ° C. (FIG. 8). Further, when the diameter of the network structure on the surface of the intima elastic plate of the blood vessel is compared at the heating temperatures of 37 ° C. and 70 ° C., the diameter of the network structure is expanded on the surface of the intima elastic plate of the blood vessel having the heating temperature of 70 ° C. I was able to confirm that. As a result of analyzing the diameter of the network structure by image analysis, the ratio of the network (number of holes) wider than 50 nm, which is the approximate diameter of the drug molecule of paclitaxel, to the total network (number of holes) is at a heating temperature of 70 ° C. It was confirmed that the heating temperature was about 1.7 times higher than the heating temperature of 37 ° C.

[Changes in hydrophobicity of the intima of blood vessels due to heating]
The porcine carotid artery was immersed in physiological saline warmed to 37 ° C., 60 ° C., and 70 ° C. in a constant temperature bath for 15 seconds. The blood vessels were taken out and immediately immersed in physiological saline at 37 ° C. for 1 minute to cool. After cooling the blood vessel, about 1 mm at both ends of the blood vessel was cut off and sliced into 20 μm with a frozen microtome. A 0.5 mM ANS (8-anilino-1-naphtalene sulfonic acid) was removed from the sliced blood vessel, and a fluorescence microscope image was obtained. ANS is a probe having a property that the quantum yield with respect to 350 nm excitation light increases about 200 times and the fluorescence peak wavelength shifts from 515 nm to 455 nm in a hydrophobic environment. FIG. 10 shows the results of analyzing the fluorescence brightness of ANS using the image analysis software Image J (NIH, USA). As shown in FIG. 10, it was confirmed that the fluorescence brightness of ANS increased as the heating temperature increased.

10 Balloon catheter 11 Balloon 12 Shaft 17 In-side tube (flow path)
18 Out side tube (flow path)
20 Optical fiber (light guide member, heating part)
22 Heat generating member (heating part)
23 Temperature sensor (detector)
24 Outer surface 30 Control device (control unit)

Claims (5)

A shaft with an in-side tube and an out-side tube through which fluid flows,
A balloon provided on the tip side of the shaft, which is inflatable by the inflow of fluid and whose outer surface is coated with a drug,
A heating unit provided on the in-side tube in the internal space of the balloon to heat the fluid flowing through the in-side tube, and a heating unit.
A pump that allows fluid to flow into the balloon,
A detector that detects the temperature of the fluid and
It includes a control unit that controls the operation of the pump and the heating temperature of the heating unit.
The control unit inflates the balloon while causing the fluid flowing through the in-side tube to flow into the balloon and flowing out of the balloon through the out-side tube to return the fluid to the balloon by the pump. At the same time, in response to the detection signal of the detection unit, the fluid flowing into the balloon is heated by the heating unit within the range of 60 ° C. to 90 ° C. and 15 seconds to 60 seconds .
The heating part
A metal heat-generating member that generates heat when irradiated with laser light,
A drug release catheter device including a light guide member that irradiates the heat generating member with an input laser beam . The drug release catheter device according to claim 1, wherein the detection unit detects the temperature of a fluid in the internal space of the balloon. It said light guide member, according to claim 1 or 2 is inserted into the shaft and extending into the interior space of the balloon, the laser light input from the distal end to the proximal end is intended to irradiate to the heat generating member The drug release catheter device according to. The drug release catheter device according to any one of claims 1 to 3 , wherein the drug is a hydrophobic drug. The drug release catheter device according to any one of claims 1 to 3 , wherein the drug is paclitaxel .

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