Ultrasonic controlled-release drug balloon catheter and application thereof

Abstract

The invention discloses an ultrasonic controlled-release drug balloon catheter which comprises a balloon with the outer surface coated with a drug coating and a catheter penetrating through the balloon, and the drug coating comprises a drug carrying layer, a hydrophilic layer located between the outer surface of the balloon and the drug carrying layer and an ultrasonic response layer located on the outer surface of the drug carrying layer; the ultrasonic response layer comprises the following components: at least one of PDMS (Polydimethylsiloxane), P (AAA) and P (NIPAM-co-AM); and an ultrasonic transducer is arranged on the catheter in the balloon. According to the ultrasonic controlled-release medicine balloon catheter, a'sandwich 'design of'hydrophilic bottom layer-medicine carrying layer-ultrasonic response layer' is adopted for the medicine coating on the surface of the balloon, and ultrasonic transducers with two or more frequencies are further arranged on the catheter in the balloon, so that the loss of the medicine coating in the conveying process can be avoided; transfer of the medicine from the balloon to the blood vessel at the treatment position is increased, the medicine can deeply permeate into the vascular tissue, vascular stenosis can be effectively inhibited for a long time, and the medicine utilization rate is effectively increased.

Description

Technical Field

[0001] The present invention relates to the technical field of medical devices, and particularly to an ultrasound-controlled drug balloon catheter and its application. Background Art

[0002] A drug balloon catheter is a medical device used for vascular interventional therapy, mainly for treating coronary artery and peripheral artery diseases, such as atherosclerosis, vascular stenosis or occlusion, etc. It mainly releases an anti-proliferative drug (such as paclitaxel) onto the vascular wall by coating the anti-proliferative drug (such as paclitaxel) on the surface of the balloon during balloon dilation to inhibit vascular restenosis and intimal hyperplasia.

[0003] Existing drug balloon catheter products still have certain deficiencies during clinical use: during the delivery process of the drug balloon, due to the flushing effect of blood, part of the drug coating is likely to fall off, resulting in a reduction in the amount of drug that can be transferred when actually reaching the treatment site and low drug utilization rate; in addition, drug release mainly depends on the mechanical pressure during balloon dilation, and drug release during the dilation process is difficult to control, which may lead to uneven drug release or insufficient release amount. Moreover, the drug attached to the inner wall of the blood vessel is also easily lost under the flushing of blood flow, and the time for maintaining an effective drug concentration in the tissue is short, resulting in poor treatment effects. Summary of the Invention

[0004] In view of this, the purpose of the present invention is to provide an ultrasound-controlled drug balloon catheter, which can avoid the loss of the drug coating during the delivery process, increase the transfer of the drug from the balloon to the blood vessel at the treatment site, and enable the drug to penetrate deeper into the vascular tissue, effectively inhibit vascular stenosis for a long time, and effectively improve the drug utilization rate.

[0005] The present invention is realized through the following technical solutions:

[0006] The present invention provides an ultrasound-controlled drug balloon catheter, which includes a balloon with a drug coating on its outer surface and a catheter passing through the balloon. The drug coating includes a drug-loading layer, a hydrophilic layer located between the outer surface of the balloon and the drug-loading layer, and an ultrasound-responsive layer located on the outer surface of the drug-loading layer; the components of the ultrasound-responsive layer include at least one of Polydimethylsiloxane (PDMS), Poly(acrylamide-co-acrylic acid) (P(AAA)), and Poly(N-Isopropylacrylamide-co-Acrylamide) (P(NIPAM-co-AM));

[0007] An ultrasound transducer is provided on the catheter inside the balloon.

[0008] Preferably, the components of the hydrophilic layer include one or more of Polyvinylpyrrolidone (PVP) and Polyethylene oxide (PEO). In the present invention, a hydrophilic layer is provided on the surface of the balloon. By using PVP, PEO or a PVP / PEO mixture and curing it with an ultraviolet lamp, a hydrophilic layer is formed on the surface of the balloon, which is beneficial for the better coating of the drug-loading layer on the balloon and its faster transfer to vascular tissue in a physiological environment.

[0009] Preferably, the drug-loading layer includes liposomes loaded with active drugs or porous nanospheres loaded with active drugs; the active drugs include one or more of paclitaxel, rapamycin and their derivatives.

[0010] Liposomes can load hydrophobic drugs within their phospholipid bilayers. The present invention provides a method for preparing a rapamycin liposome drug-loading layer, which includes the following steps: dissolving liposome components and active drugs in an organic solvent such as ethanol, acetone, chloroform, etc. according to a ratio (HSPC: DSPE: cholesterol: DSPE-PEG2000: rapamycin = 30: 30: 25: 5: 10, rapamycin concentration 3 mg / ml), slowly dropping the solution into water under stirring, and then performing ultrasonic treatment or homogenization treatment. After filtering with a 0.8 μm filter membrane to reduce the polydispersity index, the obtained liposomes have a particle size of less than 300 nm, and a drug coating is performed on the hydrophilic layer. The components and specific ratios of the liposomes can be flexibly adjusted as needed, such as replacing them with DOPC, DOPE, or adding other lipids or stabilizers, and the concentration of rapamycin or paclitaxel is 1 - 5 mg / ml.

[0011] The air contained in the internal cavity of the porous nanospheres can significantly enhance the cavitation effect, further improving the efficiency and controllability of drug release. The present invention provides a method for preparing a rapamycin porous nanosphere drug-loading layer, which includes the following steps: dissolving an appropriate amount of rapamycin and PLGA-PEG in an organic solvent, dissolving polyvinyl alcohol (PVA) in water, mixing the two, emulsifying them through a high-pressure homogenizer, and performing a drug coating on the hydrophilic layer. The nanospheres obtained through this step are relatively small in size, only 300 - 800 nm, which is beneficial for cell internalization and can play a role for a long time. Moreover, due to water absorption and subsequent water loss after drying, PEG can form a large number of pores on the surface of the microspheres, and this property has good ultrasonic response characteristics.

[0012] The drug coating method can be one of dip coating, micro pipetting or ultrasonic spraying.

[0013] Preferably, the ultrasonic response layer is prepared by ultrasonic spraying of polydimethylsiloxane, poly(acrylic acid-co-acrylamide) or poly(N-isopropylacrylamide-co-acrylamide).

[0014] Preferably, the frequency of the ultrasonic transducer is 1 - 20 MHz.

[0015] More preferably, the ultrasonic transducer at least includes ultrasonic transducer one and ultrasonic transducer two.

[0016] The frequency ratio of ultrasonic transducer one and ultrasonic transducer two is preferably 0.5 - 1.5, and more preferably 0.7 - 0.95.

[0017] In the present invention, two or more ultrasonic transducers with different frequencies are arranged on the balloon catheter. Through the interaction of two or more frequencies of ultrasound, cavitation bubbles are excited to vibrate in different resonance modes, and more secondary harmonics and combined frequencies are generated through the nonlinear effect. These additional frequency components can further promote the formation and development of cavitation bubbles, change the expansion and contraction speed of the bubbles, increase the chance of bubble collision and fusion, etc., so as to enhance the cavitation effect and oscillation intensity, promote the transfer of drugs to the blood vessels at the target site and deeper penetration into the vascular tissue, achieve long-term effective inhibition of vascular stenosis, and effectively improve the drug utilization rate.

[0018] The ultrasonic transducer is preferably a micro piezoelectric transducer; the micro piezoelectric transducer is selected from any one of a ring piezoelectric ceramic transducer or a sheet piezoelectric ceramic transducer.

[0019] A heat insulation layer is arranged on the surface of the catheter inside the balloon to prevent damage to the catheter caused by the increase in temperature due to heat release during the operation of the ultrasonic transducer. It is preferably a polyethylene (PE) heat insulation layer.

[0020] When the ultrasonic transducer is a ring piezoelectric ceramic transducer, ultrasonic transducer one and ultrasonic transducer two are alternately sleeved and evenly distributed on the heat insulation layer of the catheter inside the balloon;

[0021] When the ultrasonic transducer is a sheet piezoelectric ceramic transducer, a metal base is also sleeved on the heat insulation layer of the catheter inside the balloon, and ultrasonic transducer one and ultrasonic transducer two are alternately pasted and evenly distributed on the outside of the metal base.

[0022] As a preferred embodiment, the ultrasonic controlled release drug balloon catheter further includes a driving system, and the driving system is connected to the ultrasonic transducer through a wire for controlling the operation of the ultrasonic transducer.

[0023] As a preferred embodiment, the ultrasonic controlled release drug balloon catheter further includes a water circulation system; the water circulation system includes a water inlet pipe and a water outlet pipe; one end of the water inlet pipe is a water inlet, and the other end is connected to the inside of the balloon; one end of the water outlet pipe is a water outlet, and the other end is connected to the inside of the balloon.

[0024] The water outlet pipe is also provided with a pressure detection port, which is connected to a pressure control system for monitoring the internal pressure of the balloon. When the pressure reaches a predetermined threshold, the driving system drives the ultrasonic transducer to work.

[0025] As a preferred embodiment, the ultrasonic controlled-release drug balloon catheter further includes a temperature control system for monitoring the temperature of the ultrasonic transducer. When the temperature reaches a predetermined threshold, the driving system stops the ultrasonic transducer from working. Specifically, the temperature control system is electrically connected to the driving system to design a control circuit. By programming, a predetermined temperature threshold is set. When a microcontroller such as a digital signal processor (DSP) reads and processes the signal transmitted by the temperature monitoring circuit and determines that the temperature exceeds the predetermined threshold, a stop signal is immediately sent to the control circuit of the driving system. After receiving the signal, the control circuit quickly cuts off the power supply of the driving system, causing the ultrasonic transducer to stop working.

[0026] The present invention also provides the application of the above ultrasonic controlled-release drug balloon catheter in the preparation of medical devices for vascular intervention therapy.

[0027] The present invention has the following beneficial effects:

[0028] For the ultrasonic controlled-release drug balloon catheter of the present invention, the drug coating on the balloon surface adopts a "sandwich" design of "hydrophilic bottom layer - drug-loading layer - ultrasonic response layer", and an ultrasonic transducer is provided on the catheter inside the balloon. This can protect the drug coating from blood scouring during the transportation of the balloon, and when it reaches the vascular treatment site, the ultrasonic transducer is activated. The ultrasonic action changes the flexible state of the ultrasonic response layer, causing the surface layer to rupture. The hydrophilic bottom layer contacts water, quickly absorbs water and swells, enabling the drug coating to be rapidly released at the target site, promoting the transfer of the drug to the blood vessels at the target site and deeper penetration into the vascular tissue, achieving long-term effective inhibition of vascular stenosis and effectively improving the drug utilization rate.

[0029] The present invention further adopts ultrasonic transducers of two or more frequencies. The dual-frequency or multi-frequency ultrasonic waves are converted into a larger sound pressure value through the nonlinear effect and can reach the high sound pressure state more quickly. The high sound pressure enhances the cavitation effect. The local high temperature, high pressure, and micro-jet generated by the collapse of the cavitation bubbles can efficiently destroy the drug coating and promote its shedding. At the same time, the mechanical effects such as strong shear stress and micro-flow caused by the high sound pressure can increase the permeability of the blood vessel wall, form more micro-channels for drug penetration, and can also stimulate cells to enhance the drug uptake ability, ultimately significantly improving the drug loading and absorption efficiency. Description of the Drawings

[0030] Figure 1 It is a schematic structural diagram of an ultrasonic controlled-release drug balloon catheter provided by the present invention;

[0031] Figure 2Schematic three-dimensional structure diagram of a sheet piezoelectric ceramic transducer provided for the ultrasonic controlled-release drug balloon catheter of the present invention;

[0032] Figure 3 Schematic three-dimensional structure diagram of an annular piezoelectric ceramic transducer provided for the ultrasonic controlled-release drug balloon catheter of the present invention;

[0033] Figure 4 Schematic structure diagram of the balloon and liposome drug coating of the ultrasonic controlled-release drug balloon catheter provided for the present invention;

[0034] Figure 5 Schematic structure diagram of the balloon and porous nanosphere drug coating of the ultrasonic controlled-release drug balloon catheter provided for the present invention.

[0035] Figure 6 Schematic diagram of the detection range of the sound pressure test of the ultrasonic transducer;

[0036] Figure 7 Line graph of the sound pressure data when two 1 MHz ultrasonic transducers work simultaneously;

[0037] Figure 8 Line graph of the sound pressure data when a 1 MHz and a 1.2 MHz ultrasonic transducer work together.

[0038] Reference numerals:

[0039] 100 - catheter 801 - pressure detection port 220 - heat insulation layer

[0040] 110 - balloon 802 - water inlet 230 - metal base

[0041] 210 - ultrasonic transducer 803 - water outlet 520a - liposome loaded with active drug

[0042] 310 - water inlet pipe 510 - hydrophilic layer

[0043] 311 - water outlet pipe 520 - drug-loading layer 520b - porous nanosphere loaded with active drug

[0044] 312 - RX port 530 - ultrasonic response layer

[0045] 410 - wire 211 - ultrasonic transducer one

[0046] 420 - temperature measurement wire 212 - ultrasonic transducer two Detailed implementation manners

[0047] To elaborate on the technical content, achieved objectives, and effects of the present invention in detail, the technical solutions of the present invention will be clearly and completely described below in conjunction with the embodiments and with reference to the accompanying drawings. However, the described embodiments are only a part of the embodiments of the present invention, and the implementation and protection of the present invention are not limited thereto. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts belong to the scope of protection of the present invention. It should be noted that for the processes not specifically described in detail below, those skilled in the art can implement or understand them with reference to the prior art. Reagents or instruments without indicating the manufacturer are regarded as conventional products that can be purchased commercially.

[0048] Example 1

[0049] As Figure 1 shown, the present application provides an ultrasound-controlled release drug balloon catheter, which includes a balloon 110 with a drug coating on its outer surface and a catheter 100 passing through the balloon. The drug coating includes a drug-loading layer 520, a hydrophilic layer 510 located between the outer surface of the balloon and the drug-loading layer, and an ultrasound-responsive layer 530 located on the outer surface of the drug-loading layer; an ultrasound transducer 210 is provided on the catheter inside the balloon. The catheter 100 includes an inner tube for transporting a guide wire; the inner tube is provided with an RX port 312.

[0050] In specific applications, during the process of advancing the balloon 110 part of the ultrasound-controlled release drug balloon catheter along the guide wire to the vascular target site, the ultrasound-responsive layer 530 can prevent the drug-loading layer 520 from being washed off by blood and falling off, ensuring that there is enough drug amount on the balloon surface when reaching the target site; after the balloon 110 reaches the target site, the ultrasound transducer 210 is activated. Under the action of ultrasound, the surface layer of the ultrasound-responsive layer 530 ruptures, the hydrophilic layer 510 contacts with water, quickly absorbs water and swells, so that the drug in the drug-loading layer 520 is rapidly released and transferred to the vascular target site; at the same time, ultrasound promotes the rapid shedding of the drug coating through mechanical actions such as micro-jet and cavitation effects, and increases the permeability of the blood vessel wall, promoting the transfer of the drug to the blood vessels at the target site and deeper penetration into the vascular tissue.

[0051] As an optional implementation manner of this embodiment, the ultrasound-responsive layer is selected as a PDMS layer. PDMS has certain elasticity and flexibility. When ultrasound acts on PDMS, since ultrasound is a mechanical wave, PDMS will undergo obvious stretching and deformation. The cavitation effect will generate high temperature, high pressure, strong shock waves, and micro-jets locally, exert mechanical effects on the PDMS material, causing erosion of the material surface, damage to the internal structure, etc., so that the drug coating is released at the target site.

[0052] As an alternative implementation of this embodiment, the ultrasonic response layer is selected as the P(AAA) layer. The intermolecular hydrogen bonds between the acid and amide groups render the copolymer insoluble. During ultrasonic irradiation, the mechanical vibration energy is transferred to the molecular level, directly breaking the hydrogen bonds. Moreover, the local energy released by the ultrasonic cavitation effect is converted into heat, promoting the melting of the coating and thus effectively releasing the drug. By regulating the molar fraction and degree of polymerization of acrylamide, the ultrasonic response characteristics of the coating can be precisely optimized. It is preferable to use lower molar fractions and degrees of polymerization to shorten the molecular chains, reduce entanglement and hydrogen bond crosslinking points, lower mechanical stability, and enhance ultrasonic sensitivity. For example, the molar fraction of acrylamide is 30%-40%, and the degree of polymerization is 100-300.

[0053] As an alternative implementation of this embodiment, the ultrasonic response layer is selected as the P(NIPAM-co-AM) layer. PNIPAM exists in a branched form, endowing ultrasonic responsiveness. Below the lower critical solution temperature, the grafted chains unfold and cross-cover in water, blocking the pores and hindering drug diffusion ("off" state); during ultrasonic irradiation, on the one hand, the mechanical force generated by the cavitation effect breaks the non-covalent interactions, and on the other hand, the local thermal effect causes a slight temperature rise, prompting the grafted chains to contract and the pores to appear, allowing the drug to diffuse smoothly ("on" state). It is preferable to use 80%-85% NIPAM + 15%-20% AM, and the LCST temperature can be adjusted to 30-35 °C, quickly crossing the phase transition point when the local temperature rises under ultrasonic irradiation (∼5-10 °C), triggering the contraction of the branched chains. An appropriate amount of AM provides hydrogen bond crosslinking to ensure the sealing of the "off" state without overly hindering ultrasonic disruption. It is further preferable to have a number average molecular weight (Mn) of 20,000-40,000. The branched chains are shorter, with less entanglement, and the ultrasonic cavitation effect is more likely to break non-covalent bonds (hydrogen bonds, hydrophobic interactions), and the chains contract faster after heating.

[0054] As an alternative implementation of this embodiment, the hydrophilic layer is selected as the PVP layer, PEO layer, or PVP / PEO layer, which is beneficial for the better stable coating of the drug-loading layer on the balloon and enables faster transfer to the vascular tissue in the physiological environment.

[0055] As an alternative implementation of this embodiment, such as Figure 4As shown, the drug-loading layer is a liposome 520a loaded with an active drug. Due to its cavity structure and lipid biological fluidity, the liposome releases the active drug through the cavitation effect and acoustic streaming induced by radiation force under the action of ultrasound. After the balloon catheter is withdrawn, the ultrasound action stops, and the lipid membrane tends to restore its original impermeability, continuously releasing the drug on the blood vessel wall and inhibiting intimal hyperplasia for a long time. In vascular interventional therapy, the active drug is selected from one or more of paclitaxel, rapamycin, and their derivatives. Specifically, the preparation of the rapamycin liposome drug-loading layer is as follows: The liposome components and the active drug are dissolved in organic solvents such as ethanol, acetone, and chloroform in a ratio (HSPC: DSPE: cholesterol: DSPE-PEG2000: rapamycin = 30: 30: 25: 5: 10, rapamycin concentration 3 mg / ml), and slowly dropped into water under stirring. After ultrasonic treatment or homogenization treatment to reduce the particle size, a 0.8 μm filter membrane is used for filtration to reduce the polydispersity index. The obtained liposome has a particle size of less than 300 nm, and the drug coating is carried out on the hydrophilic layer by dip coating, micropipetting, or ultrasonic spraying. The components and specific ratios of the liposome can be flexibly adjusted according to needs, such as replacing them with DOPC, DOPE, or adding other lipids or stabilizers, and the concentration of rapamycin or paclitaxel is 1 - 5 mg / ml.

[0056] As an alternative implementation manner of this embodiment, as Figure 5 shown, the drug-loading layer is a porous nanosphere 520b loaded with an active drug. The air contained in the internal cavity of the porous nanosphere can significantly enhance the cavitation effect, further improving the efficiency and controllability of drug release. Specifically, the preparation of the rapamycin porous nanosphere drug-loading layer is as follows: An appropriate amount of rapamycin and PLGA-PEG are dissolved in an organic solvent, and polyvinyl alcohol (PVA) is dissolved in water. The two are mixed and emulsified by a high-pressure homogenizer. The drug coating is carried out on the hydrophilic layer by dip coating, micropipetting, or ultrasonic spraying. The obtained nanospheres have a small size, only 300 - 800 nm, which is beneficial for cell internalization and plays a role for a long time. Moreover, due to water absorption, PEG loses water after drying and can form a large number of pores on the surface of the microspheres, and this property has good ultrasonic response characteristics.

[0057] As an alternative implementation manner of this embodiment, the ultrasonic response layer is formed by ultrasonic spraying.

[0058] As an alternative implementation of this embodiment, the frequency of the ultrasonic transducer is 1 - 20 MHz. The ultrasonic transducer includes at least ultrasonic transducer one 211 and ultrasonic transducer two 212, and the frequency ratio of ultrasonic transducer one to ultrasonic transducer two is 0.5 - 1.5, more preferably 0.7 - 0.95. Through the interaction of two or more specific frequencies of ultrasound, cavitation bubbles are excited to vibrate in different resonance modes. At the same time, due to the nonlinear effect, more secondary harmonics and combined frequencies are generated. These additional frequency components can further promote the formation and development of cavitation bubbles, change the expansion and contraction speed of the bubbles, increase the chance of bubble collision and fusion, etc., thereby enhancing the cavitation effect and oscillation intensity, promoting the transfer of the drug in the drug-loading layer 520 to the blood vessels at the target site and deeper penetration into the vascular tissue, achieving long-term effective inhibition of vascular stenosis, and effectively improving the drug utilization rate.

[0059] For example, when a 1 MHz and a 1.2 MHz ultrasonic transducer work together, the sound field energy release efficiency is significantly improved. At a shorter time (100 μs), the average sound pressure around reaches more than twice that of the single-frequency (1 MHz dual transducer) operation, and the sound pressure jump is achieved faster than the single-frequency mode. At a longer time (within 300 μs), the maximum sound pressure increases by about 39% compared with the single-frequency mode; the sound pressure values at the left and right detection points change more diversely. From the perspective of the action mechanism: the high sound pressure enhances the cavitation effect. Through the local high temperature, high pressure, and micro-jet generated by the collapse of cavitation bubbles, the drug coating is efficiently damaged and promoted to fall off; at the same time, the mechanical effects such as strong shear stress and micro-flow caused by the high sound pressure can increase the permeability of the blood vessel wall, form more micro-channels for drug penetration, and can also stimulate cells to improve the drug uptake ability, ultimately significantly enhancing the drug loading and absorption efficiency.

[0060] Specifically, as Figure 6 , Figure 7 , Figure 8 shown by the experimental results, with the working center point of the ultrasonic transducer as the benchmark, a detection range of 100 mm is extended outward (as Figure 6 shown, the four detection points of up, down, left, and right are distributed at typical positions on the circumference). When two 1 MHz ultrasonic transducers work simultaneously, the sound pressure data within 300 μs is collected at intervals of 1 μs. From its line graph ( Figure 7 ), it can be seen that the sound pressure curves of the up and down detection points completely overlap, and the sound pressures of the left and right detection points also show the same change law. And within the 300 μs monitoring period, the maximum sound pressure is about 41 Pa. When a 1 MHz and a 1.2 MHz ultrasonic transducer work together, the sound field energy release efficiency is significantly improved. From its line graph ( Figure 8)It can be seen that in a shorter time (at 100 μs), the average sound pressure around has reached more than twice that in the single-frequency (1 MHz dual transducer) operation, achieving a faster sound pressure jump than the single-frequency mode; further observing the data within 300 μs, the maximum sound pressure has increased to 57 Pa, showing an increase of about 39% compared to the single-frequency mode; the changes in the sound pressure values at the left and right detection points are more diverse. For example, between 200 μs and 250 μs, the peak sound pressure at the left and right points is about 40%-50% higher than that of the same type of nodes in the single-frequency mode.

[0061] As an optional implementation manner of this embodiment, the ultrasonic transducer includes ultrasonic transducers with three or more frequencies. The multi-frequency ultrasonic waves are converted into a larger sound pressure value through the nonlinear effect and can reach the high sound pressure state more quickly.

[0062] In specific applications, the ultrasonic transducer is preferably a micro piezoelectric transducer with a thickness of 0.1 mm, which basically does not affect the folding diameter of the balloon catheter and has good insulation. The selectable micro piezoelectric transducers include sheet piezoelectric ceramic transducers or ring piezoelectric ceramic transducers.

[0063] As an optional implementation manner of this embodiment, as Figure 2 shown, a heat insulation layer 220 is provided on the surface of the catheter inside the balloon to prevent the temperature from rising due to heat generated during the operation of the ultrasonic transducer and damaging the catheter. Specifically, it can be selected as a polyethylene (PE) heat insulation layer. When using a sheet piezoelectric ceramic transducer, one or more metal bases 230 are sleeved and installed on the heat insulation layer. The metal base can be a hollow cuboid structure or a base with rounded corners on all sides, reducing the diameter of the base while reducing the right-angle scratch on the balloon wall; the ultrasonic transducer one and the ultrasonic transducer two are alternately arranged and evenly distributed on the outside of the metal base. Specifically, the number of ultrasonic transducers bonded to a single base is 4 pieces. Two ultrasonic ring transducers one 211 are pasted on the upper and lower surfaces, and two ultrasonic transducers two 212 are pasted on the left and right side surfaces. Multiple metal bases are evenly distributed on the catheter inside the balloon. The size and number of the metal bases are not limited, and different sizes and numbers of metal bases can be set according to the size of the balloon and the catheter to ensure that the ultrasound irradiates the entire surface of the balloon.

[0064] As an optional implementation manner of this embodiment, as Figure 3 shown, when using a ring piezoelectric ceramic transducer, this scheme does not require the installation of a metal base. The ring piezoelectric ceramic transducer is directly sleeved and installed on the heat insulation layer of the catheter inside the balloon, which can provide a more uniform energy distribution. Multiple ring piezoelectric ceramic transducers are evenly distributed on the catheter inside the balloon. The size and number of the ring piezoelectric ceramic transducers are not limited, and different sizes and numbers of ring piezoelectric ceramic transducers can be set according to the size of the balloon and the catheter to ensure that the ultrasound radiation passes through the entire surface of the balloon.

[0065] As an optional implementation of this embodiment, the ultrasonic controlled drug release balloon catheter further includes a drive motor. The drive system is connected to the ultrasonic transducer 200 via a wire 410 to control the operation of the ultrasonic transducer. Multiple ultrasonic transducers of the same frequency can be connected in series using a single wire or multiple wires. Only transducers of a single frequency can be connected to a single wire. Preferably, the wires are connected in a zigzag pattern to reduce the impact of the wire on the transducer's working area.

[0066] As a preferred embodiment, the ultrasonic controlled drug release balloon catheter further includes a water circulation system; the water circulation system includes a water inlet pipe 310 and a water outlet pipe 311; one end of the water inlet pipe is a water inlet 802, and the other end is connected to the interior of the balloon; one end of the water outlet pipe is a water outlet 803, and the other end is connected to the interior of the balloon; the water outlet pipe is also provided with a pressure detection port 801; the pressure detection port is connected to the pressure control system for monitoring the pressure inside the balloon, and when the pressure reaches a predetermined threshold, the drive system drives the ultrasonic transducer to work; it also includes a temperature control system for monitoring the temperature of the ultrasonic transducer, and when the temperature reaches a predetermined threshold, the drive system stops the ultrasonic transducer from working. The temperature measuring line 420 is installed on the metal base or the inner tube and is pulled along the wire to connect to the temperature control system. In specific applications, the folded balloon is advanced along a guidewire to the target vessel. The circulating water system, according to set parameters, injects saline solution from the water inlet at a high flow rate, instantly filling the balloon to the rated pressure, causing it to expand and adhere to the target vessel wall. The water in the balloon is then discharged from the water outlet. A pressure control system monitors and maintains the pressure in real time. When the balloon reaches the rated pressure, the drive system immediately activates the transducer, emitting ultrasound according to the set power, frequency, treatment duration, and duty cycle. The duty cycle can be set within a wide range, from 5% to 80%, significantly increasing ultrasound efficiency and improving drug delivery. This is because the circulating water continues to operate during this period, dissipating the heat generated by the ultrasonic transducer during operation. When the operating temperature reaches a predetermined threshold, the temperature sensor sends a signal to the control system, causing the drive system to stop the ultrasonic transducer 200. This allows the ultrasonic energy to be used to its full potential while minimizing damage to the vessel and tissue caused by temperature rise.

[0067] When the whole machine completes its working target, the system automatically stops working, and then the circulating water system automatically executes the withdrawal program, and the balloon shrinks to facilitate the subsequent withdrawal of the balloon.

[0068] The beneficial effects of the ultrasonic controlled-release drug balloon catheter provided by the embodiments of the present application are as follows: Compared with the prior art, in the present application, the drug coating on the balloon surface adopts a "sandwich" design of "hydrophilic bottom layer - drug-loading layer - ultrasonic response layer", and two or more frequencies of ultrasonic transducers are arranged on the catheter inside the balloon. This can protect the drug coating from blood flushing during the delivery process of the balloon. When the balloon reaches the vascular treatment site, the ultrasonic transducers are activated. The ultrasonic action changes the flexible state of PDMS, causing the surface layer to rupture. The hydrophilic bottom layer contacts water, quickly absorbs water and swells, enabling the drug coating to be rapidly released at the target site. Through the interaction of multiple frequencies of ultrasound, cavitation bubbles are excited to vibrate in different resonance modes, enhancing the cavitation effect and oscillation intensity, promoting the transfer of the drug to the blood vessels at the target site and deeper penetration into the vascular tissue, achieving long-term effective inhibition of vascular stenosis and effectively improving the drug utilization rate.

[0069] For those skilled in the art, the present invention is not limited to the details of the above exemplary embodiments, and can be implemented in other specific forms without departing from the spirit or basic characteristics of the present invention. Therefore, from any point of view, the embodiments should be regarded as exemplary and non-limiting. The scope of the present invention is defined by the appended claims rather than the above description. Therefore, all changes falling within the meaning and scope of the equivalent elements of the claims are intended to be encompassed within the present invention. Any reference signs in the claims should not be regarded as limiting the claimed rights.

[0070] All the above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited by the described embodiments. Any other changes, modifications, substitutions, combinations, and simplifications made without departing from the spirit and principle of the present invention shall be equivalent replacement methods and are all included in the protection scope of the present invention.

Claims

1. An ultrasound-controlled drug delivery balloon catheter, comprising a balloon with a drug coating on its outer surface and a catheter passing through the balloon, characterized in that, The drug coating includes a drug-loading layer, a hydrophilic layer located between the outer surface of the balloon and the drug-loading layer, and an ultrasonic response layer located on the outer surface of the drug-loading layer; the components of the ultrasonic response layer include at least one of polydimethylsiloxane, poly(acrylic acid-co-acrylamide), and poly(N-isopropylacrylamide-co-acrylamide); An ultrasonic transducer is provided on the catheter inside the balloon.

2. The ultrasound-controlled drug release balloon catheter according to claim 1, characterized in that The drug-loading layer includes liposomes loaded with active drugs or porous nanospheres loaded with active drugs; the active drugs include one or more of paclitaxel, rapamycin, and their derivatives; the components of the hydrophilic layer include one or more of polyvinylpyrrolidone and polyethylene oxide.

3. The ultrasound-controlled drug release balloon catheter according to claim 1, wherein The frequency of the ultrasonic transducer is 1-20 MHz; the ultrasonic transducer includes at least ultrasonic transducer one and ultrasonic transducer two.

4. The ultrasound-controlled drug release balloon catheter according to claim 3, characterized in that, The ultrasonic transducer is selected from a micro piezoelectric transducer; the micro piezoelectric transducer is selected from an annular piezoelectric ceramic transducer or a sheet piezoelectric ceramic transducer; a heat insulation layer is provided on the surface of the catheter inside the balloon.

5. The ultrasound-controlled drug release balloon catheter according to claim 4, characterized in that, The ultrasonic transducer is an annular piezoelectric ceramic transducer, and ultrasonic transducer one and ultrasonic transducer two are alternately sleeved and evenly distributed on the heat insulation layer of the catheter inside the balloon.

6. The ultrasound-controlled drug release balloon catheter according to claim 4, characterized in that, The ultrasonic transducer is a sheet piezoelectric ceramic transducer, and a metal base is further sleeved on the heat insulation layer of the catheter inside the balloon. Ultrasonic transducer one and ultrasonic transducer two are alternately pasted and evenly distributed on the outside of the metal base.

7. The ultrasound-controlled drug release balloon catheter according to claim 1, wherein, It further includes a driving system, and the driving system is connected to the ultrasonic transducer through a wire for controlling the operation of the ultrasonic transducer.

8. The ultrasound-controlled drug release balloon catheter according to claim 7, wherein It further includes a water circulation system; the water circulation system includes a water inlet pipe and a water outlet pipe; one end of the water inlet pipe is a water inlet, and the other end is connected to the inside of the balloon; one end of the water outlet pipe is a water outlet, and the other end is connected to the inside of the balloon.

9. The ultrasound-controlled drug release balloon catheter according to claim 8, wherein, The water outlet pipe is further provided with a pressure detection port, and the pressure monitoring port is connected to a pressure control system for monitoring the internal pressure of the balloon. When the pressure reaches a predetermined threshold, the driving system drives the ultrasonic transducer to operate.

10. The ultrasonic controlled-release drug balloon catheter according to claim 7, characterized in that, It further includes a temperature control system for monitoring the temperature of the ultrasonic transducer. When the temperature reaches a predetermined threshold, the driving system stops the ultrasonic transducer from operating.

11. The application of the ultrasonic controlled-release drug balloon catheter according to any one of claims 1-10 in the preparation of medical devices for vascular intervention therapy.

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