System for applying thrombolytic drug to coronary artery suitable for ultrasound-guided interventional technique

Abstract

The embodiment of the invention relates to the technical field of instruments for removing intravascular obstruction, in particular to a system for applying thrombolytic medicine to coronary artery suitable for ultrasonic guided intervention technology, which comprises a medicine carrying catheter arranged on a catheter assembly, when the catheter assembly is fed into the aorta, the medicine carrying catheter enters the coronary artery through the catheter assembly, and when the catheter assembly is fed into the aorta, the medicine carrying catheter is used for applying thrombolytic medicine to the coronary artery. And the drug-loading catheter releases the drug-loading microvesicles in the coronary artery. The ultrasonic device is arranged to apply ultrasonic waves to the drug-loaded microvesicles, and the drug-loaded microvesicles are broken and release the thrombolytic drug. The catheter assembly is configured to occlude a root of the aorta such that the drug-loaded microvesicles cannot move therefrom out of the aorta. By utilizing the system, the thrombolytic drug does not flow out along with the blood flow of the aorta and is not leaked to the whole body, so that the thrombolytic drug can stay in the coronary artery for a long time, the thrombolytic effect and the targeting property are favorably improved, the influence of the thrombolytic drug on a whole body blood coagulation mechanism is reduced, and the risk of cerebral hemorrhage and other visceral hemorrhage is reduced; and the safety and the reliability of treatment are improved.

Description

TECHNICAL FIELD

[0001] Embodiments of the present application relate to the technical field of devices for removing intravascular obstructions, and in particular to a system for applying thrombolytic drugs to coronary arteries suitable for ultrasound-guided intervention techniques. BACKGROUND

[0002] The statements herein are merely provided to give general background information on the present application, and do not necessarily constitute the prior art.

[0003] Coronary artery disease is a major cardiovascular disease that threatens human health, especially acute myocardial infarction, the core of which is the formation of thrombus in the coronary artery leading to blood flow interruption, ischemic necrosis of the myocardium in the blood supply area, and the key to its treatment is to restore coronary blood flow by timely unblocking the blood vessels.

[0004] Currently, to restore coronary blood flow, the main clinical treatment methods include intravenous drug thrombolytic therapy, surgical direct vision coronary artery bypass graft surgery, and percutaneous coronary intervention (PCI), but these treatment methods still have many defects and deficiencies in actual application. SUMMARY

[0005] A brief summary of the present application is given in the following to provide a basic understanding of some aspects of the present application. It should be understood that this summary is not an exhaustive overview of the present application. It is not intended to identify key or important parts of the present application, nor is it intended to limit the scope of the present application. Its purpose is merely to give some concepts in a simplified form as a prelude to the more detailed description discussed later.

[0006] Embodiments of the present application provide a system for applying thrombolytic drugs to coronary arteries suitable for ultrasound-guided intervention techniques, which includes a catheter assembly, a drug-loaded catheter, and an ultrasound device. The drug-loaded catheter is arranged in the catheter assembly, and when the catheter assembly is sent into the aorta, the drug-loaded catheter enters the coronary artery through the catheter assembly, and the drug-loaded catheter releases drug-loaded microvesicles in the coronary artery. The ultrasound device is arranged to apply ultrasound to the drug-loaded microvesicles, and the drug-loaded microvesicles rupture and release thrombolytic drugs. The catheter assembly is arranged to be able to block the root of the aorta, so that the drug-loaded microvesicles cannot move out of the aorta from there.

[0007] The system for applying thrombolytic drugs to coronary arteries provided by the embodiment of the present application is suitable for ultrasound-guided interventional technology. By arranging a catheter assembly, a drug-loaded catheter and an ultrasound device, the catheter assembly can block the root of the aorta, so that the drug-loaded microvesicles released by the drug-loaded catheter to the coronary arteries cannot move out of the aorta. Then, the ultrasound device is used to apply ultrasound to the drug-loaded microvesicles to make them burst and release the thrombolytic drugs. In this way, the thrombolytic drugs can not flow out of the aorta and leak to the whole body, so that the thrombolytic drugs can stay in the coronary arteries for a long time and fully act on the coronary artery thrombus. Therefore, local administration can be achieved, the thrombolytic effect and targeting are improved, the influence of the thrombolytic drugs on the whole body coagulation mechanism is reduced, the risk of cerebral hemorrhage and hemorrhage of other organs is reduced, and the safety and reliability of the treatment are improved. BRIEF DESCRIPTION OF DRAWINGS

[0008] Other objects and advantages of the present application will become apparent from the following description of embodiments of the present application, taken in conjunction with the accompanying drawings.

[0009] Figure 1 is a structural schematic view of the system for applying thrombolytic drugs to coronary arteries provided by the embodiment of the present application when arranged in a human body according to the embodiment of the present application; Figure 2 is an electron microscope image of the drug-loaded microvesicles provided by the embodiment of the present application.

[0010] BRIEF DESCRIPTION OF DRAWINGS: 1, aorta; 2, left coronary sinus opening; 3, right coronary sinus opening; 10, catheter assembly; 11, catheter; 12, balloon; 13, delivery sheath; 20, drug-loaded catheter; 30, ultrasound device; 31, extracorporeal ultrasound stimulation equipment; 32, transthoracic echocardiography probe; 40, drug-loaded microvesicles.

[0011] It should be noted that the drawings are not necessarily drawn to scale, but are merely shown in a schematic manner so as not to obscure the concept. DETAILED DESCRIPTION

[0012] In the following, exemplary embodiments of the present application will be described with reference to the drawings. In the description, not all features of the actual implementation are described for the sake of clarity and conciseness. It should be appreciated, however, that many implementation-specific decisions can have to be made in order to develop any such actual implementation, to implement developer-specific goals, such as compliance with system- and business-related constraints, which will vary from one implementation to another. Moreover, it should be appreciated that, while the development work can be very complex and time-consuming, it would be a routine undertaking for those of ordinary skill in the art having the benefit of this disclosure.

[0013] It should also be noted that, in order to avoid obscuring this application with unnecessary details, only the equipment structure and / or processing steps closely related to the solution according to this application are shown in the accompanying drawings, while other details that are not closely related to this application are omitted.

[0014] Intravenous thrombolysis is a treatment method that uses drugs to dissolve blood clots and restore coronary blood flow. In existing technologies, there is a method of thrombolysis in which thrombolytic drugs are directly injected into the coronary artery opening through a catheter. However, this method has poor targeting, and the thrombolytic drugs are rapidly lost under the flushing of blood flow, resulting in a short time that the drugs remain in the coronary artery and cannot fully act on the coronary artery thrombus. The thrombolytic effect is limited for larger or old thrombi. Furthermore, thrombolytic drugs are easily distributed throughout the body by blood flow, thereby disrupting the body's coagulation mechanism and posing a high risk of cerebral hemorrhage and bleeding in other organs.

[0015] Based on this, embodiments of this application provide a system for administering thrombolytic drugs to the coronary arteries using ultrasound-guided interventional techniques.

[0016] like Figure 1 As shown, Figure 1 This is a schematic diagram of the structure of a system for administering thrombolytic drugs to the coronary arteries using ultrasound-guided interventional techniques, according to an embodiment of this application, when installed in the human body.

[0017] The embodiments of this application provide a system for administering thrombolytic drugs to the coronary arteries using ultrasound-guided interventional techniques, comprising: a catheter assembly 10, a drug-loaded catheter 20, and an ultrasound device 30. The drug-loaded catheter 20 is disposed within the catheter assembly 10. When the catheter assembly 10 is inserted into the aorta 1, the drug-loaded catheter 20 passes through the catheter assembly 10 into the coronary artery, where it releases drug-loaded microvesicles 40. The ultrasound device 30 is configured to apply ultrasound to the drug-loaded microvesicles 40, causing them to rupture and release the thrombolytic drug. The catheter assembly 10 is configured to obstruct the root of the aorta 1, preventing the drug-loaded microvesicles 40 from migrating out of the aorta 1.

[0018] The embodiments of this application provide a system for administering thrombolytic drugs to the coronary arteries using ultrasound-guided interventional techniques. By configuring a catheter assembly 10, a drug-loaded catheter 20, and an ultrasound device 30, the catheter assembly 10 can block the root of the aorta 1, preventing the drug-loaded microvesicles 40 released by the drug-loaded catheter 20 from moving out of the aorta 1. The ultrasound device 30 then applies ultrasound to the drug-loaded microvesicles 40, causing them to rupture and release the thrombolytic drug. This prevents the thrombolytic drug from flowing out with the blood flow of the aorta 1 and leaking into the system, allowing it to remain in the coronary arteries for an extended period, effectively targeting the coronary thrombus. This facilitates local drug delivery, improves thrombolytic efficacy and targeting, reduces the impact of the thrombolytic drug on the systemic coagulation mechanism, lowers the risk of cerebral hemorrhage and bleeding in other organs, and improves the safety and reliability of the treatment.

[0019] like Figure 1 As shown, in some embodiments, the catheter assembly 10 may include a catheter 11, a balloon 12, a delivery sheath 13, and controls (not shown). The delivery sheath 13 is configured to deliver the catheter 11 into the aorta 1. The balloon 12 is disposed outside the catheter 11 and configured to communicate with the catheter 11. The controls are configured to control the inflation or deflation of the balloon 12, such that when the balloon 12 is inflated, it can occlude the root of the aorta 1. A drug-loaded catheter 20 enters the coronary artery through the catheter 11.

[0020] In this embodiment, by setting up a catheter 11, a balloon 12, a delivery sheath 13, and a control device, the balloon 12 is placed outside the catheter 11. When the catheter 11 is delivered into the aorta 1 through the delivery sheath 13, the balloon 12 is inserted into the root of the aorta 1, and the drug-loaded catheter 20 is inserted into the coronary artery. This allows the drug-loaded catheter 20 to release drug-loaded microvesicles 40 into the coronary artery, and the balloon 12 is controlled by the control device to expand and block the root of the aorta 1. This restricts the movement of the drug-loaded microvesicles 40 out of the aorta 1, thereby facilitating local drug delivery, improving thrombolytic effect and targeting, and reducing the impact of thrombolytic drugs on the systemic coagulation mechanism.

[0021] In some embodiments, one end of the catheter 11 extends outside the body, and the other end is connected to the drug-carrying catheter 20. The balloon 12 is disposed outside the end of the catheter 11 connected to the drug-carrying catheter 20, so that the balloon 12 can block the root of the aorta 1 and allow the drug-carrying catheter 20 to enter the coronary artery through the catheter 11.

[0022] In some embodiments, two drug-carrying catheters 20 may be configured to enter the left coronary sinus opening 2 and the right coronary sinus opening 3 respectively, so as to simultaneously release drug-carrying microvesicles 40 into the left and right coronary arteries, thereby achieving simultaneous drug delivery to the left and right coronary arteries and improving the efficiency of thrombolytic therapy.

[0023] Further, in some embodiments, the control member is configured to further enable independent release of the drug-loaded microvesicles 40 from the two drug-loaded catheters 20 to the coronary arteries respectively, so as to achieve separate drug delivery to the left or right coronary artery, thereby facilitating selective thrombolytic treatment of the left and right coronary arteries.

[0024] In some embodiments, the catheter 11 can be configured to have a first chamber, a second chamber and a third chamber formed therein and separated from each other. The first chamber is in fluid communication with the balloon 12 and an external inflation medium storage mechanism, and the control member is configured to control the inflation medium storage mechanism to deliver the inflation medium to the balloon 12 via the first chamber to inflate the balloon 12, and to control the inflation medium in the balloon 12 to flow out to the inflation medium storage mechanism via the first chamber to deflate the balloon 12. The second chamber and the third chamber are respectively in fluid communication with the two drug-loaded catheters 20 and an external drug-loaded microvesicle providing mechanism, and the control member is configured to control the drug-loaded microvesicle providing mechanism to deliver the drug-loaded microvesicles 40 to the drug-loaded catheters 20 via the second chamber and / or the third chamber to release the drug-loaded microvesicles 40 to the left and right coronary arteries separately or simultaneously.

[0025] In some embodiments, the inflation medium can be physiological saline or diluted contrast agent, etc.

[0026] In some embodiments, the outer surface of the catheter 11 can be coated with a hydrophilic coating or a low-friction coating to reduce the damage to the blood vessel when the catheter 11 is inserted into the aorta 1.

[0027] In some embodiments, the control member is further configured to limit the distance of the catheter 11 into the aorta 1, so as to reduce the risk of over-insertion under the condition of superimposition of heartbeats and operator pushing, thereby improving the controllability and safety of the operation.

[0028] In some embodiments, the material of the balloon 12 is configured to allow blood to pass through but not the drug-loaded microvesicles 40, so as to form an interception barrier for the drug-loaded microvesicles 40 without significantly blocking the passage of blood components and affecting the oxygen supply of the distal end, thereby limiting the movement of the drug-loaded microvesicles 40 out of the aorta 1 and reducing the risk of leakage of the drug-loaded microvesicles 40 into the whole body along with the blood flow in the aorta 1.

[0029] Specifically, the material of the balloon 12 can be a nano-flow-blocking film, such as a medical polymer microporous film, for example, a polytetrafluoroethylene microporous film, a polyurethane microporous film, a polycarbonate microporous film, a polyimide microporous film, etc.

[0030] Furthermore, the balloon 12 can be provided with a shape-changing frame structure, with a nano-resistance membrane coated on the inner surface of the frame structure, so that the balloon 12 can flexibly switch between inflated and contracted shapes, while increasing the structural strength of the balloon 12 and reducing its risk of damage. For example, the frame structure can be woven from shape memory alloy, and the nano-resistance membrane can be coated on the inner surface of the frame structure by means of hot pressing, bonding, laser welding or mechanical clamping.

[0031] In some embodiments, the balloon 12 is configured as a spindle-shaped structure so that after the balloon 12 is inflated, it can obtain a relatively stable radial adhesion force and axial displacement resistance, thereby stably attaching to the root of the aorta 1 in a semi-adhesive or partial manner, further restricting the movement of the drug-loaded microvesicles 40 outward from the aorta 1, and preventing the balloon 12 from obstructing the aortic valve leaflets, ensuring that the aortic valve leaflets can open and close normally, and further ensuring the safety of thrombolytic therapy.

[0032] In some embodiments, one or more side holes are formed at one end of the drug-loaded catheter 20 near the left coronary sinus opening 2 and the right coronary sinus opening 3 to facilitate the directional release of drug-loaded microvesicles 40 into the left and right coronary arteries. Compared with the release of drug-loaded microvesicles 40 by jetting, the impact on the vessel wall is smaller, which helps to reduce damage to the vessel. Furthermore, it helps to prolong the residence time of drug-loaded microvesicles 40 near the left coronary sinus opening 2 and the right coronary sinus opening 3, thereby fully acting on the coronary thrombus and improving the thrombolytic effect and targeting.

[0033] Furthermore, the position of the side hole can be set 0.5mm-10mm away from the end of the drug-carrying catheter 20 near the left coronary sinus opening 2 and the right coronary sinus opening 3, so as to balance the directionality and patency of the release of the drug-carrying microvesicles 40.

[0034] like Figure 1 As shown, in some embodiments, the ultrasound device 30 may include an external ultrasound stimulation device 31 and a transthoracic echocardiography probe 32. The external ultrasound stimulation device 31 is used to apply ultrasound stimulation to the drug-loaded microvesicles 40, and the transthoracic echocardiography probe 32 is attached to the chest wall 4 to acquire real-time dynamic images of the heart and release ultrasound waves. The external ultrasound stimulation device 31 is configured to apply ultrasound stimulation to the drug-loaded microvesicles 40 based on the images acquired by the transthoracic echocardiography probe 32, causing the transthoracic echocardiography probe 32 to release ultrasound waves, thereby causing the drug-loaded microvesicles 40 to rupture and release thrombolytic drugs.

[0035] In some embodiments, the particle size distribution of the drug-loaded microvesicles 40 can be controlled in the range of 25 μm-80 μm, so as to balance the deliverability of the drug-loaded catheter 20 to the drug-loaded microvesicles 40, the ultrasound responsiveness of the drug-loaded microvesicles 40, and make it difficult to pass through the capillary network and enter the systemic circulation, so as to improve the retention time of the drug-loaded microvesicles 40 in the coronary artery and reduce the risk of leakage to the whole body. In addition, the material of the balloon 12 is selected according to the particle size distribution of the drug-loaded microvesicles 40, for example, the pore diameter of the material is set to 20 μm, so that the balloon 12 allows the blood components (red blood cells, plasma, platelets, etc.) to pass through, and prevents the drug-loaded microvesicles 40 with a particle size greater than 20 μm from moving out of the aorta 1 with the blood flow.

[0036] In some embodiments, the drug-loaded microvesicles 40 can include a shell, a core, and a thrombolytic drug. The shell is arranged outside the core, and the thrombolytic drug is arranged in the core. The material of the core is arranged to be capable of being broken after being applied with ultrasound, so that the thrombolytic drug is released.

[0037] In the present embodiment, the drug-loaded microvesicles 40 are arranged in a structure in which the shell is arranged outside the core and the thrombolytic drug is arranged in the core, so that the drug-loaded microvesicles 40 can serve as an ultrasound imaging and positioning auxiliary carrier, facilitating the ultrasound device 30 to position the drug-loaded microvesicles 40, and facilitating the ultrasound device 30 to accurately release ultrasound waves. At the same time, the drug-loaded microvesicles 40 can also carry and release thrombolytic drugs, which is beneficial to improve the efficiency of thrombolytic therapy. In addition, by arranging the material of the core of the drug-loaded microvesicles 40 to be capable of being broken after being applied with ultrasound, the thrombolytic drug is released, so as to avoid the drug-loaded microvesicles 40 from being broken during transportation and causing the thrombolytic drug to be released in advance, which is beneficial to realize accurate drug delivery to the coronary artery, improve the effect and targeting of thrombolytic therapy, and further avoid the thrombolytic drug from flowing out of the aorta 1 with the blood flow and leaking to the whole body, thereby improving the safety of thrombolytic therapy.

[0038] In some embodiments, the material of the shell includes polylactic acid-glycolic acid copolymer, so that the shell can have a predetermined mechanical strength, facilitating the ultrasound device 30 to position the drug-loaded microvesicles 40. In addition, the shell including the material can be broken under the action of the material of the core, facilitating the release of the thrombolytic drug.

[0039] In some embodiments, the material of the core includes perfluoropentane. The perfluoropentane can undergo sonoporation and cavitation effect after being applied with ultrasound, so as to break the core and act on the shell including polylactic acid-glycolic acid copolymer, so that the shell produces cracks and is perforated, thereby facilitating the release of the thrombolytic drug.

[0040] In some embodiments, the thrombolytic drug includes recombinant tissue-type plasminogen activator, which is beneficial to effectively dissolve the coronary artery thrombus.

[0041] In some embodiments, the balloon 12 is provided with a radiographic marker, and the ultrasound device 30 can determine the position of the balloon 12 through the radiographic marker to avoid applying ultrasound to the balloon 12, so as to avoid the premature rupture of the drug-loaded microvesicles 40 and the release of the thrombolytic drug, thereby further improving the effect and targeting of the thrombolytic treatment, and avoiding the leakage of the thrombolytic drug along the blood flow of the aorta 1 and to the whole body. For example, the radiographic marker can be filled with a platinum-iridium alloy or tungsten.

[0042] In some embodiments, the drug-loaded microvesicles 40 can be prepared by the following method: S10: A predetermined amount of polylactic acid-glycolic acid copolymer is dissolved in dichloromethane.

[0043] S20: A predetermined amount of perfluoropentane and a predetermined amount of recombinant tissue-type plasminogen activator are added to the mixture obtained in step S10.

[0044] S30: The mixture obtained in step S20 is subjected to ultrasonic emulsification in an ice bath.

[0045] S40: A predetermined concentration of polyvinyl alcohol solution is added to the mixture obtained in step S30, and emulsification is repeated.

[0046] S50: The suspension of the mixture obtained in step S40 is extracted, and the suspension is transferred to an acetone solution and stirred in an ice bath for a predetermined time.

[0047] S60: The mixture obtained in step S50 is subjected to centrifugal treatment to obtain the drug-loaded microvesicles 40.

[0048] Through the above steps in this embodiment, the drug-loaded microvesicles 40 with predetermined mechanical strength can be obtained as an ultrasound imaging and positioning auxiliary carrier, which facilitates accurate positioning by the ultrasound device 30, and can carry and release the thrombolytic drug under the action of ultrasound.

[0049] Preferably, in the preparation of the drug-loaded microvesicles 40, 20 mg of polylactic acid-glycolic acid copolymer is dissolved in dichloromethane to form an oil phase; 200 μL of perfluoropentane and 200 μL of recombinant tissue-type plasminogen activator with a concentration of 20 mg / ml are added; the aforementioned mixture is subjected to ultrasonic emulsification in an ice bath; 5 ml of polyvinyl alcohol solution with a concentration of 5% (w / v) is added and emulsification is repeated; the suspension of the aforementioned mixture is extracted, and the suspension is transferred to 10 ml of acetone solution with a concentration of 2% (v / v) and stirred in an ice bath for 6 hours; and the aforementioned mixture is subjected to centrifugal treatment to obtain the drug-loaded microvesicles 40.

[0050] In some embodiments, a predetermined amount of stabilizer, such as human serum albumin, trehalose, etc., can also be added during the preparation of the drug-loaded microvesicles 40 to reduce the risk of protein denaturation, improve the stability of the thrombolytic drug load, and reduce the risk of premature rupture of the drug-loaded microvesicles 40.

[0051] As shown in Figure 2 FIG. 6 shows an electron microscope image of the drug-loaded microvesicles provided according to an embodiment of the present application.

[0052] For the embodiments of the present application, it should also be noted that the embodiments and features in the embodiments of the present application can be combined with each other to obtain new embodiments without conflict.

[0053] The above is only a specific implementation of the present application, but the protection scope of the present application is not limited thereto, and the protection scope of the present application should be subject to the protection scope of the claims.

Claims

1. A system for administering thrombolytic drugs to coronary arteries using ultrasound-guided interventional techniques, characterized in that, It includes: Catheter assembly, drug-eluting catheter, ultrasound device, The drug-carrying catheter is disposed within the catheter assembly, and when the catheter assembly is inserted into the aorta, the drug-carrying catheter passes through the catheter assembly into the coronary artery. The drug-carrying catheter releases drug-loaded microvesicles into the coronary artery. The ultrasonic device is configured to apply ultrasound to the drug-loaded microvesicles, causing the microvesicles to rupture and release the thrombolytic drug. The catheter assembly is configured to block the root of the aorta, preventing the drug-loaded microvesicles from moving out of the aorta from there.

2. The system according to claim 1, characterized in that, The catheter assembly includes a catheter, a balloon, a delivery sheath, and controls. The delivery sheath is configured to deliver a catheter into the aorta. The balloon is disposed outside the catheter and configured to communicate with the catheter. The control element is configured to control the inflation or deflation of the balloon, wherein when the balloon is inflated, the balloon can obstruct the root of the aorta. The drug-carrying catheter enters the coronary artery through the catheter.

3. The system according to claim 2, characterized in that, The balloon is made of a material that allows blood to pass through but prevents the drug-loaded microvesicles from passing through.

4. The system according to any one of claims 1-3, characterized in that, The drug-carrying catheter is configured as two, which enter the left coronary sinus opening and the right coronary sinus opening respectively.

5. The system according to any one of claims 1-3, characterized in that, The drug-loaded microvesicles include a shell, a core, and a thrombolytic drug. The shell is disposed outside the core, and the thrombolytic drug is disposed inside the core. The material of the core is configured to rupture upon application of ultrasound, thereby releasing the thrombolytic drug.

6. The system according to claim 5, characterized in that, The material of the shell includes polylactic acid-hydroxyacetic acid copolymer.

7. The system according to claim 5, characterized in that, The material of the core includes perfluoropentane.

8. The system according to claim 5, characterized in that, The thrombolytic drug includes recombinant tissue plasminogen activator.

9. The system according to claim 2, characterized in that, The balloon is equipped with radiopaque markers, and the ultrasound device can determine the position of the balloon by means of the radiopaque markers.

10. The system according to claim 1, characterized in that, The drug-loaded microvesicles were prepared using the following method: S10: Dissolve a predetermined amount of polylactic acid-glycolic acid copolymer in dichloromethane; S20: Add a predetermined amount of perfluoropentane and a predetermined amount of recombinant tissue plasminogen activator to the mixture obtained in step S10; S30: The mixture obtained in step S20 is ultrasonically emulsified in an ice bath; S40: Add a polyvinyl alcohol solution of a predetermined concentration to the mixture obtained in step S30, and repeat the emulsification process; S50: Extract the suspension of the mixture obtained in step S40, transfer the suspension to an acetone solution, and stir in an ice bath for a predetermined time; S60: Centrifuge the mixture obtained in step S50 to obtain the drug-loaded microvesicles.

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