An endovascular interventional targeted drug delivery system for treating pulmonary artery stenosis

Abstract

The application discloses an intravascular interventional targeted drug delivery system for treating pulmonary artery stenosis, and belongs to the technical field of minimally invasive interventional treatment. Compared with the prior art, the application provides an intravascular targeted drug delivery system balloon dilatation catheter which can be used for interventional treatment of chronic thromboembolic pulmonary hypertension (CTEPH). The intravascular interventional targeted drug delivery system for treating pulmonary artery stenosis provided by the application is suitable for the pulmonary artery anatomical path, and ensures the pushability and flexibility in the complex delivery process. The balloon surface is loaded with anti-proliferative drugs (such as paclitaxel and derivatives thereof or rapamycin and derivatives thereof) and anticoagulant drugs (such as heparin, tirofiban hydrochloride and the like), mechanical expansion and local targeted drug delivery are realized, and restenosis and thrombosis are inhibited.

Description

Technical Field

[0001] This invention belongs to the field of minimally invasive interventional therapy technology, specifically relating to an intravascular interventional targeted drug delivery system for treating pulmonary artery stenosis. Background Technology

[0002] Chronic thrombotic pulmonary hypertension (CTEPH) is a disease caused by the organization of pulmonary thrombosis, resulting in a mean pulmonary artery pressure ≥25 mmHg and a pulmonary capillary wedge pressure ≤15 mmHg. Current standard treatments include medication and surgical pulmonary endarterectomy (PEA), but both have limitations. Medication is a conservative treatment, but it is slow to take effect, only providing temporary relief and not addressing the underlying problem, and is only suitable for microvessels smaller than 0.5 mm. Surgical intervention requires open-chest surgery, is highly invasive, has a long recovery period, is not easily tolerated by patients, requires a high level of skill from the surgeon, and is difficult to implement clinically. More than 40% of patients are not suitable for PEA. Resourceful clinicians have adopted methods similar to cardiac and peripheral vascular interventions, using non-specialized balloon angioplasty to perform interventional treatments. The advantages of interventional treatment are minimal invasiveness and ease of operation. Currently, the preferred treatment for CTEPH in European and American guidelines is pulmonary endarterectomy (PEA), but for patients who cannot undergo PEA, experience postoperative recurrence, or have persistent hypertension, balloon pulmonary angioplasty (BPA) has become an effective alternative. BPA (Baltic Artery Balloon Angiography) is characterized by minimal invasiveness and low risk, and can significantly reduce right ventricular systolic pressure and improve pulmonary artery stenosis. However, it relies on cardiac, neurological, and peripheral vascular interventional devices, and lacks a dedicated pulmonary artery balloon catheter, affecting the precision and safety of the procedure. Furthermore, existing interventional techniques have the following technical limitations: Insufficient device compatibility: Existing balloon catheters are not specifically designed for the anatomical structure of the pulmonary artery, making it difficult to meet the requirements for 180° turning and push compliance when passing through the jugular vein or femoral artery, right atrium, right ventricle to the pulmonary artery branches.

[0003] Treatment limitations: Simple balloon dilation only temporarily relieves stenosis and cannot inhibit smooth muscle proliferation, pulmonary artery wall microvascular proliferation, inflammatory response, and vascular damage repair, increasing the risk of vascular re-blockage or hemoptysis.

[0004] To address the aforementioned issues, developing a balloon dilation catheter for pulmonary hypertension that can both deliver medication locally and dilate blood vessels has become a crucial and urgent task. Summary of the Invention

[0005] Therefore, the purpose of this invention is to provide an endovascular interventional targeted drug delivery system for treating pulmonary artery stenosis, adapted to the pulmonary artery anatomical pathway, ensuring delivery and compliance during complex processes. The balloon surface is loaded with antiproliferative drugs (such as paclitaxel and its derivatives or rapamycin and its derivatives) and anticoagulants (such as heparin, tirofiban hydrochloride, etc.), achieving mechanical dilation and local targeted drug delivery, inhibiting restenosis and thrombus formation.

[0006] To achieve the above objectives, the present invention provides the following technical solution: This invention provides an intravascular targeted drug delivery system for treating pulmonary hypertension, comprising, from distal to proximal, a catheter body, a stress tube, and a catheter seat. The catheter body includes a distal rod and a proximal rod. The distal rod includes an inner tube, an outer tube, and a drug-coated balloon communicating with the outer tube. The distal rod is a flexible structure made of a polymer material, and the drug-coated balloon is in a folded state.

[0007] Based on the above technical solution, the outer tube surface is further coated with a hydrophilic coating or a hydrophobic coating, the drug-coated balloon surface is coated with a drug coating, the inner lumen of the inner tube is a guidewire exchange channel, the proximal end of the inner tube passes through the outer tube wall, the inner tube port is a guidewire exchange port, and a marker ring is provided on the inner tube surface corresponding to the shoulder position of the drug-coated balloon.

[0008] The distances between the marker ring and the tip are 900mm±100mm and 1000mm±100mm, respectively.

[0009] Based on the above technical solution, the drug coating is further located between the shoulder of the drug-coated balloon.

[0010] Based on the above technical solution, further, the drug-coated balloon has a diameter of 1.0-10.0 mm, a length of 8-50 mm, and an expansion pressure of 6 atm-22 atm; the drug-coated balloon has a variable diameter structure or a papillary structure; the effective total length of the drug delivery system is 1400 mm-1600 mm, and the proximal rod is a rigid structure made of metal material.

[0011] Based on the above technical solution, the diameter of the drug-coated balloon is 1.0-5.0 mm, and the diameter of the guide wire used is no greater than 0.014 inch.

[0012] Based on the above technical solution, the diameter of the drug-coated balloon is 6.0-10.0 mm, and the diameter of the guide wire used is no greater than 0.018 inch.

[0013] Based on the above technical solution, the drug coating further includes an antiproliferative drug and an anticoagulant drug. The antiproliferative drug includes one or more of paclitaxel, paclitaxel derivatives, rapamycin, and rapamycin derivatives. The anticoagulant drug includes one or more of heparin, tirofiban hydrochloride, argatroban, and levofloxacin.

[0014] The main functions of the drug coating are anticoagulation and antithrombosis, inhibiting cell mitosis and preventing proliferation. The antiproliferative and anticoagulant drugs are uniformly mixed using an amphiphilic drug as a carrier. The drug coating contains at least two active drugs, including lipophilic or hydrophilic drugs, exerting anti-inflammatory, anticoagulant, antithrombotic, antiproliferative, or immunomodulatory activities. The antiproliferative drugs are lipophilic drugs such as paclitaxel and its derivatives, and hydrophilic drugs such as rapamycin and its derivatives. The anticoagulant drugs are heparin, tirofiban hydrochloride, argatroban, and other similar drugs; these are hydrophilic drugs.

[0015] Based on the above technical solution, the surface of the drug-coated balloon is further treated by plasma; the drug coating is prepared by ultrasonic spraying with a power of 100KHz-1000KHz and a thickness of 0.1-100μm.

[0016] The drug-coated balloon surface is pretreated with plasma to increase its surface activity, and the drug coating process uses ultrasonic spraying to mix the drug solution and evenly cover the inflated balloon surface.

[0017] The drug coating process employs a pre-coating and post-folding technique.

[0018] In ultrasonic spraying, the high-frequency ultrasonic energy transforms the drug solution into fine droplets, which are then precisely deposited on the target surface to form a uniform coating. The droplet size (D) is determined by the drug solution properties (density ρ, surface area γ) and the ultrasonic frequency (f), with an approximate formula as follows. After impacting the surface, the droplets rapidly spread, and after solvent evaporation, a continuous or porous film is formed. The coating thickness is precisely controlled by adjusting the spraying time, atomization rate, and solution concentration, ranging from 0.1 to 100 μm. The ultrasonic frequency used in this method is 100 kHz to 500 kHz. The drug solution ratio is paclitaxel: tirofiban hydrochloride: amphiphilic solvent = 2:1:1 to 5:1:1.

[0019] .

[0020] In the formula: D: droplet size, ρ: density, γ: surface tension, f: ultrasonic frequency.

[0021] Among them, tirofiban hydrochloride is positively charged (containing -NH3) at physiological pH, paclitaxel is a hydrophobic drug, and amphiphilic polymers (such as PLGA-PEG, alcohol, β-cyclodextrin, etc.) are used as carriers. The hydrophobic segment encapsulates paclitaxel through van der Waals forces, and the hydrophilic segment (PEG) binds to tirofiban hydrochloride through hydrogen bonds.

[0022] Tirofiban hydrochloride is a hydrophilic drug, and rapamycin is a hydrophilic drug. When the two are mixed, a small molecule protein is selected as a carrier. The two drugs are mixed more evenly by ultrasonic spraying. The small molecule protein adheres to the surface of the balloon, which increases the stability of the coating and reduces drug loss during the delivery process of the intravascular interventional targeted drug delivery system.

[0023] When the drug coating reaches the target lesion site in the blood vessel, tirofiban hydrochloride is rapidly released, while paclitaxel or rapamycin is released slowly and rapidly absorbed by the blood vessel wall.

[0024] Based on the above technical solution, the folding state is further described as a three-fold fold, a four-fold fold, a five-fold fold, or a six-fold fold.

[0025] The components are connected together by welding or bonding. The outer tube is welded or bonded to the inner tube, the distal end of the outer tube is bonded or welded to the proximal end of the balloon, and the distal end of the balloon is welded or bonded to the inner tube. The inner lumen of the inner tube serves as a guidewire channel, and a marker ring is forged on the outer surface of the inner tube. The marker ring is made of radiopaque materials such as platinum-iridium alloy or tungsten metal.

[0026] Compared with the prior art, the present invention has the following beneficial effects: 1. This invention provides an intravascular targeted drug delivery system balloon dilation catheter that can be used for interventional treatment of chronic thrombotic pulmonary hypertension (CTEPH).

[0027] 2. This invention provides an endovascular interventional targeted drug delivery system for treating pulmonary artery stenosis, adapted to the anatomical pathway of the pulmonary artery to ensure delivery flexibility and smoothness during complex processes. The balloon surface is loaded with antiproliferative drugs (such as paclitaxel and its derivatives or rapamycin and its derivatives) and anticoagulants (such as heparin, tirofiban hydrochloride, etc.), achieving mechanical dilation and local targeted drug delivery to inhibit restenosis and thrombus formation. Attached Figure Description

[0028] To more clearly illustrate the embodiments of the present invention, the accompanying drawings involved in the embodiments will be briefly described below.

[0029] Figure 1 This is a schematic diagram of the structure of an intravascular interventional targeted delivery system according to the present invention; Figure 2 This is a partial schematic diagram of the drug-coated balloon structure of the present invention; Figure 3 This is a schematic diagram of the folded cross-section of the drug-coated balloon of the present invention; Figure 4 This is a schematic diagram of the structure of a variable diameter balloon intravascular interventional targeted drug delivery system according to the present invention; Figure 5 This is a schematic diagram of the structure of a mastoid balloon vascular intervention targeted drug delivery system according to the present invention; Figure 6 This is a schematic diagram of a multi-balloon intravascular interventional targeted drug delivery system according to the present invention; Figure 7 This is a schematic diagram of the main connection positions of an intravascular targeted interventional drug delivery system according to the present invention; Figure 8 This is a schematic diagram of the distal rod of a targeted interventional drug delivery system with continuous intravascular dilation according to the present invention. In the diagram: 1. Catheter seat; 2. Stress tube; 3. Catheter body; 3-1. Proximal rod; 3-2. Distal rod; 3-2-1. Drug-coated balloon; 3-2-1-1. Drug coating; 3-2-2. Inner tube; 3-2-3. Outer tube; 3-2-4. Guidewire exchange port; 3-2-5. Inflation port; 3-2-6. Marker ring; 3-2-7. Guidewire exchange channel; 4. Connection position between proximal and distal rods. Detailed Implementation

[0030] The present invention will be described in detail below with reference to the embodiments. However, the implementation of the present invention is not limited thereto. Obviously, the embodiments described below are only some embodiments of the present invention. For those skilled in the art, other similar embodiments can be obtained without creative effort and all fall within the protection scope of the present invention. Example 1

[0031] Figure 1 This is a schematic diagram of an intravascular targeted drug delivery system. The catheter is a rapid-exchange balloon catheter, consisting of three parts: a catheter hub, a proximal stem, and a distal stem. The proximal stem is made of metal, while the distal stem comprises an outer tube, an inner tube, a drug-coated balloon, a guidewire channel, and marker rings. The balloon is located at the distal end of the distal section and can be inflated to a specific diameter at recommended pressure. Two marker bands are located on the shoulder of the balloon for intravascular imaging and positioning. The guidewire channel is compatible with guidewire sizes of 0.014 inches, 0.018 inches, or 0.035 inches. The catheter hub is used to connect to an inflation pump to inflate the balloon. Example 2

[0032] The balloon surface is pre-treated with plasma to enhance its activity. The mixed drug is then uniformly coated onto the balloon surface using ultrasonic spraying, resulting in a drug coating thickness of 1–100 μm. This process enhances drug stability, increases the surface area between the drug and the blood vessel wall, and improves bioavailability. Example 3

[0033] like Figure 3 The balloon can be constructed with three or five folds. Applying the drug coating to the balloon surface using an ultrasonic coating followed by folding can further reduce drug loss during delivery. Example 4

[0034] The antiproliferative drug paclitaxel is lipophilic, while the anticoagulant is hydrophilic. Using an amphiphilic drug as a carrier, the two are uniformly mixed. When delivered to the target lesion by the intravascular targeted drug delivery system, the anticoagulant is rapidly released, dissolving the local thrombus and reducing its local blood concentration. This facilitates the release of the lipophilic drug to the target lesion site and its rapid absorption by the blood vessel wall. Results showed that the drug was rapidly released while dilating blood vessels, with a release rate of 85%, and approximately 20% of the paclitaxel was absorbed by the blood vessel wall. Example 5

[0035] Rapamycin, an antiproliferative drug, is a hydrophilic drug, as is the anticoagulant. Small molecule proteins are used to mix the two together, and ultrasonic spraying is used to mix the drugs evenly and adhere them to the surface of the balloon.

[0036] like Figure 4 The balloon size of the endovascular interventional targeted drug delivery system can be designed with a large proximal diameter and a small distal diameter to adapt to the anatomical features of the pulmonary artery with many branches. Example 6

[0037] like Figure 5 The balloon surface of the endovascular interventional targeted drug delivery system can be designed with a papillary structure, which is suitable for the dilation and treatment of hard calcified lesions or severe thrombotic lesions. Example 7

[0038] like Figure 6 The distal end of the endovascular interventional targeted drug delivery system can be designed with two balloons, which are suitable for the dilation and treatment of long diffuse stenosis lesions. The total length of the two balloons is less than 3 of the total catheter length. Example 8

[0039] like Figure 7This is an intravascular interventional targeted drug delivery system that allows for continuous expansion and flow, with an irregularly shaped balloon. After inflation, the balloon is partially not fully attached to the vessel wall, providing a channel for blood flow to the distal end, thus ensuring expansion time and increasing blood supply to the distal vascular tissue. Example 9

[0040] Endovascular targeted drug delivery systems are used to dilate stenosis in pulmonary artery lesions. During use, the puncture site can be the patient's femoral artery or internal jugular vein. The catheter is inserted into the pulmonary artery and delivered to the location of the lesion. Pressure is applied to the inside of the balloon to inflate it, allowing paclitaxel and tirofiban hydrochloride to adhere evenly and rapidly to the target vessel wall, resulting in immediate revascularization. The balloon is inflated for at least 30 seconds. Paclitaxel applied to the lesion blocks mitosis of vascular cells, thereby inhibiting excessive proliferation of the neointima and restoring blood flow. This treatment method not only achieves vasodilation and prevents restenosis but also allows the vessel to maintain its original anatomical structure and normal diastolic and systolic blood pressure. Anticoagulants reduce the risk of thrombus formation and distal embolus aspiration, further improving patient prognosis. Example 10

[0041] Feasibility and safety studies conducted in the Bama pig pulmonary artery model revealed that the product performed well in terms of delivery performance, compatibility with other devices, retraction and imaging performance, and no vascular dissection or other complications were observed under angiography. Example 11

[0042] An in vivo clinical trial using an intravascular targeted drug delivery system was conducted on 100 subjects, targeting a total of 522 vessels. After passing a guidewire through the pulmonary artery stenosis, a pulmonary artery drug-eluting balloon was inserted and the lesion was directly dilated. Test results showed that the intravascular targeted drug delivery system successfully delivered the drug, and the balloon was successfully inflated and withdrawn without balloon rupture or device defects. The results showed that 100% of subjects experienced an immediate improvement of grade 1 or higher in blood flow compared to pre-operative levels. Two-month follow-up showed that mean pulmonary artery pressure (mPAP) decreased to 3.08±5.56 mmHg, a reduction of 8.0%, while the six-minute walk distance increased by 23.43±55.23 m, an increase of 5.6%. The WHO functional classification improved in 15% of subjects, indicating an improvement in clinical symptoms and hemodynamic parameters. Immediately after surgery, the minimum lumen diameter of the target lesion increased by 1.94±1.05 mm compared to the preoperative diameter, and the degree of stenosis of the lumen diameter decreased by 47.88±21.29%. Two months after surgery, the minimum lumen diameter of the target lesion increased by 1.52±1.01 mm compared to the preoperative diameter, and the degree of stenosis of the lumen diameter decreased by 37.49±21.53%. Example 12

[0043] The drug-coated balloon has a diameter of 1.0 mm, a length of 8 mm, and an expansion pressure of 6 atmatm; the drug-coated balloon has a variable diameter structure, a papillary structure, or an irregular structure; the effective total length of the drug delivery system is 1400 mm, and the proximal rod is a hypotube made of metal.

[0044] The drug-coated balloon has a diameter of 1.0 mm, and the guidewire used has a diameter of no more than 0.014 inches.

[0045] The drug-coated balloon has a diameter of 6.0 mm, and the guidewire used has a diameter of no more than 0.018 inches.

[0046] The surface of the drug-coated balloon was treated with plasma; the drug coating was prepared by ultrasonic spraying with a power of 100 kHz and a thickness of 0.1 μm. Example 13

[0047] The drug-coated balloon has a diameter of 10.0 mm, a length of 50 mm, and an expansion pressure of 22 atm. The drug-coated balloon has a variable diameter structure, a papillary structure, or an irregular structure. The effective total length of the drug delivery system is 1600 mm, and the proximal rod is a hypotube made of metal.

[0048] The drug-coated balloon has a diameter of 5.0 mm, and the guidewire used has a diameter of no more than 0.014 inches.

[0049] The drug-coated balloon has a diameter of 10.0 mm, and the guidewire used has a diameter of no more than 0.018 inches.

[0050] The surface of the drug-coated balloon was treated with plasma; the drug coating was prepared by ultrasonic spraying with a power of 1000 kHz and a thickness of 100 μm.

[0051] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. An endovascular interventional targeted drug delivery system for treating pulmonary artery stenosis, characterized in that, From distal to proximal, the catheter includes a catheter body, a stress tube, and a catheter seat. The catheter body includes a distal rod and a proximal rod. The distal rod includes an inner tube, an outer tube, and a drug-coated balloon connected to the outer tube. The distal rod is a flexible structure made of polymer material, and the drug-coated balloon is in a folded state.

2. The endovascular interventional targeted drug delivery system for treating pulmonary artery stenosis according to claim 1, characterized in that, The outer tube surface is coated with a hydrophilic or hydrophobic coating, the drug-coated balloon surface is coated with a drug coating, the inner tube lumen is a guidewire exchange channel, the proximal end of the inner tube passes through the outer tube wall, the inner tube port is a guidewire exchange port, and a marker ring is provided on the inner tube surface corresponding to the shoulder position of the drug-coated balloon.

3. The endovascular interventional targeted drug delivery system for treating pulmonary artery stenosis according to claim 2, characterized in that, The drug coating is located between the shoulder and the shoulder of the drug-coated balloon.

4. The endovascular interventional targeted drug delivery system for treating pulmonary artery stenosis according to claim 1, characterized in that, The drug-coated balloon has a diameter of 1.0-10.0 mm, a length of 8-50 mm, and an expansion pressure of 6 atm-22 atm; the drug-coated balloon has a variable diameter structure or a papillary structure; the effective total length of the drug delivery system is 1400 mm-1600 mm, and the proximal rod is a hypotube made of metal material.

5. The endovascular interventional targeted drug delivery system for treating pulmonary artery stenosis according to claim 4, characterized in that, The drug-coated balloon has a diameter of 1.0-5.0 mm, and the guide wire used has a diameter of no more than 0.014 inches.

6. The endovascular interventional targeted drug delivery system for treating pulmonary artery stenosis according to claim 4, characterized in that, The drug-coated balloon has a diameter of 6.0-10.0 mm, and the guide wire used has a diameter of no more than 0.018 inch.

7. The endovascular interventional targeted drug delivery system for treating pulmonary artery stenosis according to claim 5, characterized in that, The surface of the drug-coated balloon is treated with plasma; the drug coating is prepared by ultrasonic spraying with a power of 100KHz-1000KHz and a thickness of 0.1-100μm.

8. The endovascular interventional targeted drug delivery system for treating pulmonary artery stenosis according to claim 1, characterized in that, The folding state is a three-fold fold, a four-fold fold, a five-fold fold, or a six-fold fold.

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