A drug coated balloon catheter and methods of making and using the same

Abstract

This invention provides a drug-coated balloon catheter, its preparation method, and its application, relating to the field of medical device technology. The drug-coated balloon catheter includes a balloon catheter and a drug coating disposed on the surface of the balloon catheter; the drug coating includes an active drug and an excipient; the active drug is a flavonoid. The drug-coated balloon catheter utilizes flavonoids, which combine the advantages of low toxicity and high water solubility. While reducing the toxic side effects of the drug coating, it achieves rapid release and efficient absorption of the drug. Furthermore, through a dual mechanism of anti-proliferation and anti-inflammation, it effectively solves the problems of potential toxic side effects, limited transport efficiency, and limited functionality that may exist in existing products at high dose densities.

Description

Technical Field

[0001] This invention relates to the field of medical device technology, and more specifically, to a drug-coated balloon catheter, its preparation method, and its application. Background Technology

[0002] Percutaneous coronary intervention (PCI) is a crucial modern medical treatment for vascular stenosis and related cardiovascular diseases, primarily restoring blood flow by opening narrowed or blocked vessels. In this field, drug-coated balloons (DCBs) have demonstrated significant value in clinical applications due to their unique local drug delivery mechanism. As a "non-implantable" interventional medical device, DCBs release anti-proliferative drugs to the vessel wall through balloon dilation, inhibiting restenosis while avoiding the long-term risks associated with permanent metal stent implantation. They are particularly important in the treatment of small vessel disease (SVD), in-stent restenosis (ISR), and bifurcation lesions (BL). Currently, these devices are widely used in coronary artery, peripheral vascular, and neurointerventional procedures. Their clinical efficacy is typically assessed using endpoints such as late lumen loss, major adverse cardiovascular events (MACE), and target lesion revascularization (TLR).

[0003] In existing technologies, the core functional unit of drug-coated balloons that are already on the market or in the research stage lies in the drug coating on the balloon surface. This coating is typically composed of an active pharmaceutical ingredient and an excipient (or carrier material). Due to the special environment and pharmacological requirements of intravascular drug delivery, the types of active pharmaceutical ingredients that can be used in drug-coated balloons are currently extremely limited, mainly focusing on a few chemical drugs such as paclitaxel, rapamycin (sirolimus), and its derivatives (such as BA9). These drugs primarily maintain vascular patency by inhibiting the migration and proliferation of smooth muscle cells, and are currently the mainstream choice for the prevention and treatment of restenosis.

[0004] However, the aforementioned existing drug systems have significant physicochemical and biological limitations in practical applications. First, paclitaxel, as the most common antiproliferative drug, while potent, exhibits significant cytotoxicity at high concentrations. Its mechanism of action, while inhibiting smooth muscle proliferation, also induces endothelial cell apoptosis, leading to delayed vascular endothelial repair and potentially causing complications such as late-stage thrombosis, arrhythmia, and bradycardia. Some studies even suggest it may increase the risk of late-stage mortality in patients. Second, while rapamycin and its derivatives are superior to paclitaxel in terms of cytotoxicity and have higher safety, their low water solubility results in poor burst release. Because the contact time between the drug-eluting balloon and the vessel wall during interventional procedures is extremely short (usually less than 1 minute), the highly lipophilic rapamycin cannot quickly dissolve and transfer to the vessel wall tissue within such a short time, resulting in most of the drug being lost or washed away by the bloodstream during delivery, leading to low bioavailability. Although existing technologies attempt to improve this problem through methods such as drug loading on microspheres or encapsulation with complex excipients, these methods often result in cumbersome preparation processes, complex excipient components, and high costs, and still cannot fundamentally resolve the contradiction between rapid drug absorption and retention in the blood vessel wall.

[0005] In summary, the current field of drug-coated balloons mainly faces the challenges of a narrow range of drug choices and the difficulty in balancing drug performance. Existing drug systems cannot simultaneously achieve highly efficient anti-proliferative activity, rapid release and transport capabilities, and excellent biocompatibility. On the one hand, there are potential toxicity risks and endothelial repair barriers associated with highly active drugs; on the other hand, low-toxicity drugs suffer from low transport efficiency and excessive loss due to their physicochemical properties. Therefore, how to achieve rapid and efficient delivery and absorption of drugs locally in blood vessels while ensuring biocompatibility is a pressing technical problem to be solved in this field. Compared with traditional drugs used in drug-coated balloons, flavonoids have unique molecular characteristics and excipient synergistic mechanisms. Flavonoids have a lower molecular weight and a moderate partition coefficient logP, which enhances the efficiency of passive drug diffusion. Flavonoids have a polyphenolic hydroxyl chemical structure, which enhances their affinity for endothelial cell membranes through hydrogen bonds.

[0006] In view of this, the present invention is hereby proposed. Summary of the Invention

[0007] The purpose of this invention is to provide a drug-coated balloon catheter, its preparation method, and its application. The drug-coated balloon catheter uses flavonoid drugs to achieve efficient and low-toxicity rapid delivery, and overcomes the defects of existing products, such as toxic side effects, limited transport efficiency, and single function, at high dose densities, by using a dual mechanism of anti-inflammatory and anti-proliferative effects.

[0008] In order to achieve the above-mentioned objectives of the present invention, the following technical solution is adopted: In a first aspect, the present invention provides a drug-coated balloon catheter, comprising a balloon catheter and a drug coating disposed on the surface of the balloon catheter; The drug coating comprises an active drug and excipients; The active drug is a flavonoid.

[0009] In optional embodiments, the flavonoid drugs include at least one of baicalin, luteolin, apigenin, kaempferol, myricetin, wogonin, glycyrrhizin, hesperidin, dihydroquercetin, dihydromocarboxin, morin, quercetin, stigmosiderin, puerarin, daidzein, daidzein, ginkgolide, neostigmine, stigmosiderin, thiocyanate, anthocyanin, quercetin, kaempferol, safflower enzyme, and Ophiopogon japonicus isoflavone A, and derivatives thereof with chemically modified functional groups; and / or, The excipients include at least one of iopromide, iohexol, urea, shellac, shellac ammonium salt, cholesterol, polydopamine, polysorbate, polyethylene glycol, polylactic acid, gallate, polylactic-co-glycolic acid, hydroxypropyl-β-cyclodextrin, chitosan, polyethylene oxide, triglycerides, poloxamer, magnesium stearate, butylated hydroxytoluene, polyvinylpyrrolidone, phospholipid bilayer, and PLGA-PEG.

[0010] The molecular weight of the flavonoid drug is 250 g / mol to 920 g / mol; Preferably, the partition coefficient logP of the flavonoid drug is 1.5 to 4.0; Preferably, the dosage concentration of the flavonoid drug is 2.0 μg / mm. 2 ~3.5 μg / mm 2 .

[0011] The flavonoid drugs are baicalin and / or luteolin; Preferably, the partition coefficient logP of the flavonoid drug is 2.2 to 2.6.

[0012] In an optional embodiment, the excipient is PLGA-PEG; Preferably, the molecular weight of PLGA is 15 kDa to 25 kDa; Preferably, the PEG molecular weight is 3-4 kDa.

[0013] In optional embodiments, the mass ratio of the active pharmaceutical ingredient to the excipient is 1:0.05 to 1:12; preferably, the pharmaceutical ingredient / excipient mass ratio is 1:1.5 to 1:4; and / or, The active drug exists in the drug coating in the form of nanoscale microcrystals, with an average particle size of 50-500 nm and an aspect ratio ≤3:1; and / or, The mass density of the drug in the drug coating is 0.5 µg / mm². 2 ~6µg / mm 2 ; and / or, The thickness of the drug coating is 3µm to 15µm.

[0014] In an optional embodiment, the balloon catheter is a standard balloon catheter, a cutting balloon catheter, a notched balloon catheter, a spinous process balloon catheter, a mastoid process balloon catheter, or an infusion balloon catheter.

[0015] In an optional embodiment, the balloon catheter is an infusion balloon catheter, which includes an infusion balloon and a support catheter; Preferably, the effective perfusion length of the perfusion balloon is 10mm to 30mm; Preferably, the support catheter has a dual-lumen structure, including an independent irrigation lumen and a dilation lumen; Preferably, the infusion cavity has symmetrically distributed side holes; Preferably, the side holes of the infusion cavity include four proximal holes and four distal holes; Preferably, the diameter of the side hole of the infusion cavity is 0.3mm to 0.5mm.

[0016] In an optional embodiment, the balloon catheter is a cutting balloon catheter; Preferably, the cutting balloon catheter includes a balloon and 2 to 10 microblades; Preferably, the microblade is made of nickel-titanium alloy or stainless steel; Preferably, the height of the microblade is 0.1mm to 0.3mm; Preferably, the length of the microblade is 5mm to 80mm; Preferably, the microblade is the same length as the working section of the balloon; Preferably, the diameter of the balloon is 1.0 mm to 8.0 mm; Preferably, the length of the balloon is 5mm to 80mm.

[0017] In a second aspect, the present invention provides a method for preparing a drug-coated balloon catheter as described in any of the foregoing embodiments, comprising: Prepare solutions containing flavonoids and excipients; The solution is coated onto the surface of the balloon catheter; The coated balloon catheter is dried to obtain the drug-coated balloon catheter. Preferably, the drying temperature of the drying process is 25℃~45℃; Preferably, the drying time for the drying process is 0.5 hours to 3 hours.

[0018] This invention provides a drug-coated balloon catheter, its preparation method, and its application. Compared with existing technologies, the drug-coated balloon catheter uses flavonoids as the active ingredient in the balloon catheter coating, significantly improving the biocompatibility of interventional therapy. Compared to traditional drugs such as paclitaxel, which are prone to causing complications such as endothelial cell apoptosis, late thrombosis, and arrhythmia at high concentrations, flavonoids have lower cytotoxicity. This low toxicity advantage allows the product to effectively inhibit vascular restenosis while better protecting vascular endothelial function, reducing the risk of serious adverse cardiovascular events in patients after surgery, and solving the problem of existing drugs struggling to balance high anti-proliferative efficacy with biocompatibility.

[0019] Simultaneously, this product improves drug delivery efficiency and bioavailability to the vascular wall. Addressing the shortcomings of existing drugs (such as rapamycin) due to their low water solubility and poor burst release, which hinder rapid transfer to the vascular wall during short-term contact, flavonoids, with their better water solubility and smaller molecular weight, can achieve rapid burst release within the brief window of balloon dilation and blood flow occlusion. Their tendency to form nanoscale microcrystals further promotes rapid uptake and absorption by vascular endothelial cells, significantly reducing drug loss during delivery and thus increasing drug retention in target lesion tissue.

[0020] Furthermore, the application of flavonoids has diversified therapeutic effects. Unlike existing products that focus solely on anti-proliferative effects, flavonoids possess dual pharmacological activities, including both anti-cell proliferation and anti-inflammation. By inhibiting kinase activity, scavenging reactive oxygen species, and regulating inflammatory pathways, this product can not only specifically prevent and treat restenosis but also effectively reduce local vascular inflammation, providing a multi-mechanism synergistic treatment approach for coronary and peripheral vascular diseases, overcoming the limitations of existing products with single functions. Attached Figure Description

[0021] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0022] Figure 1 This is a schematic flowchart illustrating the preparation method of the drug-coated balloon catheter in the embodiments of this application. Detailed Implementation

[0023] The embodiments of the present invention will be described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are for illustrative purposes only and should not be considered as limiting the scope of the invention. Unless otherwise specified in the examples, conventional conditions or conditions recommended by the manufacturer are followed. Reagents or instruments whose manufacturers are not specified are all commercially available conventional products.

[0024] This application provides a drug-coated balloon catheter, including a balloon catheter and a drug coating disposed on the surface of the balloon catheter; the drug coating includes an active drug and an excipient; the active drug is a flavonoid drug.

[0025] The aforementioned product mainly consists of two physical parts: a balloon catheter and a drug coating. The drug coating is not independent but is applied to the surface of the balloon catheter. The "drug coating" in this product is a mixture or composite of specific components, which may include: (1) Active drugs: The core components that play a therapeutic role, specifically flavonoid drugs.

[0026] (2) Excipients (or excipients / additives): components used to carry drugs, assist in coating formation, or control drug release.

[0027] The aforementioned active drugs (flavonoids) function to provide therapeutic effects. Based on their chemical structural properties, flavonoids can exert a dual effect of anti-cell proliferation (inhibiting vascular endothelial proliferation) and anti-inflammation when the balloon dilates and contacts the blood vessel wall.

[0028] The function of the excipients mentioned above is to ensure a uniform drug coating, minimize drug loss during delivery, promote drug penetration into the arterial wall, and achieve efficient drug release.

[0029] The aforementioned drug coating, acting as a carrier for drug delivery, comes into contact with the blood vessel wall during balloon dilation, transferring the drug to the vascular endothelium.

[0030] The basic working principle of this product is to deliver drugs to the lesion site using a balloon catheter, and release the drugs by expanding the balloon to bring the coating into contact with the blood vessel wall.

[0031] Flavonoids (such as baicalein) contain specific functional groups (such as ketone and hydroxyl groups) in their chemical structure, which can inhibit kinase activity. For example, the ketone group of baicalein forms a hydrogen bond with vascular endothelial growth factor receptor 2 (VEGFR2), preventing endothelial cell proliferation; or it inhibits HIF-1α-mediated VEGF expression by scavenging reactive oxygen species (ROS) through its catechol structure. Luteolin and other flavonoids inhibit cell mitosis by blocking the PI3K / Akt-dependent pathway or inhibiting p70 S6 kinase phosphorylation.

[0032] Flavonoids can regulate the Toll-like receptor (TLR) / NFκB axis, inhibit the activity of cyclooxygenase and lipoxygenase, and reduce the formation of inflammatory metabolites, thereby preventing inflammation.

[0033] Flavonoid drugs (such as baicalein, chemically known as 5,6,7-trihydroxyflavone) typically possess specific hydrophilic groups (e.g., multiple phenolic hydroxyl groups), which gives them a certain degree of hydrophilicity (e.g., baicalein has a logP of 2.58, and luteolin has 2.28), facilitating rapid dissolution and release in the bloodstream. A partition coefficient (logP) between 1.5 and 4.0, while satisfying a molecular weight range of 250–920 μg / mol, is suitable for balloon catheters. If the drug's logP is too low, acylation or alkylation modifications can increase the logP value to meet the appropriate range. If the drug's logP is too high, sulfonation or polyethylene glycol chain modification can lower the logP, thereby directionally adjusting the hydrophilicity to the suitable range. If the logP is below the above range, the hydrophilicity is too high, resulting in rapid dissolution in the blood and increased drug coating delivery loss; if the logP is above the above range, the lipophilicity is too high, leading to poor burst release and low drug utilization at the target site. If the molecular weight is greater than the above range, the number of moles of drug loaded on the balloon surface decreases, resulting in insufficient vascular permeability; if the molecular weight is less than the above range, the drug is cleared by the kidneys too quickly, making it difficult to maintain an effective therapeutic concentration.

[0034] Drug-coated balloon catheters using flavonoids as the active pharmaceutical ingredient (API) exhibit lower cytotoxicity compared to traditional drugs (such as paclitaxel), avoiding complications such as endothelial cell apoptosis, late thrombosis, and arrhythmia caused by high drug concentrations. Furthermore, flavonoids (such as baicalein and luteolin) have better water solubility and smaller molecular weights (e.g., baicalein 270 g / mol vs. paclitaxel 864 g / mol) compared to paclitaxel (logP 3.54) or rapamycin, facilitating the formation of nanoscale microcrystals. This allows for faster drug dissolution and absorption by vascular endothelial cells during the brief contact between the balloon and the vessel wall (e.g., 30-45 seconds), improving bioavailability and reducing drug residues after delivery. Moreover, this approach overcomes the limitation of existing drug-coated balloons with only anti-proliferative effects; flavonoids endow the product with dual therapeutic effects of anti-proliferation and anti-inflammation, which helps reduce the incidence of restenosis.

[0035] In some embodiments, the flavonoid drugs include at least one of baicalin, luteolin, apigenin, kaempferol, myricetin, wogonin, glycyrrhizin, hesperidin, dihydroquercetin, dihydromocarboxin, morin, quercetin, stigmosiderin, puerarin, daidzein, daidzein, ginkgoside, neosafflower glycoside, safflower glycoside, thiocyanate, anthocyanin, quercetin, kaempferol, safflower enzyme, and Ophiopogon japonicus isoflavone A, and derivatives thereof with chemically modified functional groups.

[0036] In some embodiments, the flavonoids include baicalein and / or luteolin.

[0037] Furthermore, the molecular weight of flavonoid drugs ranges from 250 g / mol to 920 g / mol. For example, they can be 250 g / mol, 324 g / mol, 398 g / mol, 473 g / mol, 547 g / mol, 622 g / mol, 696 g / mol, 771 g / mol, 845 g / mol, 920 g / mol, etc.

[0038] Furthermore, the partition coefficient logP of flavonoid drugs ranges from 1.5 to 4.0. For example, it can be 1.5, 1.8, 2.1, 2.3, 2.6, 2.9, 3.2, 3.4, 3.7, 4.0, etc.

[0039] Furthermore, the dosage concentration of flavonoids was 2.0 μg / mm. 2 ~3.5μg / mm 2 For example, it can be 2.00 μg / mm. 2 2.17 μg / mm 2 2.33 μg / mm 2 2.50 μg / mm 2 2.67 μg / mm 2 2.83 μg / mm 2 3.00 μg / mm 2 3.17 μg / mm 2 3.33 μg / mm 2 3.50 μg / mm 2Etc. The preferred flavonoids mentioned above are baicalin and / or luteolin. It should be noted that baicalin exhibits significant anti-proliferative activity among flavonoids. As the only flavonoid that can simultaneously inhibit NLRP3 inflammasome assembly and 5-lipoxygenase (5-LOX), baicalin comprehensively blocks IL-1β and leukotrienes production. Baicalin has a long-lasting effect, its quinone structure circulating in the vascular wall redox cycle, and a longer half-life compared to other flavonoids, providing sustained inhibition of proliferation with a single dose. Luteolin binds firmly to its target TGF-β1 protein, exhibiting a strong effect in preventing vascular wall thickening. Luteolin can bind to plaque-specific SR-B1 receptors, actively recognizing vascular lesion areas and accumulating higher drug concentrations at the lesion site, allowing the drug to penetrate deep into the vascular wall.

[0040] The listed drugs (such as baicalein and luteolin) all belong to the flavonoid class of compounds, and their molecular structures usually contain a ketone group and multiple hydroxyl groups (such as baicalein, which is a 5,6,7-trihydroxyflavone).

[0041] These specific drugs exert their anti-vascular endothelial cell proliferation effects through their chemical structures. For example, baicalin inhibits HIF-1α-mediated VEGF expression by forming hydrogen bonds with vascular endothelial growth factor receptor 2 (VEGFR2) via its ketone group or by scavenging reactive oxygen species (ROS) through its catechol structure; luteolin inhibits cell mitosis by blocking the PI3K / Akt pathway and inhibiting p70 S6 kinase phosphorylation. These drugs also have the ability to modulate the Toll-like receptor (TLR) / NFκB axis, inhibiting cyclooxygenase and lipoxygenase activity, thereby reducing the formation of inflammatory metabolites.

[0042] In some embodiments, the excipients include at least one selected from iopromide, iohexol, urea, shellac, shellac ammonium salt, cholesterol, polydopamine, polysorbate, polyethylene glycol, polylactic acid, gallate, polylactic-co-glycolic acid, hydroxypropyl-β-cyclodextrin, chitosan, polyethylene oxide, triglycerides, poloxamer, magnesium stearate, butylated hydroxytoluene, polyvinylpyrrolidone, phospholipid bilayer, and PLGA-PEG.

[0043] The listed excipients (such as PLGA-PEG, iopromide, urea, etc.) bind to the aforementioned flavonoid drugs through intermolecular forces such as hydrogen bonds, π-π stacking, or electrostatic adsorption, achieving drug loading and dispersion. Formulation testing identifies excipients with strong interactions with baicalein, enhancing the stability of the drug coating. The amphiphilic block polymer poly(lactic-co-glycolic acid)-polyethylene glycol (PLGA-PEG) has two binding sites with baicalein. The ester bonds of PLGA form hydrogen bonds with the hydroxyl groups of baicalein, while the ether bonds of PEG can also form hydrogen bonds with baicalein. The hydrophobic segments of PLGA interact with hydrophobic balloon surface materials (such as PEBAX) through van der Waals forces.

[0044] Based on the aforementioned intermolecular forces, the PLGA-PEG excipient significantly enhances the encapsulation efficiency of baicalein compared to iopromide, resulting in a tighter interaction between the excipient and the drug and the fabrication of a uniform drug coating. Furthermore, PLGA and PEG materials exhibit good biocompatibility, making them suitable for cardiovascular medical devices and reducing the risk of adverse reactions caused by the materials themselves. In addition, PLGA-PEG-loaded baicalein exhibits a longer retention time on the surface of vascular endothelial cells than iopromide because PEG forms a hydration layer within the blood vessel, leading to a hydration layer-mediated adhesion effect with the vascular endothelium. This enhances the adhesion of the drug coating, surpassing the physical adsorption of traditional coatings on the vascular endothelial surface, thus prolonging the retention time and improving in vivo drug absorption.

[0045] The function of excipients is to ensure uniform coating and to assist in the transfer of drugs from the balloon surface to the blood vessel wall, reducing losses during delivery.

[0046] The specific drugs and excipients (or combinations thereof) provided in this embodiment, in terms of physicochemical properties, compared with paclitaxel (logP 3.54, molecular weight 864 g / mol), have more suitable hydrophilicity (e.g., baicalein logP 2.58, luteolin logP 2.28) and smaller molecular weight (e.g., baicalein 270 g / mol, luteolin 286 g / mol). The concentration of these drugs (g / mol) not only improves their solubility in blood and enhances their burst release from the balloon surface, but also facilitates the formation of nanoscale microcrystals, thereby significantly improving the bioavailability and absorption rate of vascular endothelial cells. Secondly, in terms of safety, these drugs have lower cytotoxicity than paclitaxel, effectively reducing the risk of endothelial cell apoptosis and late thrombosis caused by drug toxicity. Thirdly, in terms of cost, the extraction or synthesis costs of these drugs, which are mainly derived from natural medicinal plants, are lower than those of some complex chemically synthesized drugs. Finally, the combination with excipients with good biocompatibility (such as PLGA-PEG) further enhances the stability of the drug coating and promotes efficient penetration and sustained release of the drug into the vascular wall.

[0047] In some embodiments, the excipient is the amphiphilic block polymer PLGA-PEG. Preferably, the PLGA has a molecular weight of 15 kDa to 25 kDa; for example, it can be 15 kDa, 16 kDa, 17 kDa, 18 kDa, 19 kDa, 20 kDa, 21 kDa, 22 kDa, 23 kDa, 24 kDa, 25 kDa, etc. Preferably, the PEG has a molecular weight of 3 kDa to 4 kDa; for example, it can be 3 kDa, 3.2 kDa, 3.5 kDa, 3.8 kDa, 4 kDa, etc.

[0048] The excipients mentioned above are limited to the amphiphilic block polymer PLGA-PEG. This polymer is composed of two segments: PLGA (polylactic-co-glycolic acid) and PEG (polyethylene glycol). "Amphiphilic block" means that the molecular structure contains both a hydrophilic portion (PEG) and a hydrophobic portion (PLGA).

[0049] Furthermore, PLGA-PEG can form hydrogen bonds with the flavonoid drug through ester and ether bonds.

[0050] The excipient molecules described above provide specific chemical bonds as binding sites. Specifically, the ester bonds in the PLGA chain form hydrogen bonds with flavonoid drug molecules (such as the hydroxyl groups of baicalin); at the same time, the ether bonds in the PEG chain can also form hydrogen bonds with flavonoid drugs.

[0051] This double hydrogen bonding effect of "ester bond + ether bond" allows the excipient to tightly encapsulate or adsorb the active drug, enhancing the compatibility between the drug and the excipient.

[0052] Furthermore, the hydrophobic segments of PLGA bind to the surface of the balloon catheter via van der Waals forces.

[0053] PLGA segments are hydrophobic. Since the surface material of the balloon catheter (usually nylon or PEBAX, etc.) is also hydrophobic, the hydrophobic segments of PLGA interact with the balloon surface through van der Waals forces, thereby anchoring the coating onto the balloon catheter.

[0054] In this embodiment, PLGA-PEG is used as the excipient and, based on the above-mentioned binding principle, compared to traditional excipients (such as iopromide, which relies solely on weak van der Waals forces), this approach significantly enhances the encapsulation efficiency and binding force of the excipient for flavonoid drugs by introducing strongly interacting hydrogen bonds. This results in a more uniform and dense drug coating, making it less prone to detachment during delivery.

[0055] In some embodiments, the mass ratio of the active pharmaceutical ingredient to the excipient is from 1:0.05 to 1:12. For example, the mass ratio can be 1:0.05, 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:12, etc.

[0056] In some embodiments, the active drug is present in the form of nanoscale microcrystals in the drug coating.

[0057] In this embodiment, the active drug is defined as existing in the coating in the form of nanoscale microcrystals. This means that after the coating dries, the drug molecules do not amorphously accumulate or crystallize into large particles, but rather form a tiny crystalline structure with a size at the nanoscale.

[0058] In some embodiments, the mass density of the drug in the drug coating is 0.5 µg / mm².2 ~6µg / mm 2 For example, it can be 0.5µg / mm. 2 1µg / mm 2 2µg / mm 2 3µg / mm 2 4µg / mm 2 5µg / mm 2 6µg / mm 2 etc.

[0059] The thickness of the drug coating ranges from 3µm to 12µm. For example, it can be 3µm, 4µm, 5µm, 6µm, 7µm, 8µm, 9µm, 10µm, 11µm, 12µm, etc.

[0060] It should be noted that flavonoids (such as baicalein with a molecular weight of 270 g / mol and luteolin with a molecular weight of 286 g / mol) have smaller molecular weights compared to traditional drugs (such as paclitaxel with a molecular weight of 864 g / mol). This small molecule characteristic makes them easier to crystallize into smaller nanoscale crystals during coating preparation. Flavonoids also have suitable hydrophilicity (e.g., baicalein logP is 2.58 and luteolin logP is 2.28). Combined with the high specific surface area of ​​the aforementioned nanoscale crystals, the drugs can rapidly dissolve and be burst-released from the coating during the brief window of blood flow occlusion during balloon dilation (typically 30 to 45 seconds).

[0061] In some implementations, the balloon catheter can be a standard balloon catheter used to treat cardiovascular diseases. It can also be a specialized balloon catheter, such as a cutting balloon catheter, a notched balloon catheter, a spinous process balloon catheter, a mastoid balloon catheter, or an infusion balloon catheter.

[0062] The aforementioned specialized balloon catheters can be made by incorporating microblades or protrusions on the surface of a conventional balloon catheter, which physically cut or score the vessel wall or plaque during dilation. For example, cutting and scoring balloon catheters can create microchannels 100-200 µm deep in tissue, thereby increasing the depth of drug penetration. At the moment of cutting, the drug is physically compressed into the tissue, facilitating better absorption and diffusion.

[0063] In some embodiments, the balloon catheter is an infusion balloon catheter; such balloon catheters, through a specific flow channel design, allow blood to still flow distally when the balloon inflates and expands to dilate the blocked blood vessel.

[0064] The infusion balloon catheter includes an infusion balloon and a support catheter.

[0065] Preferably, the effective perfusion length of the perfusion balloon is 10mm to 30mm; for example, it can be 10mm, 20mm, 30mm, etc.

[0066] Furthermore, the infusion balloon has a dual-lumen structure, including a separate infusion lumen (for blood flow) and an expansion lumen (for inflating the balloon).

[0067] Furthermore, the infusion cavity has symmetrically distributed side holes; Furthermore, the side holes of the infusion cavity include four proximal holes and four distal holes; Furthermore, the diameter of the side holes in the infusion chamber is 0.3mm to 0.5mm. For example, it can be 0.3mm, 0.4mm, 0.5mm, etc.

[0068] As the balloon inflates and adheres to the vessel wall, proximal blood enters the perfusion chamber through the proximal side port, bypasses the balloon's occlusion segment, and flows out through the distal side port. This design maintains distal blood flow perfusion, preventing myocardial ischemia and hypoxia. Because it solves the problem of myocardial ischemia caused by blood flow obstruction, the balloon can maintain its inflated state within the vessel for a prolonged period. Compared to traditional balloons that only contact the vessel wall for 30 seconds to 1 minute, the drug-eluting coating of the perfusion balloon can maintain contact with the vascular endothelium for 3 to 10 minutes.

[0069] By extending the contact time between the drug and the blood vessel wall from the traditional <1 minute to 3-10 minutes, the duration of drug action can be prolonged by more than ten times. This maximizes the absorption rate of the drug by vascular endothelial cells, reaching over 85%-95%, significantly superior to traditional balloons (commercially available products have a drug transfer rate of only 50%-85%). The dual-lumen and side-port design ensures maintained myocardial oxygen supply during prolonged drug administration, enhancing not only efficacy but also ensuring safety during the procedure.

[0070] In some implementations, the balloon catheter is a cutting balloon catheter.

[0071] Furthermore, the product integrates a microblade system on the surface of the balloon. Specifically, the cutting balloon catheter includes the balloon and 2 to 10 microblades; for example, it can be 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.

[0072] Furthermore, the microblade is made of nickel-titanium alloy or stainless steel.

[0073] Furthermore, the height of the microblade is 0.1mm to 0.3mm; for example, it can be 0.1mm, 0.2mm, 0.3mm, etc.

[0074] Furthermore, the length of the microblade is 5mm to 80mm; for example, it can be 5mm, 10mm, 15mm, 20mm, 30mm, 40mm, 50mm, 60mm, 70mm, 80mm, etc.

[0075] Furthermore, the microblade is the same length as the working section of the balloon; this means that the cutting range of the blade is perfectly matched with the effective length of the balloon dilation for treatment, ensuring uniform physical intervention and drug release throughout the entire treatment area.

[0076] Furthermore, the diameter of the balloon is 1.0mm to 8.0mm; for example, it can be 1.0mm, 2.0mm, 3.0mm, 4.0mm, 5.0mm, 6.0mm, 7.0mm, 8.0mm, etc.

[0077] Furthermore, the length of the balloon ranges from 5mm to 80mm. For example, it can be 5mm, 10mm, 20mm, 30mm, 40mm, 50mm, 60mm, 70mm, 80mm, etc.

[0078] Through the aforementioned specific structural constraints, an integrated cutting-and-drug delivery treatment mode is formed. The microchannels created by the blade act as drug "reservoirs," not only increasing the depth of drug penetration but also significantly reducing drug loss during delivery and expansion. By using physical means (cutting and squeezing) to assist the absorption of chemical drugs, the drugs can enter vascular tissue more quickly and deeply, achieving highly efficient drug release, especially during the peak period of smooth muscle cell proliferation.

[0079] refer to Figure 1 This application also provides a method for preparing a drug-coated balloon catheter as described in any of the foregoing embodiments, comprising: Step S1: Prepare a solution containing flavonoids and excipients.

[0080] This step refers to dissolving or dispersing the active pharmaceutical ingredient and excipient ingredients in a solvent to prepare a liquid mixture suitable for subsequent coating processes.

[0081] Specifically, flavonoid drugs (such as baicalein or luteolin) can be selected as solutes, and excipients (such as PLGA-PEG or urea) can be selected as carrier materials.

[0082] One or more of the following solvents can be used: ethanol, isopropanol, acetone, ethyl acetate, acetonitrile, diethyl ether, methanol, dichloromethane, chloroform, tetrahydrofuran, and dimethyl sulfoxide.

[0083] The drug can be mixed with the solvent, stirred, and then dissolved by ultrasound and filtered to obtain solution 1; the excipient can be mixed with the solvent, stirred, and then dissolved by ultrasound at 25~40℃ and filtered to obtain solution 2; finally, solution 1 and solution 2 can be mixed and stirred evenly.

[0084] This step ensures uniform mixing of the drug and excipients at the molecular level, laying the foundation for the subsequent formation of a uniform and stable coating.

[0085] Step S2: Coat the balloon catheter surface with the solution.

[0086] This step refers to using physical or mechanical means to transfer and attach the mixed solution prepared in step one to the surface of the balloon catheter.

[0087] Specifically, ultrasonic atomization spraying, electrostatic spraying, or dip coating processes can be used.

[0088] The specific parameters for ultrasonic atomization spraying may include (but are not limited to) the following parameters: The ultrasonic frequency is controlled at 80~120kHz, and the atomizing air pressure is controlled at 0.2~0.8bar. During the spraying process, the balloon rotation speed is set to 500~1000rpm, the nozzle movement speed is set to 1~10mm / s, and the spraying distance is controlled at 10~40mm.

[0089] Through the aforementioned precisely controlled process (especially ultrasonic spraying), the solution can be uniformly covered on the surface of the balloon, and the coating thickness can be controlled within the range of 3~12µm, ensuring the uniformity of the coating thickness.

[0090] Step S3: Dry the coated balloon catheter to obtain the drug-coated balloon catheter.

[0091] This step refers to removing volatile solvents from the coating under specific environmental conditions, allowing the liquid coating to solidify and form the final solid drug coating.

[0092] Specifically, the coated balloon can be treated at a temperature of 25℃~45℃ (40℃ in practice). The drying time is maintained at 0.5 hours~3 hours (30 min~3 hours), thus finally obtaining a balloon catheter with a solid drug coating on the surface. The drug can form small nanoscale microcrystals in the coating.

[0093] This drying process helps baicalin / luteolin form nanoscale microcrystals, which is beneficial for the bioavailability and rapid absorption of vascular endothelial cells. Proper drying treatment ensures good affinity between the drug coating and the balloon surface material, less shedding during folding and squeezing, fewer particle shedding, and less drug residue after delivery.

[0094] Furthermore, the drying temperature for the drying process is 25℃~45℃; for example, it can be 25℃, 30℃, 35℃, 40℃, 45℃, etc.

[0095] Furthermore, the drying time for the drying process is 0.5 hours to 3 hours. For example, it can be 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, etc.

[0096] This application also provides the application of a drug-coated balloon catheter as described in any of the foregoing embodiments in the preparation of a medical device for treating vascular diseases.

[0097] In some implementations, vascular disease includes at least one of primary small vessel disease, in-stent restenosis, bifurcation disease, coronary artery disease, and peripheral vascular disease.

[0098] Based on the technical solution of this application, the drug-coated balloon catheter provided by this invention has broad application value in the preparation of medical devices for treating vascular diseases. Specifically, this drug-coated balloon catheter is suitable for interventional treatment of coronary artery disease and peripheral vascular disease, and shows significant advantages, especially in the treatment of complex clinical indications such as primary small vessel disease (SVD), in-stent restenosis (ISR), and bifurcation lesions. By releasing flavonoid drugs through balloon dilation, this device utilizes the dual anti-proliferative and anti-inflammatory mechanisms of the drugs to effectively inhibit the proliferation of vascular smooth muscle cells and inflammatory responses while clearing blood vessels, thereby reducing the incidence of restenosis and realizing the treatment concept of "intervention without implantation," avoiding the long-term risks associated with permanent metal implants.

[0099] The present invention will be further illustrated below with specific embodiments. However, it should be understood that these embodiments are merely for the purpose of more detailed illustration and should not be construed as limiting the present invention in any way.

[0100] Example 1 In this embodiment, a balloon catheter is prepared.

[0101] Experimental methods: 1. Raw material composition: Active drug: baicalin; Excipients: Amphiphilic block polymer PLGA (20kDa)-PEG (3.4kDa); Formulation ratio: The mass ratio of drug to excipient is 1:2; 2. Preparation steps: (1) Solution preparation: Solution 1 (drug solution): Mix baicalein drug with solvent, stir, sonicate to dissolve, and filter to obtain a clear solution.

[0102] Solution 2 (Excipient Solution): The PLGA-PEG excipient was mixed and stirred with the solvent, dissolved by ultrasonication at 40°C, and filtered to obtain a clear solution.

[0103] Mixing: Mix solution 1 and solution 2 in the same mass ratio of 1:2 as described above, stir until homogeneous, and obtain the spraying solution.

[0104] (2) Coating process (ultrasonic atomization spraying): The above mixed solution is loaded into an ultrasonic atomizing spraying device.

[0105] Spraying parameter settings: ultrasonic frequency set to 120kHz, atomization pressure set to 0.5bar.

[0106] Balloon motion parameters: Balloon rotation speed is set to 600 rpm, nozzle movement speed is set to 50 mm / s, and spraying distance is controlled at 20 mm.

[0107] (3) Drying treatment: The sprayed balloons are left to dry at 40°C for 1 hour to allow the solvent to evaporate, thus obtaining the final drug balloons.

[0108] 3. Preparation results: Drug coating thickness: The obtained drug coating thickness is 12µm.

[0109] Examples 2-16 In the above embodiments, a balloon catheter was prepared.

[0110] The experimental methods are basically the same as those in Example 1, with differences shown in Table 1.

[0111] Comparative Example 1 In this comparative example, a balloon catheter was prepared.

[0112] The experimental methods are basically the same as those in Example 1, with differences shown in Table 1.

[0113] Table 1. Key parameters in the examples and comparative examples

[0114] Test Experiment 1. Testing method: (1) Uniformity of the thickness of the drug coating after spraying: 3~15µm.

[0115] (2) Determine the amount of drug in the medium in the in vitro experiment by HPLC or UV method. The drug achieves a release efficiency of 70% to 90%.

[0116] (3) The drug residue rate after drug delivery by the drug balloon was quantified by HPLC.

[0117] (4) Use a laser particle size analyzer to measure the amount of particles detached (>50μm) to prevent vascular embolism. Use a drug-eluting balloon with a specification of 3.0mm x 20mm.

[0118] (5) Flavonoids are less toxic than paclitaxel.

[0119] (6) The effect of flavonoids on inhibiting the proliferation of smooth muscle cells in vitro.

[0120] (7) Clinical trials compared the anti-inflammatory effects of baicalin and control paclitaxel drug capsules.

[0121] 2. Test Results:

[0122] Cell experiments, using live cell counting methods, determined that paclitaxel had a greater killing effect on live cells when treated with the same concentrations of flavonoids and paclitaxel. Human aortic endothelial cells were treated with baicalin and paclitaxel respectively, and the cell viability was determined. With 100% viability of untreated endothelial cells as a control, the viability of endothelial cells treated with baicalin was 95.2%, while the viability of paclitaxel-treated endothelial cells was 65.4%.

[0123] To test the effect of flavonoids on inhibiting smooth muscle cell proliferation in vitro, human aortic smooth muscle cells were treated with 10 µM baicalein or luteolin, and cell viability was detected. Baicalein inhibited smooth muscle cell proliferation by 82.6%, while luteolin inhibited smooth muscle cell proliferation by 75.5%.

[0124] This prospective, randomized controlled clinical trial enrolled 120 patients with stable coronary artery disease and vascular inflammation. Preoperative vascular inflammation markers met the criteria of high-sensitivity C-reactive protein (hs-CRP) ≥3 mg / L or interleukin-6 (IL-6) ≥5 pg / mL. Patients were randomly assigned to either the baicalein-treated balloon catheter group (drug loading 3.2 μg / mm²) or the paclitaxel-treated balloon catheter group (drug loading 3 μg / mm²). All patients underwent testing before the procedure, 24 hours post-procedure, and one month post-procedure. Quantitative assessment of vascular endothelial inflammation was performed using immunoturbidimetry to detect serum hs-CRP and chemiluminescence immunoassay to detect serum IL-6. Clinically, the biochemical markers of vascular inflammation indicate that the baicalein-treated balloon catheter has significant therapeutic efficacy in treating cardiovascular inflammation, unlike the paclitaxel-treated balloon catheter, which only has a single anti-proliferative effect.

[0125]

[0126] 3. Analysis: Tests showed that the coating thickness of drug-eluting balloons prepared with baicalein or luteolin and excipients ranged from 7-15 µm, with a drug release rate of 77-90% as determined by high-performance liquid chromatography (HPLC), higher than the paclitaxel-based control balloon. After delivery via the balloon catheter, the drug residue rate on the balloon surface was 5%-14%, superior to the paclitaxel-based control balloon. Compared to paclitaxel in traditional drug-eluting balloons, baicalein exhibited lower toxicity to vascular endothelial cells, resulting in higher product safety as a drug-eluting balloon. Both flavonoids, baicalein and luteolin, showed significant inhibitory effects on smooth muscle cells. Baicalein-based drug-eluting balloon catheters demonstrated significant inhibitory effects on vascular inflammation in clinical trials, significantly different from the paclitaxel-based control group. These test results confirm the technological advantages of flavonoid-based drug-eluting balloons.

[0127] 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. A drug-coated balloon catheter, characterized in that, Includes a balloon catheter and a drug coating disposed on the surface of the balloon catheter; The drug coating comprises an active drug and excipients; The active drug is a flavonoid.

2. The drug-coated balloon catheter as described in claim 1, characterized in that, The flavonoid drugs include at least one of the following: baicalin, luteolin, apigenin, kaempferol, myricetin, wogonin, glycyrrhizin, hesperidin, dihydroquercetin, dihydromocarboxin, morin, quercetin, stigmosiderin, puerarin, daidzein, daidzein, ginkgolide, neostigmine, stigmosiderin, thiocyanate, anthocyanin, quercetin, kaempferol, safflower enzyme, and Ophiopogon japonicus isoflavone A, and its derivatives with chemically modified functional groups; and / or, The excipients include at least one of iopromide, iohexol, urea, shellac, shellac ammonium salt, cholesterol, polydopamine, polysorbate, polyethylene glycol, polylactic acid, gallate, polylactic-co-glycolic acid, hydroxypropyl-β-cyclodextrin, chitosan, polyethylene oxide, triglycerides, poloxamer, magnesium stearate, butylated hydroxytoluene, polyvinylpyrrolidone, phospholipid bilayer, and PLGA-PEG.

3. The drug-coated balloon catheter according to claim 1, characterized in that... The molecular weight of the flavonoid drug is 250 g / mol to 920 g / mol; Preferably, the partition coefficient logP of the flavonoid drug is 1.5 to 4.0; Preferably, the dosage concentration of the flavonoid drug is 2.0 μg / mm. 2 ~3.5μg / mm 2 .

4. The drug-coated balloon catheter as described in claim 1, characterized in that, The flavonoid drugs are baicalin and / or luteolin; Preferably, the partition coefficient logP of the flavonoid drug is 2.2 to 2.

6.

5. The drug-coated balloon catheter according to claim 1, characterized in that, The excipient is PLGA-PEG; Preferably, the molecular weight of PLGA is 15 kDa to 25 kDa; Preferably, the molecular weight of PEG is 3 kDa to 4 kDa.

6. The drug-coated balloon catheter as described in claim 1, characterized in that, The mass ratio of the active pharmaceutical ingredient to the excipient is 1:0.05 to 1:12; preferably, the drug / excipient mass ratio is 1:1.5 to 1:4; and / or, The active drug exists in the drug coating in the form of nanoscale microcrystals, with an average particle size of 50-500 nm and an aspect ratio ≤3:1; and / or, The mass density of the drug in the drug coating is 0.5 µg / mm². 2 ~6µg / mm 2 ; and / or, The thickness of the drug coating is 3µm to 15µm.

7. The drug-coated balloon catheter as described in claim 1, characterized in that, The balloon catheter is a cutting balloon catheter, a notched balloon catheter, a spinous process balloon catheter, a mastoid process balloon catheter, or an infusion balloon catheter.

8. The drug-coated balloon catheter as described in claim 1, characterized in that, The balloon catheter is an infusion balloon catheter; Preferably, the infusion balloon catheter includes an infusion balloon and a support catheter. The effective infusion length of the infusion balloon is 10mm~30mm; Preferably, the support catheter has a dual-lumen structure, including an independent irrigation lumen and a dilation lumen; Preferably, the infusion cavity has symmetrically distributed side holes; Preferably, the side holes of the infusion cavity include four proximal holes and four distal holes; Preferably, the diameter of the side hole of the infusion cavity is 0.3mm to 0.5mm.

9. The drug-coated balloon catheter as described in claim 1, characterized in that, The balloon catheter is a cutting balloon catheter; Preferably, the cutting balloon catheter includes a balloon and 2 to 10 microblades; Preferably, the microblade is made of nickel-titanium alloy or stainless steel; Preferably, the height of the microblade is 0.1mm to 0.3mm; Preferably, the length of the microblade is 5mm to 80mm; Preferably, the microblade is the same length as the working section of the balloon; Preferably, the diameter of the balloon is 1.0 mm to 8.0 mm; Preferably, the length of the balloon is 5mm to 80mm.

10. A method for preparing a drug-coated balloon catheter as described in any one of claims 1-9, characterized in that, include: Prepare solutions containing flavonoids and excipients; The solution is coated onto the surface of the balloon catheter; The coated balloon catheter is dried to obtain the drug-coated balloon catheter. Preferably, the drying temperature of the drying process is 25℃~45℃; Preferably, the drying time for the drying process is 0.5 hours to 3 hours.

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