Drug balloon catheter and method of making same

Abstract

The application relates to a drug balloon catheter and a preparation method thereof. The drug balloon catheter comprises a balloon, a plurality of first coating layers and a plurality of second coating layers. The plurality of first coating layers and the plurality of second coating layers are arranged on different regions of the surface of the balloon, and the first coating layers and the second coating layers are alternately and adjacently arranged. The first coating layers contain first efficacy substances, the second coating layers contain second efficacy substances, the first efficacy substances and the second efficacy substances are respectively selected from any one or more of paclitaxel and derivatives thereof, paclitaxel and derivative microspheres, rapamycin and derivatives thereof and rapamycin and derivative microspheres, and the first efficacy substances and the second efficacy substances are not completely the same. The drug balloon catheter can take into account the immediate effect and long-term effect of the drug.

Description

Technical Field

[0001] This application relates to the field of medical device technology, and in particular to a drug-eluting balloon catheter and its preparation method. Background Technology

[0002] Drug-eluting balloon catheters are therapeutic balloon drug delivery technologies developed based on interventional techniques such as balloon angioplasty. The balloon surface is coated with cell-inhibiting or cytotoxic drugs. When the balloon reaches the lesion site and the vessel wall, it inflates. Upon contact with the vessel intima, the drug is rapidly released and transported into the local vessel wall, inhibiting intimal hyperplasia and preventing restenosis after interventional procedures. The drugs chosen for drug-eluting balloon catheters are mostly paclitaxel and its derivatives, and rapamycin (sirolimus) and its derivatives. Paclitaxel and its derivative balloon catheters have a rapid drug release rate, affecting long-term efficacy, and have a smaller safety margin; high local concentrations may lead to vessel wall inflammation or necrosis. Rapamycin and its derivative balloon catheters have more controllable safety, but their transport and absorption rates in tissues are lower, affecting immediate efficacy. Summary of the Invention

[0003] Therefore, it is necessary to provide a drug-eluting balloon catheter and its preparation method to balance the immediate and long-term efficacy of the drug.

[0004] One aspect of this application provides a drug-eluting balloon catheter, comprising a balloon, a plurality of first coatings, and a plurality of second coatings, wherein the plurality of first coatings and the plurality of second coatings are disposed in different regions on the surface of the balloon, and the first coatings and the second coatings are alternately and adjacently disposed; the first coatings contain a first active ingredient, and the second coatings contain a second active ingredient, wherein the first active ingredient and the second active ingredient are selected from any one or more of paclitaxel and its derivatives, paclitaxel and its derivative microspheres, rapamycin and its derivatives, and rapamycin and its derivative microspheres, and the first active ingredient and the second active ingredient are not completely identical.

[0005] This application achieves both immediate and long-term efficacy of a drug through two different drugs: paclitaxel and its derivatives, and rapamycin and its derivatives; or, through two different drug forms: pure drug and drug microspheres, it achieves both immediate and long-term efficacy of a drug.

[0006] Specifically, this application alternately arranges coatings containing different types of drugs, namely, coatings containing paclitaxel and its derivatives and coatings containing rapamycin and its derivatives, on the surface of the balloon. Utilizing the different mechanisms of action of paclitaxel and its derivatives in arresting the smooth muscle cell cycle at the G2 / M phase and rapamycin-paclitaxel and its derivatives in arresting the cell cycle at the G1 phase, the anti-endometrial hyperplasia effect is synergistically enhanced, while reducing the local exposure concentration of paclitaxel and its derivatives alone, improving safety performance, and achieving both immediate and long-term efficacy. Furthermore, this application alternately arranges coatings containing only the drug and coatings containing drug microspheres on the surface of the balloon. The immediate therapeutic effect is achieved by utilizing the characteristic of rapid drug release during balloon expansion of the drug-only coating, while the long-term efficacy is achieved by utilizing the characteristic of slow degradation and drug release of the drug-containing microsphere coating. The two work together synergistically to achieve a long-term inhibitory effect on smooth muscle cell proliferation.

[0007] In some embodiments, the first coating and the second coating are arranged alternately along the surface of the balloon, and the tilt angle of the first coating and the second coating is α, where 0°≤α<180°;

[0008] Optionally, the first coating and the second coating are arranged alternately along the axial direction of the balloon, and the tilt angle α of the first coating and the second coating is 90°.

[0009] Optionally, the first coating and the second coating are arranged alternately along the circumferential direction of the balloon, and the tilt angle α of the first coating and the second coating is 0°.

[0010] In some embodiments, the first coating or the second coating satisfies at least one of the following conditions:

[0011] (1) The unfolded plane is rectangular;

[0012] (2) Width is 1mm~200mm;

[0013] (3) The thickness is 0.005mm~0.5mm;

[0014] (4) The width ratio of the first coating to the second coating is 1:6 to 6:1;

[0015] (5) The width of the blank area between adjacent first and second coatings is 0~5mm.

[0016] In some embodiments, the first coating or the second coating satisfies at least one of the following conditions:

[0017] (1) Width is 10mm~40mm;

[0018] (2) The thickness is 0.02mm~0.1mm;

[0019] (3) The width ratio of the first coating to the second coating is 1:4 to 4:1;

[0020] (4) The dosage density of the drug in the first coating is 0.5 μg / mm. 2 ~5μg / mm 2 ;

[0021] (5) The dosage density of the drug in the second coating is 0.5 μg / mm². 2 ~5μg / mm 2 .

[0022] In some embodiments, the first active ingredient and the second active ingredient are selected from any two of paclitaxel and its derivatives, paclitaxel and its derivative microspheres, rapamycin and its derivatives, and rapamycin and its derivative microspheres.

[0023] Optionally, the first active ingredient is rapamycin and its derivatives, and the second active ingredient is rapamycin and its derivative microspheres;

[0024] Optionally, the first active ingredient is paclitaxel and its derivatives, and the second active ingredient is paclitaxel and its derivative microspheres.

[0025] In some embodiments, the first active ingredient is selected from any one or more of paclitaxel and its derivatives and paclitaxel and its derivative microspheres, and the second active ingredient is selected from any one or more of rapamycin and its derivatives and rapamycin and its derivative microspheres.

[0026] A second aspect of this application provides a method for preparing a drug-eluting balloon catheter as described in the first aspect, comprising the following steps:

[0027] The first slurry containing the first functional substance and the second slurry containing the second functional substance are alternately coated on different areas of the balloon surface and then dried to obtain the balloon catheter.

[0028] In some embodiments, the concentration of the drug in the first slurry and the second slurry is 5 mg / mL to 50 mg / mL, and the drug is one or more of paclitaxel and its derivatives, rapamycin and its derivatives.

[0029] In some embodiments, the first active ingredient and the second active ingredient are selected from any two of paclitaxel and its derivatives, paclitaxel and its derivative microspheres, rapamycin and its derivatives, and rapamycin and its derivative microspheres; optionally, the first active ingredient is rapamycin and its derivatives, and the second active ingredient is rapamycin and its derivative microspheres.

[0030] The active ingredient in the slurry is selected from paclitaxel and its derivatives or rapamycin and its derivatives. The slurry also includes a first excipient and a first solvent. The first excipient includes one or more of shellac, shellac ammonium salt, 2,6-di-tert-butyl-p-cresol, magnesium stearate and iopromide. The first solvent includes one or more of ethanol, methanol, isopropanol, acetonitrile, ethyl acetate and acetone.

[0031] In some embodiments, the active ingredient in the slurry is selected from paclitaxel and its derivative microspheres or rapamycin and its derivative microspheres, and the corresponding slurry includes a second excipient and a second solvent.

[0032] The second excipient includes one or more of cholesterol and phospholipids; and / or,

[0033] The second solvent includes one or more of alkanes, alcohols and mixed solvents of alkanes, and alcohols and water. Attached Figure Description

[0034] Figure 1 This is a schematic diagram of the structure of a balloon catheter according to one embodiment.

[0035] Figure 2 This is a schematic diagram of the structure of a balloon catheter according to another embodiment.

[0036] Figure 3 This is a schematic diagram of the balloon catheter according to the third embodiment.

[0037] Explanation of reference numerals in the attached figures:

[0038] 1. First coating; 2. Second coating. Detailed Implementation

[0039] To facilitate understanding of this application, a more complete description will be provided below with reference to the accompanying drawings. Preferred embodiments of this application are shown in the drawings. However, this application can be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided to provide a thorough and complete understanding of the disclosure of this application.

[0040] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0041] Percutaneous transluminal angioplasty (PTA) is a minimally invasive interventional treatment primarily used to dilate narrowed or occluded blood vessels and restore blood flow. A balloon is delivered to the lesion site via a catheter, and pressure is applied to dilate the vessel, improving vascular patency. It is often combined with stent implantation to maintain the effect and is suitable for diseases such as arteriosclerosis, diabetic foot, and renal artery stenosis. Drug-eluting balloon catheters, on the other hand, are therapeutic balloon drug delivery techniques developed based on interventional techniques such as PTA. The balloon surface is coated with cell-inhibiting or cytotoxic drugs. When the balloon reaches the vessel wall at the lesion site, it is inflated and contacts the vessel intima, rapidly releasing and transferring the drug into the local vessel wall. This inhibits intimal hyperplasia and leaves no implanted tissue, preventing restenosis after interventional procedures.

[0042] Drug-eluting balloon catheters typically use paclitaxel and its derivatives, or rapamycin (sirolimus) and its derivatives. Paclitaxel and its derivatives work by accelerating microtubule polymerization and inhibiting its depolymerization, causing cell cycle arrest at the G2 / M phase, thereby inhibiting intimal hyperplasia. Rapamycin and its derivatives work by binding to FKBP12; the RAPA-FKBP12 complex binds to mammalian target of sirolimus (mTOR), inhibiting the proliferation of T and B lymphocytes induced by various stimuli, causing vascular smooth muscle cells to arrest in the late G1 phase of the cell cycle, thus inhibiting intimal hyperplasia.

[0043] Paclitaxel and its derivatives are highly lipophilic and can rapidly enter vascular tissues. By regulating tubulin, they inhibit cell division and proliferation, and have a significant effect on promoting cell apoptosis. However, they have a small safety margin and are highly cytotoxic. At high local concentrations, they may cause inflammation or necrosis of the vascular wall, and their long-term efficacy is poor. Rapamycin and its derivatives are more evenly distributed in the vascular wall, have a larger safety margin, and their safety is more controllable. However, as weakly lipophilic drugs, they have poor transport and absorption rates in tissues, and their immediate efficacy is poor.

[0044] Based on this, one aspect of this application provides a drug-eluting balloon catheter, including a balloon, a plurality of first coatings 1 and a plurality of second coatings 2, wherein the plurality of first coatings 1 and the plurality of second coatings 2 are disposed in different regions on the surface of the balloon, and the first coatings 1 and the second coatings 2 are alternately and adjacently disposed; the first coating 1 contains a first active substance, and the second coating 2 contains a second active substance, wherein the first active substance and the second active substance are selected from any one or more of paclitaxel and its derivatives, paclitaxel and its derivative microspheres, rapamycin and its derivatives, and rapamycin and its derivative microspheres, and the first active substance and the second active substance are not completely identical.

[0045] This application achieves both immediate and long-term efficacy of a drug by using two different drugs, paclitaxel and its derivatives and rapamycin and its derivatives; or by using two different drug forms, a pure drug and a carrier drug, to achieve both immediate and long-term efficacy of a drug.

[0046] Specifically, this application alternately arranges coatings containing different types of drugs, namely, coatings containing paclitaxel and its derivatives and coatings containing rapamycin and its derivatives, on the surface of the balloon. Utilizing the different mechanisms of action of paclitaxel and its derivatives in arresting the smooth muscle cell cycle at the G2 / M phase and rapamycin-paclitaxel and its derivatives in arresting the cell cycle at the G1 phase, the anti-endometrial hyperplasia effect is synergistically enhanced, while reducing the local exposure concentration of paclitaxel and its derivatives alone, improving safety performance, and achieving both immediate and long-term efficacy. Furthermore, this application alternately arranges coatings containing only the drug and coatings containing drug microspheres on the surface of the balloon. The immediate therapeutic effect is achieved by utilizing the characteristic of rapid drug release during balloon expansion of the drug-only coating, while the long-term efficacy is achieved by utilizing the characteristic of slow degradation and drug release of the drug-containing microsphere coating. The two work together synergistically to achieve a long-term inhibitory effect on smooth muscle cell proliferation.

[0047] Understandably, paclitaxel and its derivatives microspheres refer to biodegradable microspheres loaded with one or more of paclitaxel and its derivatives.

[0048] Understandably, rapamycin and its derivative microspheres refer to biodegradable microspheres loaded with one or more of rapamycin.

[0049] Understandably, in this application, paclitaxel and its derivatives and rapamycin and its derivatives refer to the respective compounds and do not contain a carrier.

[0050] In some embodiments, the first coating 1 and the second coating 2 are arranged alternately along the surface of the balloon, and both the first coating 1 and the second coating 2 are a, where 0°≤a<180°.

[0051] Understandably, the tilt angle refers to the angle at which the first coating 1 or the second coating 2 deviates from the balloon axis, such as... Figure 1 and Figure 3 The tilt angle α shown above.

[0052] In some of these implementations, please refer to Figure 1 The first coating 1 and the second coating 2 are arranged alternately along the axial direction of the balloon. In other words, the first coating 1 and the second coating 2 are arranged alternately along the axial direction of the balloon; for example, a first coating 1 and a second coating 2 are arranged alternately in sequence.

[0053] In some of these implementations, please refer to Figure 1 The first and second coatings surround the entire circumference of the balloon.

[0054] Further, the first coating and the second coating are alternately arranged along the axial direction of the balloon, and the inclination angles of both the first coating and the second coating are 90°.

[0055] In some embodiments, refer to Figure 2 , the first coating 1 and the second coating 2 are alternately arranged along the circumferential direction of the balloon. In other words, in the circumferential direction of the balloon, the first coating 1 and the second coating 2 are alternately arranged; for example, one first coating 1 and one second coating 2 are alternately arranged sequentially.

[0056] In some embodiments, refer to Figure 2 , the first coating 1 and the second coating 2 extend axially through the balloon from one end of the circumferential surface of the balloon to the other end of the circumferential surface of the balloon. The balloon is cylindrical, and the circumferential surface of the balloon refers to the cylindrical surface of the cylinder.

[0057] Further, the first coating and the second coating are alternately arranged along the circumferential direction of the balloon, and the inclination angles of both the first coating and the second coating are 0°.

[0058] In some embodiments, the first coating 1 and the second coating 2 are alternately arranged in an inclined manner, the inclination angle of the first coating and the second coating is a, where 0°<a<90° or 90°<a<180°.

[0059] Further, refer to Figure 3 , the first coating 1 and the second coating 2 are alternately arranged in an inclined manner, and the inclination angle a of both the first coating 1 and the second coating 2 is 45°.

[0060] In some embodiments, the expanded plane of the first coating 1 or the second coating 2 is rectangular.

[0061] In some embodiments, the width of the first coating 1 or the second coating 2 is 1 mm to 200 mm.

[0062] It can be understood that the width refers to the dimension along the alternate arrangement direction of the first coating 1 and the second coating 2.

[0063] As an example, the width of the first coating 1 or the second coating 2 is 1mm, 5mm, 10mm, 15mm, 20mm, 25mm, 30mm, 35mm, 40mm, 45mm, 50mm, 55mm, 60mm, 65mm, 70mm, 75mm, 80mm, 85mm, 90mm, 95mm, 100mm, 105mm, 110mm, 115mm, 120mm, 125mm, 130mm, 135mm, 140mm, 145mm, 150mm, 155mm, 160mm, 165mm, 170mm, 175mm, 180mm, 185mm, 190mm, 195mm, or 200mm, or it can be a range formed by any two of the aforementioned point values ​​as endpoints.

[0064] Furthermore, the width of the first coating 1 or the second coating 2 is 10mm to 40mm. This results in a more suitable and stable drug release rate, further improving the safety and effectiveness of the treatment.

[0065] In some embodiments, the thickness of the first coating 1 or the second coating 2 is 0.005 mm to 0.5 mm.

[0066] As an example, the thickness of the first coating 1 or the second coating 2 is 0.005 mm, 0.01 mm, 0.05 mm, 0.1 mm, 0.2 mm, 0.3 mm, 0.4 mm, or 0.5 mm, or it can be a range formed by any two of the aforementioned point values ​​as endpoints. A more suitable and stable drug release rate can further improve the safety and effectiveness of the treatment.

[0067] Furthermore, the thickness of the first coating 1 or the second coating 2 is 0.02 mm to 0.1 mm. This can further improve the safety and effectiveness of the treatment.

[0068] In some embodiments, the width ratio of the first coating 1 to the second coating 2 is 1:6 to 6:1.

[0069] Furthermore, the width ratio of the first coating 1 or the second coating 2 is 1:4 to 4:1.

[0070] Furthermore, the width ratio of the first coating 1 or the second coating 2 is 1:1.

[0071] In some embodiments, the width of the blank area between adjacent first coating 1 and second coating 2 is 0~5mm.

[0072] In some embodiments, the drug dose density in the first coating 1 is 0.5 μg / mm². 2 ~5μg / mm 2Drugs refer to the active substances paclitaxel and its derivatives, and rapamycin and its derivatives.

[0073] As an example, the drug dosage density in the first coating 1 can be 0.5 μg / mm². 2 1μg / mm 2 2μg / mm 2 3μg / mm 2 4μg / mm 2 or 5μg / mm 2 Alternatively, it can be a range formed by any two of the aforementioned point values ​​as endpoints.

[0074] Furthermore, the drug dosage density in the first coating 1 is 4 μg / mm². 2 ~5μg / mm 2 .

[0075] In some embodiments, the drug dose density of the second coating 2 is 0.5 μg / mm². 2 ~5μg / mm 2 Drugs refer to the active substances paclitaxel and its derivatives, and rapamycin and its derivatives.

[0076] As an example, the drug dosage density of the second coating 2 can be 0.5 μg / mm². 2 1μg / mm 2 2μg / mm 2 3μg / mm 2 4μg / mm 2 or 5μg / mm 2 Alternatively, it can be a range formed by any two of the aforementioned point values ​​as endpoints.

[0077] Furthermore, the drug dose density in the second coating 2 is 4 μg / mm². 2 ~5μg / mm 2 .

[0078] In some embodiments, the first and second active ingredients are selected from any two of paclitaxel and its derivatives, paclitaxel and its derivative microspheres, rapamycin and its derivatives, and rapamycin and its derivative microspheres.

[0079] Understandably, among the active ingredients, paclitaxel and its derivatives are the first type, paclitaxel and its derivative microspheres are the second type, rapamycin and its derivatives are the third type, rapamycin and its derivative microspheres are the fourth type, and "any two" means any two can be selected from the aforementioned four active ingredients.

[0080] In some embodiments, the first active ingredient is rapamycin and its derivatives, and the second active ingredient is rapamycin and its derivative microspheres. Combining a drug-only compound (without a carrier) with drug microspheres allows the drug to be transferred and absorbed within cells and tissues in a short period, enhancing immediate therapeutic effects; the drug microspheres allow for long-term release of the drug within cells and tissues, enhancing long-term therapeutic effects.

[0081] Furthermore, the primary active ingredient is rapamycin, and the secondary active ingredient is rapamycin microspheres.

[0082] In some embodiments, the first active ingredient is paclitaxel and its derivatives, and the second active ingredient is paclitaxel and its derivative microspheres. This approach can achieve both immediate and long-term therapeutic effects.

[0083] Furthermore, the primary active ingredient is paclitaxel, and the secondary active ingredient is paclitaxel microspheres.

[0084] In some embodiments, the first active ingredient is selected from one or more of paclitaxel and its derivatives and paclitaxel and its derivative microspheres, and the second active ingredient is selected from one or more of rapamycin and its derivatives and rapamycin and its derivative microspheres. Combining paclitaxel and rapamycin can further enhance the inhibitory effect on cell proliferation while reducing drug toxicity and adverse reactions, thereby improving the safety and efficacy of the treatment.

[0085] Furthermore, the primary active ingredient is paclitaxel and its derivatives, and the secondary active ingredient is rapamycin and its derivatives.

[0086] Furthermore, the primary active ingredient is paclitaxel and its derivatives, and the secondary active ingredient is rapamycin and its derivative microspheres.

[0087] Furthermore, the primary active ingredient is paclitaxel and its derivative microspheres, and the secondary active ingredient is rapamycin and its derivatives.

[0088] Furthermore, the primary active ingredient is paclitaxel and its derivative microspheres, and the secondary active ingredient is rapamycin and its derivative microspheres.

[0089] In some embodiments, the first active ingredient is selected from either paclitaxel or paclitaxel microspheres, and the second active ingredient is selected from either rapamycin or rapamycin microspheres.

[0090] Furthermore, the primary active ingredient is paclitaxel, and the secondary active ingredient is rapamycin.

[0091] Furthermore, the primary active ingredient is paclitaxel, and the secondary active ingredient is rapamycin microspheres.

[0092] A second aspect of this application provides a method for preparing a drug-eluting balloon catheter, comprising the following steps:

[0093] A first slurry containing a first functional substance and a second slurry containing a second functional substance are alternately coated on different areas of the balloon surface and then dried to obtain a balloon catheter.

[0094] In some embodiments, the concentration of the drug in the first slurry and the second slurry is 5 mg / mL to 50 mg / mL, and the drug is one or more of paclitaxel and its derivatives, rapamycin and its derivatives.

[0095] In some embodiments, the first and second active substances are selected from any two of paclitaxel and its derivatives, paclitaxel and its derivative microspheres, rapamycin and its derivatives, and rapamycin and its derivative microspheres.

[0096] When the active ingredient in the slurry is selected from paclitaxel and its derivatives or rapamycin and its derivatives, the slurry also includes a first excipient and a first solvent; the first excipient includes one or more of shellac, shellac ammonium salt, 2,6-di-tert-butyl-p-cresol, magnesium stearate and iopromide; the first solvent includes one or more of ethanol, methanol, isopropanol, acetonitrile, ethyl acetate and acetone.

[0097] In some embodiments, when the active ingredient in the slurry is selected from paclitaxel and its derivative microspheres or rapamycin and its derivative microspheres, the corresponding slurry includes a second excipient and a second solvent; the second excipient includes one or more of cholesterol and phospholipids; the second solvent includes one or more of alkanes, alcohols and mixed solvents of alkanes, and alcohols and water.

[0098] Furthermore, alkanes include one or more of pentane, hexane, and heptane.

[0099] In some embodiments, the paclitaxel spray coating paste is prepared by blending amorphous or crystalline paclitaxel with excipients and organic solvents.

[0100] In some embodiments, the rapamycin spray coating slurry is prepared by blending amorphous or crystalline rapamycin with excipients and organic solvents.

[0101] Furthermore, the same excipients and the same organic solvents can be used to prepare rapamycin spray coating paste and paclitaxel spray coating paste.

[0102] In some embodiments, the preparation method of paclitaxel microsphere spraying slurry is as follows: one or more liposomes are added to an alkane, sealed, and ultrasonicated at 30°C to 50°C until the liposomes are completely dissolved to obtain a blend; after cooling the blend to room temperature, paclitaxel microspheres are added to make the paclitaxel microspheres uniformly suspended in the blend to obtain the paclitaxel microsphere spraying slurry.

[0103] In some embodiments, the preparation method of rapamycin microsphere spraying slurry is as follows: one or more liposomes are added to an alkane, sealed, and ultrasonicated at 30°C to 50°C until the liposomes are completely dissolved to obtain a blend; after cooling the blend to room temperature, rapamycin microspheres are added to make the rapamycin microspheres uniformly suspended in the blend to obtain the rapamycin microsphere spraying slurry.

[0104] Furthermore, the same alkanes and liposomes can be used to prepare rapamycin microsphere spraying slurry and paclitaxel microsphere spraying slurry.

[0105] To make the objectives, technical solutions, and advantages of this application clearer and more concise, the following specific embodiments are used for illustration, but this application is by no means limited to these embodiments. The embodiments described below are merely preferred embodiments of this application and can be used to describe this application, but should not be construed as limiting the scope of this application. It should be noted that any modifications, equivalent substitutions, and improvements made within the spirit and principles of this application should be included within the protection scope of this application.

[0106] To better illustrate this application, the following description, in conjunction with specific embodiments, further explains its content. The following are specific embodiments.

[0107] Example 1

[0108] A drug-eluting balloon catheter, please refer to Figure 1 The device includes a balloon, multiple first coatings 1 and multiple second coatings 2. The first coatings 1 and second coatings 2 are alternately disposed on the surface of the balloon along its axial direction. The tilt angle α of both the first coatings 1 and second coatings 2 is 90°. Adjacent first coatings 1 and second coatings 2 are adjacent and have no gaps. The first coating 1 contains a first active ingredient, and the second coating 2 contains a second active ingredient. The first active ingredient is rapamycin, and the second active ingredient is rapamycin microspheres. The unfolded planes of the first coatings 1 and second coatings 2 have the same area and are both rectangular. The width of both the first coatings 1 and second coatings 2 is 25 mm, and the thickness is 0.05 mm. The drug dose density of the first coating 1 is 1 μg / mm². 2 The drug dose density of the second coating 2 is 1 μg / mm². 2 The balloon has a diameter of 4.0 mm and a length of 150 mm.

[0109] The preparation method of the above-mentioned drug-eluting balloon catheter is as follows:

[0110] S1: Rapamycin was selected as the primary active ingredient, and rapamycin microspheres were selected as the secondary active ingredient.

[0111] S2: Add the first excipient 2,6-di-tert-butyl-p-cresol and the first solvent isopropanol to rapamycin, dissolve by ultrasonication, and prepare rapamycin spray slurry. The concentration of rapamycin in the rapamycin spray slurry is 40 mg / mL, and the mass ratio of rapamycin to 2,6-di-tert-butyl-p-cresol is 1:0.1.

[0112] A second excipient, namely three liposomes, DEPC, DOPE-PEG, and cholesterol, was added to the second solvent, n-hexane. After sealing, the mixture was sonicated at 40°C until the three liposomes were completely dissolved, resulting in a mixture of the second excipient and the second solvent. The mixture was cooled to room temperature, and then rapamycin microspheres (biodegradable microspheres loaded with rapamycin) were added. The mixture was shaken to suspend the rapamycin microspheres uniformly in the mixture, thus preparing a rapamycin microsphere spraying slurry. The concentration of rapamycin in the rapamycin microsphere spraying slurry was 20 mg / mL, and the mass ratio of DEPC, DOPE-PEG, and cholesterol was 10:1:5.

[0113] S3: Use a 25mm wide shielding fixture to shield the balloon surface at 25mm intervals along the axial direction. Load the rapamycin spraying slurry into the syringe of the spraying equipment and spray the unshielded parts of the balloon surface.

[0114] Remove all the shielding fixtures, load the rapamycin microsphere spraying slurry into the syringe of the spraying equipment, and spray the exposed parts of the balloon surface after removing the shielding fixtures to obtain the balloon catheter preform.

[0115] S4: The balloon catheter preform is dried, and a first coating 1 with a width of 25 mm and a thickness of 0.05 mm is formed by spraying rapamycin slurry. The drug dosage density of the first coating 1 is 1 μg / mm². 2 Rapamycin microspheres were sprayed to form a second coating 2 with a width of 25 mm and a thickness of 0.05 mm. The drug dosage density of the second coating 2 was 1 μg / mm². 2 There is no gap between the first coating 1 and the second coating 2.

[0116] Example 2

[0117] A drug-eluting balloon catheter, please refer to Figure 1The device includes a balloon, multiple first coatings 1 and multiple second coatings 2. The first coatings 1 and second coatings 2 are alternately disposed on the surface of the balloon along its axial direction. The tilt angle α of both the first coatings 1 and second coatings 2 is 90°. Adjacent first coatings 1 and second coatings 2 are adjacent and have no gaps. The first coating 1 contains a first active ingredient, and the second coating 2 contains a second active ingredient. The first active ingredient is paclitaxel, and the second active ingredient is paclitaxel microspheres. The unfolded planes of the first coatings 1 and second coatings 2 have the same area and are both rectangular. The width of both the first coatings 1 and second coatings 2 is 10 mm, and the thickness is 0.05 mm. The drug dose density of the first coating 1 is 3 μg / mm². 2 The drug dose density of the second coating 2 is 1 μg / mm². 2 The balloon has a diameter of 4.0 mm and a length of 150 mm.

[0118] The preparation method of the above-mentioned drug-eluting balloon catheter is as follows:

[0119] S1: Paclitaxel is selected as the primary active ingredient, and paclitaxel microspheres are selected as the secondary active ingredient;

[0120] S2: Add the first excipient, shellac ammonium salt, and the first solvent, ethanol, to paclitaxel and dissolve them by ultrasonication to prepare paclitaxel spraying slurry. The concentration of paclitaxel in the paclitaxel spraying slurry is 30 mg / mL, and the mass ratio of paclitaxel to shellac ammonium salt is 1:1.

[0121] A second excipient, namely three liposomes, DEPC, DOPE-PEG, and cholesterol, was added to the second solvent, n-hexane. After sealing, the mixture was sonicated at 40°C until the three liposomes were completely dissolved, resulting in a mixture of the second excipient and the second solvent. After cooling the mixture to room temperature, paclitaxel microspheres (biodegradable microspheres loaded with paclitaxel) were added. The mixture was shaken to suspend the paclitaxel microspheres uniformly in the mixture, thus preparing a paclitaxel microsphere spraying slurry. The concentration of paclitaxel in the paclitaxel microsphere spraying slurry was 10 mg / mL, and the mass ratio of DEPC, DOPE-PEG, and cholesterol was 10:1:5.

[0122] S3: Use a 10mm wide shielding tool to shield the balloon surface at 10mm intervals along the axial direction, load the paclitaxel spraying slurry into the syringe of the spraying equipment, and spray the unshielded parts of the balloon surface.

[0123] Remove all the shielding fixtures, load the paclitaxel microsphere spraying slurry into the syringe of the spraying equipment, and spray the exposed parts of the balloon surface after removing the shielding fixtures to obtain the balloon catheter preform.

[0124] S4: The balloon catheter preform is dried, and a first coating 1 with a width of 10 mm and a thickness of 0.05 mm is formed by spraying paclitaxel slurry. The drug dosage density of the first coating 1 is 3 μg / mm². 2 The paclitaxel microspheres were sprayed to form a second coating 2 with a width of 10 mm and a thickness of 0.05 mm. The drug dosage density of the second coating 2 was 1 μg / mm². 2 There is no gap between the first coating 1 and the second coating 2.

[0125] Example 3

[0126] A drug-eluting balloon catheter, please refer to Figure 2 The device includes a balloon, multiple first coatings 1 and multiple second coatings 2. The first coatings 1 and second coatings 2 are alternately applied to the surface of the balloon along its circumference. The tilt angle α of both the first coatings 1 and second coatings 2 is 0°. Adjacent first coatings 1 and second coatings 2 are adjacent and have no gaps. Each first coating 1 contains a first active ingredient, and each second coating 2 contains a second active ingredient. The first active ingredient is paclitaxel, and the second active ingredient is rapamycin. The unfolded planes of the first coatings 1 and second coatings 2 have the same area and are both rectangular. The width of each first coating 1 and second coating 2 is 5 mm, and the thickness is 0.05 mm. The areal density of the first coating 1 is 3 μg / mm². 2 The areal density of the second coating 2 is 3 μg / mm². 2 The balloon has a diameter of 7.0 mm and a length of 60 mm.

[0127] The preparation method of the above-mentioned drug-eluting balloon catheter is as follows:

[0128] S1: Paclitaxel is selected as the primary active ingredient, and rapamycin is selected as the secondary active ingredient;

[0129] S2: Add shellac ammonium salt as the first excipient and ethanol as the first solvent to paclitaxel, dissolve by ultrasonication, and prepare paclitaxel spraying slurry with a concentration of paclitaxel of 30 mg / mL.

[0130] Rapamycin was added to the second solvent, isopropanol, and dissolved by ultrasonication to obtain a rapamycin spraying slurry with a concentration of 40 mg / mL.

[0131] S3: Use a 5mm wide shielding tool to shield the surface of the balloon at 5mm intervals along the circumference of the balloon. Load the paclitaxel spraying slurry into the syringe of the spraying equipment and spray the unshielded parts of the balloon surface.

[0132] Remove all the shielding fixtures, load the rapamycin spraying slurry into the syringe of the spraying equipment, and spray the exposed parts of the balloon surface after removing the shielding fixtures to obtain the balloon catheter preform.

[0133] S4: The balloon catheter preform is dried, and a first coating 1 with a width of 5 mm and a thickness of 0.05 mm is formed by spraying paclitaxel slurry. The drug dosage density of the first coating 1 is 3 μg / mm². 2 Rapamycin spray slurry forms a second coating 2 with a width of 5 mm and a thickness of 0.05 mm, and the drug dosage density of the second coating 2 is 3 μg / mm². 2 There is no gap between the first coating 1 and the second coating 2.

[0134] Example 4

[0135] A drug delivery balloon catheter includes a balloon, multiple first coatings 1 and multiple second coatings 2. The first coatings 1 and second coatings 2 are alternately disposed on the balloon surface along its axial direction. The inclination angle α of both the first coatings 1 and second coatings 2 is 90°. Adjacent first coatings 1 and second coatings 2 are adjacent and have no gaps. The first coating 1 contains a first active ingredient, and the second coating 2 contains a second active ingredient. The first active ingredient is paclitaxel, and the second active ingredient is rapamycin microspheres. The unfolded planes of the first coatings 1 and second coatings 2 have the same area and are both rectangular. The width of each first coating 1 is 20 mm, and its thickness is 0.05 mm. The width of each second coating 2 is 30 mm, and its thickness is 0.05 mm. The areal density of the first coating 1 is 3 μg / mm². 2 The areal density of the second coating 2 is 0.5 μg / mm². 2 The balloon has a diameter of 4.0 mm and a length of 150 mm.

[0136] The preparation method of the above-mentioned drug-eluting balloon catheter is as follows:

[0137] S1: Paclitaxel was selected as the primary active ingredient, and rapamycin microspheres were selected as the secondary active ingredient;

[0138] S2: Add shellac ammonium salt as the first excipient and ethanol as the first solvent to paclitaxel, dissolve by ultrasonication, and prepare paclitaxel spraying slurry with a concentration of paclitaxel of 30 mg / mL.

[0139] A second excipient, namely three liposomes, DEPC, DOPE-PEG, and cholesterol, was added to the second solvent, n-heptane. After sealing, the mixture was sonicated at 35°C until the three liposomes were completely dissolved, resulting in a mixture of the second excipient and the second solvent. The mixture was cooled to room temperature and then rapamycin microspheres (biodegradable microspheres loaded with rapamycin) were added. The mixture was shaken to suspend the paclitaxel microspheres uniformly in the mixture, thus preparing a rapamycin microsphere spraying slurry. The concentration of paclitaxel in the rapamycin microsphere spraying slurry was 15 mg / mL, and the mass ratio of DEPC, DOPE-PEG, and cholesterol was 10:1:1.

[0140] S3: Use multiple 30mm wide shielding fixtures to shield the balloon surface at 20mm intervals along the axial direction, load paclitaxel spraying slurry into the syringe of the spraying equipment, and spray the unshielded parts of the balloon surface.

[0141] Remove all the shielding fixtures, load the rapamycin microsphere spraying slurry into the syringe of the spraying equipment, and spray the exposed parts of the balloon surface after removing the shielding fixtures to obtain the balloon catheter preform.

[0142] S4: The balloon catheter preform is dried, and a first coating 1 with a width of 2 mm and a thickness of 0.05 mm is formed by spraying paclitaxel slurry. The drug dosage density in the first coating 1 is 3 μg / mm². 2 Rapamycin microspheres were sprayed to form a second coating 2 with a width of 3 mm and a thickness of 0.05 mm. The drug dosage density in the second coating 2 was 0.5 μg / mm². 2 There is no gap between the first coating 1 and the second coating 2.

[0143] Example 5

[0144] Example 5 is basically the same as Example 2, except that the drug dosage density of the first coating 1 is 5 μg / mm². 2 The drug dose density of the second coating 2 is 5 μg / mm². 2 .

[0145] Example 6

[0146] Example 6 is basically the same as Example 2, except that the width of the first coating 1 is 10mm and the width of the second coating 2 is 40mm.

[0147] Example 7

[0148] Example 7 is basically the same as Example 2, except that the width of the first coating 1 and the second coating 2 is 50mm.

[0149] Example 8

[0150] Example 8 is basically the same as Example 2, except that the thickness of the first coating 1 and the second coating 2 is 0.2 mm.

[0151] Comparative Example 1

[0152] Comparative Example 1 is basically the same as Example 2, except that the second coating 2 is replaced by the first coating 1 (the entire surface of the balloon is the first coating 1, and its active ingredient is only paclitaxel).

[0153] Comparative Example 2

[0154] Comparative Example 2 is basically the same as Example 2, except that the first coating 1 is replaced by the second coating 2 (the entire surface of the balloon is the second coating 2, and its active ingredient is only paclitaxel microspheres).

[0155] Comparative Example 3

[0156] Comparative Example 3 is basically the same as Example 4, except that the first coating 1 is replaced by the second coating 2 (the entire surface of the balloon is the second coating 2, and its active ingredient is only rapamycin microspheres).

[0157] This application also tested the drug release rate of paclitaxel microspheres and rapamycin microspheres. The test method was as follows: 10 mg of microspheres (paclitaxel microspheres or rapamycin microspheres) were placed in 5 ml of phosphate-buffered saline (PBS) to simulate a physiological environment. After shaking at 37°C and 250 rpm, the PBS was sampled, and the amount of drug released was measured by high-performance liquid chromatography (HPLC) using an HC-C18 column. Drug release rate / % = Amount of drug released / Initial amount of drug.

[0158] The test results are shown in Table 1.

[0159] Table 1

[0160]

[0161] The balloon catheters prepared in each embodiment and comparative example were subjected to performance tests, and the test results are shown in Table 2 below.

[0162] The drug-eluting balloon catheter was placed in 5 ml of phosphate-buffered saline (PBS) for expansion and release to simulate a physiological environment. After shaking at 37°C and 250 rpm, the PBS was sampled, and the amount of drug released was tested by high-performance liquid chromatography (HPLC) using an HC-C18 column.

[0163] Table 2

[0164]

[0165] As shown in Table 2 above, this application achieves both immediate and long-term efficacy through two different drugs: paclitaxel and its derivatives, and rapamycin and its derivatives; or, through two different drug forms: the pure drug and the carrier drug, it achieves both immediate and long-term efficacy. However, the drug in Comparative Example 1 is released rapidly in the short term, failing to achieve long-term efficacy; Comparative Examples 2 and 3 have poor drug release rates in the short term, failing to achieve short-term efficacy.

[0166] Compared with single drugs, the combination of two pure drugs has similar drug release, but the two drugs have different mechanisms of action. They synergistically enhance the inhibition of smooth muscle cell proliferation and reduce the local exposure concentration of paclitaxel and its derivatives. The coating containing pure drugs and the coating containing drug microspheres are alternately arranged on the surface of the balloon, which has better long-term release than pure drugs and better immediate release than drug microspheres.

[0167] Furthermore, the width of the first coating and the second coating is 10mm~40mm, the thickness is 0.02mm~0.1mm, the width ratio of the first coating to the second coating is 1:1, or the dosage density of the drug in the first coating and the second coating is 4μg / mm². 2 ~5μg / mm 2 This can further enhance the immediate and long-term efficacy of the drug.

[0168] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0169] The embodiments described above are merely illustrative of several implementation methods of this application, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of this application, and these all fall within the protection scope of this application. Therefore, the protection scope of this patent application should be determined by the appended claims.

Claims

1. A drug-eluting balloon catheter, characterized in that, The device includes a balloon, multiple first coatings, and multiple second coatings. The multiple first coatings and multiple second coatings are disposed in different regions on the surface of the balloon, and the first coatings and second coatings are alternately and adjacently disposed. The first coating contains a first active ingredient, and the second coating contains a second active ingredient. The first active ingredient and the second active ingredient are selected from any one or more of paclitaxel and its derivatives, paclitaxel and its derivative microspheres, rapamycin and its derivatives, and rapamycin and its derivative microspheres, and the first active ingredient and the second active ingredient are not completely identical.

2. The drug-eluting balloon catheter as described in claim 1, characterized in that, The first coating and the second coating are arranged alternately along the surface of the balloon, and the tilt angle of the first coating and the second coating is α, where 0°≤α<180°.

3. The drug-eluting balloon catheter as described in claim 1, characterized in that, The first coating and the second coating are arranged alternately along the axial direction of the balloon, and the tilt angle α of the first coating and the second coating is 90°.

4. The drug-eluting balloon catheter as described in claim 1, characterized in that, The first coating and the second coating are arranged alternately along the circumference of the balloon, and the tilt angle α of the first coating and the second coating is 0°.

5. The drug-eluting balloon catheter as described in claim 1, characterized in that, The first coating or the second coating satisfies at least one of the following conditions: (1) The unfolded plane is rectangular; (2) Width is 1mm~200mm; (3) The thickness is 0.005mm~0.5mm; (4) The width ratio of the first coating to the second coating is 1:6 to 6:1; (5) The width of the blank area between adjacent first and second coatings is 0~5mm.

6. The drug-eluting balloon catheter according to any one of claims 1 to 5, characterized in that, The first coating or the second coating satisfies at least one of the following conditions: (1) Width is 10mm~40mm; (2) The thickness is 0.02mm~0.1mm; (3) The width ratio of the first coating to the second coating is 1:4 to 4:1; (4) The dosage density of the drug in the first coating is 0.5 μg / mm. 2 ~5μg / mm 2 ; (5) The dosage density of the drug in the second coating is 0.5 μg / mm². 2 ~5μg / mm 2 .

7. The drug-eluting balloon catheter according to any one of claims 1 to 5, characterized in that, The first and second active ingredients are selected from any two of paclitaxel and its derivatives, paclitaxel and its derivative microspheres, rapamycin and its derivatives, and rapamycin and its derivative microspheres.

8. The drug-eluting balloon catheter as described in claim 7, characterized in that, The first active ingredient is rapamycin and its derivatives, and the second active ingredient is rapamycin and its derivative microspheres.

9. The drug-eluting balloon catheter as described in claim 7, characterized in that, The first active ingredient is paclitaxel and its derivatives, and the second active ingredient is paclitaxel and its derivative microspheres.

10. The drug-eluting balloon catheter according to any one of claims 1 to 5, characterized in that, The first active ingredient is selected from any one or more of paclitaxel and its derivatives and paclitaxel and its derivative microspheres, and the second active ingredient is selected from any one or more of rapamycin and its derivatives and rapamycin and its derivative microspheres.

11. A method for preparing a drug-eluting balloon catheter as described in any one of claims 1 to 10, characterized in that, Includes the following steps: The first slurry containing the first functional substance and the second slurry containing the second functional substance are alternately coated on different areas of the balloon surface and then dried to obtain the balloon catheter.

12. The method for preparing the drug-eluting balloon catheter as described in claim 11, characterized in that, The concentration of the drug in the first slurry and the second slurry is 5 mg / mL to 50 mg / mL, and the drug is one or more of paclitaxel and its derivatives, rapamycin and its derivatives.

13. The method for preparing the drug-eluting balloon catheter as described in claim 11 or 12, characterized in that, The first and second active ingredients are selected from any two of paclitaxel and its derivatives, paclitaxel and its derivative microspheres, rapamycin and its derivatives, and rapamycin and its derivative microspheres; the active ingredient in the slurry is selected from paclitaxel and its derivatives or rapamycin and its derivatives, and the corresponding slurry also includes a first excipient and a first solvent; the first excipient includes one or more of shellac, shellac ammonium salt, 2,6-di-tert-butyl-p-cresol, magnesium stearate, and iopromide; and / or, the first solvent includes one or more of ethanol, methanol, isopropanol, acetonitrile, ethyl acetate, and acetone.

14. The method for preparing the drug-eluting balloon catheter as described in claim 13, characterized in that, The first active ingredient is rapamycin and its derivatives, and the second active ingredient is rapamycin and its derivative microspheres.

15. The method for preparing the drug-eluting balloon catheter as described in claim 14, characterized in that, The active ingredients in the slurry are selected from paclitaxel and its derivative microspheres or rapamycin and its derivative microspheres, and the corresponding slurry includes a second excipient and a second solvent. The second excipient includes one or more of cholesterol and phospholipids; and / or, The second solvent includes one or more of alkanes, alcohols and mixed solvents of alkanes, and alcohols and water.

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