Drug-loaded balloon as well as preparation method and application thereof

Abstract

The invention relates to the field of medicines, and provides a medicine-carrying balloon as well as a preparation method and application thereof. The medicine carrying balloon comprises a balloon and a medicine coating; the drug coating comprises a carrier and a drug, and the carrier comprises one or more of iopromide, butylated hydroxytoluene, phospholipid, cholesterol, dopamine, mussel mucin, 3, 4-dihydroxyphenylalanine, polydopamine, magnesium stearate, polylactic acid, polysorbate, polyethylene glycol, lac and lauryl sodium sulfate. The carrier serves as molecular glue, adheres to the medicine and the balloon and is combined with the medicine to form composite particles, and a firm medicine coating is formed. After transshipment at the target blood vessel, the'molecular glue 'exerts the adhesion effect, so that the composite particles are adhered to the target blood vessel for a long time, and the slow-release effect of the medicine is realized.

Description

Technical Field

[0001] The present invention relates to the field of medicines, and in particular to a drug-loaded balloon and a preparation method and application thereof. Background Art

[0002] Vascular stenosis caused by atherosclerosis and other diseases is a common disease in the population, and its incidence rate is increasing year by year and showing a trend of younger patients. Percutaneous transluminal angioplasty is the main means of treating vascular stenosis at present. Its standard interventional treatment procedure is drug-eluting stent (DES) implantation. However, due to delayed endothelialization of DES and other reasons, even in the era of new generation DES, in-stent restenosis (ISR) and late thrombosis after arterial stent implantation are still common clinical problems. Therefore, in the past decade, the concept of "intervention without implantation" has developed rapidly in the field of arterial interventional treatment, providing space for the widespread use of bioresorbable stents and drug-coated balloons (DCB) in clinical practice. Among them, the drug-coated balloon can achieve rapid drug absorption and long-term inhibition of endothelial cell proliferation by releasing drugs once. At the same time, since no foreign body is implanted, this treatment method retains the opportunity for patients to receive follow-up treatment. Drug-coated balloons have the advantages of high drug concentration, uniform drug coverage, and short dual antiplatelet time, and have been widely used in clinical practice.

[0003] Paclitaxel is an antiproliferative drug. It is widely used in drug-coated balloons because of its strong lipophilicity, rapid passage through cell membranes, irreversible binding to microtubules, and sustained inhibition of cell division. However, in recent years, scholars have found that paclitaxel drug-coated balloons have some shortcomings: (1) The drug coating is easy to fall off during balloon delivery, which limits the delivery time and distorts the accuracy of the actual dose applied to the blood vessels; (2) The drug coating that falls off during delivery is poorly water-soluble and can easily cause distal microcirculatory embolism; (3) Paclitaxel has a narrow therapeutic window and potential safety risks.

[0004] Limulus drugs are a type of immunosuppressant with a wide therapeutic range, a high safety margin, and a large amount of clinical research data to support them. This type of drug has better tissue inhibition than paclitaxel, but due to its relatively low lipophilicity, it has a short retention time in tissues and cannot be sustained, making it difficult to apply to drug balloons. Summary of the invention

[0005] Therefore, the technical problem to be solved by the present invention is to overcome the defects of the prior art that limus drugs have a short retention time in tissues and cannot be sustained and released, thereby providing a drug-loaded balloon and a preparation method and application thereof.

[0006] To this end, the present invention provides the following technical solutions:

[0007] The present invention provides a drug-loaded balloon, which comprises a balloon and a drug coating;

[0008] The drug coating comprises a carrier and a drug, wherein the carrier comprises one or more of iopromide, butylated hydroxytoluene, phospholipid, cholesterol, dopamine, mussel mucin, 3,4-dihydroxyphenylalanine, polydopamine, magnesium stearate, polylactic acid, polysorbate, polyethylene glycol, shellac and sodium lauryl sulfate.

[0009] The carrier and the drug form composite particles that are evenly distributed on the balloon surface to form a drug coating.

[0010] In an optional embodiment, the particle size of the composite particles is 200 nm to 75 μm; particles in this particle size range can, on the one hand, achieve firm adhesion to the balloon, i.e., the washout loss rate in the blood is extremely low; on the other hand, it can ensure that the particles scattered when the balloon expands are small, thereby avoiding the risk of distal embolism.

[0011] In the carrier, iopromide, butylated hydroxytoluene, dopamine, mussel mucin, 3,4-dihydroxyphenylalanine, polydopamine, magnesium stearate, polylactic acid, and polyethylene glycol are nanoparticles with a particle size of 10-1500nm. The small size and huge specific surface area of ​​these carriers can be filled between drug molecules in all directions, play the role of "molecular glue", and stably wrap and adhere around drug molecules.

[0012] In the carrier, butylated hydroxytoluene, dopamine, mussel mucin, 3,4-dihydroxyphenylalanine, polydopamine, magnesium stearate, polylactic acid, polyethylene glycol, shellac and sodium dodecyl sulfate are charged, and the absolute value of the zeta potential of the carrier is ≥10mV. These carriers can directly adhere to the target blood vessels, and the presence of their charges will disrupt the cell repair process, slow down the cell proliferation rate, and prevent excessive proliferation of the intima.

[0013] In the carrier, phospholipids, cholesterol, polysorbate, polyethylene glycol, shellac and sodium dodecyl sulfate can be used as solubilizers and dispersants to adjust the uniformity and stability of the drug solution (a mixed solution of the drug, the organic solvent and the carrier).

[0014] The carrier contains electron-rich structures such as amino groups, hydroxyl groups, benzene rings, double bonds, etc. to varying degrees, and can be combined with drugs through hydrogen bonds, π-π stacking, electrostatic adsorption and other forces to form stable composite particles; the hydrophobic groups such as benzene rings and alkyl groups in the carrier can bind to the phospholipid bilayer on the cell membrane through hydrophobic interaction, thereby achieving a tissue adhesion effect.

[0015] By selecting one or several of the above-mentioned different carriers to prepare drug-loaded balloons, the composite particles on the drug coating in the obtained drug-loaded balloons can fully exert their adhesion to tissues and prolong the drug's action time in the body. The sustained release time can be greater than 28 days, greatly reducing the risk of vascular restenosis.

[0016] In an optional embodiment, the mass ratio of the carrier to the drug is 1:(1-50).

[0017] Optionally, the mass density of the drug on the drug-loaded balloon is 0.5-6.0 μg / mm 2 .

[0018] In an optional embodiment, the drug comprises a limus drug.

[0019] Optionally, the limus drugs include one or more of sirolimus, tacrolimus, everolimus, temsirolimus, umimerosimus and pimecrolimus.

[0020] The drug is crystalline particles or disordered amorphous particles, and the particle size of the drug is 200nm-70μm.

[0021] In an optional embodiment, the balloon includes a common balloon or a functional balloon;

[0022] Optionally, the functional balloon includes a mastoid balloon, a spinous process balloon, a high-pressure balloon, a scored balloon or a high-pressure cutting balloon.

[0023] In an optional embodiment, the ordinary balloon is purchased from Shanghai Yingtai Medical Device Co., Ltd., the mastoid balloon is purchased from Lepu (Beijing) Medical Device Co., Ltd., the spinous process balloon is purchased from Shanghai Yingtai Medical Device Co., Ltd., the high-pressure balloon is purchased from Shanghai MicroPort Cardiovascular Medical Technology (Group) Co., Ltd., the scored balloon is purchased from Dingke Medical Technology (Suzhou) Co., Ltd., and the high-pressure cutting balloon is purchased from Guangdong Bomai Medical Technology Co., Ltd.

[0024] In an optional embodiment, the molecular weight of the polyethylene glycol is 4000-8000.

[0025] The present invention also provides a method for preparing the drug-loaded balloon, comprising the following steps:

[0026] (1) mixing the drug, the organic solvent and the carrier to obtain a mixed solution;

[0027] (2) Loading the mixed solution onto the outer surface of the balloon, and obtaining the drug-loaded balloon after drying.

[0028] In an optional embodiment, the organic solvent in step (1) includes one or more of water, acetonitrile, acetone, dichloromethane, ethanol, ethyl acetate, petroleum ether, n-heptane, tetrahydrofuran and isopropanol.

[0029] In an optional embodiment, the mass ratio of the drug, organic solvent and carrier in step (1) is (1-50):(62-5000):1.

[0030] In an optional embodiment, the mixing in step (1) comprises the following steps:

[0031] The drug and the organic solvent are first stirred to obtain a first solution; and the first solution and the carrier are second stirred to obtain a mixed solution.

[0032] Optionally, the first stirring time is 0.5-8h; the second stirring time is 8-24h.

[0033] In an optional embodiment, the loading method in step (2) is spraying or dipping.

[0034] Optionally, the spraying comprises the following steps: filling the balloon to 0-18atm, maintaining the temperature of the mixed solution at 10-30°C, controlling the liquid inlet flow rate of the liquid inlet to 0-2mL / min, providing a stirring device on the liquid inlet, the stirring speed of the stirring device to be 50-1000rpm, providing an ultrasonic device at the outlet of the liquid inlet, and the ultrasonic power to be 0.5-5.5W, using ultrasonic atomization spraying technology to evenly load the mixed solution onto the balloon, and adjusting the number of spraying times to adjust the amount of drug loaded onto the balloon and the thickness of the drug coating.

[0035] Optionally, the dip coating comprises the following steps: filling the balloon to 0-18 atm, maintaining the temperature of the mixed solution at 10-30°C, controlling the stirring speed of the mixed solution at 200-1000 rpm, ensuring that the mixed solution can completely immerse the balloon of corresponding length, placing the balloon vertically into the mixed solution, stabilizing for 1-5 minutes, then taking it out vertically, drying for 1-10 minutes, and repeating the "put in-take out" process 1-5 times to adjust the amount of drug loaded on the balloon and the thickness of the drug coating.

[0036] Optionally, the drying in step (2) is low-temperature vacuum drying or low-temperature oven drying, the drying temperature is ≤60°C, and the drying time is 1-24h.

[0037] Drying at low temperature can protect the stability of the drug and the carrier, while reducing the residual solvent rate on the drug coating.

[0038] In an optional embodiment, after the drying in step (2) is completed, the obtained sample is folded, pressed, and packaged in sequence to obtain the drug-loaded balloon.

[0039] The present invention also provides application of the drug-loaded balloon in preparing drugs for treating vascular stenosis.

[0040] The technical solution of the present invention has the following advantages:

[0041] 1. The present invention provides a drug-loaded balloon, comprising a balloon and a drug coating; the drug coating comprises a carrier and a drug, and the carrier comprises one or more of iopromide, butylated hydroxytoluene, phospholipids, cholesterol, dopamine, mussel mucin, 3,4-dihydroxyphenylalanine, polydopamine, magnesium stearate, polylactic acid, polysorbate, polyethylene glycol, shellac and sodium lauryl sulfate.

[0042] In the drug-loaded balloon provided by the present invention, the carrier is combined with the drug molecules to form composite particles through non-covalent bonding (hydrogen bonding, π-π stacking, electrostatic adsorption, etc.). On the one hand, the composite particles can adhere to the blood vessels for a long time due to the high adhesion of the carrier, so that the drug can play a role in the target lesion for a long time; on the other hand, the presence of the carrier slows down the absorption time of the drug in the target lesion, so that it can achieve a long-term sustained release effect.

[0043] The carrier acts as a "molecular glue" to adhere to the drug and the balloon, and combines with the drug to form a composite particle, forming a firm drug coating. After being transferred to the target blood vessel, the "molecular glue" exerts its adhesion effect, allowing the composite particles to adhere to the target blood vessel for a long time, achieving a sustained release effect of the drug.

[0044] The presence of the carrier can enable more than one limus drug to achieve high transfer, high adhesion and long-term sustained release, and the crystal form of the modified limus drug is not essential. The presence of the carrier simplifies the preparation method of the drug balloon.

[0045] In the carrier, iopromide, butylated hydroxytoluene, dopamine, mussel mucin, 3,4-dihydroxyphenylalanine, polydopamine, magnesium stearate, polylactic acid, and polyethylene glycol are nanoparticles with a particle size of 10-1500nm. The small size and huge specific surface area of ​​the carrier can be filled between drug molecules in all directions, playing the role of "molecular glue" and stably wrapping and adhering to the drug molecules. The nano "molecular glue" carrier is evenly scattered among the drug molecules to construct a drug sustained-release delivery system with an "endoplasmic reticulum-like" structure in which the nanocarrier and the drug molecules are intertwined, achieving a drug coating loss rate of less than 20% during the delivery process; it can be efficiently adhered to the target blood vessel once and exert a long-term sustained-release effect. On the other hand, the extremely small size of the carrier at the nano level is not easy to produce large-size particle risks in the body, and the coating is highly safe.

[0046] Among the carriers, butylated hydroxytoluene, dopamine, mussel mucin, 3,4-dihydroxyphenylalanine, polydopamine, magnesium stearate, polylactic acid, polyethylene glycol, shellac and sodium dodecyl sulfate are charged, and the absolute value of the carrier's Zeta potential is ≥10mV. These carriers can directly adhere to the target blood vessels, and the presence of their charge will disrupt the cell repair process, slow down the cell proliferation rate, and prevent excessive proliferation of the intima.

[0047] In the carrier, phospholipids, cholesterol, polysorbate, polyethylene glycol, shellac and sodium dodecyl sulfate can act as solubilizers and dispersants to adjust the uniformity and stability of the drug solution (a mixed solution of the drug, organic solvent and carrier).

[0048] The carrier contains electron-rich structures such as amino groups, hydroxyl groups, benzene rings, and double bonds to varying degrees, and can combine with drugs to form stable composite particles through hydrogen bonds, π-π stacking, electrostatic adsorption and other forces; the hydrophobic groups such as benzene rings and alkyl groups in the carrier can bind to the phospholipid bilayer on the cell membrane through hydrophobic interaction, thereby achieving a tissue adhesion effect.

[0049] By selecting one or several of the above-mentioned different carriers to prepare drug-loaded balloons, the composite particles on the drug coating in the obtained drug-loaded balloons can fully exert their adhesion to tissues and prolong the drug's action time in the body. The sustained release time can be greater than 28 days, greatly reducing the risk of vascular restenosis.

[0050] 2. The carrier and the drug form composite particles, which are evenly distributed on the balloon surface to form a drug coating. The particle size of the composite particles is 200nm to 75μm; particles in this particle size range can achieve firm adhesion on the balloon, that is, the loss rate of erosion in the blood is extremely low, and on the other hand, it can ensure that the particles scattered during balloon expansion are small, avoiding the risk of distal embolism.

[0051] 3. In the preparation method, the drying is low-temperature vacuum drying or low-temperature oven drying. Drying at low temperature can protect the stability of the drug and the carrier, and reduce the residual solvent rate on the drug coating. BRIEF DESCRIPTION OF THE DRAWINGS

[0052] In order to more clearly illustrate the specific implementation methods of the present invention or the technical solutions in the prior art, the drawings required for use in the specific implementation methods or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are some implementation methods of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0053] Figure 1 is a morphological characterization diagram of the composite particles in the mixed solution of Example 1;

[0054] Figure 2This is a morphology characterization diagram of the composite particles in the mixed solution of Example 2;

[0055] Figure 3 This is a morphology characterization diagram of the drug-loaded balloon in Example 3;

[0056] Figure 4 It is a schematic diagram of the in vitro test results of different drug-loaded balloons;

[0057] Figure 5 Schematic diagram of coating firmness of drug-loaded balloon at different delivery times in Example 4. DETAILED DESCRIPTION

[0058] The following examples are provided for a better understanding of the present invention, but are not intended to limit the best mode of implementation, nor to limit the content and protection scope of the present invention. Any product identical or similar to the present invention obtained by anyone under the inspiration of the present invention or by combining the features of the present invention with other prior arts shall fall within the protection scope of the present invention.

[0059] If no specific experimental steps or conditions are specified in the examples, the conventional experimental steps or conditions described in the literature in the field can be used. If no manufacturer is specified for the reagents or instruments used, they are all conventional reagent products that can be obtained commercially.

[0060] Example 1

[0061] Weigh 50 mg of the drug (sirolimus, disordered amorphous particles, particle size of 500 nm-7 μm), add it to 8900 mg of tetrahydrofuran, stir for 2 hours to disperse it evenly, and obtain a first solution; then, add 15 mg of the carrier (the carrier is 12 mg of polyethylene glycol (particle size of 400-800 nm, molecular weight of 6000) and 3 mg of cholesterol) to the first solution, continue stirring for 10 hours, so that the carrier and sirolimus are fully combined to obtain a mixed solution.

[0062] The dip coating method was adopted, and a common balloon (PTCA balloon dilatation catheter S025010-4 purchased from Shanghai Yingtai Medical Instrument Co., Ltd.) was selected. The balloon was filled to 3 atm, the temperature of the mixed solution was maintained at 25 °C, and the stirring speed of the mixed solution was controlled to 600 rpm to ensure that the mixed solution could completely immerse the balloon. The balloon was placed vertically in the mixed solution and kept stable for 2 minutes, then taken out vertically and dried naturally for 3 minutes. The operation was repeated twice, and the mass density of the drug loaded on the balloon was controlled to be 2.0 μg / mm 2 .

[0063] The sample obtained above was dried at 50° C. under low temperature vacuum for 12 h. After drying, it was folded, pressed, and packaged in sequence to obtain the drug-loaded balloon.

[0064] The composite particles (i.e., composite particles formed by the carrier and the drug) in the mixed solution prepared in this example were characterized in morphology to obtain a morphological characterization diagram of the composite particles in the mixed solution of this example, as shown in FIG. Figure 1 As shown. Figure 1 As can be seen in the figure, the composite particles are irregular in size, ranging from 500nm to 15μm, which indicates that they can exert their effects continuously at the target lesion.

[0065] Example 2

[0066] The other conditions in Example 1 were kept unchanged, and the type of carrier was replaced with magnesium stearate (particle size of 10-1000 nm), and finally the drug-loaded balloon was prepared.

[0067] The composite particles (i.e., composite particles formed by the carrier and the drug) in the mixed solution prepared in this example were characterized in morphology to obtain a morphological characterization diagram of the composite particles in the mixed solution of this example, as shown in FIG. Figure 2 As shown. Figure 2 It can be seen that the composite particles as a whole are composed of a mixture of irregular drug particles and relatively uniform nanocarriers with smaller particle sizes. The composite particles are evenly distributed, which is conducive to the uniform transfer of the drug coating to the surface of the target blood vessels, giving full play to the overall effect of the composite particles, namely tissue adhesion and long-term sustained release.

[0068] Example 3

[0069] The other conditions in Example 1 were kept unchanged, and the ordinary balloon was replaced with a spinous process balloon (coronary spinous process balloon dilatation catheter SDC22515140 purchased from Shanghai Yingtai Medical Instrument Co., Ltd.); the dipping method was replaced by spraying, the balloon was filled to 5 atm, the temperature of the mixed solution was maintained at 25°C, the liquid inlet flow rate of the inlet was controlled to be 0.5 mL / min, the stirring device on the inlet was stirred at a stirring speed of 500 rpm, an ultrasonic device was provided at the outlet of the inlet, the ultrasonic power was 1 W, the number of spraying was adjusted to 10 times, and the mass density of the drug loaded on the balloon was controlled to be 2.0 μg / mm 2 ; Finally, the drug-loaded balloon was prepared.

[0070] The drug-loaded balloon prepared in this example was subjected to morphological characterization to obtain a morphological characterization diagram of the drug-loaded balloon in this example, as shown in FIG. Figure 3 As shown. Figure 3 It can be seen that the drug coating of the drug-loaded balloon is uniform and complete, and the presence of the spinous process filaments does not affect the uniformity of the entire balloon coating.

[0071] Example 4

[0072] While keeping other conditions in Example 1 unchanged, the ordinary balloon (PTCA balloon dilatation catheter S025010-4 purchased from Shanghai Yingtai Medical Instrument Co., Ltd.) was replaced with an ordinary balloon (PTCA balloon dilatation catheter S025030-4 purchased from Shanghai Yingtai Medical Instrument Co., Ltd.), and finally a drug-loaded balloon was prepared.

[0073] Comparative Example 1

[0074] The other conditions in Example 1 were kept unchanged, and no carrier was added; that is, the balloon was placed vertically into the first solution by dipping, and finally a drug-loaded balloon was prepared.

[0075] Comparative Example 2

[0076] The other conditions in Example 1 remain unchanged, except that the carrier is replaced with tartaric acid, and finally the drug-loaded balloon is prepared.

[0077] Experimental Example 1

[0078] The drug-loaded balloons prepared in Example 1 and Comparative Examples 1-2 were subjected to in vitro experiments, and silicone tubes of appropriate sizes (diameter of drug-loaded balloon: inner diameter of silicone tube = 1.1-1.3) were selected to replace the target blood vessels, and PBS solution (pH 7.4) was selected as simulated blood. The solution temperature was controlled to be 37±2°C, and the solution flow rate through the silicone tube was adjusted to 70mL / min. The three drug-loaded balloons prepared in Example 1 and Comparative Examples 1-2 were expanded to the nominal pressure of the balloon on the silicone tube, and the pressure was maintained for 60s. After the drug coating was fully transferred to the silicone tube, the balloon was withdrawn from the solution, and the silicone tube after the transfer operation was kept continuously flushed under the above conditions. The flushing time was set to 0 time, 1 day, 7 days, 10 days, 14 days, etc. After a fixed time, the silicone tube of the drug coating transfer section was cut off, and an appropriate amount of acetonitrile was added. The drug concentration was tested by high-performance liquid chromatography, and the residual amount of the drug on the silicone tube at different time periods was investigated, thereby characterizing the in vitro sustained release time and effect of the drug coating. A schematic diagram of the in vitro test results of different drug-loaded balloons was obtained, as shown Figure 4 As shown; Figure 4 In the figure, the drug transfer rate on the ordinate = the drug content measured at the corresponding time point / the drug content measured at the initial time (0 time) * 100%. Figure 4 It can be seen that the drug coating on the silicone tube of Comparative Example 1 had no detectable presence of drug at 7 days, and the drug coating on the silicone tube of Comparative Example 2 had no detectable presence of drug at 10 days, while the drug transfer rate of the drug coating in Example 1 was still 7.97% at 14 days.

[0079] Experimental Example 2

[0080] The drug-loaded balloons prepared in Example 1 and Comparative Examples 1-2 were subjected to in vivo experiments. Six white pigs (labeled Z1, Z2, Z3, Z4, Z5, and Z6) were selected as animal models for the in vivo experiments. Three coronary arteries were selected for each white pig. The experiment was conducted at a vascular position matching the diameter of the drug-loaded balloon (the coronary artery diameter was measured by DSA imaging technology, and the diameter of the drug-loaded balloon was 1.1-1.3 times the diameter of the blood vessel), simulating actual clinical PCI (percutaneous coronary intervention) surgery. Z1, Z2 The blood vessels of Z1, Z3 and Z4 were given the drug-loaded balloon corresponding to Example 1, the blood vessels of Z5 and Z6 were given the drug-loaded balloon corresponding to Comparative Example 2, and the drug-loaded balloon was expanded to the nominal pressure at the target blood vessel, and the pressure was maintained for 60 seconds before being withdrawn from the body. Two time points, immediately (Z1, Z3 and Z5) and 28 days (Z2, Z4 and Z6), were set respectively. The corresponding target blood vessels were dissected during the corresponding follow-up period to perform tissue drug concentration tests, and the in vivo test results of different drug-loaded balloons were obtained, as shown in Table 1.

[0081] Among them, the test method for vascular tissue drug concentration (μg / g, the mass of drug contained in each gram of vascular tissue) is as follows: weigh a certain amount of sample, add 1mL of acetonitrile and then add zirconium oxide grinding beads to grind for 10 minutes, then centrifuge at 13000rpm for 10 minutes at 4°C, and finally filter with a 0.22μm filter membrane, and take the filtrate for high performance liquid chromatography analysis.

[0082] Table 1 In vivo test results of different drug-loaded balloons

[0083]

[0084]

[0085] In Table 1, BLQ means not detected.

[0086] It can be seen from Table 1 that the average immediate vascular tissue drug concentration at the target blood vessel of the animal in Comparative Example 1 is only 4.35 μg / g, and that in Comparative Example 2 is 4.61 μg / g, and no drug can be detected in Comparative Example 1 and Comparative Example 2 after 28 days; while the average immediate vascular tissue drug concentration at the target blood vessel of the animal in Example 1 is 167.06 μg / g, and the target blood vessel tissue still has 32.93 μg / g of drug effect after 28 days.

[0087] Experimental Example 3

[0088] The drug-loaded balloon prepared in Example 4 was selected, and actual clinical PCI surgery was simulated on white pigs through puncture and intravenous injection of heparin. The anterior descending branch was selected as the experimental target vessel, and the drug-loaded balloon was positioned by the developing point. After being delivered to the same position, the flushing time (1, 2, 3, 5, 10 minutes) was started to simulate the actual delivery process of the drug-coated balloon in clinical practice.

[0089] After the timing was over, the drug-loaded balloon was removed from the body, and the drug-loaded balloons at 1, 2, 3, 5, and 10 minutes after flushing were collected and tested for drug content. The nominal value (the nominal value refers to the mass density of the drug on the balloon - 2.0 μg / mm 2 ) comparison, drug coating firmness = drug density after flushing / nominal value * 100%, and finally the schematic diagram of coating firmness of the drug-loaded balloon at different delivery times in Example 4 is obtained, as shown in Figure 5 As shown. Figure 5 It can be seen that under the experimental conditions, the drug-loaded balloon prepared in Example 4 was flushed in the animal body for 10 minutes with almost no drug loss, and its firmness was still close to 100%.

[0090] Obviously, the above embodiments are merely examples for the purpose of clear explanation, and are not intended to limit the implementation methods. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. The obvious changes or modifications derived therefrom are still within the scope of protection of the invention.

Claims

1. A drug-loaded balloon, characterized in that: The drug-loaded balloon comprises a balloon and a drug coating; The drug coating comprises a carrier and a drug, wherein the carrier comprises one or more of iopromide, butylated hydroxytoluene, phospholipid, cholesterol, dopamine, mussel mucin, 3,4-dihydroxyphenylalanine, polydopamine, magnesium stearate, polylactic acid, polysorbate, polyethylene glycol, shellac and sodium lauryl sulfate.

2. The drug-loaded balloon according to claim 1, characterized in that: The mass ratio of the carrier to the drug is 1:(1-50); Optionally, the mass density of the drug on the drug-loaded balloon is 0.5-6.0 μg / mm 2 .

3. The drug-loaded balloon according to claim 1, characterized in that: The drugs include limus drugs; Optionally, the limus drugs include one or more of sirolimus, tacrolimus, everolimus, temsirolimus, umimerosimus and pimecrolimus.

4. The drug-loaded balloon according to claim 1, characterized in that: The balloon includes a common balloon or a functional balloon; Optionally, the functional balloon includes a mastoid balloon, a spinous process balloon, a high-pressure balloon, a scored balloon or a high-pressure cutting balloon.

5. The drug-loaded balloon according to claim 1, characterized in that: The molecular weight of the polyethylene glycol is 4000-8000.

6. The method for preparing the drug-loaded balloon according to any one of claims 1 to 5, characterized in that: It includes the following steps: (1) mixing the drug, the organic solvent and the carrier to obtain a mixed solution; (2) Loading the mixed solution onto the outer surface of the balloon, and obtaining the drug-loaded balloon after drying.

7. The method for preparing the drug-loaded balloon according to claim 6, characterized in that: The organic solvent in step (1) includes one or more of water, acetonitrile, acetone, dichloromethane, ethanol, ethyl acetate, petroleum ether, n-heptane, tetrahydrofuran and isopropanol.

8. The method for preparing the drug-loaded balloon according to claim 6, characterized in that: The mass ratio of the drug, organic solvent and carrier in step (1) is (1-50):(62-5000):

1.

9. The method for preparing the drug-loaded balloon according to claim 6, characterized in that: The loading method in step (2) is spraying or dipping; Optionally, the drying temperature in step (2) is ≤60°C and the drying time is 1-24h.

10. Use of the drug-loaded balloon according to any one of claims 1 to 5 in the preparation of a drug for treating vascular stenosis.

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