CN109954198B

CN109954198B - Drug balloon and preparation method thereof

Info

Publication number: CN109954198B
Application number: CN201711425242.5A
Authority: CN
Inventors: 卢金华; 龙汉
Original assignee: Lifetech Scientific Shenzhen Co Ltd
Current assignee: Lifetech Scientific Shenzhen Co Ltd
Priority date: 2017-12-25
Filing date: 2017-12-25
Publication date: 2021-10-12
Anticipated expiration: 2037-12-25
Also published as: CN109954198A

Abstract

The invention discloses a medicine balloon and a preparation method thereof. A drug-loaded balloon comprises a balloon body, wherein a drug-loaded layer is formed on the surface of the balloon body, the material of the drug-loaded layer comprises a carrier and a drug mixed with the carrier, the drug-loaded layer comprises a transition layer formed on the surface of the balloon body and a crystallization layer formed on the surface of the transition layer, the drug in the transition layer is in at least one state selected from amorphous state, nanocrystalline state and microcrystalline state, and the drug in the crystallization layer is in a crystalline state. The drug-carrying layer of the drug balloon is tightly combined with the balloon and can be released for a long time.

Description

Drug balloon and preparation method thereof

Technical Field

The invention relates to a medical appliance, in particular to a medicine balloon and a preparation method thereof.

Background

With the change of life style and the aging of population, cardiovascular diseases have become non-infectious diseases seriously harming human life and health. According to the report of the World Health Organization (WHO), the number of patients WHO die of cardiovascular diseases in developed countries increases from 100 to 600 ten thousand in 2000 to 2020. Low-income and medium-income countries will have 900 ten thousand patients who die during this period from 1000 to 1900 ten thousand patients. Therefore, prevention and treatment of cardiovascular diseases are becoming a focus of common attention of doctors all over the world.

Since the success of Swiss experts in 1977 in human first Percutaneous Transluminal Coronary Angioplasty (PTCA), the treatment of coronary heart disease has made a major advance, and PTCA has gradually become an important choice for the treatment of coronary artery disease following drug and surgical treatment, known as the first milestone in interventional cardiology. Although coronary stenosis can be eliminated by a simple balloon dilatation, the incidence rate of restenosis of a blood vessel after PTCA (percutaneous transluminal coronary angioplasty) is high due to elastic retraction, intimal hyperproliferation, intimal tear and the like generated by the blood vessel wall, and the restenosis rate is as high as 30-50% 3-6 months after the PTCA, the use of a metal bare stent (BMS) can immediately eliminate the restenosis of the blood vessel and also can greatly reduce the incidence rate of acute reocclusion of the blood vessel, but the incidence rate of restenosis of a target blood vessel is still as high as 30%, the incidence rate of restenosis of the target blood vessel is greatly reduced to about 5% by the occurrence of a drug-eluting stent (DES), and the drug eluting stent is also called as the third milestone in the field of interventional cardiology. The use of a Drug Eluting Stent (DES) is the most successful treatment mode currently used, but the polymer coating matrix on the surface of the DES can induce inflammatory reaction and delay wound healing, and the coating drug can inhibit the proliferation of smooth muscle cells and the regeneration of endothelial cells at the same time, so that the vascular endothelialization process is delayed after the stent is implanted, and the formation of late stent thrombosis is increased, thereby bringing threat to the life safety of patients. In addition, the fields of in-stent restenosis, small vessel lesions, bifurcation lesions, peripheral vessel lesions, etc. also limit the application of DES. In this case, Drug Coated Balloons (DCB) have come into play, and the emergence of DCB offers a new option for the management of the above-mentioned conditions, bringing new hopes for the long-term prognosis of coronary intervention.

DCB is prepared by coating the surface of balloon with medicine, and releasing the medicine to the vascular wall to play the antiproliferative role when the balloon is expanded, so as to prevent the occurrence of restenosis in blood vessel. For example, paclitaxel is currently marketed as a balloon for anti-tissue proliferation drugs, which has the characteristics of lipophilicity, high adsorption rate and the like, can be rapidly absorbed by the intima, and can produce a continuous and effective inhibition effect on smooth muscle cell proliferation even if the paclitaxel is applied in a short (0-3min) single dose due to the irreversible influence of the paclitaxel on the cytoskeleton.

When the medicine in the medicine coating of the medicine balloon exists in an amorphous shape, the medicine coating has excellent coating uniformity, particles formed in the medicine release process are smaller, the medicine conveying loss of the medicine balloon in the conveying process is smaller, large-particle medicine accumulation cannot be formed due to the even medicine coating, the medicine can be uniformly transferred to tissues, and tissue medicine toxicity caused by overhigh concentration of the taxol in local tissues cannot be formed; when the medicine is in a crystalline state, the uniformity of the surface of the medicine coating layer is poorer along with the increase of the crystal size of the medicine, particles with larger sizes are easier to form, the binding force between the medicine and a balloon material is influenced, the medicine conveying loss of a medicine balloon in the conveying process is increased, the increase of the crystal size possibly causes the medicine concentration of local tissues to be larger, and the medicine toxicity of the local tissues is caused.

Thus, the presence of the drug balloon as amorphous or small crystals is advantageous in terms of the safety of the drug balloon, but the presence of the drug balloon as large-sized crystals is advantageous in terms of the sustained effectiveness of the drug balloon. The current drug loaded on the surface of the drug balloon is difficult to realize both the two aspects.

Disclosure of Invention

Based on this, there is a need for a drug balloon that is tightly bonded to the balloon and can release drug for a long time, and a method for manufacturing the same.

A drug-loaded balloon comprises a balloon body, wherein a drug-loaded layer is formed on the surface of the balloon body, the material of the drug-loaded layer comprises a carrier and a drug mixed with the carrier, the drug-loaded layer comprises a transition layer formed on the surface of the balloon body and a crystallization layer formed on the surface of the transition layer, the drug in the transition layer is in at least one state selected from amorphous state, nanocrystalline state and microcrystalline state, and the drug in the crystallization layer is in a crystalline state.

Above-mentioned medicine sacculus, through setting up transition layer and crystallization layer, the medicine existence state in the transition layer is selected from at least one kind in amorphous form, nanometer crystalline state and the microcrystal state, the transition layer surface is even, combine closely between the sacculus surface, even and inseparable transition layer is favorable to the adhesion of crystallization layer, the medicine is the crystalline state in the crystallization layer, through the cooperation of transition layer and crystallization layer, both favorable to the medicine to have sufficient retention time on vascular tissue during the use, fully restrain the hyperplasia of smooth muscle cell, guarantee simultaneously can not have a large amount of accumulations of medicine crystal, avoid local tissue drug concentration too high and the medicine toxicity that leads to.

Drawings

FIG. 1 is a schematic diagram of a drug balloon according to one embodiment;

FIG. 2 is a SEM of the transition layer of example 1 at 2000 Xmagnification;

FIG. 3 is a SEM photograph of the crystalline layer of example 1 at 2000 Xmagnification.

Detailed Description

To facilitate an understanding of the invention, the invention will now be described more fully with reference to the accompanying drawings. Preferred embodiments of the present invention are shown in the drawings. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.

Unless defined otherwise, 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 invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.

Referring to fig. 1, a drug balloon according to an embodiment includes a balloon 1, a drug-loaded layer is formed on a surface of the balloon 1, the drug-loaded layer includes a carrier and a drug mixed with the carrier, the drug-loaded layer includes a transition layer 2 formed on the surface of the balloon 1 and a crystalline layer 3 formed on the surface of the transition layer 2, a state of the drug in the transition layer 2 is selected from at least one of an amorphous state, a nanocrystalline state and a microcrystalline state, and the drug in the crystalline layer 3 is a crystalline state.

It should be noted that, depending on the manufacturing process of the drug balloon, the boundary between the transition layer 2 and the crystalline layer 3 is not very clear in some embodiments, but the transition layer 2 and the crystalline layer 3 should be considered to be present as long as there is an outer layer of the drug that is substantially crystalline and an inner layer of the drug that is in at least one of an amorphous state, a nanocrystalline state, and a microcrystalline state. The drug in the crystalline layer 3 is in a crystalline state, which means that most of the drug in the crystalline layer 3 is in a crystalline state, and the drug which is not crystallized may be less due to the preparation process, and the identification of the crystalline layer 3 is not affected.

In one embodiment, the grain size of the drug in the crystallization layer 3 is 5-30 μm.

In one embodiment, the microcrystalline drug has a grain length of no greater than 5 μm.

In one embodiment, the content of the drug in the transition layer 2 is 10% to 50% of the total content of the drug in the drug-loaded layer.

In one embodiment, the mass ratio of the carrier to the medicine is 1: 9-5: 5.

In one embodiment, the drug is selected from at least one of an anti-intimal hyperplasia drug, an anticoagulant drug, an anti-platelet adhesion drug, an anti-infective drug, an antibacterial drug, and an antineoplastic drug.

The anti-intimal hyperplasia drug is at least one selected from everolimus, rapamycin, paclitaxel, docetaxel, taxol, probucol and colchicine.

The anticoagulant is at least one of heparin, warfarin sodium and vitamin K antagonist.

The anti-platelet adhesion drug is at least one selected from aspirin, prostaglandin, salvianolic acid, nitrate drug, lysine and dipyridamole. Further, the nitrate medicine is at least one selected from nitroglycerin, isosorbide dinitrate, nifedipine and nitronicotinate.

The anti-infective drug is at least one of ampicillin, cefamycin, sulfadiazine and streptomycin sulfate.

The antibacterial agent is at least one selected from chitosan, chitosan derivatives, cefoxitin, nalidixic acid and pipemidic acid. Further, the chitosan derivative is selected from at least one of chitosan acylation, chitosan alkylation, chitosan hydroxylation, chitosan aldehyde imino, chitosan carboxymethylation and chitosan sulfation.

The antineoplastic agent is at least one selected from daunorubicin, adriamycin, carboplatin and macrolides.

In one of the two casesIn an embodiment, the carrier contains a polar group, and the carrier is at least one selected from a polar organic substance and a polar polymer. Further, the polar group is selected from-OH and-SO₃H、-NH₂At least one of, -NHR and-COOH, wherein R represents alkyl.

In one embodiment, the polar organic substance is selected from at least one of sodium ferulate, L-phenylalanine, benzoate, methionine, proline, lysine, leucine, hydroxypropyl- β -cyclodextrin, sorbitol, L-valine, nicotinamide, acetamide, meglumine, L-isoleucine, glucose, maltose, tween 80, mannitol, lecithin, tryptophan, L-threonine, salicylic acid, sodium p-aminosalicylate, sodium heparin, and vitamin C.

In one embodiment, the polar polymer is selected from at least one of polyethylene glycol, polylysine, sodium hyaluronate, poloxamer, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene oxide, polyacrylate, and polyacrylamide.

Above-mentioned medicine sacculus, through setting up transition layer 2 and crystallization layer 3, the medicine existence state in transition layer 2 is selected from amorphous form, at least one in nanometer crystalline state and the microcrystalline state, transition layer 2 surface is even, combine closely between the sacculus 1 surface, even and inseparable transition layer 2 is favorable to the adhesion of crystallization layer 3, the medicine is the crystalline state in crystallization layer 3, through transition layer 2 and the cooperation of crystallization layer 3, both favorable to the medicine to have sufficient retention time on vascular tissue during the use, fully restrain the hyperplasia of smooth muscle cell, guarantee simultaneously not to have a large amount of accumulations of medicine crystal, avoid local tissue medicine concentration too high and the medicine toxicity that leads to.

The preparation method of the medicine balloon comprises the following steps:

step S210, providing a drug-loaded solution.

The drug-carrying solution contains a carrier, a drug and a solvent.

Wherein the concentration of the carrier in the drug-carrying solution is 0.1 mg/ml-50 mg/ml, and the concentration of the drug in the drug-carrying solution is 0.1 mg/ml-30 mg/ml.

In one embodiment, the preparation of the drug-loaded solution comprises:

step S211, preparing a drug solution.

The drug solution comprises a first solvent and a drug dissolved in the first solvent.

Further, the first solvent is at least one selected from methanol, ethanol, acetone, dimethyl sulfoxide, acetonitrile and chloroform.

Furthermore, the concentration of the medicine in the medicine solution is 0.1 mg/ml-30 mg/ml.

Step S212, preparing a carrier solution.

The carrier solution includes a second solvent and a carrier dissolved in the second solvent.

Further, the second solvent includes water. Of course, in some embodiments, the second solvent also includes an aqueous solvent. Specifically, the aqueous solvent is at least one selected from ethanol, methanol, acetone and tetrahydrofuran. The second solvent is only required to be capable of dissolving the carrier and to be miscible with the first solvent. Preferably, the water is water for injection.

Further, the concentration of the carrier in the carrier solution is 0.1mg/ml to 30 mg/ml.

And step S213, mixing the drug solution with the carrier solution to obtain a drug-loaded solution.

In one embodiment, the volume percentage of the carrier solution in the drug-loaded solution is 0.1-50%.

Of course, step S212 may be limited to step S211, or may be performed in synchronization with both.

The drug-loaded solution prepared by the method has the advantage that the solvent in the drug-loaded solution is a mixture of the first solvent and the second solvent. Of course, in other embodiments, the drug-loaded solution may be prepared by directly dissolving the drug and the carrier in a solvent.

In other embodiments, the pre-loaded solution may be purchased or provided by other suppliers or upstream entities, and step S210 may be omitted.

Step S220, the surface of the balloon 1 is pretreated to enable the surface of the balloon 1 to have hydrophilicity or to enable the surface of the balloon 1 to be roughened.

In one embodiment, the pretreatment comprises at least one of an alcoholization treatment, a plasma treatment, and an etch-trench treatment.

Further, the alcoholization treatment comprises: immersing the saccule 1 into ethanol water solution with volume concentration of 50-99.5% for 5-120 minutes at 10-70 ℃, taking out and drying.

The process parameters of the plasma treatment are as follows: the used gas is at least one of nitrogen, oxygen and argon, the output power is 50W-2000W, the frequency is 10 MHz-100 MHz, the processing time is 5 seconds-30 minutes, and the air pressure is 1 Pa-100 Pa.

It is understood that step S220 may be omitted.

And step S230, coating and preparing a transition layer 2 on the surface of the balloon 1.

In one embodiment, the transition layer 2 is obtained by spraying the drug-loaded solution onto the surface of the balloon 1 by ultrasonic atomization and drying.

In one embodiment, the process parameters for ultrasonic atomization spraying of the drug-loaded solution onto the surface of the balloon 1 are as follows: the flow rate of the drug-carrying solution is 0.01 ml/min-0.05 ml/min, the ultrasonic frequency is 25 KHz-180 KHz, the rotating speed of the balloon 1 is 1.0 r/s-5.0 r/s, the feeding speed is 0.1 mm/s-5.0 mm/s, and the spraying height is 10 mm-40 mm.

By controlling the parameters of ultrasonic atomization spraying, the concentration of the medicine in the medicine carrying solution sprayed to the surface of the balloon 1 can be controlled to be low, the spraying speed is high, the medicine cannot be crystallized in time, and therefore the medicine in the transition layer 2 is mainly in at least one of an amorphous state, a nano-crystalline state and a microcrystalline state. Further, the grain length of the microcrystalline state is less than or equal to 5 μm.

In one embodiment, the drying is at least one selected from the group consisting of room-temperature air drying, forced air drying, vacuum drying, freeze drying, and heat drying. Further, the temperature for heating and drying is 30-60 ℃.

In one embodiment, the drying time is not less than 1 hour. Preferably, the drying time is 1 to 6 hours.

It should be noted that the transition layer 2 may be prepared by spraying once, or by spraying for multiple times, and during spraying for multiple times, drying is performed after each spraying.

And S240, coating the surface of the transition layer 2 to prepare a crystallization layer 3.

In one embodiment, the drug-loaded solution is sprayed onto the surface of the transition layer 2 by ultrasonic atomization and dried to obtain the drug coating, and then the solvent is sprayed onto the surface of the drug coating by ultrasonic atomization to crystallize the drug in the drug coating.

The technological parameters of ultrasonic atomization spraying of the drug-loaded solution to the surface of the transition layer 2 are as follows: the flow rate of the drug-carrying solution is 0.05 ml/min-0.20 ml/min, the ultrasonic frequency is 25 KHz-180 KHz, the rotating speed of the balloon 1 is 1.0 r/s-5.0 r/s, the feeding speed is 0.05 mm/s-5.0 mm/s, and the spraying height is 10 mm-40 mm.

And in the operation of spraying the drug-loaded solution to the surface of the transition layer 2 by ultrasonic atomization and drying to obtain the drug coating, the drying is at least one selected from normal-temperature air drying, forced air drying, vacuum drying, freeze drying and heating drying. Further, the temperature for heating and drying is 30-60 ℃. The drying time is not less than 1 hour. Preferably, the drying time is 1 to 6 hours.

Through the parameter of control ultrasonic atomization spraying, can control the concentration of spraying medicine in the medicine carrying solution to transition layer 2 surface great, the solvent relative content is less, and the speed of feeding is slow, and the medicine can crystallize on transition layer 2 surface, forms the great crystal of granule.

The technological parameters of ultrasonic spraying the solvent on the surface of the drug coating are as follows: the flow rate of the solvent is 0.01ml/min to 0.05ml/min, the ultrasonic frequency is 25KHz to 180KHz, the rotating speed of the saccule 1 is 1.0r/s to 5.0r/s, the feeding speed is 0.05mm/s to 5.0mm/s, and the spraying height is 30mm to 60 mm.

In one embodiment, the solvent is sprayed on the surface of the drug coating layer by ultrasonic wave to crystallize the drug in the drug coating layer, and then the drug coating layer is dried. Further, the drying is at least one selected from the group consisting of normal-temperature air drying, forced air drying, vacuum drying, freeze drying and heat drying. Further, the temperature for heating and drying is 30-60 ℃. The drying time is not less than 1 hour. Preferably, the drying time is 1 to 6 hours.

In one embodiment, the solvent for spray coating is selected from at least one of methanol, ethanol, acetone, dimethyl sulfoxide, acetonitrile and chloroform.

The crystalline layer 3 can be prepared once or for multiple times, and when the crystalline layer is prepared for multiple times, the crystalline layer is sprayed with the drug-loaded solution and then dried, and the drug-loaded solution is repeatedly sprayed and dried for multiple times; then spraying the solvent and drying, and repeating the spraying of the solvent and drying for multiple times.

Step S230 and step S240 are to prepare the transition layer 2 and the crystallization layer 3, respectively, and the transition layer 2 and the crystallization layer 3 constitute a drug-loaded layer.

And S250, fully drying the drug balloon.

In one embodiment, the drying time is not less than 12 hours. Preferably, the drying time is 12 hours to 24 hours.

Step S260, flap winding of the drug balloon.

Flap winding may be accomplished by a balloon flap machine, or other tooling fixture, or other external force.

The preparation method of the drug balloon comprises the steps of forming a drug-loaded layer structure comprising a transition layer 2 and a crystallization layer 3 by controlling spraying process parameters, adjusting the existing states of the drugs in the transition layer 2 and the crystallization layer 3, enabling the existing state of the drugs in the transition layer 2 to be selected from at least one of an amorphous state, a nano-crystalline state and a micro-crystalline state, enabling the drugs in the crystallization layer 3 to be in a crystalline state, enabling the drugs and carriers to be uniformly dispersed in an effective area of the balloon 1 by virtue of a two-layer structure, avoiding the accumulation of the drugs, increasing the binding force between the drug-loaded layer and the balloon 1 by virtue of the transition layer 2, ensuring the uniform transfer of the drugs, enabling the drugs to be continuously present in a blood vessel tissue for a long time by virtue of the crystallization layer 3, ensuring that the drugs can be retained in a target tissue for a long time, fully inhibiting the proliferation of smooth muscle cells, simultaneously ensuring that no large amount of drug crystals are accumulated, and avoiding drug toxicity caused by overhigh drug concentration in a local tissue, the safety and the effectiveness of the clinical use of the drug balloon are improved; the preparation method of the medicine balloon is simple.

It should be noted that, in the above preparation method of the drug balloon, the concentrations of the drug-carrying solutions used for preparing the transition layer 2 by spraying and preparing the crystallization layer 3 by spraying are the same, and the actual concentrations of the drug-carrying solutions sprayed to the surface of the balloon 1 and the surface of the transition layer 2 are changed by controlling the spraying process parameters, so that the concentration of the drug in the drug-carrying solution sprayed to the surface of the balloon 1 is less than the concentration of the drug in the drug-carrying solution sprayed to the surface of the transition layer 2. Of course, in other embodiments, two concentrations of drug-loaded solutions may be configured, so that the concentration of the drug in the drug-loaded solution used in the step of preparing the transition layer 2 is less than the concentration of the drug in the drug-loaded solution used in the step of preparing the crystal layer 3, in short, regardless of the control of the raw material (drug-loaded solution) or the control of the process parameters, as long as the concentration of the drug in the drug-loaded solution actually attached to the surface of the balloon 1 is less than the concentration of the drug in the drug-loaded solution actually attached to the surface of the transition layer 2, so that the crystallinity of the drug in the crystal layer 3 is high and the crystal grains are large.

The following is a more detailed description with reference to specific examples.

Example 1

In the embodiment, paclitaxel is selected as a medicine, absolute ethyl alcohol is used as a solvent to prepare a medicine solution with the concentration of 10mg/ml, a carrier sodium benzoate is dissolved in water for injection to prepare a carrier solution with the concentration of 30mg/ml, the carrier solution is slowly added into the medicine solution to obtain a medicine carrying solution, and the volume of the carrier solution in the medicine carrying solution accounts for 20 percent.

In a ten-thousand-level clean environment, a PTA balloon 1 catheter (with the diameter of 3mm and the length of 40mm and the nylon balloon 1) is subjected to surface pretreatment by a plasma machine, the plasma pretreatment gas is a mixed gas of argon and oxygen, and the volume ratio is V_{Argon gas}：V_{Oxygen gas}1: 1, the plasma treatment power is 500W, the frequency is 30MHz, the treatment time is 10min, and the air pressure is 50 Pa.

Atomizing and spraying the drug-loaded solution to an effective area of the balloon 1 by adopting ultrasonic spraying equipment, wherein the flow rate of the drug-loaded solution is 0.05ml/min, the ultrasonic frequency is 50KHz, the rotating speed of the balloon 1 is 3.0r/s, the feeding speed is 3.5mm/s, the spraying height is 30mm, the spraying frequency is 4 times, and after the spraying is finished, airing at room temperature for 5 hours to obtain a transition layer 2 for later use;

continuously applying the drug-loaded solution to the surface of the transition layer 2 by adopting an ultrasonic spraying mode, wherein the flow rate of the drug-loaded solution is 0.10ml/min, the ultrasonic frequency is 60KHz, the rotating speed of the balloon 1 is 3.5r/s, the feeding speed is 3.5mm/s, and the spraying height is 35 mm; spraying for 8 times, and airing at room temperature for 1h after spraying to obtain a drug coating for later use;

the method comprises the steps of wetting a medicine coating by spraying an absolute ethyl alcohol solvent on the surface of the medicine coating by adopting ultrasonic spraying equipment, wherein the flow rate of the absolute ethyl alcohol solvent during spraying is 0.02ml/min, the ultrasonic frequency is 120KHz, the rotating speed of a balloon 1 is 4.0r/s, the feeding speed is 3.5mm/s, the spraying height is 50mm, the medicine coating is slowly crystallized after being dried for 1h at room temperature, the spraying and drying operations are continuously repeated for 2 times, and the paclitaxel is conveniently continuously crystallized to the proper crystallization size. And (5) airing the drug balloon at room temperature for 12h after the recrystallization process is finished, and fully drying the drug balloon.

And (4) carrying out flap winding by using a balloon 1 flap folding machine, sleeving a protective sleeve, putting a coil pipe, packaging and sterilizing.

Example 2

Rapamycin is selected as a medicine, acetone is used as a solvent to prepare a rapamycin/acetone solution with the concentration of 0.1mg/ml, a carrier nicotinamide is dissolved in water for injection to prepare a carrier solution with the concentration of 0.1mg/ml, the carrier solution is slowly added into the medicine solution to obtain a medicine carrying solution, and the volume of the carrier solution in the medicine carrying solution accounts for 50 percent.

In a ten thousand grade clean environment, a PTA balloon 1 catheter (diameter is 5mm, length is 60mm, nylon balloon 1) is subjected to surface pretreatment by adopting an alcoholization method, the balloon 1 is immersed in an ethanol solution with the volume concentration of 99.5% for 120 minutes at 10 ℃, and then taken out and dried.

Atomizing and spraying the drug-loaded solution to an effective area of the balloon 1 by adopting ultrasonic spraying equipment, wherein the flow rate of the drug-loaded solution is 0.1ml/min, the ultrasonic frequency is 180KHz, the rotating speed of the balloon 1 is 5.0r/s, the feeding speed is 5.0mm/s, the spraying height is 40mm, the spraying frequency is 5 times, and after the spraying is finished, airing at room temperature for 1h to obtain a transition layer 2 for later use;

continuously applying the drug-loaded solution to the surface of the transition layer 2 by adopting an ultrasonic spraying mode, wherein the flow rate of the drug-loaded solution is 0.10ml/min, the ultrasonic frequency is 60KHz, the rotating speed of the balloon 1 is 3.5r/s, the feeding speed is 3.5mm/s, and the spraying height is 35 mm; spraying for 10 times, and airing at room temperature after spraying to obtain a drug coating for 1h for later use;

the method comprises the steps of wetting a medicine coating by spraying a tetrahydrofuran solvent on the surface of the medicine coating by adopting ultrasonic spraying equipment, wherein the flow rate of the tetrahydrofuran solvent during spraying is 0.01ml/min, the ultrasonic frequency is 120KHz, the rotating speed of a balloon 1 is 4.0r/s, the feeding speed is 3.5mm/s, the spraying height is 60mm, the medicine is dried at room temperature for 1h to slowly crystallize rapamycin in the coating, and the spraying and drying operations are continuously repeated for 1 time, so that the rapamycin medicine is conveniently continuously crystallized to reach the proper crystallization size. And (5) airing the drug balloon at room temperature for 12h after the recrystallization process is finished, and fully drying the drug balloon.

Example 3

In the embodiment, paclitaxel is selected as a medicine, methanol is used as a solvent to prepare a medicine solution with the concentration of 30mg/ml, a carrier mannitol is dissolved in water for injection to prepare a carrier solution with the concentration of 30mg/ml, the carrier solution is slowly added into the medicine solution to obtain a medicine carrying solution, and the volume of the carrier solution in the medicine carrying solution accounts for 10 percent.

In a ten thousand-level clean environment, a PTA balloon 1 catheter (with the diameter of 3mm and the length of 40mm and the nylon balloon 1) is subjected to surface pretreatment by a plasma machine, the plasma pretreatment gas is a mixed gas of nitrogen and oxygen, and the volume ratio is V_{Nitrogen gas}：V_{Oxygen gas}1: 2, the plasma treatment power is 2000W, the frequency is 10MHz, the treatment time is 5min, and the air pressure is 50 Pa.

Atomizing and spraying the drug-loaded solution to an effective area of the balloon 1 by adopting ultrasonic spraying equipment, wherein the flow rate of the drug-loaded solution is 0.01ml/min, the ultrasonic frequency is 25KHz, the rotating speed of the balloon 1 is 1.0r/s, the feeding speed is 3.5mm/s, the spraying height is 10mm, the spraying frequency is 2 times, and after the spraying is finished, airing at room temperature for 1h to obtain a transition layer 2 for later use;

continuously applying the drug-loaded solution to the surface of the transition layer 2 by adopting an ultrasonic spraying mode, wherein the flow rate of the drug-loaded solution is 0.10ml/min, the ultrasonic frequency is 60KHz, the rotating speed of the balloon 1 is 3.5r/s, the feeding speed is 3.5mm/s, and the spraying height is 35 mm; spraying for 4 times, and airing at room temperature for 1h after spraying to obtain a drug coating for later use;

the method comprises the steps of wetting a medicine coating by spraying a methanol solvent on the surface of the medicine coating by using ultrasonic spraying equipment, wherein the flow rate of the methanol solvent during spraying is 0.01ml/min, the ultrasonic frequency is 180KHz, the rotating speed of a balloon 1 is 4.0r/s, the feeding speed is 3.5mm/s, the spraying height is 30mm, the medicine coating is dried at room temperature for 1h so that paclitaxel in the medicine coating is slowly crystallized, and the operations of spraying the solvent and drying are continuously repeated for 1 time, so that the paclitaxel is continuously crystallized to reach the proper crystallization size. And (5) airing the drug balloon at room temperature for 12h after the recrystallization process is finished, and fully drying the drug balloon.

Example 4

Selecting everolimus as a medicine, using absolute ethyl alcohol as a solvent to prepare a medicine solution with the concentration of 15mg/ml, dissolving a carrier meglumine in water for injection to prepare a carrier solution with the concentration of 20mg/ml, and slowly adding the carrier solution into the medicine solution to obtain a medicine carrying solution, wherein the volume of the carrier solution in the medicine carrying solution accounts for 30 percent.

In a ten thousand-level clean environment, a PTA balloon 1 catheter (with the diameter of 6mm and the length of 40mm and a nylon balloon 1) is subjected to surface pretreatment by a plasma machine, the plasma pretreatment gas is a mixed gas of nitrogen and oxygen, and the volume ratio is V_{Nitrogen gas}：V_{Oxygen gas}1: 2, the plasma treatment power is 2000W, the frequency is 10MHz, the treatment time is 5min, and the air pressure is 50 Pa.

Atomizing and spraying the drug-loaded solution to an effective area of the balloon 1 by adopting ultrasonic spraying equipment, wherein the flow rate of the drug-loaded solution is 0.02ml/min, the ultrasonic frequency is 100KHz, the rotating speed of the balloon 1 is 3.0r/s, the feeding speed is 3.5mm/s, the spraying height is 40mm, the spraying frequency is 4 times, and after the spraying is finished, airing at room temperature for 4 hours to obtain a transition layer 2 for later use;

continuously applying the drug-loaded solution to the surface of the transition layer 2 by adopting an ultrasonic spraying mode, wherein the flow rate of the drug-loaded solution is 0.15ml/min, the ultrasonic frequency is 80KHz, the rotating speed of the balloon 1 is 3.5r/s, the feeding speed is 3.5mm/s, and the spraying height is 30 mm; spraying for 8 times, and airing at room temperature for 4h after spraying to obtain a drug coating for later use;

the method comprises the steps of wetting a medicine coating by spraying an absolute ethyl alcohol solvent on the surface of the medicine coating by adopting ultrasonic spraying equipment, wherein the flow rate of the absolute ethyl alcohol solvent during spraying is 0.03ml/min, the ultrasonic frequency is 100KHz, the rotating speed of a balloon 1 is 3.5r/s, the feeding speed is 3.5mm/s, the spraying height is 30mm, the everolimus medicine in the medicine coating is slowly crystallized after being dried for 2 hours at room temperature, the spraying and drying operations are continuously repeated for 2 times, and the everolimus medicine is conveniently continuously crystallized to reach a proper crystallization size. And (5) airing the drug balloon at room temperature for 12h after the recrystallization process is finished, and fully drying the drug balloon.

Comparative example

Selecting paclitaxel as a medicine, using absolute ethyl alcohol as a solvent to prepare a medicine solution with the concentration of 10mg/ml, dissolving a carrier sodium benzoate in water for injection to prepare a carrier solution with the concentration of 30mg/ml, slowly adding the carrier solution into the medicine solution to obtain a medicine carrying solution, wherein the volume of the carrier solution in the medicine carrying solution accounts for 20 percent, and forming the medicine carrying solution.

Applying a drug-loaded solution to an effective area on the surface of the balloon 1 by adopting an ultrasonic spraying mode, wherein the flow rate of the drug-loaded solution is 0.10ml/min, the ultrasonic frequency is 60KHz, the rotating speed of the balloon 1 is 3.5r/s, the feeding speed is 3.5mm/s, and the spraying height is 35 mm; spraying for 12 times, and airing at room temperature for 24 hours after spraying to obtain a medicinal balloon for later use;

And (3) testing and comparing loss in the conveying process:

the loss of the drug balloon (DEB) delivery process refers to the loss of the drug during the period from the insertion of the guiding catheter, the pushing of the balloon 1 to the target lesion site, to the time before the DEB is expanded. Drug loss during delivery can be used to directly assess the binding of the drug to the balloon 1.

The test method comprises the following steps: inserting the drug balloon dilatation catheter into an in-vitro simulated blood vessel model, simulating the conveying conditions in the actual use process, controlling the conveying time to be 90s, and analyzing the content of the residual drug on the balloon 1 by using high performance liquid chromatography, wherein the detection conditions of the high performance liquid chromatography are as follows: japanese shimadzu model LC-20A high performance liquid chromatograph, column: aglilent ZOBAX SB-C184.6X 250mm, 5um, mobile phase: methanol acetonitrile water 230:360:410, column temperature: 30 ℃, detection wavelength: 227nm (ultraviolet detector), flow rate: 1.0 mL/min.

3 drug balloons prepared in example 1 and comparative example were selected respectively (sample 1, sample 2, and sample 3) to perform a loss test in the delivery process, and the bonding force between the DEB drug coating prepared by the two processes and the balloon 1 was compared by the test, and the test results are shown in table 1.

TABLE 1

Order of item	Example 1	Comparative example
			Total dose of the drug	765.1	747.5
Sample 1 remaining dose after delivery (μ g)	648.2	411.3
			Sample 2 remaining dose after delivery (μ g)	605.4	387.3
Sample 3 remaining dose after delivery (μ g)	616.8	535.2
			Transport loss + standard deviation	18.5％±2.9％	40.5％±10.6％

As can be seen from table 1, the loss rate of the drug balloon of example 1 during the delivery process is much lower than that of the comparative example, and it can be seen that the drug-loaded layer of the drug balloon of example 1 is tightly bonded to the balloon 1 material; the comparative example is a coating formed by direct drug spraying, the structure of the coating is relatively single, and the lack of excess between the coating and the material of the balloon 1 causes drug accumulation in partial areas of the coating, so that drug crystals in the coating are easily washed away by blood during the delivery process, thereby increasing the loss during the delivery process. The results of the test, in which the loss rate of example 1 in the delivery process is 18.5% + -2.9% and the loss rate of the comparative example in the delivery process is 40.5% + -10.6% in table 1, are significantly lower than the loss rate of the comparative example in the delivery process, also indicate that the composite coating structure is beneficial for increasing the bonding force between the coating and the balloon 1 material and reducing the loss of the drug in the delivery process.

And (3) testing and comparing of the particles:

the test method is that a medicine balloon sample passes through an in-vitro test model to simulate the delivery path and the use process of the medicine balloon in a human body, flowing liquid adopted by the in-vitro test model is purified water, the water is kept at the constant temperature of 37 ℃, the medicine balloon is firstly delivered along a guide wire and reaches an expansion site through a delivery pipeline, an inflation device is adopted to expand the balloon for 12min, the balloon 1 is deflated, a balloon 1 catheter is withdrawn, purified water in the whole simulated use process is collected, a particle tester is adopted to carry out testing, and the particle level of the sample is evaluated by counting the particle size and the number distribution in the purified water. 1 of the drug balloons prepared in example 1 and the comparative example were selected and tested, and the test results are shown in table 2. The balloon gauge was 3.0 x 40, i.e. 3.0mm in diameter and 40mm in length.

TABLE 2

Order of item	Example 1	Comparative example
			10～25(μm)	184,654	146,658
25～50(μm)	18,112	20,147
			50～100(μm)	1,804	2,340
＞100(μm)	110	366

Table 2 statistics were made of the number of particles in the different size particle size intervals during the simulated use of the drug balloons in example 1 and the comparative example. In the embodiment 1, a medicine-carrying layer structure of a transition layer 2+ a crystallization layer 3 is adopted, and medicines in the medicine-carrying layer are uniformly distributed without obvious medicine accumulation; the comparative example applies the drug coating by directly spraying the drug solution, and during the formation of the drug coating, the coating lacks the protection of the transition layer 2 due to repeated spraying impact of the drug solution, and drug accumulation and drug agglomeration are easily formed on the surface of the balloon 1 material. The test results in Table 2 also show that the number of particles in example 1 is lower than that in the comparative example in the range of larger particle size, which shows that the composite coating structure in example 1 is beneficial to the dispersion of the drug in the coating, avoids drug accumulation and agglomeration, and reduces the risk of drug coating particles.

Referring to fig. 2 and 3, fig. 2 is a scanning electron microscope photograph of example 1 at 2000 times magnification of the transition layer, fig. 3 is a scanning electron microscope photograph of example 1 at 2000 times magnification of the crystallization layer, and as can be seen from fig. 2 and 3, after the first spraying, the solvent is rapidly volatilized due to the small spraying flow rate, so that the drug is not ready to crystallize or is not ready to form large crystals in the process of forming the transition layer by the drug solution, and the drug in the transition layer can only exist in an amorphous or microcrystalline form, as shown in fig. 2; after the second spraying and recrystallization to form the crystalline layer, the drug is fully crystallized and grown to form larger drug crystals, as shown in fig. 3.

The technical features of the above embodiments can be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the above embodiments are not described, but should be considered as the scope of the present specification as long as there is no contradiction between the combinations of the technical features.

The above examples only show some embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.

Claims

1. A drug balloon comprises a balloon body and is characterized in that a drug-loaded layer is formed on the surface of the balloon body, the material of the drug-loaded layer comprises a carrier and a drug mixed with the carrier, the drug-loaded layer comprises a transition layer formed on the surface of the balloon body and a crystallization layer formed on the surface of the transition layer, the drug in the transition layer is in a nanocrystalline state or a microcrystalline state, or the drug in the transition layer is in at least two states selected from an amorphous state, a nanocrystalline state and a microcrystalline state, the drug in the crystallization layer is in a crystalline state, and the grain size of the drug in the crystallization layer is larger than that of the drug in the transition layer.

2. The drug balloon of claim 1, wherein the drug in the crystalline layer has a grain size of 5-30 μ ι η; and/or

The grain length of the drug in the microcrystalline state is not more than 5 μm.

3. The drug balloon of claim 1, wherein the carrier contains polar groups, the carrier being selected from at least one of a polar organic or a polar polymer.

4. The drug balloon of claim 3, wherein the polar group is selected from-OH, -SO₃H、-NH₂At least one of, -NHR and-COOH, wherein R represents alkyl.

5. The drug balloon of claim 1, wherein the drug content in the transition layer is 10% to 50% of the total drug content in the drug-loaded layer; and/or

The mass ratio of the carrier to the medicine is 1: 9-5: 5.

6. The method for preparing the drug balloon according to any one of claims 1 to 5, which is characterized by comprising the following steps:

coating the surface of the balloon to prepare the transition layer; and

and coating the surface of the transition layer to prepare the crystallization layer.

7. The method of making a drug balloon of claim 6, further comprising the steps of: providing a drug-carrying solution, wherein the drug-carrying solution contains a carrier, a drug and a solvent;

in the step of preparing the transition layer and the step of preparing the crystallization layer, the same drug-loaded solution is used for coating.

8. The preparation method of the drug balloon according to claim 7, wherein the step of coating the surface of the balloon with the transition layer is specifically: carrying out ultrasonic atomization spraying on the drug-loaded solution to the surface of the balloon and drying to obtain the transition layer;

the step of coating the surface of the transition layer to prepare the crystallization layer specifically comprises the following steps: ultrasonic atomization spraying the drug-loaded solution to the surface of the transition layer and drying to obtain a drug coating, and then performing ultrasonic spraying on the surface of the drug coating, wherein the solvent makes the drug in the drug coating crystallize to obtain the crystallization layer.

9. The method for preparing a drug balloon according to claim 8, wherein the concentration of the drug in the drug-loaded solution attached to the balloon surface is made smaller than the concentration of the drug in the drug-loaded solution attached to the transition layer surface by adjusting parameters of ultrasonic atomization spraying.

10. The preparation method of the drug balloon according to claim 9, wherein the process parameters of the ultrasonic atomization spraying of the drug-loaded solution to the surface of the balloon are as follows: the flow rate of the drug-carrying solution is 0.01 ml/min-0.05 ml/min, the ultrasonic frequency is 25 KHz-180 KHz, the rotating speed of the saccule is 1.0 r/s-5.0 r/s, the feeding speed is 0.1 mm/s-5.0 mm/s, and the spraying height is 10 mm-40 mm; and/or

The technological parameters of the ultrasonic atomization spraying of the drug-loaded solution to the surface of the transition layer are as follows: the flow rate of the drug-carrying solution is 0.05 ml/min-0.20 ml/min, the ultrasonic frequency is 25 KHz-180 KHz, the rotating speed of the saccule is 1.0 r/s-5.0 r/s, the feeding speed is 0.05 mm/s-5.0 mm/s, and the spraying height is 10 mm-40 mm; and/or

The technological parameters of the ultrasonic spraying of the solvent on the surface of the drug coating are as follows: the flow rate of the solvent is 0.01ml/min to 0.05ml/min, the ultrasonic frequency is 25KHz to 180KHz, the rotating speed of the saccule is 1.0r/s to 5.0r/s, the feeding speed is 0.05mm/s to 5.0mm/s, and the spraying height is 30mm to 60 mm.