CN115337523A

CN115337523A - Medicine balloon and preparation method thereof

Info

Publication number: CN115337523A
Application number: CN202110517558.7A
Authority: CN
Inventors: 刘全祖; 王刚; 张�雄
Original assignee: Lifetech Scientific Shenzhen Co Ltd
Current assignee: Lifetech Scientific Shenzhen Co Ltd
Priority date: 2021-05-12
Filing date: 2021-05-12
Publication date: 2022-11-15

Abstract

The invention provides a preparation method of a drug balloon, which comprises the following steps: mixing a medicine, a carrier and a solvent to obtain a mixed solution, wherein the carrier is selected from one of an emulsifier, a combination of the emulsifier and a gel, or a combination of the emulsifier, the gel and a biological adhesive, and the mass ratio of the medicine to the carrier is 100: (10-50), wherein the mass ratio of the medicine to the solvent is (0.1-5) to 100; and spraying the mixed solution on the bare balloon, and placing the bare balloon under the conditions of constant temperature and constant humidity to form a drug coating on the surface of the bare balloon, thereby forming the drug balloon. The medicine balloon prepared by the preparation method at least has the advantages of high reprinting and slow release. The invention also provides a drug balloon.

Description

Medicine balloon and preparation method thereof

Technical Field

The invention relates to the field of medical instruments, in particular to a medicine balloon and a preparation method thereof.

Background

In recent years, drug-coated stents have had great success in treating vascular stenosis. However, long-term clinical test results show that the drug-coated stent can generate side reactions caused by metal frameworks and polymer carriers and risks of late thrombus in blood vessels to human bodies, and postoperative in-stent restenosis also becomes another troublesome problem. In the subsequent study of new devices and therapeutic techniques, drug eluting balloons (hereinafter "DCB" or "drug balloon") have become an emerging means of treating in-stent restenosis and have gained widespread use due to their unique advantages.

The DCB has the action mechanism that the anti-cell proliferation medicine is uniformly coated on the surface of the balloon, and after the DCB is conveyed to a blood vessel pathological change part, the blood vessel is torn and extruded through the short-time expansion of the balloon, so that the medicine is quickly released and adhered to the blood vessel wall and is withdrawn from the balloon, and the purpose of long-time treatment effect can be achieved through the short-time exposure of the medicine. The unique construction of DCB avoids side reactions caused by the metal framework and the polymeric carrier. The DCB has the advantages that the medicine is uniformly coated on the surface of the balloon, and is uniformly released on the blood vessel wall in the expansion process, so that the toxic and side effects of the whole body of a human body caused by the enrichment of the medicine in a part of the blood vessel wall area are avoided. The drug components in the DCB coating on the market at present mainly use paclitaxel, and the effectiveness of the paclitaxel-based drug balloon catheter in inhibiting the restenosis of the vascular lumen is highly determined in a large number of clinical studies and after-market studies, but the safety of the drug balloon catheter is questioned. In view of the FDA's risk alerts for paclitaxel drug-coated products at 2019 on days 1, 17, 3, 15, and 6, 19, the end-stage mortality rate for patients treated with lower limb arterial disease using paclitaxel drug-eluting balloons and drug-eluting stents may increase. "FDA final requirements for approval of marketed products increase in" warning and preventive measures "in its specification: after "patients treated popliteal artery stenosis with paclitaxel coated balloons and paclitaxel eluting stents, a signal of increased risk of late death was observed approximately 2-3 years post-surgery compared to non-drug coated products. There is uncertainty as to the extent and mechanism of increased risk of late death, including whether it originates from the effects of other products. The physician should discuss and explain the potential for increased risk of late death with the patient, as well as the benefits and risks of different treatment regimens. "therefore, for the next generation of drug coated devices, rapamycin is now the primary drug of choice.

Compared with taxol, the rapamycin has obvious advantages and disadvantages, the effect of rapamycin on inhibiting smooth muscle cell and intimal hyperplasia is similar to that of taxol, and the rapamycin is obviously superior to the taxol in the aspects of accelerating apoptosis, safe dosage, resisting restenosis and the like. But has the disadvantages of slow tissue uptake and short residence time on the vessel wall. Therefore, a high-load (the drug coating is loaded on the blood vessel wall) drug coating is designed, and the key to the success of the rapamycin-based coating balloon is the slow-release (the retention time of the drug on the blood vessel wall).

Disclosure of Invention

Based on this, there is a need for a method for preparing a drug balloon, which has at least the advantages of high loading and slow release.

A preparation method of a drug balloon comprises the following steps:

mixing a medicine, a carrier and a solvent to obtain a mixed solution, wherein the carrier is selected from one of an emulsifier, a combination of the emulsifier and a gel, or a combination of the emulsifier, the gel and a biological adhesive, and the ratio of the mass of the medicine to the mass of the carrier is in a range of 100: (10-50), the mass ratio of the drug to the solvent being in the range of (0.1-5): 100;

and spraying the mixed solution on a bare balloon, and placing the bare balloon under a constant temperature and humidity condition to form a drug coating on the surface of the bare balloon, thereby forming the drug balloon.

Further, the emulsifier is at least one selected from sorbitan monooleate, hexadecanol, octadecanol, lauric acid and fatty glyceride; the gel is selected from at least one of thioxylan, polyvinylpyrrolidone, sodium alginate, sodium carboxymethyl cellulose and carboxyvinyl copolymer; the biological adhesive is at least one of isobutyl cyanoacrylate, starch, protein, animal glue, shellac and polyacrylic acid.

Further, the solvent is at least one selected from tetrahydrofuran, ethyl acetate, ethanol, acetonitrile, methanol, acetone, benzene, n-heptane, toluene, xylene, cyclohexanone, dioxane and water.

Further, the step of mixing the drug, the carrier and the solvent to obtain a mixed solution comprises the following steps: dissolving the medicine in the solvent and then shaking to obtain a medicine solution; dissolving the carrier in the solvent and then oscillating to obtain a carrier solution; and mixing the drug solution and the carrier solution to obtain the mixed solution.

Further, the mixed liquid is sprayed on the bare balloon by adopting a medicine balloon spraying machine, wherein the spraying ultrasonic atomization power range is 1-5W, the spraying flow range is 0.01-1 ml/min, the spraying height range is 10-60 mm, and the spraying air pressure range is 0.05-0.1 Mpa.

Further, the time period of the standing in the constant temperature and humidity condition is in the range of 6 to 24 hours, the temperature range is 20 to 40 ℃, the humidity range is 40 to 70% RH in the constant temperature and humidity condition.

Further, when the carrier is the emulsifier, the formed drug coating is a nano microsphere crystalline drug coating; when the carrier is the combination of the emulsifier and the gel, the drug coating is formed, and the nano microsphere crystallized drug is bound in the pores of the gel net; when the carrier is the combination of the emulsifier, the gel and the biological adhesive, the drug coating is formed, the nano microsphere crystallized drug is bound in the pores of the gel net, and a smooth biological adhesive film is arranged on the surface of the drug coating.

Further, when the carrier is a combination of the emulsifier and the gel, the mass ratio between the emulsifier and the gel is in a range of 1: (0.5 to 1); when the carrier is the combination of the emulsifier, the gel and the biological adhesive, the mass ratio of the emulsifier to the gel to the biological adhesive is in a range of 1: (0.5-1): (0.6-1).

Further, the preparation method of the drug balloon further comprises the following steps: and (3) coiling the drug saccule in a split manner, and sleeving a protective sleeve on the drug saccule, wherein the split number ranges from 3 to 6, and the temperature range for coiling in the split manner ranges from 40 to 70 ℃.

A drug balloon prepared by the preparation method of the drug balloon.

The preparation method of the drug balloon adopts the mode of selecting different carriers, controlling the proportion among the drug, the carriers and the solvent and spraying in one step, is simple and easy to operate, and has the advantages of high drug loading rate, long retention time and good slow release effect, thereby meeting the clinical requirements. In the preparation process of the medicine balloon, the balloon is not required to be physically or chemically modified, the mechanical property and the service life of the balloon are effectively maintained, the operation is simple, special processing equipment is not required, and the production cost is greatly reduced compared with other similar technologies.

Drawings

Fig. 1 is a scanning electron micrograph of the drug balloon coating provided in example 1.

Fig. 2 is a scanning electron micrograph of the drug balloon coating provided in example 2.

Fig. 3 is a scanning electron micrograph of the drug balloon coating provided in example 3.

Fig. 4 is a scanning electron micrograph of the drug balloon coating provided in comparative example 1.

Fig. 5 is a scanning electron micrograph of the drug balloon coating provided in comparative example 2.

Detailed Description

In order to make the aforementioned objects, features and advantages of the present invention comprehensible, embodiments accompanied with figures are described in detail below. In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein, but rather should be construed as broadly as the present invention is capable of modification in various respects, all without departing from the spirit and scope of the present invention.

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.

The embodiment of the invention provides a preparation method of a medicine balloon, which comprises the following steps:

step one, mixing a medicine, a carrier and a solvent to obtain a mixed solution, wherein the carrier is selected from one of an emulsifier, a combination of the emulsifier and a gel, or a combination of the emulsifier, the gel and a biological adhesive, and the ratio of the mass of the medicine to the mass of the carrier is in a range of 100: (10-50), the mass ratio of the drug to the solvent is (0.1-5): 100.

And secondly, spraying the mixed solution on the bare balloon, and placing the bare balloon under the conditions of constant temperature and constant humidity to form a drug coating on the surface of the bare balloon, thereby forming the drug balloon.

Specifically, in the first step, the emulsifier is at least one selected from sorbitan monooleate, hexadecanol, octadecanol, lauric acid and fatty glyceride; the gel is at least one selected from the group consisting of thioxylan, polyvinylpyrrolidone, sodium alginate, sodium carboxymethylcellulose, and carboxyvinyl copolymer; the biological adhesive is at least one of isobutyl cyanoacrylate, starch, protein, animal glue, shellac and polyacrylic acid.

The solvent is at least one selected from tetrahydrofuran, ethyl acetate, ethanol, acetonitrile, methanol, acetone, benzene, n-heptane, toluene, xylene, cyclohexanone, dioxane and water.

In one embodiment, the step of mixing the drug, the carrier and the solvent to obtain the mixed solution specifically comprises the following steps: dissolving a medicine in a solvent and then shaking to obtain a medicine solution; dissolving a carrier in a solvent and then oscillating to obtain a carrier solution; mixing the drug solution and the carrier solution to obtain a mixed solution. In other embodiments, the drug, the carrier and the solvent can be directly and uniformly mixed.

In this example, the ratio of the mass of the drug to the mass of the carrier ranged from 100: (10-50), the mass ratio of the drug to the solvent is (0.1-5): 100. The carrier amount is too small to play a role in dispersing the medicine, promoting the crystallization of the medicine and subsequent transshipment and absorption, but the promoting effect is not obvious after the carrier amount reaches a certain value, and meanwhile, the medicine coating of the saccule containing the same medicine amount is thickened, the outline outer diameter of the saccule behind the subsequent flap is increased, and the difficulty of the saccule in the blood vessel conveying process is increased due to the large outline outer diameter. The solvent is too little, the concentration of the solution is high, and the subsequent atomization is difficult, so that the spraying is not facilitated; too much solvent, low drug concentration, the same drug saccule, prolonged spraying time, and unfavorable production.

In the second step, the mixed liquid is sprayed on the bare sacculus by adopting a medicine sacculus spraying machine, wherein the spraying ultrasonic atomization power range is 1-5W, the spraying flow range is 0.01-1 ml/min, the spraying height range is 10-60 mm, and the spraying air pressure range is 0.05-0.1 Mpa. The spraying ultrasonic atomization power is too low to atomize the solution and the solution cannot be sprayed; the spraying ultrasonic atomization power is too high, the atomization is serious and close to vaporization, and the mixed liquid can not be controlled to effectively fall to the surface of the saccule, so that an ideal coating can not be formed. The spraying flow is too low, too little medicine accumulated on the saccule in the same time is not beneficial to the formation of the crystallized microballoon, and the spraying time is prolonged; the spraying flow is too high and difficult to atomize, and the spraying cannot be carried out. The spraying height is too short, the surface of the balloon can not be effectively covered by spraying, and an effective coating is difficult to form; the spraying height is too long, the solvent is volatilized too much when the mixed solution falls on the surface of the saccule, the formation of the crystallization of the medicine microsphere is influenced, and meanwhile, the solution is wasted seriously. In other embodiments, manual dispensing may also be used.

Wherein the time of standing in the constant temperature and humidity condition is in the range of 6 to 24 hours, the temperature is in the range of 20 to 40 ℃ and the humidity is in the range of 40 to 70% RH in the constant temperature and humidity condition. Too high or too low temperature or humidity easily influences solvent volatilization and medicine crystallization. The time for placing the coating in the constant temperature and humidity condition is too short, and the solvent residue is high, so that the formation of the coating is influenced.

When the carrier is an emulsifier, the formed drug coating is a nano microsphere crystalline drug coating. The nano microsphere crystallized medicine particles can prolong the release time of the medicine, and can inhibit cell proliferation and blood vessel restenosis at the required treatment concentration for a long time after transferring to blood vessels.

When the carrier is the combination of the emulsifier and the gel, the formed drug coating layer is bound in the pores of the gel net by the nano microsphere crystallized drug. The nano microsphere crystallized drug particles can delay the release of the drug, the drug is bound in the gel net, and the release time of the drug can be further prolonged. After the nanometer microsphere crystal drug bound in the gel net is transferred to the blood vessel, the nanometer microsphere crystal drug is bound by the gel net, so the nanometer microsphere crystal drug can inhibit cell proliferation and blood vessel restenosis within a long time at a required treatment concentration. In this example, the mass ratio between the emulsifier and the gel ranges from 1: (0.5-1), wherein too little gel is added, rapamycin drug microspheres cannot be effectively bound, and the slow release effect is not obvious; excessive addition of gel makes release of rapamycin drug microspheres from the coating difficult, and satisfactory treatment effect cannot be achieved at the early stage of blood vessel treatment by the drug balloon.

When the carrier is the combination of the emulsifier, the gel and the biological adhesive, in the formed drug coating, the nano microsphere crystallized drug is bound in the pores of the gel net, and a layer of smooth biological adhesive film is arranged on the surface of the drug coating. The nano microsphere crystallized medicine particles can delay the release of the medicine, the medicine is bound in the gel net, simultaneously the release time of the medicine can be further prolonged, and the medicine can inhibit cell proliferation and inhibit vascular restenosis at the required treatment concentration for a longer time after being transferred to blood vessels. The biological adhesive film can avoid the drug in the drug coating of the instrument in the in vivo delivery process to be eluted, thereby reducing the drug loss, making the drug coating more even when the delivery reaches the focus, and simultaneously the biological adhesive film also increases the transfer amount of the drug coating from the instrument to the vessel wall, so that the drug in the expansion process of the drug balloon is more evenly and efficiently released on the vessel wall. The mass ratio range of the emulsifier, the gel and the biological adhesive is 1: (0.5-1): (0.6-1) if the amount of the bioadhesive is too small, the adhesion of the drug coating to the vessel wall is small and the amount of the drug coating transferred to the vessel wall is small in the process of transferring the drug coating to the vessel wall; if the biological adhesive is too much, the transfer amount of the drug coating cannot be further increased, and the release time of the drug cannot be further effectively delayed to inhibit the restenosis of the blood vessel.

In one embodiment, the method for preparing the drug balloon further comprises: and step three, the medicine saccule is wound in a split mode and sleeved with a protective sleeve. Wherein the number of the split is 3-6, and the temperature of split coiling is 40-70 ℃. The balloon with the number of the divided sections of 3-6 is convenient for the balloon to be rolled to have smaller outline outer diameter and better trafficability in blood vessels; the split coiling process is essentially a process of heat setting the saccule again, the saccule cannot be softened at a low temperature to heat set the saccule, and the saccule is seriously softened at a high temperature to reduce the physical performance of the saccule.

The embodiment also provides the drug balloon prepared by the preparation method of the drug balloon.

Example 1

The preparation method of the drug balloon provided by the embodiment comprises the following steps:

step one, mixing a drug (rapamycin), a carrier (emulsifier lauric acid) and a solvent (ethyl acetate) to obtain a mixed solution, wherein the mass ratio of the drug to the carrier is 100:10, the mass ratio of the drug to the solvent is 0.1.

And step two, spraying the mixed solution on the bare balloon by adopting a medicine balloon spraying machine (Beijing Oriental Jinrong ultrasonic electric appliance Co., ltd., model number: UC 510), and placing the bare balloon under the conditions of constant temperature and constant humidity to form a medicine coating on the surface of the bare balloon so as to form the medicine balloon. Wherein the spraying ultrasonic atomization power is 5W, the spraying flow rate is 1ml/min, the spraying height is 60mm, the spraying air pressure is 0.05MPa, the standing time is 24h under the conditions of constant temperature and constant humidity, the temperature is 20 ℃, and the humidity is 40% RH.

And step three, the medicine saccule is wound in a split mode and sleeved with a protective sleeve. Wherein, the number of the split is 3; the temperature of the split winding is 40 ℃.

Fig. 1 is a scanning electron microscope image of the drug balloon coating according to the embodiment, in which fig. 1 shows a nanoparticle crystallized drug 1, and the formed drug coating is a nanoparticle crystallized drug coating.

Example 2

step one, mixing a drug (rapamycin), a carrier (gel thioxylan and emulsifier lauric acid, the mass ratio of the two is 1): 30, the mass ratio of the drug to the solvent is 1.

And step two, spraying the mixed solution on the bare balloon by adopting a medicine balloon spraying machine (Beijing Oriental Jinrong ultrasonic electric appliance Co., ltd., model number: UC 510), and placing the bare balloon under the conditions of constant temperature and constant humidity to form a medicine coating on the surface of the bare balloon so as to form the medicine balloon. Wherein the spraying ultrasonic atomization power is 2.8W, the spraying flow rate is 0.15ml/min, the spraying height is 40mm, the spraying air pressure is 0.06MPa, the standing time is 18h under constant temperature and humidity conditions, the temperature is 27 ℃, the humidity is 60% RH.

And step three, the medicine saccule is wound in a split mode and sleeved with a protective sleeve. Wherein, the number of the split is 5; the temperature of the split coiling is 65 ℃.

Fig. 2 is a scanning electron microscope image of the drug balloon coating of the present embodiment, wherein, in fig. 2, there are a nanoparticle crystallized drug 1 and a gel network 2 binding the nanoparticle crystallized drug. In the formed drug coating, the nano microsphere crystallized drug 1 is bound in the pores of the gel network 2.

Example 3

mixing a drug (rapamycin), a carrier (biological adhesive isobutyl cyanoacrylate, gel thioxylan and emulsifier lauric acid, wherein the mass ratio of the drug to the carrier is 1: 35, the ratio of the mass of the drug to the mass of the solvent is 0.9.

And secondly, spraying the mixed solution on the bare balloon by using a drug balloon spraying machine (Beijing Oriental Jinrong ultrasonic electric appliance Co., ltd., model: UC 510), and placing the bare balloon on a constant temperature and humidity condition to form a drug coating on the surface of the bare balloon so as to form the drug balloon. Wherein the ultrasonic atomization power for spraying is 2.8W, the spraying flow rate is 0.20ml/min, the spraying height is 48mm, the spraying pressure is 0.068MPa, the standing time is 24h under the conditions of constant temperature and constant humidity, the temperature is 27 ℃, and the humidity is 65% RH.

And step three, the medicine saccule is wound in a split mode and sleeved with a protective sleeve. Wherein, the number of the split is 3; the temperature of the split winding is 55 ℃.

Fig. 3 is a scanning electron microscope image of the drug balloon coating of the present embodiment, wherein fig. 3 shows a nano microsphere crystallized drug 1, a gel network 2 binding the microsphere crystallized drug, and a bio-adhesive film 3. In the formed drug coating, the nano microsphere crystal drug 1 is bound in the pores of the gel net 2, and a smooth biological adhesive film 3 is arranged on the surface of the drug coating.

Comparative example 1

The preparation method of the drug balloon provided by the comparative example comprises the following steps:

step one, mixing a drug (rapamycin), a carrier (common auxiliary materials, namely dibutyl hydroxy toluene) and a solvent (ethyl acetate and water, wherein the ratio of the mass of the drug to the mass of the carrier is 1): 50, the mass ratio of the drug to the solvent is 5.

And secondly, spraying the mixed solution on the bare balloon by using a drug balloon spraying machine (Beijing Oriental Jinrong ultrasonic electric appliance Co., ltd., model: UC 510), and placing the bare balloon on a constant temperature and humidity condition to form a drug coating on the surface of the bare balloon so as to form the drug balloon. Wherein the ultrasonic atomization power of the spraying is 1W, the spraying flow rate is 0.01ml/min, the spraying height is 10mm, the spraying air pressure is 0.1MPa, the standing time under the constant temperature and humidity condition is 6h, the temperature is 40 ℃, and the humidity is 70 percent RH.

Step three, coiling the drug saccule in a split manner, and sleeving a protective sleeve. Wherein, the number of the split is 6; the temperature of the split winding is 40 ℃.

In comparative example 1, unlike the above examples, the carrier used was dibutylhydroxytoluene, which is a common adjuvant. Fig. 4 is a scanning electron microscope image of the drug balloon coating of the present comparative example, in which the drug coating formed is an amorphous coating.

Comparative example 2

step one, mixing a drug (rapamycin), a carrier (emulsifier) and a solvent (ethyl acetate and ethanol, wherein the ratio of the mass of the drug to the mass of the carrier is 1): 5, the mass ratio of the drug to the solvent is 5.

And step three, the medicine saccule is wound in a split mode and sleeved with a protective sleeve. Wherein, the number of the split is 6; the temperature of the split coiling is 40 ℃.

In comparative example 1, unlike the above examples, the ratio of the mass of the drug to the mass of the carrier was 100:5, resulting in less mass of the carrier. Fig. 5 is a scanning electron micrograph of the drug balloon coating of this comparative example, wherein the drug coating formed is also an amorphous coating.

Drug transfer and slow release effect comparison:

samples of drug balloon catheters (balloon diameter 4mm, length 40 mm) prepared in examples 1, 2, 3 and 1 were subjected to rabbit experiments. Fixing, anaesthetizing and sterilizing a new zealand rabbit for experiments, puncturing and inserting a guide wire from a carotid artery, placing a sheath tube, leading a balloon catheter to pass through the sheath tube through the guide wire, starting timing, and conveying the balloon to a balloon dilatation site (abdominal aorta) under DSA. The time from the entry of the balloon into the sheath to the expansion is controlled to be about 70 s. Then the drug balloon is rapidly expanded to 8atm, maintained for 2min and decompressed. The rabbits in the group 0 were sacrificed 30min later, the proximal chest was opened for bleeding, the contralateral femoral artery was punctured, about 10ml of physiological saline was quickly pushed into the proximal chest by a syringe, and the procedure was repeated 1 to 3 times to wash away blood and drugs possibly adhered to the inner wall of the blood vessel as much as possible. After the washing, the blood vessel of the dilated part of the ball is taken, and the gauze is dipped in water on the surface. The rabbits of 28 days are fed with normal diet, and after 28 days, the blood vessels are washed and then the blood vessels at the bulbar expansion part are intercepted according to the same method.

The amount of drug in the cut blood vessel was measured by using a Japanese Shimadzu LC-20A high performance liquid chromatograph, and the test results are shown in Table 1. As can be seen from the table, the amorphous coating group has low reloading to the proportion 1, and the slow release effect of the drug on the vascular wall is poor, and the drug content is hardly measured after 28 days; and in the embodiment 3 of the gel-coated nano microsphere crystalline coating with the surface attached with the biological adhesive film, the drug transfer is highest, the retention time is long, the slow release effect is good, and the clinical requirements of the rapamycin drug balloon are met.

The drug content of the group blood vessel/the total drug content of the drug balloon at the moment when the transfer rate = 0; residual rate = group vessel drug content for 28 days/group vessel drug content at time 0.

TABLE 1

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

The above-mentioned embodiments only express several 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. The preparation method of the medicine balloon is characterized by comprising the following steps of:

2. The method of manufacturing a drug balloon according to claim 1, wherein the emulsifier is selected from at least one of sorbitan monooleate, cetyl alcohol, stearyl alcohol, lauric acid, and fatty acid glycerides; the gel is selected from at least one of thio-chitosan, polyvinylpyrrolidone, sodium alginate, sodium carboxymethyl cellulose and carboxyvinyl copolymer; the biological adhesive is at least one of isobutyl cyanoacrylate, starch, protein, animal glue, shellac and polyacrylic acid.

3. The method for preparing a drug balloon according to claim 1, wherein the solvent is at least one selected from tetrahydrofuran, ethyl acetate, ethanol, acetonitrile, methanol, acetone, benzene, n-heptane, toluene, xylene, cyclohexanone, dioxane, and water.

4. The method for preparing a drug balloon according to claim 1, wherein the step of mixing the drug, the carrier and the solvent to obtain a mixed solution comprises the steps of: dissolving the medicine in the solvent and then shaking to obtain a medicine solution; dissolving the carrier in the solvent and then oscillating to obtain a carrier solution; and mixing the drug solution and the carrier solution to obtain the mixed solution.

5. The preparation method of the drug balloon according to claim 1, wherein the mixed solution is sprayed on the bare balloon by a drug balloon spraying machine, wherein the ultrasonic atomization power of the spraying is 1-5W, the spraying flow rate is 0.01-1 ml/min, the spraying height is 10-60 mm, and the spraying pressure is 0.05-0.1 Mpa.

6. The method of manufacturing a drug balloon according to claim 1, wherein the time period of the placing in the constant temperature and humidity condition is in a range of 6 to 24 hours, the temperature range is 20 to 40 ℃, the humidity range is 40 to 70% rh in the constant temperature and humidity condition.

7. The method of making a drug balloon according to claim 1, wherein when the carrier is the emulsifier, the drug coating formed is a nanosphere crystalline drug coating; when the carrier is the combination of the emulsifier and the gel, the drug coating is formed, and the nano microsphere crystallized drug is bound in the pores of the gel net; when the carrier is the combination of the emulsifier, the gel and the biological adhesive, the drug coating is formed, the nano microsphere crystallized drug is bound in the pores of the gel net, and a smooth biological adhesive film is arranged on the surface of the drug coating.

8. The method for preparing a drug balloon according to claim 1, wherein when the carrier is a combination of the emulsifier and the gel, the mass ratio between the emulsifier and the gel is in a range of 1: (0.5-1); when the carrier is the combination of the emulsifier, the gel and the biological adhesive, the mass ratio of the emulsifier to the gel to the biological adhesive is in a range of 1: (0.5-1): (0.6-1).

9. The method of manufacturing a drug balloon of claim 1, further comprising: and (3) coiling the drug saccule in a split manner, and sleeving a protective sleeve on the drug saccule, wherein the split number range is 3-6, and the temperature range of split coiling is 40-70 ℃.

10. A drug balloon prepared by the method of claim 1.