Drug balloon and its preparation method

Abstract

The present invention provides a drug balloon and a preparation method thereof, including: providing a balloon body; pretreating the surface of the balloon body with a target reagent to improve the cleanliness and roughness of the surface of the balloon body; performing seeding treatment on the surface of the pretreated balloon body with a dispersion liquid containing nano-drug particles and a dispersant, so as to attach nano-drug particles to the surface of the balloon body in a physically adsorbed manner to form a seed layer; performing crystal growth treatment on the surface of the balloon body with a supersaturated solution of the active pharmaceutical ingredient to grow drug crystals precipitated from the saturated solution on the seed layer, which can adsorb pure drugs on the balloon surface without using excipients, is not easy to fall off, and is convenient for eluting and transferring drugs.

Description

Technical Field

[0001] The present invention relates to the technical field of medical devices, and more particularly, to a drug balloon and a preparation method thereof. Background Art

[0002] Atherosclerosis (AS) is the main pathological basis of ischemic cardiovascular and cerebrovascular diseases such as coronary heart disease, cerebrovascular diseases, and thromboembolic diseases. Atherosclerosis is a chronic inflammatory disease, and the inflammatory response can be divided into: biological inflammation, caused by vascular wall infection and extravascular infection by pathogens; immune inflammation, involving cellular immunity, humoral immunity, and the body's non-specific immune response; and chemical inflammation, involving inflammatory cytokines, inflammatory mediators, adhesion molecules, and chemotactic factors. It has now been proven that anti-inflammatory treatment is a new approach to preventing and treating atherosclerosis.

[0003] Anti-inflammatory treatment includes intravascular interventional techniques. Intravascular interventional techniques originated from peripheral blood vessels and have been introduced into the prevention and treatment of cerebrovascular diseases in the past 30 years or so. They mainly include arterial stent systems and balloon dilation catheters. Among them, 20-30% of in-vessel restenosis will occur after stent implantation. Although the currently developed drug-eluting stents have reduced the incidence of in-vessel stent restenosis to a certain extent, the metal stents remaining in the body will still cause foreign body reactions and produce adverse effects. Under the guidance of medical imaging equipment, the balloon catheter can be pushed to the vascular stenosis site, and then the balloon is dilated so that the vascular stenosis site is dilated to improve blood circulation without implanting a stent. However, problems such as vascular elastic recoil, endothelial cell hyperplasia, and intimal tear will still occur after vascular dilation. Therefore, it is necessary to deliver anti-proliferative and anti-inflammatory active drugs to the lesion site, such as the existing drug balloons can carry drugs such as paclitaxel and rapamycin. When the drug balloon reaches the lesion position, the balloon is dilated and contacts the intima of the blood vessel wall. By tearing the intima of the blood vessel wall and releasing it under pressure, the drug is transferred into the lesion blood vessel wall, so that the drug plays an anti-vascular intimal hyperplasia role at the lesion blood vessel wall. However, the adhesion force between the surface of the existing balloon and the coated drug is small, not only the drug loading rate is low, but also the drug is easily detached during the delivery process, so that a sufficient amount of drug cannot be released to the blood vessel wall after balloon dilation, which limits the efficacy of the drug balloon. In addition, most of the current coated drug technologies use excipients (such as polymers or non-polymers) to mix with the drug to improve the adhesion of the coated drug on the balloon surface. Although the biocompatibility of foreign substances such as excipients is good, they still belong to foreign bodies and are likely to increase the risk of inflammation, so they cannot achieve good therapeutic effects. Moreover, after using excipients, the content of the drug itself in the coating is also reduced, resulting in a decrease in the drug loading.

[0004] Therefore, for those skilled in the art, how to design a drug balloon that can improve the adhesion between the coated drug and the balloon surface without using excipients and its preparation method is a technical problem that urgently needs to be solved at present.

[0005] It should be noted that the information disclosed in the background art part of this application is only intended to deepen the understanding of the general background art of this application, and should not be regarded as an admission or any form of implication that this information constitutes the prior art known to those skilled in the art. Summary of the Invention

[0006] In view of the above technical problems, the present invention provides a drug balloon and its preparation method, which can improve the adhesion between the coated drug and the balloon surface without using excipients, avoid the inflammatory risk caused by excipients, improve the drug loading capacity and drug release rate of the drug balloon, and reduce drug loss during delivery.

[0007] The present invention provides a preparation method of a drug balloon, which includes:

[0008] Step S100: Provide a balloon body;

[0009] Step S200: Pretreat the surface of the balloon body with at least a target reagent to improve the cleanliness and roughness of the surface of the balloon body; the Ra value of the surface roughness of the balloon body is 0.12 μm to 0.2 μm;

[0010] Step S300: Perform seeding treatment on the surface of the balloon body pretreated on the surface with a dispersion liquid containing nano-drug particles and a dispersant, so as to physically adsorb nano-drug particles on the surface of the balloon body to form a seed layer; the particle size of the nano-drug particles is less than 1.0 μm, and at least 50% of the particles in the nano-drug particles are less than 0.5 μm;

[0011] Step S400: Perform crystal growth treatment on the surface of the balloon body on which the seed layer has been formed with a supersaturated solution of the active pharmaceutical ingredient, so as to grow drug crystals precipitated from the saturated solution on the seed layer.

[0012] Optionally, the absolute value of the difference between the solubility parameters of the target reagent and the balloon body is 1.8 to 2.1.

[0013] Optionally, the step S200 includes:

[0014] Place the inflated balloon body in the target reagent, and under the first ultrasonic oscillation condition, pretreat the surface of the balloon body, and then dry the balloon body pretreated on the surface.

[0015] Optionally, step S200 includes: placing the inflated balloon body in the target reagent for soaking for 30 min to 60 min, performing surface pretreatment on the surface of the balloon body, and then drying the balloon body after surface pretreatment.

[0016] Optionally, before seeding, the balloon body treated with the target reagent is further subjected to plasma treatment.

[0017] Optionally, the first ultrasonic oscillation conditions include a first oscillation temperature, a first oscillation duration, a first oscillation frequency, a first oscillation power, and a first oscillation number. The first oscillation temperature is 25°C ± 5°C, the first oscillation duration is 1 min to 10 min, the first oscillation frequency is 50 kHz to 100 kHz, the first oscillation power is 300 W to 500 W, and the first oscillation number is 1 to 2 times.

[0018] Optionally, step S300 includes:

[0019] Step S301: Processing the raw drug into nano-drug particles with a particle size less than 1.0 μm;

[0020] Step S302: Mixing the nano-drug particles with the dispersant. After mixing, under the second ultrasonic oscillation conditions, performing ultrasonic oscillation treatment on the dispersion liquid to make the nano-drug particles uniformly dispersed in the dispersion liquid;

[0021] Step S303: Placing the balloon body after surface pretreatment in the dispersion liquid, and under the third ultrasonic oscillation conditions, enabling the nano-drug particles in the dispersion liquid to adsorb on the surface of the balloon body after surface pretreatment, and then forming the seed layer on the surface of the balloon body;

[0022] Step S304: Performing light-shielding drying on the balloon body formed with the seed layer.

[0023] Optionally, using the media grinding method to grind the raw drug into the nano-drug particles with a particle size less than 1.0 μm, wherein the grinding time is 60 min to 120 min, and the grinding rotation speed is 2000 r / min to 3000 r / min.

[0024] Optionally, the grinding time is 90 min, and the grinding rotation speed is 3000 r / min.

[0025] Optionally, the size of the grinding media is 0.2 mm to 1.0 mm, the mass-volume ratio of the raw drug to the grinding solvent is 15 mg / m to 25 mg / ml, and the dosage of the grinding media is 10 to 20 times the dosage of the raw drug.

[0026] Optionally, the second ultrasonic oscillation condition includes a second oscillation duration and a second oscillation power. The second oscillation duration is 5 min to 20 min, and the second oscillation power is 300 W to 500 W. And / or, the third ultrasonic oscillation condition includes a third oscillation duration and a third oscillation temperature. The third oscillation duration is 5 min to 20 min, and the third oscillation temperature is 25°C to 35°C.

[0027] Optionally, in the step S302, the concentration of the nano drug particles in the dispersant is 0.25 mg / ml to 1 mg / ml.

[0028] Optionally, in the step S301, it further includes: filtering the treated raw drug multiple times to obtain the nano drug particles, and performing vacuum drying on the nano drug particles obtained through multiple filtrations.

[0029] Optionally, the step S400 includes:

[0030] Step S401: Provide a raw drug solution;

[0031] Step S402: Add an antisolvent to the raw drug solution under a water bath condition to form a supersaturated solution;

[0032] Step S403: Place the balloon body for forming the seed layer in the supersaturated solution under the same water bath condition as in the step S402 for crystal growth;

[0033] Step S404: After crystal growth, perform light-shielding drying on the balloon body.

[0034] Optionally, the water bath condition includes a water bath temperature of 25°C to 35°C, and the crystal growth time is 0.5 min to 30 min.

[0035] Optionally, the target reagent is one of purified water, n-heptane, n-hexane, methanol, ethyl acetate, and diethyl ether, and / or the dispersant is one of purified water, n-heptane, n-hexane, and diethyl ether.

[0036] Based on the same inventive concept, the present invention also provides a drug balloon prepared by the preparation method of any one of the above-mentioned drug balloons.

[0037] Compared with the prior art, the drug balloon and its preparation method provided by the present invention have the following advantages:

[0038] When preparing a drug balloon, first, at least the surface of the balloon body is pretreated with a target reagent to improve the cleanliness and roughness of the balloon surface. Then, nano-drug particles are attached to the surface of the pretreated balloon body by physical adsorption. During this process, a dispersant helps the nano-drug particles to be densely and evenly distributed on the surface of the balloon body, thereby forming a seed layer composed of nano-drug particles on the surface of the balloon body. Further, drug crystals are grown on the seed layer to increase the drug loading capacity. In this way, without using excipients, the drug can be directly coated on the surface of the bare balloon, and the drug can be well adsorbed on the balloon surface, not easily falling off. At the same time, the drug is also easily eluted and fully transferred to the lesion site, thereby increasing the drug loading capacity, reducing drug loss, and also improving the drug release rate. Since no excipients are used, the risk of inflammation caused by excipients can be avoided, and the drug utilization rate can be improved. In addition, when pretreating the surface of the balloon body, the aim is to improve the cleanliness and roughness of the balloon surface without affecting the mechanical properties of the balloon itself. Description of the Drawings

[0039] Those of ordinary skill in the art will understand that the provided drawings are used to better understand the present invention and do not constitute any limitation to the scope of the present invention. Among them:

[0040] Figure 1 is the preparation flow chart of the drug balloon of the present invention;

[0041] Figure 2 are the experimental data of the balloon surface roughness and the drug loading capacity of the seed layer obtained when the balloon of the present invention is not surface-treated and when the balloon is surface-treated with different treatment methods;

[0042] Figure 3 are the experimental data of the drug loading capacity, the surface morphology of the balloon before seed sowing, and the surface morphology of the balloon after seed sowing obtained when the balloon of the present invention is not surface-treated and when the balloon is surface-treated;

[0043] Figure 4 is a curve graph showing the change of the particle size of drug particles obtained by grinding the raw drug at different grinding speeds with the grinding time. The abscissa is the grinding time (unit: min), and the ordinate is the particle size (unit: μm);

[0044] Figure 5 are the experimental data related to the particle size and the drug loading capacity of the seed layer of the present invention;

[0045] Figure 6 are the experimental data related to the in vitro release rate and the coating firmness of the present invention. Detailed Description of the Invention

[0046] To make the objectives, advantages, and features of the present invention more clear, the following further elaborates on the present invention in conjunction with the accompanying drawings and specific embodiments. It should be noted that the accompanying drawings are in very simplified forms and not drawn to scale, only serving to conveniently and clearly assist in explaining the objectives of the embodiments of the present invention. In addition, the structures shown in the accompanying drawings are often part of the actual structures. In particular, the emphasis to be shown in each of the accompanying drawings is different, and sometimes different scales are used. As used in this specification, the singular forms "a", "an", and "the" include plural objects unless the content clearly indicates otherwise. As used in this specification, the term "or" is generally used in the sense of including "and / or" unless the content clearly indicates otherwise.

[0047] One objective of the present invention is to solve the problems existing in existing drug balloons, namely, the small adhesion force between the balloon surface and the coated drug, the low drug loading amount, the easy shedding during the delivery process, and thus the low drug release rate.

[0048] Another objective of the present invention is to solve the problem that existing coated drug technologies need to use excipients to improve the adhesion of the coated drug on the balloon surface, which not only increases the risk of inflammation but also reduces the drug loading amount.

[0049] Based on this, the present invention provides a drug balloon and its preparation method, which can improve the adhesion between the coated drug and the balloon surface without using excipients, avoid the inflammation risk caused by excipients, improve the drug loading amount and drug release rate of the drug balloon, reduce the drug loss during the delivery process, and can preferably solve the problems existing in existing drug balloons.

[0050] The following is an explanation with reference to the accompanying drawings.

[0051] Figure 1 Schematically shows the preparation process of the drug balloon provided by the embodiment of the present invention. As Figure 1 shown, the preparation process of the drug balloon includes step S100 to step S400.

[0052] Step S100 is: providing a balloon body.

[0053] The balloon body is a bare balloon, and the bare balloon can be inflated and deflated. The present application has no special restrictions on the shape and size of the bare balloon. The bare balloon can be prepared from existing balloon materials, and there are no requirements for the specific materials. Currently, copolymers or blends of materials such as polyvinyl chloride (PVC), polyethylene (PE), polyethylene terephthalate (PET), nylon, silica gel, polyurethane (PU), etc. are mostly used to prepare the bare balloon, and currently new balloon materials are mainly obtained by copolymerizing or blending the above copolymer materials.

[0054] Since the balloon needs to come into contact with human tissues and blood, the balloon usually needs to meet the following performance requirements: a. It has good thermal stability and can withstand the sterilization process; b. It has good chemical stability and corrosion resistance; c. It has good blood compatibility and will not cause allergic reactions; d. It has good mechanical properties and processability. Therefore, polyamide-polyether block polymer (PEBAX) is often selected as the current balloon material, which can better balance softness and strength to enable the balloon to meet the performance requirements for clinical applications. Although this article illustrates with a balloon body made of PEBAX, in fact, it is not limited to this kind of balloon material.

[0055] Step S200: Pretreat the surface of the balloon body with at least a target reagent to improve the cleanliness and roughness of the surface of the balloon body.

[0056] The cleanliness refers to that the surface of the balloon body is basically free of impurities and oil stains. Thus, by improving the cleanliness of the balloon surface, the adsorption sites on the balloon surface can be increased, which is convenient for the adsorption of drug particles on the balloon surface.

[0057] The roughness refers to the microscopic geometric shape characteristics composed of peaks and valleys on the surface of the balloon body. Thus, by increasing the roughness of the balloon surface, the adsorption sites on the balloon surface can be increased, and the adhesion performance of the balloon surface can be improved. It should also be understood that after the surface of the balloon body is pretreated, the adhesion between the balloon surface and the coated drug can be improved, and the balloon surface can also adsorb nano-drug particles by physical adsorption. Furthermore, during the delivery process, the coated drug is not easy to fall off, and the coated drug can still be eluted and fully transferred to the lesion site after the balloon is expanded.

[0058] It should be noted that the target reagent used for pretreatment is a chemical reagent, and the selection criterion of this chemical reagent is only to change the micro-surface morphology of the balloon body without changing the physical structure and size of the balloon body. Therefore, the target reagent can be any reagent that can clean the balloon surface and increase the roughness of the balloon surface. Usually, target reagents such as water (such as purified water), n-heptane, n-hexane, methanol, ethyl acetate, and ether can be selected. In the following description, although n-heptane is used for illustration, it should be recognized that in other embodiments, other target reagents with the same or similar properties can be used as long as they can achieve the target roughness.

[0059] Step S300: Perform seeding treatment on the surface of the surface-pretreated balloon body with a dispersion liquid containing nano-drug particles and a dispersant, so as to attach nano-drug particles to the surface of the balloon body by physical adsorption to form a seed layer.

[0060] It should be understood that during the seeding treatment, the dispersant helps the nano-drug particles to be evenly dispersed in the dispersion liquid, so that the nano-drug particles are densely and evenly distributed on the surface of the balloon. It should also be understood that the seed layer is only composed of nano-drug particles without a dispersant. The nano-drug particles are drug seeds with a particle size less than 1.0 μm. In addition, the seeding can be understood as placing the pretreated balloon body in the dispersion liquid, so that the nano-drug particles in the dispersion liquid are adsorbed on the surface of the balloon body, and finally the nano-drug particles are attached to the surface of the balloon body by physical adsorption to form a seed layer. This seed layer can directly physically adsorb to the balloon surface. Without the need for a shaping agent, it can also ensure the adhesion between the seed layer and the balloon surface, and the coating is not easy to fall off. Moreover, the seed layer is also used to grow drug crystals to increase the drug loading capacity through crystal growth.

[0061] There is no special limitation on the dispersant in this application, as long as it can uniformly disperse the nano-drug particles. For example, it can be selected from common dispersants such as purified water, n-heptane, n-hexane or ether.

[0062] Preferably, the concentration of the nano-drug particles in the dispersant is 0.25 mg / ml to 1 mg / ml. This concentration can not only avoid waste of the drug, but also ensure that a sufficient amount of nano-drug particles are dispersed on the balloon surface, which is beneficial to the dense and uniform distribution of the seed layer on the balloon surface and facilitates crystal growth.

[0063] Step S400: Use a supersaturated solution of the active pharmaceutical ingredient to perform crystal growth treatment on the surface of the balloon body with the formed seed layer, so as to grow drug crystals precipitated from the saturated solution on the seed layer.

[0064] It should be noted that in step S400, the raw material of the active pharmaceutical ingredient is the same as that of the nano-drug particles. The nano-drug particles can be prepared from the active pharmaceutical ingredient, and the supersaturated solution can also be prepared from the active pharmaceutical ingredient.

[0065] As mentioned above, it should be understood that although a seed layer has been formed on the balloon surface, after all, the size of the seed layer is small and the amount of drug is small. On this basis, to increase the drug loading capacity, it is necessary to grow drug crystals on the seed layer to meet the requirements of the drug loading capacity.

[0066] After the crystal growth is completed, a coated drug is directly formed on the surface of the balloon body. This coated drug only contains the drug without a shaping agent, and the coated drug is attached to the surface of the balloon body by physical adsorption.

[0067] Therefore, when preparing the drug balloon, the above steps S200, S300, and S400 complement each other, preferably solving the problems existing in the existing drug balloons. The unexpected effect is that without using excipients, the adhesion between the coated drug and the balloon surface is improved, avoiding the inflammatory risk caused by excipients, increasing the drug loading capacity and drug release rate of the drug balloon, and reducing drug loss during delivery. The safety and effectiveness of such a drug balloon are also better.

[0068] Therefore, the present invention attempts to solve the problem of drug setting on the balloon surface from different perspectives. Through the above steps S200, S300, and S400, pure drugs can be attached to the balloon surface. At this time, the coated drug is not easily detached, and can be eluted and fully transferred to the lesion site after balloon dilation, without affecting the mechanical properties of the balloon itself. In addition, without damaging the balloon, the adhesion between the drug and the balloon surface should not be too small or too large. If the adhesion is too strong, the drug is not easily eluted and fully transferred to the lesion site; if the adhesion is too weak, the drug is easily detached. Therefore, while solving the problem of coating detachment, the problem of easy elution of the coating also needs to be considered. To address this problem, it is intended to adsorb nano-drug particles through physical action, that is, the nano-drug particles and the pretreated balloon surface are adsorbed to each other through physical action, and the main adsorption force between the two is van der Waals force rather than covalent bond force, preferably solving the problems of coating detachment and coating elution, and not affecting the mechanical properties of the balloon itself.

[0069] Furthermore, the preparation process of the drug balloon further includes:

[0070] After crystal growth is completed, the balloon body is dried in the dark. Drying in the dark can prevent the drug from undergoing denaturation, decomposition, and other failure reactions after being exposed to light. After crystal growth is completed, the preferred drying time of the balloon body in the dark is 1h to 12h to ensure sufficient drying, avoid the residue of substances other than the drug, and also enable the coated drug to be fully cured.

[0071] Generally, after drying in the dark, the drug balloon with the formed coated drug also needs to be folded and crimped to obtain the final product.

[0072] In addition, based on the same inventive concept, the embodiments of the present invention further provide a drug balloon, which is prepared by the preparation method of the drug balloon provided by the embodiments of the present invention.

[0073] In the drug balloon provided by the present invention, a coated drug is formed on the surface of the balloon body. When the drug balloon is delivered to the lesion site, the balloon expands and contacts the blood vessel wall, and is pressurized and released to transfer the coated drug into the lesion blood vessel wall, enabling the drug to play a relevant therapeutic role at the lesion blood vessel wall.

[0074] Compared with the prior art, the adhesion between the surface of the drug balloon provided by the present invention and the coated drug is increased, the drug loading rate is high, and the drug is not easily detached during the delivery process. Furthermore, a sufficient amount of drug can be released to the blood vessel wall after balloon dilation, improving the efficacy of the drug balloon. In particular, the drug balloon does not use excipients, can also improve the adhesion of the coated drug to the balloon surface, and avoid the inflammatory risk caused by excipients, thus achieving a better therapeutic effect.

[0075] Optionally, the coated drug is prepared from one drug or a combination of multiple drugs. However, the specific types of drugs are not limited in this application, but can be any therapeutic substance that needs to be delivered to the lesion site through a drug balloon, including but not limited to rapamycin and rapamycin derivatives. Combinations of rapamycin and its derivatives can also be used, or combinations of other one or more drugs. In this embodiment, macrolide drugs rapamycin and rapamycin derivatives are used, such as but not limited to everolimus, tacrolimus, and zotarolimus. Generally, the selected drugs are those that can inhibit the proliferation of vascular smooth muscle cells, thereby further inhibiting vascular stenosis.

[0076] The preparation process of the drug balloon provided by the present invention will be described in more detail below.

[0077] (1) Pretreatment of the balloon surface (i.e., step S200)

[0078] When pretreating the surface of the balloon body, the mechanical properties of the balloon should be affected as little as possible. Therefore, when selecting the target reagent, the solubility in the balloon material needs to be considered. If the solubility parameter of the target reagent in the balloon material is too small, the target reagent has good solubility in the balloon material, and the target reagent will damage the balloon structure, resulting in a decrease in the mechanical properties of the balloon and easy rupture during the balloon treatment process or use. If the solubility parameter of the target reagent in the balloon material is too large, the target reagent has poor solubility in the balloon material and cannot play a role in improving the surface roughness.

[0079] One way is to judge the solubility of the target reagent in the balloon material by the absolute value of the difference in solubility parameters, and select a target reagent that has little impact on the balloon material and can improve the surface cleanliness and roughness of the balloon. Another way is to judge the solubility of the target reagent in the balloon material by the surface roughness and strength of the balloon.

[0080] Furthermore, it is found that when the absolute value of the difference between the solubility parameters of the target reagent and the balloon material is 1.8 to 2.1, the balloon can be in a better state, which will neither reduce the mechanical properties of the balloon, while the roughness of the balloon surface can preferably meet the requirements for adsorbing drug particles, and also make the coated drug easy to elute. Thus, when the absolute value of the difference between the solubility parameters of the target reagent and the balloon material is 1.8 to 2.1, the adsorption of drug particles on the balloon surface can be significantly improved, and a denser and more uniform seed layer can be obtained, providing a good basis for further crystal growth, and then increasing the drug loading of the entire coated drug.

[0081] As described above, the nano-drug particles and the balloon surface are physically adsorbed to each other. Therefore, the main adsorption force is the van der Waals force, which is generated by the molecular attraction and the polarization between the surface atoms and the adsorbed atoms. Thus, after the surface of the balloon body is pretreated with the target reagent, the surface charge of the balloon body changes, the polarity increases, the surface tension of the balloon increases, and the adsorption capacity is stronger. The increase in roughness will make the true surface area larger than the apparent surface area, which will increase the adsorption effect on drug particles. For example, the roughness can be represented by the arithmetic mean deviation of the profile. The larger the value of the roughness Ra, the greater the distance from the peak to the valley of the material surface, that is, the higher the surface roughness. Then, the roughness value of the balloon surface after being treated with the target reagent is higher than that of the untreated balloon surface, significantly increasing the roughness of the balloon surface, which plays a crucial role in the further adsorption of drug particles.

[0082] In the present invention, after pretreatment, the roughness Ra value of the surface of the balloon body is 0.12 μm to 0.2 μm, and more preferably 0.15 μm to 0.18 μm. Thus, it can avoid damage to the physical properties of the balloon caused by excessive roughness of the balloon surface, and also avoid too small roughness resulting in the shedding of the coated drug, ultimately achieving a balance between the physical properties of the balloon and the roughness of the balloon surface.

[0083] In one embodiment, the pretreatment of the surface of the balloon body with the target reagent may include the following steps:

[0084] Place the inflated balloon body in the target reagent, and under the first ultrasonic oscillation condition, pretreat the surface of the balloon body, and then dry the balloon body after surface pretreatment.

[0085] Among them, the first ultrasonic oscillation conditions include the first oscillation temperature, the first oscillation duration, the first oscillation frequency, the first oscillation power, and the first oscillation times. Preferably, the first oscillation temperature is 25°C ± 5°C, the first oscillation duration is 1 min to 10 min, the first oscillation frequency is 50 kHz to 100 kHz, the first oscillation power is 300 W to 500 W, and the first oscillation times are 1 to 2 times. Thus, impurities and oil stains on the surface of the balloon can be sufficiently cleaned, and the surface of the balloon can reach the required roughness and cleanliness.

[0086] In addition, after the pretreatment, the balloon body can be air-dried, such as natural air-drying or mechanical air-drying, to remove the target reagent on the surface of the balloon body through air-drying and dry the balloon body. The drying time can be 10 min to 30 min to sufficiently dry the balloon body and avoid the residue of the target reagent.

[0087] Therefore, only need to inflate the balloon, then immerse it in the target reagent for ultrasonic treatment, and dry it after the ultrasonic treatment. This pretreatment process is relatively simple and easy to implement.

[0088] In other embodiments, the pretreatment of the surface of the balloon body with the target reagent can also be: placing the inflated balloon body in the target reagent for soaking, and the soaking duration is 30 min to 60 min to pretreat the surface of the balloon body, and then drying the balloon body after the surface pretreatment. Thus, through the long-time soaking, the cleanliness and roughness of the surface of the balloon body are improved.

[0089] Preferably, before the seeding, the balloon body after being treated with the target reagent is further subjected to plasma treatment. This plasma treatment is also a pretreatment, aiming to further improve the roughness of the surface of the balloon body.

[0090] It should also be noted that after the entire pretreatment, the Ra value of the surface roughness of the balloon body can reach 0.12 μm to 0.2 μm. Here, the pretreatment at least includes the treatment with the target reagent, and then can further include the plasma treatment.

[0091] As above, in order to improve the adsorption force of the drug on the balloon surface, the pretreatment of the bare balloon surface is very crucial. In the present invention, first, a target reagent with a solubility parameter of 1.8 to 2.1 is selected, and then the relevant parameters for the pretreatment of the bare balloon are further adjusted, and finally, both the surface roughness of the balloon and the drug loading amount of the seed layer are in a relatively optimal state. Taking n-heptane as the target reagent below, the experimental results are as Figure 2 shown.

[0092] Among them, Comparative Sample 1 is a balloon without surface treatment; Comparative Sample 2 is: only the inflated balloon is immersed in n-heptane solvent for 10 minutes with 1 immersion; Experimental Sample 1 is: the inflated balloon is immersed in n-heptane solvent and ultrasonic oscillation is carried out for 1 time with an ultrasonic oscillation time of 5 minutes; Experimental Sample 2 is: the inflated balloon is immersed in n-heptane solvent and ultrasonic oscillation is carried out for 2 times with an ultrasonic oscillation time of 5 minutes each time; Experimental Sample 3 is: the inflated balloon is immersed in n-heptane solvent and ultrasonic oscillation is carried out for 1 time with an ultrasonic oscillation time of 10 minutes.

[0093] It can be known from the experiment that for balloons without surface treatment and balloons with simple immersion treatment, the surface roughness of the balloon is low. Furthermore, when coating drugs on the balloon surface, the drug loading amount of the seed layer adsorbed on the balloon surface is very small (0.01 μg / mm 2 ), and due to the small adsorption amount of drug particles, it is not conducive to subsequent crystal growth. Therefore, the balloon surface needs to be treated to increase the roughness. However, during pretreatment, ultrasonic oscillation is beneficial to increasing the balloon surface. However, when performing ultrasonic oscillation, it is also necessary to strictly control the ultrasonic oscillation time and the number of ultrasonic oscillations. If the ultrasonic oscillation time is too short, the roughness may not meet the requirements. If the ultrasonic oscillation time is too long, the balloon will be damaged. When the ultrasonic oscillation time is fixed, ultrasonic treatment can be carried out once or multiple times to meet the target roughness requirements. Additionally, for Experimental Samples 1 to 3, the surface roughness of the balloon has all increased. Correspondingly, the drug loading amount of the seed layer has also increased. However, Experimental Sample 3 is better. This sample has obtained a relatively good surface roughness Ra value of 0.188 μm and a drug loading amount of the seed layer of 0.47 μg / mm 2 , thus having a large adsorption amount and being conducive to subsequent crystal growth.

[0094] Therefore, compared with simple immersion, ultrasonic oscillation can well improve the surface roughness of the balloon. For ultrasonic oscillation, the number of ultrasonic oscillations and the ultrasonic time will also affect the surface roughness of the balloon. When the number of ultrasonic oscillations is the same, the longer the ultrasonic time, the higher the surface roughness of the balloon. Correspondingly, the drug loading amount of the seed layer is also higher. When the total ultrasonic time is constant, the effect of single ultrasonic treatment is better than that of multiple ultrasonic treatments. Then, according to Figure 2 , the optimal parameters for balloon surface treatment can be selected, that is, ultrasonic treatment is carried out on the surface of the bare balloon for 10 minutes with 1 ultrasonic oscillation. On this basis, further drug coating is carried out.

[0095] Furthermore, the advantages of balloon pretreatment can also be referred to Figure 3 to understand. Figure 3To compare the experimental results of the comparative examples and the embodiments of the present invention. During the experiment, the difference between the comparative examples and the embodiments of the present invention is that the surface of the balloon in the embodiments of the present invention is treated with the target reagent, while the surface of the balloon in the comparative examples is not treated with the target reagent, and other experimental conditions are the same.

[0096] As Figure 3 shown, after being treated with the target reagent, the surface of the balloon in the embodiments of the present invention is smooth (observed under a microscope), without impurity particles, the surface roughness of the bare balloon is increased, and the surface adsorption sites are increased (specifically, the number of pits or protrusions is increased); while when not treated with the target reagent, there are many impurity particles on the surface of the balloon in the comparative examples, which will affect the adsorption of drug particles, and the surface roughness of the balloon is low, and it is not easy to adsorb drug particles.

[0097] Furthermore, after the balloons of the comparative examples and the embodiments of the present invention are both subjected to seeding treatment, it can be seen under a microscope that the seed layer on the surface of the balloon in the embodiments of the present invention is more densely and evenly distributed and is not easy to fall off, while the seed layer on the surface of the balloon in the comparative examples is sparsely and unevenly distributed and is easy to fall off.

[0098] Thus, after the balloons of the comparative examples and the embodiments of the present invention are subjected to crystal growth treatment, there are also significant differences in the drug loading amounts of the two. It can be seen that the drug loading amount of the balloon in the embodiments of the present invention can reach 4.0 ± 0.4 μg / mm 2 , while the drug loading amount of the balloon in the comparative examples is only 2.4 ± 0.9 μg / mm 2 . Therefore, the preparation method of the drug balloon provided by the embodiments of the present invention can significantly increase the drug loading amount of the drug balloon, and thus effectively improve the drug efficacy.

[0099] (2) Preparation of nano-drug particles

[0100] Before the seeding treatment, it is necessary to first prepare nano-drug particles, and the nano-drug particles are drug seeds. The drug seeds refer to directly refining the raw drug to prepare nano-drug particles with a particle size less than 1.0 μm.

[0101] Before preparing the dispersion liquid, step S301 is performed: first prepare nano-drug particles, including: treating the raw drug into nano-drug particles with a particle size less than 1.0 μm.

[0102] In a preferred embodiment, after the active pharmaceutical ingredient is directly refined, the particle size distribution of the formed nano-drug particles is D10 = 0.07 μm, D50 = 0.16 μm, and D90 = 0.75 μm. Among them, D10 refers to the particle size corresponding to when the cumulative particle size distribution percentage of a sample reaches 10%. In this embodiment, the value of D10 is 0.07 μm. The volume content of particles smaller than this particle size accounts for 10% of all particles. In other words, 10% of the drug particles in the nano-drug particles have a particle size smaller than 0.07 μm. D50 refers to the particle size corresponding to when the cumulative particle size distribution percentage of a sample reaches 50%. In the preferred embodiment, the value of D50 is 0.16 μm. This value is the median particle size. The volume content of particles smaller than this particle size accounts for 50% of all particles. In other words, 50% of the drug particles in the nano-drug particles have a particle size smaller than 0.16 μm. D90 refers to the particle size corresponding to when the cumulative particle size distribution percentage of a sample reaches 90%. In this embodiment, the value of D90 is 0.75 μm. The volume content of particles smaller than this particle size accounts for 90% of all particles. In other words, 90% of the drug particles in the nano-drug particles have a particle size smaller than 0.75 μm.

[0103] In the present invention, after the active pharmaceutical ingredient is processed, the particle size of the drug particles should be less than 1 μm, so that the drug particles are not too large and the process difficulty can be reduced. Theoretically, the smaller the particle size of the drug particles, the better, which is beneficial to the adsorption of the drug particles on the surface of the balloon. However, the smaller the particle size, the greater the process difficulty, which will not only increase the processing time, but also increase the energy consumption and the efficiency is low. In the present invention, D50 is less than 0.5 μm, that is, at least 50% of the drug particles in the nano-drug particles have a particle size less than 0.5 μm. If D50 is too large, the overall size of the nano-drug particles is relatively large. Although the particle size of the overall drug particles is also less than 1 μm, the particles are not delicate enough, which is not conducive to the adsorption of the nano-drug particles on the surface of the balloon in the "seed seeding" step.

[0104] Actually, one way to prepare nano-drug particles is the "Top-down" top-down technology, and the other way is the "Bottom-up" bottom-up technology. The top-down technology means that the active pharmaceutical ingredient reduces the particle size of the drug particles through certain mechanical forces such as grinding or homogenization to obtain nano-drug crystals with a particle size in the nano range. Common methods include media grinding method, high-pressure homogenization method, etc. The bottom-up technology is to add a solution containing the drug to a poor solvent of the drug to make the drug supersaturated and precipitate crystals. Common methods include micro-precipitation method, supercritical fluid method, etc.

[0105] A schematic illustration is given for the media milling method. When using the media milling technology, milling media and a milling solvent need to be provided. Among them, glass beads or ceramic beads (zirconia, alumina) can be used as the milling media, and water or an organic solvent (i.e., a poor solvent for the drug, such as n-heptane, ether, etc.) can be selected as the milling solvent. The API is dispersed in the milling solvent to provide a liquid environment for milling. It should be understood that the advantage of milling in a liquid environment is that the uniformity of the drug particles obtained by milling is relatively high; the drug particles are suspended and dispersed in the solvent, which helps to achieve fine milling and obtain smaller drug particle sizes. The advantages of the media milling method are simple preparation process, strong operability, and stable process.

[0106] First, weigh an appropriate amount of API and milling media, and then place these substances on a mill. Then, under the preset milling conditions, mill the API to the nanoscale. Among them, the preset milling conditions include milling time, milling speed, and the size of the milling media.

[0107] Preferably, the milling time is 60 min to 120 min, and the milling speed is 2000 r / min to 3000 r / min. More preferably, the milling time is 90 min and the milling speed is 3000 r / min, and nanosized drug particles with relatively excellent particle size values can be obtained. Thus, by controlling the milling time and milling speed, the particle size of the drug particles after the API is processed can be controlled, so that the particle size of the drug particles after milling treatment is less than 1.0 μm, and at least 50% of the particles in the nanosized drug particles are less than 0.5 μm.

[0108] Preferably, the size of the milling media is 0.2 mm to 1.0 mm, the mass-volume ratio of the API to the milling solvent is 15 mg / mL to 25 mg / mL, and the dosage of the milling media is 10 to 20 times that of the API. Thus, by controlling the size of the milling media and the amount of raw materials, it can be ensured that drug particles with a particle size less than 1.0 μm can be obtained after milling treatment.

[0109] After milling, collect the prepared nanosized drug particles (i.e., drug seeds). At this time, the nanosized drug particles and the milling media can be separated by filtration separation. Preferably, the processed API is filtered multiple times to obtain the nanosized drug particles, such as repeating filtration 2 - 4 times to fully collect the drug seeds. After multiple filtrations, the collected drug seeds are then subjected to vacuum drying treatment. The collected drug seeds can be placed in a vacuum oven for drying. The drying temperature is 50 °C to 60 °C, the drying duration is 5 h to 15 h, and the vacuum degree is -0.01 Mpa. Thus, it can avoid damaging the drug structure due to too high drying temperature and avoid reducing the drying effect due to too low temperature.

[0110] It should be noted that when preparing drug particles, it is necessary to strictly control the particle size to be less than 1 μm, so that the nanoscale drug particles can be more evenly and densely dispersed on the balloon surface and have a certain adsorption force, thereby improving the firmness of the coating. At the same time, through the pretreatment of the balloon surface with the target reagent, the adhesion performance of the drug coating on the balloon surface can be further improved, thereby improving the firmness of the coating, reducing the delivery loss. At the same time, this physical adsorption can also achieve drug transfer in the target blood vessel and improve the curative effect.

[0111] (III) Preparation of the dispersion

[0112] After obtaining the nano drug particles, step S300 further includes:

[0113] Step S302: Prepare a dispersion of nano drug particles and a dispersant, including:

[0114] Mix the nano drug particles with the dispersant. After mixing, under the second ultrasonic oscillation condition, perform ultrasonic oscillation treatment on the dispersion to make the nano drug particles evenly dispersed in the dispersion.

[0115] Furthermore, the second ultrasonic oscillation condition includes a second oscillation duration and a second oscillation power. Preferably, the second oscillation duration is 5 min to 20 min, and the second oscillation power is 300 W to 500 W. In this way, the nano drug particles can be evenly dispersed in the dispersion.

[0116] (IV) Seeding

[0117] After preparing the dispersion, step S300 further includes:

[0118] Step S303: Place the surface-pretreated balloon body in the dispersion, and under the third ultrasonic oscillation condition, make the nano drug particles in the dispersion adsorb on the surface of the surface-pretreated balloon body, and then form a seed layer on the surface of the balloon body.

[0119] After seeding, the seed layer is densely and evenly distributed on the balloon surface.

[0120] Among them, the third ultrasonic oscillation condition includes a third oscillation duration and a third oscillation temperature. Preferably, the third oscillation duration is 5 min to 20 min, and the third oscillation temperature is 25 °C to 35 °C. Thus, the nano drug particles are densely and evenly distributed on the balloon surface.

[0121] After forming the seed layer, it further includes:

[0122] Step S304: Dry the balloon body with the formed seed layer in the dark. Here, the duration of the dark drying treatment can be 0.5 h to 3.0 h, so that the balloon body with the formed seed layer is fully dried and the dispersant is removed.

[0123] (V) Crystal Growth

[0124] After forming a seed layer on the surface of the balloon body, drug crystals are further grown on the seed layer to achieve the required drug loading. In the crystal growth process, the balloon seeded with drug crystals is further placed into a supersaturated solution of the same active pharmaceutical ingredient for crystal growth of the drug.

[0125] In this regard, step S400 may further include:

[0126] Step S401: Provide an active pharmaceutical ingredient solution; common good solvents for the active pharmaceutical ingredient include, for example but not limited to, methanol, ethanol, acetone, and chloroform, and solvents with lower toxicity are preferably selected.

[0127] Step S402: Under water bath conditions, add a poor solvent to the active pharmaceutical ingredient solution until a supersaturated solution is formed;

[0128] Step S403: Under the same water bath conditions, place the balloon body with the formed seed layer in the supersaturated solution for crystal growth;

[0129] Step S404: After crystal growth is completed, dry the balloon body after crystal growth in the dark.

[0130] It should be understood that the preparation of the supersaturated solution utilizes the different solubilities of the solute in different solvents. First, the solution is added to a certain amount of poor solvent, so that the solute becomes supersaturated and precipitates. For drugs, the active pharmaceutical ingredient is dissolved in a good solvent to form a drug solution, and then a certain amount of poor solvent is added to the drug solution. With the addition of the poor solvent, due to the low solubility of the poor solvent in the solute and its miscibility with the solvent, the drug concentration gradually increases, reaching or even exceeding the supersaturated concentration, and the nucleation process begins. The crystal nuclei also further grow, and the concentration in the solution decreases. When it is close to the saturated concentration, crystal growth stops and the crystal growth process is completed. Therefore, by controlling the time of the balloon in the saturated solution, the crystal growth size can be controlled, and further its drug loading can be controlled.

[0131] Crystal growth needs to be carried out in a water bath environment. For example, crystal growth is implemented by placing it in a water bath pot. The water bath temperature is 25°C to 35°C. After adding the poor solvent to the drug solution, immediately place the drug balloon with the seed layer into the supersaturated solution, let it stand for a period of time, and carry out crystal growth.

[0132] It should be noted that when crystal growth is carried out, the grown drug crystals should not be too large or too small. If they are too large, it is easy to cause embolism. If they are too small, the drug loading cannot be increased. Preferably, the crystal size is less than 50 μm. In this regard, the growth size of the drug crystals is ensured by controlling the crystal growth time. Preferably, the crystal growth time is 0.5 min to 30 min

[0133] After the crystal growth is completed, in step S404, the balloon body is dried away from light, and the drying time is preferably 1 h to 12 h.

[0134] Examples 1, 2 and 3 are given below to further illustrate the beneficial effects of the preparation method of the drug balloon according to the embodiments of the present invention.

[0135] Example 1

[0136] In this example, the raw drug is treated by a media grinding technique, and the raw drug is ground into drug particles with a particle size of less than 1.0 μm. During the grinding process, the grinding media is glass beads, the grinding solvent is n-heptane, the size of the grinding media is 300 μm, the raw drug is rapamycin, the mass-volume ratio of the raw drug to the grinding solvent is 20 mg / ml, and the amount of the grinding media used is 20 times the amount of the raw drug used. On this basis, the effects of different grinding speeds and grinding times on the obtained drug particles are further studied, and then the grinding time and grinding speed for obtaining a smaller particle size distribution are selected.

[0137] During the experiment, the grinding speeds are set to 1000 rpm, 2000 rpm, 3000 rpm and 4000 rpm respectively, and the grinding sampling times are: 0 min, 5 min, 10 min, 15 min, 20 min, 30 min, 40 min, 60 min, 90 min. Here, 0 min represents sampling once before grinding to measure the size of the raw drug, and the rest of the time is the grinding time. The size of the raw drug is 20 μm. After the grinding is completed, the nano-particle size distribution is tested by a laser nano-particle size analyzer.

[0138] According to Figure 4 It can be seen that at different grinding speeds, as the grinding time increases, the particle size of the drug particles gradually decreases, and the raw drug can be ground into drug particles with a particle size of less than 1.0 μm. Moreover, the greater the grinding speed, the faster the particle size changes, and the grinding time can be shorter, but it has little impact on the particle size of the final product. Finally, through the comparison of the particle size distribution, it can be known that when the grinding speed is 3000 r / min and the grinding time is 90 min, the optimal particle size distribution can be obtained, that is, the median particle size value (D50) is less than 0.5 μm, and preferably the median particle size value (D50) is 0.157 μm. At this time, the drug particles are fine, which is convenient for the adsorption of nano-drug particles on the balloon surface in the "seed sowing" step, and the grinding speed and grinding time are both appropriate, and it will not increase the energy consumption and reduce the production efficiency.

[0139] Next, through Figure 5 To further illustrate the influence of the particle size of the drug particles on the adsorption. From Figure 5It can be seen that after the active pharmaceutical ingredient (API) is ground, the particle size of the drug particles affects the drug loading amount of the seed layer, which in turn affects the adsorption of the drug on the balloon surface. Basically, when the maximum particle size exceeds 1.0 μm, the drug loading amount of the seed layer on the balloon surface is very small, and especially, the larger the particle size, the less the drug loading amount of the seed layer. By Figure 5 It can also be seen that too large a median particle size value is not conducive to the adsorption of the drug on the balloon surface. When the median particle size is large, the drug loading amount of the seed layer is low. To facilitate the adsorption of nano drug particles on the balloon surface, after the API is ground, the maximum particle size of the drug particles should be less than 1.0 μm, and the median particle size value (D50) is preferably less than 0.5 μm.

[0140] Example 2

[0141] In this example, the drug is rapamycin, the balloon material is PEBAX, the dispersant and the target reagent are both n-heptane, and the solvent in the API solvent is methanol.

[0142] Specifically, the drug balloon is prepared through the following steps:

[0143] a1. Pretreatment of the balloon surface

[0144] Place the inflated balloon in n-heptane solvent (target reagent) for ultrasonic treatment. The ultrasonic time is 10 min, the ultrasonic power is 300 W, and the ultrasonic temperature is 30 °C. After the ultrasonic treatment, take out the balloon, dry it in a fume hood, and keep it in the dark for standby.

[0145] a2. Grinding of the API

[0146] Weigh 100 mg of rapamycin API and 2 g of glass beads (grinding medium), put them into a 10-ml glass bottle, then add 5 ml of n-heptane (grinding solvent), and then seal the glass bottle. Then, place the glass bottle in a vortex mixer (grinder) for vortex grinding. The grinding time is 90 min, and the grinding speed is 3000 rpm. After the vortex grinding, filter the solution to separate the glass beads and the drug seeds. Rinse the grinding glass bottle several times to fully collect the drug seeds. Repeat this process 3 times. Finally, put the collected drug seeds and the grinding solvent in a vacuum oven. The drying time is 10 hours, the drying temperature is 60 °C, and the vacuum degree is -0.01 Mpa. After 10 hours, collect the drug seeds and seal them, and store the drug seeds at a low temperature of 4 °C. During the drying process, n-heptane (grinding solvent) evaporates.

[0147] a3. Seeding

[0148] Weigh 4 mg of the drug seed crystal and add 10 ml of n - heptane. Then, perform ultrasonic dispersion for 20 min with an ultrasonic power of 400 W and an ultrasonic temperature of 30 °C. After the ultrasonic dispersion is completed, immerse the pre - treated drug balloon into the seed crystal dispersion liquid and continue ultrasonic treatment for 20 min with an ultrasonic power of 400 W and an ultrasonic temperature of 30 °C. After the ultrasonic treatment ends, a drug balloon with a seed crystal layer can be obtained, and then the drug balloon with the obtained seed crystal layer is dried in the dark.

[0149] a4 Crystal growth

[0150] Weigh 50 mg of the rapamycin raw material drug and add 3 ml of methanol (a good solvent for rapamycin) to fully dissolve the rapamycin drug to form a rapamycin drug solution. After 5 min, add 7 ml of n - heptane (a poor solvent for rapamycin) to the rapamycin drug solution and aspirate or stir - mix it evenly 2 times. The whole process is carried out in a water bath at 35 °C to obtain a supersaturated solution of the rapamycin drug. Then immerse the balloon obtained in the previous step (seed sowing) into this supersaturated solution, let it stand for 10 min to allow the crystals to grow fully. After growing for a certain period of time, take out the balloon and dry it in the dark for 10 h.

[0151] After the treatments in the above steps a1 - a4, a drug balloon with pure drug can be obtained.

[0152] Finally, the drug balloon can be folded and crimped for storage.

[0153] Comparative example

[0154] The difference between the comparative example and Example 2 is that the bare balloon is not pretreated with the target reagent, and the other treatment processes are the same as those in Example 2, so they will not be elaborated here.

[0155] Furthermore, the samples obtained from Example 2 and the comparative example are tested for in vitro release and coating firmness, including simulating the coating firmness during the drug balloon delivery process and the in vitro release rate after simulating reaching the target site. The higher the in vitro release rate, the more fully the drug is transferred and the less residue remains on the balloon surface. Among them, the in vitro release rate is the content of the drug released from the drug balloon into the simulated blood vessel; the coating firmness is the loss of the drug during the whole delivery process, and the lower the loss rate, the better the coating firmness. For specific experimental results, please refer to Figure 6 .

[0156] Figure 6They are the experimental data related to the samples of Example 2 and the Comparative Example. Five test samples were provided for the preparation process of Example 2, and five test samples were also provided for the Comparative Example, and the in vitro release rate and coating firmness under different balloon surface roughnesses (Ra) were compared. According to the experimental results, the in vitro transfer rate (i.e., the in vitro release rate) of the process of Example 2 is significantly improved compared with that of the process of the Comparative Example, and at the same time, the coating firmness is increased, which has unexpected beneficial effects and can provide an effective basis for subsequent animal experiments and clinical experiments.

[0157] Therefore, the drug balloon provided by the present invention can be prepared by the preparation method of the drug balloon of any one of the above optional embodiments. The coating drug is physically adsorbed on the surface of the prepared drug balloon, and the coating drug only contains the drug.

[0158] The above description is only a description of the preferred embodiments of the present invention, and does not limit the scope of the present invention in any way. Any changes and modifications made by those of ordinary skill in the art of the present invention according to the above disclosure are within the protection scope of the technical solution of the present invention.

Claims

1. A preparation method of a drug balloon, characterized in that, Including: Step S100: Provide a balloon body; Step S200: Pretreat the surface of the balloon body with at least a target reagent, including: placing the inflated balloon body in the target reagent, and pretreating the surface of the balloon body under a first ultrasonic oscillation condition, and then drying the balloon body with the surface pretreated to improve the cleanliness and roughness of the surface of the balloon body; the Ra value of the roughness of the surface of the balloon body is 0.12μm to 0.2μm; the absolute value of the difference between the solubility parameters of the target reagent and the balloon body is 1.8 to 2.1; the target reagent is one of purified water, n-heptane, n-hexane, methanol, ethyl acetate, and diethyl ether; the first ultrasonic oscillation condition includes a first oscillation temperature, a first oscillation duration, a first oscillation frequency, a first oscillation power, and a first oscillation number, the first oscillation temperature is 25°C ± 5°C, the first oscillation duration is 1 min to 10 min, the first oscillation frequency is 50 kHz to 100 kHz, the first oscillation power is 300 W to 500 W, and the first oscillation number is 1 to 2 times; Step S300: Perform seeding treatment on the surface of the balloon body pretreated on the surface with a dispersion liquid containing nano drug particles and a dispersant, including: placing the balloon body pretreated on the surface in the dispersion liquid, and under a third ultrasonic oscillation condition, adsorbing the nano drug particles in the dispersion liquid on the surface of the balloon body pretreated on the surface, so as to attach nano drug particles to the surface of the balloon body in a physical adsorption manner to form a seed layer; the particle size of the nano drug particles is less than 1.0μm, and at least 50% of the particles in the nano drug particles are less than 0.5μm; the dispersant is one of purified water, n-heptane, n-hexane, and diethyl ether; Step S400: Perform crystal growth treatment on the surface of the balloon body with the seed layer formed with a supersaturated solution of the active pharmaceutical ingredient, including: placing the balloon body with the seed layer formed in the supersaturated solution, and growing drug crystals precipitated from the saturated solution on the seed layer under a water bath condition of 25°C to 35°C.

2. The preparation method of the drug balloon according to claim 1, wherein Before seeding, further perform plasma treatment on the balloon body treated with the target reagent.

3. The preparation method of the drug balloon according to claim 1, characterized in that, The step S300 includes: Step S301: Process the active pharmaceutical ingredient into the nano drug particles with a particle size less than 1.0μm; Step S302: Mix the nano drug particles with the dispersant, and after mixing, perform ultrasonic oscillation treatment on the dispersion liquid under a second ultrasonic oscillation condition to make the nano drug particles disperse evenly in the dispersion liquid; Step S303: Place the balloon body pretreated on the surface in the dispersion liquid, and under a third ultrasonic oscillation condition, adsorb the nano drug particles in the dispersion liquid on the surface of the balloon body pretreated on the surface, and then form the seed layer on the surface of the balloon body; Step S304: Light-shield the balloon body forming the seed layer and dry it.

4. The preparation method of the drug balloon according to claim 3, characterized in that, Grind the raw drug substance into the nano drug particles with a particle size less than 1.0 μm by the media milling method, wherein the milling time is 60 min to 120 min and the milling speed is 2000 r / min to 3000 r / min.

5. The preparation method of the drug balloon according to claim 4, characterized in that, The milling time is 90 min and the milling speed is 3000 r / min.

6. The preparation method of the drug balloon according to claim 4, characterized in that, The size of the milling media is 0.2 mm to 1.0 mm, the mass-volume ratio of the raw drug substance to the milling solvent is 15 mg / ml to 25 mg / ml, and the dosage of the milling media is 10 to 20 times the dosage of the raw drug substance.

7. The preparation method of the drug balloon according to claim 3, wherein The second ultrasonic oscillation conditions include a second oscillation duration and a second oscillation power. The second oscillation duration is 5 min to 20 min, and the second oscillation power is 300 W to 500 W. And / or, the third ultrasonic oscillation conditions include a third oscillation duration and a third oscillation temperature. The third oscillation duration is 5 min to 20 min, and the third oscillation temperature is 25 °C to 35 °C.

8. The preparation method of the drug balloon according to claim 3, characterized in that, In the step S302, the concentration of the nano drug particles in the dispersant is 0.25 mg / ml to 1 mg / ml.

9. The preparation method of the drug balloon according to claim 3, characterized in that, In the step S301, it further includes: filtering the treated raw drug substance multiple times to obtain the nano drug particles, and subjecting the nano drug particles obtained through multiple filtrations to vacuum drying treatment.

10. The preparation method of the drug balloon according to claim 1, characterized in that, The step S400 includes: Step S401: Provide a raw drug substance solution; Step S402: Under a water bath condition, add a poor solvent to the raw drug substance solution to form a supersaturated solution; Step S403: Under the same water bath condition as in the step S402, place the balloon body forming the seed layer in the supersaturated solution for crystal growth; Step S404: After crystal growth, light-shield the balloon body and dry it.

11. The preparation method of the drug balloon according to claim 10, characterized in that, The crystal growth time is 0.5 min to 30 min.

12. A drug balloon, characterized in that, Prepared by the preparation method of the drug balloon according to any one of claims 1-11.

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